Beruflich Dokumente
Kultur Dokumente
Stadtmauer
Ilan Tur-Kaspa
Editors
Ultrasound Imaging in
Reproductive Medicine
Advances in
Infertility Work-up,
Treatment, and ART
123
Ultrasound Imaging in Reproductive
Medicine
Laurel A. Stadtmauer • Ilan Tur-Kaspa
Editors
Ultrasound Imaging in
Reproductive Medicine
Advances in Infertility Work-up,
Treatment, and ART
Editors
Laurel A. Stadtmauer, MD, PhD Ilan Tur-Kaspa, MD
Jones Institute for Reproductive Institute for Human Reproduction (IHR)
Medicine Department of Obstetrics
Department of Obstetrics and Gynecology
and Gynecology The University of Chicago
Eastern Virginia Medical School Chicago, IL
Norfolk, VA USA
USA
vii
Preface
ix
Acknowledgments
xi
Contents
xiii
xiv Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Contributors
xv
xvi Contributors
but lower penetration, hence the need to be closer Table 1.1 Values of ISPTA by modality and year of
definition
to the organs being examined. Diagnostic ultra-
sound is not continuous but pulsed. There are 1976 1986 1992
pulses separated by silent intervals. The number of Ophthalmic 17 17 17
pulses occurring in 1 s is the pulse repetition fre- Fetal imaging 46 94 (104 %) 720 (667 %)
quency (PRF). The fraction of time that the pulsed Cardiac 430 430 720 (67 %)
ultrasound is on (duty factor) is very important Peripheral vessel 720 720 720
from a potential bioeffect aspect. When the PRF Adapted from Refs. [11–13]
All are derated values in mW/cm2
increases, so does the duty factor. Since the ultra-
sound wave is sinusoidal, there are alternating
periods of positive and negative pressure which below, all epidemiological information available
allow the wave to propagate through tissues by regarding fetal effects predates 1992. A further
means of particles motions. The speed of propaga- remarkable fact is that intensity for ophthalmic
tion is related both to the beam and several of the examination has not changed from the original
tissue properties. The average speed of sound 17 mW/cm2, a value approximately 42.5 times
propagation in biological tissues is estimated at lower than the present allowed maximal value for
1,540 m/s. When pressure is exerted on the resist- fetal scanning. Furthermore, pelvic imaging
ing insonated tissue, work is produced. The ability (abdominal or transvaginal) is not specified in
of the wave to do this is its energy (in joules), and Table 1.1.
the rate at which the energy is transformed from
one form to another is the power (in watts or mil-
liwatts, mW). When expressed as a function of Tissue Characteristics
area unit (in cm2), this is intensity (generally in
mW/cm2). Bioeffects are conventionally related to When the ultrasound wave travels through a
the acoustic intensity. As stated above, pulses of medium, its intensity diminishes with distance
energy are intermingled with periods where no [14]. Biological tissues are nonhomogeneous and
energy is emitted. When describing an ultrasound weakening (attenuation) of the signal results
wave, several parameters can be described in rela- from absorption and scattering, as well as reflec-
tion to time or space. By combining peak and aver- tion. Absorption is the sound energy being con-
age values in time and space, six intensities can be verted to other forms of energy, and scattering is
defined. The spatial peak-temporal average (ISPTA) the sound being reflected in directions other than
is the most practical and most commonly referred its original direction of propagation. Since atten-
to and corresponds to the energy averaged over a uation is proportional to the square of sound fre-
period of time. The maximal permitted values, quency, it becomes evident why higher-frequency
based on various clinical application being consid- transducers have less penetration (but better reso-
ered, were first determined in 1976 by the US lution). Acoustic impedance can be described as
Food and Drug Administration ( FDA) [11] but the opposition to transmission of the ultrasound
were modified in 1986 [12]. The most recent defi- wave. It is proportional to the velocity of sound
nition dates from 1992 [13]. These values (in mW/ in the tissue (estimated at 1,540 ms/s, see above)
cm2) are shown in Table 1.1 for the various appli- and to the tissue density.
cations (left column) as a function of the year they
were implemented (modified from references [10–
12]). The numbers in parentheses indicate the per- Instrument Outputs
centage increase, compared to the previously
allowed intensity. Publications of various instruments outputs
It is interesting to observe from Table 1.1 that, are available [15]. From a clinical standpoint,
for fetal imaging, the ISPTA was allowed to increase there is no easy way to verify the actual output
by a factor of almost 16 from 1976 to the most of the instrument in use. In addition, each attached
recent values in 1992, yet, as will be described transducer will generate a specific output, further
1 Ultrasound in Reproductive Medicine: Is It Safe? 5
complicated by which mode is being applied user increase the power. Fine-tuning per-
[16]. When comparing modes, the ISPTA increases formed by the examiner to optimize the image
from B-mode (34 mW/cm2, average) to M-mode influences output but with no visible effect
to color Doppler to spectral Doppler (1,180 mW/ (except if one follows TI and/or MI displays,
cm2). Average values of the temporal averaged see below). Controls that regularize output
intensity are 1 W/cm2 in Doppler mode but can include focal depth (usually with greatest
reach 10 W/cm2 [17]. Therefore, precaution is power at deeper focus but, occasionally on
needed when applying this mode. Most measure- some machines, with highest power in the
ments are obtained from manufacturers’ manu- near field), increasing frame rate, and limiting
als, having been derived in laboratory conditions the field of view (for instance, by high-
which may be different from real-life clinical resolution magnification or certain zooms). In
conditions [18]. Furthermore, machine settings Doppler mode, changing sample volume and/
which are under the control of the clinician can or velocity range (all done to optimize
alter the output. For instance, the degree of tem- received signals) changes output. A very
perature elevation is proportional to the product important control is receiver gain. It often has
of the amplitude of the sound wave by the pulse similar effects to the above controls on the
length and the PRF. Hence, it is evident why recorded image but none on the output of the
any change (augmentation) in these properties outgoing beam and is, therefore, completely
can add to the risk of elevating the temperature, safe to manipulate. In addition, over the years,
a potential mechanism for bioeffects. The three as seen in Table 1.1, output of instruments has
important parameters under end-user control are increased [17]
the operating mode (including choice of trans- 3. Dwell time is directly under the control of the
ducer), the system setup/output control, and the examiner. It is the time during which the ultra-
dwell time. sound beam remains at the same point in the
1. Scanning mode: as mentioned above, B-mode tissue. Interestingly, dwell time is not taken
carries the lowest risk and spectral Doppler into account in the calculation of the safety
the highest (with M-mode and color Doppler indices (TI and MI) nor, in general, until now,
in between). High pulse repetition frequencies reported in clinical or experimental studies.
are used in pulsed Doppler techniques, gener- Directly associated with dwell time is exam-
ating greater temporal average intensities and iner experience in terms of knowledge of
powers than B- or M-mode and hence greater anatomy, bioeffects, instrument controls, and
heating potential. In spectral Doppler, the scanning techniques, since, presumably, the
beam needs to be held in relatively constant more experienced the examiner, the less scan-
position over the vessel of interest, which may ning time is needed.
add to the risk of a larger increase in temporal
average intensity. Naturally, transducer
choice is of great consequence since trans- Ultrasound Bioeffects
ducer frequency will determine penetration,
resolution, and field of view. Why is this even an issue? The average ultra-
2. System setup: starting or default output power sound professional (and the lay people) will state
is very often high to allow better imaging, and that ultrasound is obviously safe and that it is not
end users will, generally, keep it as such, X-rays [19]. Ultrasound, similarly to any sound,
mostly out of lack of concern for bioeffects. is a form of energy. The waveform has positive
Excellent, diagnostic images can be obtained and negative pressures (see above). When such a
at lower output powers (see Fig. 1.1). Recently waveform travels through any tissue, some of
major manufacturers have responded to this energy is transformed into heat (thermal
requests from involved individuals and are effects), and some may cause movements of tis-
now offering a low output power in Doppler sues or membranes as well as some more com-
as their default. Only if needed can the end plex mechanical results (nonthermal or
6 J.S. Abramowicz
mechanical effects). Cavitation is one of these radicals and hydrogen [23]. If the bubble does
nonthermal effects. This refers to reaction of not collapse during the ultrasound exposure, the
small gaseous bodies (bubbles) when exposed to condition is referred to as stable cavitation with
an ultrasound field [20]. In inertial cavitation the bubble oscillating as the waveform pro-
(formerly known as transient cavitation [21]), the gresses. Absence of cavitation foci (gas bubbles),
bubble changes volume (expands under negative as is the case in fetal lungs and bowels and, pre-
pressure and contracts under positive pressure) sumably, in the vicinity of the ovary and the
until the vibration amplitude of the bubble wall developing follicle, renders this phenomenon
increases so much that the bubble implodes. This extremely improbable.
implosion generates highly localized shock These effects occur whenever a tissue is
waves and is also associated with extremely high insonated, thus the designation bioeffects [24].
local temperatures, up to 10,000 K [22]. This is Many in vitro models, such as cells or tissue cul-
localized on a tiny area and for a very brief tures, have been used to investigate ultrasound
moment, and no heat is actually exchanged (adia- bioeffects and to gain a better understanding of
batic reaction). However, in addition to the tem- the possible mechanisms of interaction between
perature elevation, the implosion may result in ultrasound and biological tissue [25]. Studies on
the generation of free radicals such as hydroxyl relatively simple nonmammalian organisms,
1 Ultrasound in Reproductive Medicine: Is It Safe? 7
such as insects, amphibians, and avians, are help- in 1994 the FDA revised its guidance on diagnos-
ful in understanding the mechanisms of interac- tic ultrasound 510(k) submissions to allow the
tion between ultrasound and biological systems use of the MI in place of the ISpPa in determining
[26]. However, from a clinical standpoint, bioef- substantial equivalence of devices. This revision
fect studies of mammalian species are of more assumes that on-system displays of numerical
relevance. Most of these studies were performed indices, including MI and TI, will inform the user
on small rodents, such as mice or rats. The about the potential for either thermal or nonther-
extrapolation of experimental results to humans mal bioeffects associated with the actual exami-
can be difficult, at best. A very comprehensive, nation settings of the imaging system. This
albeit dated, review of the effects of ultrasound enables the clinician to increase acoustic power
on mammalian development was prepared by output beyond the existing FDA guidelines when
Sikov [27]. He evaluated bioeffects depending on clinically warranted (see Table 1.1). Before the
gestational age and thus attempted to extract 1994 FDA revision, such an increase was not
information on the relation between exposure possible. The maximum available acoustic out-
parameters and stage of development at exposure put was limited by the manufacturer’s software,
Experimental studies indicate that intact mam- which would not allow the output to exceed FDA
malian systems (in vivo) do not show a signifi- guidelines for maximum exposure. It must be
cant rise in temperature when exposed to pulsed stressed that with the implementation of the
imaging equipment [27–29]. However, periph- ODS, diagnostic ultrasound systems can have a
eral vessel pulsed and continuous-wave (CW) higher output limit. With the higher limits comes
Doppler equipment, when used for a relatively the potential for increased risk to the patient, so
long time (1–10 min), may be an exception [30, the clinician must make a careful risk/benefit
31]. Therefore, Doppler should be used with analysis. Therefore, the purpose of the ODS is to
care, especially during applications in which help the clinician implement the ALARA (as low
Doppler is used for the assessment of blood as reasonably achievable) principle and minimize
velocities in ovarian vessels in ART and studies the potential for bioeffects. A very important
of the first trimester fetus [32]. Reports on the use aspect of the implementation of the ODS as
of new technologies, such as three- and four- explicitly emphasized in the original recommen-
dimensional (3D/4D) ultrasound, are beginning dations for adoption was education of the end
to appear in the art literature [33], but these do users about bioeffects of ultrasound and safety-
not appear to expose tissues to higher levels of related issues. This particular goal appears to not
acoustic energy [34]. have been very successful as indicated by the fact
that 70–80 % of end users worldwide know very
little about bioeffects and the safety indices
The Output Indices [35– 38]. Furthermore, sonographers and ob/gyn
residents and fellows in the USA seem to be simi-
Because of the two main mechanisms (described larly unfamiliar [39, 40].
above) involved in bioeffects of ultrasound, The thermal index (TI) provides some indica-
a Standard for Real-Time Display of Thermal tion of potential temperature increase, and the
and Mechanical Indices on Diagnostic Ultrasound mechanical index (MI) provides indication of
Equipment, generally known as the Output potential for nonthermal (i.e., mechanical) effects
Display Standard or ODS, consisting of two indi- [22, 25, 41]. The TI is the ratio of instantaneous
ces—thermal (TI) and mechanical (MI)—was total acoustic power to the acoustic power esti-
implemented in the USA around 1992–1994 [11, mated to be required to increase tissue tempera-
13, 22]. Secondary to end users’ desire for better ture by a maximum of 1 °C. It is an estimate of
imaging and as a result of discussions that the maximal temperature rise at a given exposure.
involved the FDA, the AIUM, and the National It is not a measurement of the actual or assumed
Electrical Manufacturers Association (NEMA), temperature. Some correlation exists with
8 J.S. Abramowicz
temperature rise in degrees Celsius, but in no way could be used to closely follow the ovarian cycle
does TI allow an estimate or a guess as to what [45] and, subsequently, with the realization that
that temperature change actually is in the tissue. this was an excellent tool in induction of ovula-
There are three variants: TI for soft tissue (TIS), tion and many other ART procedures [46–48].
for early pregnancy when ossification is minimal; Questions regarding safety of the procedure
TI for bones (TIB), to be used when the ultra- were raised immediately with the rapid adapta-
sound beam impinges on bone, at or near the tion by clinicians [2, 49–51], with description of
beam focus, such as late second and third trimes- premature ovulation [2], reduced fertility in rats
ters of pregnancy; and TI for transcranial studies [49], reduction in pregnancy rates in ultrasound-
(TIC) when the transducer is essentially against monitored groups [50], and lower fertilization
bone, mostly for examinations in adult patients. rate in women undergoing artificial insemination
In ART, TIS is recommended. These indices were and who were monitored by ultrasound as com-
required to be displayed if equal to or over 0.4. pared with those who were not monitored by
There are several issues with TI, in particular the ultrasound, and furthermore, those who were
fact it does not take exposure time into account. monitored took significantly longer to become
Thus, several authors have suggested modifica- pregnant [51]. No mechanism for the findings is
tions or frank changes in the way thermal effects proposed in any of these publications. Later,
can be assessed [42–44]. Doppler assessment of ovarian vasculature was
The MI has been developed as an on-screen also introduced [52–56]. Intraovarian vessels can
indicator of the potential for nonthermal damage be interrogated by color and spectral Doppler to
or cavitation-like phenomena related to B-mode predict ovarian response [57]. The acoustic out-
operation. MI is inversely proportional to the puts of these modalities are much higher than in
center transducer frequency, i.e., the higher the conventional grayscale B-mode, but excellent,
frequency (as is used in ART), the lower the risk diagnostic images may be obtained with low out-
of mechanical effects. It is important to know that puts as documented by low TI and MI, as can be
the MI is not based on actual in situ measure- seen in Fig. 1.1. Further novel technologies to
ments. It is a theoretical formulation of the ratio investigate ovarian vasculature, described in var-
of the pressure to the square root of the ultra- ious chapters in this book, include three-dimen-
sound frequency. Both the TI and MI can and sional (3D) ultrasound [33, 58, 59] and the use of
should be followed as an indication of change in contrast agents [60, 61]. While 3D ultrasound
output during the clinical examination. appears safe [34], the injection of contrast agents
A complicating factor is uncertainties in TI into the body greatly increases the risks of harm-
(and MI) calculations. The error may be a factor ful bioeffects by introducing cavitation foci (see
of 2 or even 6. It is usual to consider a factor of 2 above). Ovarian scanning carries specific wor-
in risk evaluation. Hence, a TI of 2 may indicate ries. In transabdominal scanning, a lot of energy
a potential raise of temperature from 1 °C (half of is absorbed by the (sometimes thick) subcutane-
2) to 4 °C (two times 2). This limits their useful- ous layers. In endovaginal scanning, this “safety
ness but, at the moment, this remains the best tool net” does not exist since the probe is relatively
we have. close to the organ of interest, thus less absorption
occurs. Higher frequencies of the vaginal probes,
however, are protective. In addition, besides the
Ovarian Scanning direct effects of the ultrasound waveform, probe
heating has to be considered. It is known that the
Although the first described use of ultrasound in surface of the probe can heat up by several
ob/gyn was for the diagnosis of an ovarian cyst degrees Celsius [62]. Most of this heat is dissi-
[1], most research and publications have pated by the abdominal wall tissues before
concentrated on obstetrics. This, however, reaching the ovary (or the fetus), but much less
changed with the recognition that ultrasound heat loss occurs with the endovaginal approach.
1 Ultrasound in Reproductive Medicine: Is It Safe? 9
Ultrasound and the Ovum terms of pregnancy rate, number of corpora lutea,
implantations, pups, and mean pup and placental
As stated in the introduction, a study from 1982 weights at autopsy on day 22 of pregnancy [67].
demonstrated premature ovulation in women Others have claimed an increase in the success
who underwent ultrasound examination of the rate, allowing ultrasound monitoring of follicular
ovaries (B-mode) in the late follicular phase [2]. growth [68], although, evidently, this is not a
The authors compared patients in induced ovula- direct effect of ultrasound but of improved tim-
tion cycles and investigated timing of follicle ing. An attempt to clarify this was described by
rupture after the onset of LH surge or administra- Mahadevan and colleagues [66]. They wanted to
tion of hCG. Rupture never occurred before the determine how oocytes obtained under ultra-
37th hour in control patients (no ultrasound in the sound guidance affected the pregnancy rate. The
follicular phase). However, ovulation (prema- results obtained with 3.5 MHz probes suggest
ture) was observed at 26–36 h in about 50 % of that exposure of human oocytes to ultrasonic
cases in the study group (ultrasound during the waves during the different phases of meiosis does
previous 3 days or in the 36 h immediately fol- not significantly influence the developmental
lowing the ovulatory stimulus). This study was potential of the in vitro fertilized embryos.
very concerning but has never been reproduced. Unfortunately, no researcher describes any of the
Since its description 30 years ago [47, 63], relevant exposure parameters discussed earlier,
ultrasound-guided oocyte aspiration for in vitro except for ultrasound frequency.
fertilization and embryo transfer has now become
routine. There are only a few, relatively dated,
studies aimed at determining the interaction Embryo/Fetus Susceptibility
between ultrasound exposure and successful fer-
tilization. Most are, in fact, concerned with suc- The growing embryo/fetus is particularly sensi-
cess or lack thereof of the procedure in terms of tive to external influences. For instance, certain
pregnancy rates and not possible bioeffects. This medications or drug of abuse taken by the preg-
has not been studied with epidemiological meth- nant woman, exposure to X-rays, and elevated
ods but is, arguably, as important as analysis of temperature, secondary to infectious diseases, are
embryonic/fetal effects. Some researchers have all known teratological agents [69]. This is espe-
reported deleterious effects of ultrasound on the cially true in the first 10–12 weeks of gestation.
menstrual cycle, particularly decrease in ovula- Gestational age is thus a vital issue when dealing
tion rates in mice [64] and premature ovulation with possible bioeffects: milder exposure during
[2], as well as reduced cumulative pregnancy the preimplantation period can have similar con-
rates in mice [49] and in humans [50]. Others sequences to more severe exposures during
have demonstrated no effects on the ovulation embryonic and fetal development and can result
process or egg quality, including DNA and RNA in prenatal death and abortion or a wide range of
synthesis [65], nor on fertilization rate and structural and functional defects.
embryonic development following in vitro fertil- Several studies on the influence of ultrasound
ization and embryo transfer [66]. In general, the exposure in the preimplantation period are avail-
clinically available data on ultrasound exposure able. For instance, pregnant rats were exposed to
of oocytes during meiosis are confusing. Some a 2.5 MHz ultrasound field on the second and
researchers reported a deleterious effect on the third day of gestation, at spatial average intensi-
fertility of patients undergoing artificial insemi- ties of 150 mW/cm2, comparable to human
nation with a reduction in the cumulative rate of exposure [70]. No increase in prenatal mortality
pregnancy [50]. A study of ultrasound exposure was found. Similarly, no increase in the rate of
of meiotically active, preovulatory oocytes postnatal malformation was found after 20 min
showed no differences between rats exposed to exposures. In another experiment, pregnant mice
ultrasound after the LH surge and controls in were exposed to ultrasound in the first 3 days of
10 J.S. Abramowicz
gestation [71]. Spatial average intensity was and no consistent increase in mortality was
determined to be 1 W/cm2. A decreased uninter- observed nor did the authors detect any other
rupted pregnancy rate was noted after exposure abnormalities. Evidence, however, of the possi-
for 5 min on the third day and after exposure for bility of ultrasonically produced embryolethal
200 s on day 0. In addition, a reduction in neona- effects during organogenesis has been described
tal weight (after delivery) was observed at certain [80]. Sikov and colleagues exposed an exterior-
thresholds for exposure on day 0 or 1. In another ized rat uterus to various frequencies, some of
series of studies by the same authors [72], ultra- them clinically relevant (0.8, 2, and 3.2 MHz), at
sound exposure led to damage of maternal tissue, day 9 and evaluated the offspring at day 20 [81].
as reflected in increased mortality, decreased The exposure was performed at different inten-
weight gain, and paralysis of the pups. One of the sity levels, with exposure times at 5 or 15 min.
major concerns is whether ultrasound can raise No effect on fetal weight was observed, even at
the temperature of the developing embryo/fetus. spatial average intensities as high as 30 W/cm2,
This concern stems from the fact that, under cer- but prenatal mortality at 15–20 W/cm2 (spatial
tain conditions, ultrasound may indeed cause a average) clearly increased with increasing expo-
rise of temperature and, on the other hand, it is sure time. The cause of this was ascribed to a
well known that hyperthermia is teratogenic. thermal mechanism. A recent controversial study
Most at risk is the fetal central nervous system looked at neuronal migration in rat pups after
(CNS) due to a lack of compensatory growth of maternal exposure to ultrasound [75]. Neurons of
damaged neuroblasts [73]. In experimental ani- the cerebral neocortex in many animals (includ-
mals the most common defects are of the neural ing humans) are generated during fetal life in the
tube as well as microphthalmia, cataract, and brain proliferative zones and then migrate to their
microencephaly, with associated functional and final destinations by following an inside-to-
behavioral problems [74]. More subtle effects are outside sequence. In Ang’s experiment neurons
possible, such as abnormal neuronal migration generated at embryonic day 16 and destined for
with unclear potential results [75]. Other promi- the superficial cortical layers were chemically
nent defects are seen in craniofacial development labeled in over 335 rats. A small but statistically
(more specifically facial clefts), the skeleton, the significant number of neurons failed to acquire
body wall, the teeth, and the heart [74]. their proper position and remained scattered
Hyperthermia in utero (for instance, due to within inappropriate cortical layers and/or in the
maternal influenza) has long been known to subjacent white matter when exposed to ultra-
potentially induce structural anomalies in the sound for a total of 30 min or longer during the
fetus [76], but, relatively recently, it has been period of their migration. The magnitude of dis-
described as an environmental risk factor for psy- persion of labeled neurons was variable but
chological/behavioral disturbances [77] and, increased with duration of exposure to ultrasound
more particularly, schizophrenia [78]. It is (although not linearly, with the most extended
stressed that these are not ultrasound-induced exposure yielding less effect than the one imme-
hyperthermia effects and that it is suggested that diately lower). It is not clear whether a relatively
temperature elevation under 38.9 °C is probably small misplacement, in a relatively small number
not harmful. Yet, ultrasound has been shown to of cells that retain their origin cell class, is of any
induce temperature increase in vivo [41], albeit clinical significance. It is also important to note
not in humans. There is, however, a serious lack that there are several major differences between
of data examining the effects of ultrasound while the experimental setup of Ang et al. and the
rigorously excluding other confounding factors. clinical use of ultrasound in humans [8]. Most
On the one hand, McClain and associates [79] noticeable was the exposure duration, up to 7 h in
exposed rats to 10 mW/cm2 CW Doppler ultra- Ang’s setup, and the fact that scans were per-
sound for up to 2 h at frequencies of 2.25 and formed over a period of several days. Furthermore,
2.5 MHz. The fetuses were examined on day 20, embryos received whole-brain exposure to the
1 Ultrasound in Reproductive Medicine: Is It Safe? 11
beam, which is rare in humans. Brains of mice has to be kept in mind for ultrasound examina-
are much smaller than those in humans and tions in which an endocavity (e.g., endovaginal)
develop over days. This should not completely transducer is used, although in experiments, the
deter from the study which encourages caution. effects on the fetus seemed to be negligible after
Another study which demonstrates potential 2 cm penetration [78].
harmful effects of ultrasound (when spectral It must be emphasized, once more, that there
Doppler is used) showed that even relatively are very few human studies, and those which
short insonation of chick embryos to clinically have been performed do not preclude the possi-
relevant Doppler resulted in short-term and bility that adverse effects may be found under
medium-term memory loss and a reduced ability certain conditions. One of the rare studies in
to learn [82]. humans examined activation of various sub-
There are relatively few papers containing stances involved in the apoptotic cascade, after
information which is pertinent from a human exposures to diagnostic endovaginal ultrasound
clinical standpoint and no epidemiological stud- [85]. Pregnant patients scheduled for interruption
ies of ultrasound in early gestation. One scientific of pregnancy at 7–8 weeks were scanned with
publication dating a few years indicated that fetal 5 MHz endovaginal probes for 0, 10, 20, and
exposure was, most likely, within the upper lim- 30 min. Chorionic villi were obtained 4 h later
its, recommended, at that time [83]. A landmark and analyzed for activation of caspase-3 and
study in the field of ultrasound bioeffects corre- cytochrome release (believed to commit the cell
lated temperature with exposure time [84]. No to apoptosis). According to the authors, ISPTA was
thermal bioeffects were observed at temperature 13 mW/cm2. Unfortunately no indication on TI or
elevations of 39 °C, regardless of how long the MI is given. No or minimal activation of the
ultrasound exposure lasts. However, for each above pathway was seen in controls (0 min expo-
increasing degree of temperature elevation, to sure) or in those exposed for 10 min. The cleav-
stay within safety limits, the duration of ultra- age products of caspase-3 and cytochrome c were
sound examination must be reduced by a factor greatly increased after 20 and 30 min exposure,
of four. More specifically, the review indicated indicating a potential harmful effect of the ultra-
that the maximum safe duration for a temperature sound. Besides this study, all other published
of 43 °C is 1 min and for 42 °C it is 4 min. studies relate to scanning in the late first or sec-
Similarly, at 41 °C the exposure time may be ond trimesters and not to ART or very early ges-
increased to 16 min, and at 40 °C the duration of tation. Epidemiological studies would be needed
examination may be as long as 64 min. Based on to clearly demonstrate an effect or lack thereof
the data available, the survey concluded that if [10]. The very limited epidemiological data
the maximum temperature rise during the ultra- available indicate that no relation has been found
sound exposure is kept less than 2 °C, any bio- between prenatal exposure to ultrasound and sub-
logical effect (in an afebrile patient) is highly sequent postnatal changes in children [86], but
unlikely. As already addressed (see above) find- statistical considerations show that minor chemi-
ings indicating that the ultrasound imaging trans- cal and behavioral changes, long-term delayed
ducer may act as a substantial heat source [62, effects, and certain genetic effects could easily
78] are of particular interest in ART and in the escape detection [4].
early stages of pregnancy because of the univer- Thus, it appears that in vivo exposure to ultra-
sal use of endovaginal scanning. The temperature sound at spatial average intensities below 1 W/
at a clinically operated Doppler transducer was cm2 (which is arguably the case in ART as well as
reported to increase by 10 °C when the Doppler early gestation) does not affect embryos/fetuses
was applied to skin with a standard coupling gel in the early stages of gestation. Limited data,
[78]. Although tissue heating from the transducer however, suggest that levels of ultrasound of
is most likely limited to the tissue volume in the 1 W/cm2 may lead to undesirable changes in
immediate vicinity of the transducer, this effect maternal tissue. If one considers together the
12 J.S. Abramowicz
facts that hyperthermia is potentially harmful to output of medical ultrasound instruments was
the fetus and that ultrasound may, under certain allowed to be greatly increased [89]. The words
circumstances, elevate tissue temperature, then of Francis Duck in 1999 are still particularly
precaution has to be recommended, particularly valid: “No epidemiological or other evidence
in early gestation and especially with modes was then or is now available to support the asser-
known to emit higher acoustic energy levels tion of safety at these higher exposures.” [90]
(such as pulsed Doppler [87]). This recommen-
dation is supported by experimental data. Further
prospective studies on ultrasound safety in ART Summary and Recommendations
and pregnancy are highly recommended.
Several statement and guidelines are available
[91–97]. As already mentioned, based on various
Safety Aspects of Ultrasound sources, it appears that acoustic output (as
in Ovulation Induction and Early expressed by various intensities) can be much
Gestation higher in Doppler mode: for instance, 34 mW/cm2
for the ISPTA in B-mode versus 1,180 mW/cm2 for
There are many valid medical indications to per- spectral Doppler and with color Doppler some-
form ultrasound in early gestation [88]. These what in between [98]. Concerns about the fact that
include, among others, bleeding, accurate gesta- outputs are much higher in Doppler applications
tion dating, confirmation of viability, and verifi- were already expressed approximately 10 years
cation of number of fetuses. In addition, ago in three editorials [90, 99, 100]. In one of
ultrasound is invaluable in ART. All of these these, the question was even raised whether
examinations are primarily performed with research involving Doppler in the first trimester
B-mode, a mode with relatively low acoustic out- should even be considered for publication [100].
put. However, more recently, screening for Despite this, as detailed above, ultrasound is rou-
genetic abnormalities and early assessment of tine in ART, and in more recent years, there has
structural abnormalities are described in the lit- been a recrudescence in the usage of Doppler in
erature in early (11–15 weeks) pregnancy. While the 1st trimester and furthermore in the early
most of these are also performed with B-mode, stages of the first trimester. A very important rec-
Doppler is often used to detect blood vessels and/ ommendation, already mentioned, is to limit expo-
or to visualize and analyze cardiac valves, poten- sure to be as short as possible, compatible with an
tially exposing the fetus to much higher energy adequate diagnosis (as low as reasonably achiev-
levels. One needs to keep in mind that, even with able [ALARA] principle). A very useful method
B-mode, dwell time is important since prolonged to keep risk at a minimum is to use published
examination can result in higher exposure levels. guidelines in the USA [91] as well as BMUS-
The evidence of ultrasonically induced bioef- recommended limits [98]. These can be summa-
fects in humans is perhaps the most important rized in a few easy-to-remember bullet points:
information from the clinician’s point of view. As • Perform a scan only when medically
pointed out by Ziskin and Petitti, “No matter how indicated.
many laboratory experiments show a lack of • Know your machine and how controls change
effect from diagnostic ultrasound, it will always the output.
be necessary to study directly its effect in human • Start at low output and increase only when
populations before any definitive statement necessary.
regarding risk can be made.” [4] Indeed, a lack of • Keep TI and MI below 1.
demonstrated effects is not equivalent to a factual • Watch the clock and keep the examination as
lack of effects. All published epidemiological brief as possible (but enough to obtain diag-
studies in humans were performed with pre-1992 nostic accuracy).
machines, a time when the maximal acoustic • Be cautious when using Doppler.
1 Ultrasound in Reproductive Medicine: Is It Safe? 13
30. Stewart HF, Stratmeyer ME. An overview of ultra- 47. Lenz S, Lauritsen JG, Kjellow M. Collection of
sound theory, measurement, medical applications and human oocytes for in vitro fertilisation by
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32. Dickey RP. Doppler ultrasound investigation of uter- Med. 1981;165:353–8.
ine and ovarian blood flow in infertility and early 49. Bologne R, Demoulin A, Schaaps JP, Hustin J,
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Periovulatory follicular volume and vascularization 381–7.
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Principles of 3D Ultrasound
2
Maximilian Murtinger, Dietmar Spitzer,
and Nicolas Herbert Zech
reduce the number of orientations, special types nal computer. However, the rendering was also
of ultrasound transducer systems were devel- limited in ability to provide a set of orthogonal
oped, allowing the acquisition of information planes orientated images in strict relation to the
through only one viewing direction by electronic axis of the probe. Additionally, special scan
focusing. transducers were needed for this instrument.
In 1984, Kazunori Baba first described a 3D They had to be held by their larger side, thus
ultrasound system. In 1986, he was the first per- making them rather difficult to handle. This
son on the globe to obtain 3D images of a drawback was removed in the majority of the
19-week fetus by processing the raw 2D images later US instruments by a 90° rotation of the 3D
on a minicomputer in 1986 [7, 8]. In 1987 Olaf US device. In 1998, the Voluson 530D 3D system
T. von Ramm and Steven W. Smith patented “An implemented a technology that displayed not
acoustic pulse echo imaging system capable of only the 3D sectional images, but also processed
producing an image of a three-dimensional the data of the entire volume in real time. With
object utilizing a two-dimensional display. In the the commercial launch of this 3D instrument
system angular relationships of targets at all platform, 3D ultrasound technology competed
ranges are maintained for display. The system with the higher priced CT and MRI instruments;
uses a two-dimensional transducer array of it allowed effective grayscale imaging, spectral
piezoelectric elements; the array is steered to Doppler, color Doppler, and Angio Color Imaging
assume transmit and receive orientations in both [11]. Two years later, the medical equipment
azimuth and elevation by producing (1) a manufacturer GE Healthcare introduced a new
directed transmit pulse and many similarly generation of clinical US systems, the Voluson
directed receive orientations or (2) a non-directed 730 with real-time acquisition of volumes (16
transmit pulse and many directed receive orien- volumes/s). Now, it is possible to detect and ana-
tations. For each transmit pulse a parallel pro- lyze even moving objects such as a fetus. With
cessing system produces several unique image the beginning of the new millennium, several
points whose locations in the image correspond new software programs became available that
to the tangents of the angles of the receive orien- significantly improved the image quality.
tations in the azimuth and elevation planes. The Currently, numerous 3D US instruments are
brightness of each image point is the weighted available (most of them semi- or fully auto-
integral of the echo data received along each mated), and it is extremely likely that dozens
receive path. As an option, range discrimination of new machines will become available in the
capability is provided by means of a range next few years. The systems have become faster
dependent gain control, brightness shading as a and more advanced. Furthermore, the number
function of range or a color display in which data of compatible software programs exceeds the
originating from different ranges is displayed in amount of instruments sold. Virtual naviga-
different hues [9].” tion, different modes of presentation (such as
Two years later, the first commercially avail- tomographic ultrasound imaging (TUI) volume,
able 3D US instrument was marketed in 1989 by contrast imaging (VCI) and automated volume
the Austrian company Kretztechnik (Zipf/ calculation (SonoAVC), computer-aided analy-
Austria) which was founded by the engineer Paul sis (VOCAL) calculation), and other techniques
Kretz after the Second World War. are now available; they are reliable, fast, and
This instrument, the Combison 330 equipped user friendly [12]. With these features, the pos-
with 7.5 MHz and integrated 3D system was pre- sibilities for clinical application become almost
sented at the French radiology congress in Paris unlimited; furthermore, use is increasing in the
in 1989 [10]. It utilized mechanical abdominal clinical setting. Many post-processing tools
volume scan transducers with the mechanical such as speckle reduction imaging, electronic
swept-volume approach. Although the acquisi- scalpel, and filters for brightness and contrast
tion of the volume took only 1–2 s, rendering of facilitate handling. Data transfer and long-term
the image took up to almost 20 min on an exter- storage are now possible without any quality
2 Principles of 3D Ultrasound 19
loss. Although most procedures are still con- transducer can remain stationary and elec-
ducted with 2D scans, for a number of rea- tronic scanning can be used to sweep a broad
sons, it is likely that the 3D technology will ultrasound beam over the entire volume under
be a supplementary tool—and in some cases, examination [16].
a replacement—for 2D instruments in the field 4. A fourth possibility is mechanical assemblies:
of ART in the future. The transducer is moved either (1) linear,
(2) tilted, or (3) in a rotational movement about
its central axis by a mechanical assembly.
Basic Techniques of 3D US
Fig. 2.1 Tomographic ultrasound image (TUI) of multiple follicles in a stimulated ovary
the final quality still depends on the accu- Moreover, it might reduce medical malpractice
racy of the scanned volumes (also see next and might prove to be an essential step towards
paragraph). Nevertheless, as previously men- standardization in this field.
tioned, various software-based tools are cur-
rently available. Post-processing is done via
the electronic scalpel (Kretztechnik, Zipf, Advantages and Shortcomings
Austria), contrast and brightness regulation, of 3D US Techniques
or speckle reduction imaging (SRI). SRI was
established on the Voluson platform in 2004 Three-dimensional US allows visualization of all
by GE Healthcare. The electronic scalpel three image planes (sagittal, transverse, and cor-
allows for the removal of pre-located obscur- onal) of the analyzed object, including planes
ing structures in three steps: (1) rotation of not accessible by 2D US. The viewed planes can
the rendered image into a position where the be chosen or changed by the user to view the
obscuring structures can be cut; (2) the selec- desired region under investigation. Using the
tion of the cutting mode; and (3) creation of conventional 2D technique, the referring physi-
the outline for the cut and activation of the cian often had to integrate all the received 2D
cutting mode [27]. Speckles are recurrent images in a three-dimensional form to obtain an
problems in sonography due to interference impression about the anatomy and possible
of ultrasound echoes; they produce difficul- pathologies.
ties in differentiating anatomical structure. The use of 2D ultrasound for measurement of
Many approaches have been attempted with organs, such as the uterus or follicle volume, is
the goal of reducing or even of eliminating variable and at times inaccurate. Some diagnostic
speckles. Most significantly, the increased and treatment IVF procedures require accurate
computer processing power and speed of volume measurements (such as follicle monitor-
calculation within recent years have allowed ing). The accurate acquisition of volumes is only
more complex image-processing techniques possible with 3D US, especially when the ana-
to reduce these artifacts without impair- lyzed structures are not spherical but complex
ing image quality [28]. In addition, filter- (i.e., follicles within a multi-follicular growth
ing is widely used for undesired echoes that complex; this problem will be discussed in a
are a recurrent phenomenon in sonography. subsequent chapter). 3D US is a relatively new
Filtering allows the suppression of unwanted technique for gynecology and IVF. However,
background noise or the enhancement of the studies have already been published reporting
desired information (suppressing and enhanc- high accuracy.
ing filters) [29]. Use of the 3D technique together with the
Initially, data storage was a problem with 3D appropriate software allows for the accessed 3D
technology. This problem has been resolved by volumes to be digitally stored. This is a tremen-
the improved storage capacity of the hard disk. dous advantage for later post-processing and
The acquired data can be readily stored without evaluation. Thus, the stored data can be reformat-
quality loss either at the US systems itself or on ted and analyzed in various ways. Beyond all the
external media (CD, DVD, USB, or external hard technical improvements, 3D US is still based on
drive). The data can still be post-processed with conventionally received 2D US data. Thus, poor
medical software and can be transferred, for US scanning techniques cannot be improved by
example, via (virtual private network) VPN this innovative technique. Inadequate resolution
tunneling to another physician. Most importantly, of 2D scans results in poor image quality of the
the data can be reloaded and subjected to an three-dimensional structures. Therefore the 2D
additional expert opinion or used for education scans must be optimized in regard to (1) bright-
[30]. This is an invaluable feature. Currently, ness, (2) the depth of field, and (3) the correct
this capability facilitates optimal patient care. positioning of focus. The correct setting to
22 M. Murtinger et al.
achieve the optimal 2D scan is therefore a prereq- studies concerning 3D US in the context of IVF
uisite for the best possible 3D calculation. therapies are still limited. Conversely, 3D US in
In addition, most artifacts, which are common monitoring is commonly used during pregnancy
in 3D or 4D US, are also similar to those of 2D and a crucial tool in prenatal diagnosis because
US because both techniques are based on the the volumes of fetal organs can be accessed more
same principle. Improper calibration and opera- accurately by the new 3D techniques rather than
tion is one major source of the production of infe- by conventional 2D US. Thus, fetal anomalies
rior data as well as for poor interobserver can be recognized more readily [31, 32].
reliability. This holds true for both, 2D and 3D The applications of 3D US in IVF are also
US. One exception might be the appearance of summarized in the Chap. 20. However, an over-
artifacts due to the movement of the examined view of the applications of 3D sonography will
objects with 4D US. However, the application of be presented here. The investigation of the uterus,
4D US does not play a dominant role in ART ovaries, and fallopian tubes are a prerequisite of
because most of the analyzed structures are an IVF cycle. Uterine pathology such as myo-
immotile. However, it is not unequivocally clear mas, malformations (see Figs. 2.2 and 2.3) and
whether the 4D technique might be of future carcinomas can significantly impair the outcome
value for ART. For example, endometrial blood of IVF therapy [33], and sometimes patient
flow analyzed by 4D US might become an addi- health. In addition to MRI and CT, 2D US was
tional parameter for the prediction of embryo and is currently used for the detection of congeni-
implantation in the future. tal malformations of the female reproductive sys-
The 3D visualization technique offers no tem. However, it lacks specificity and image
additional advantages in regard of reducing the quality [34–37]. Three-dimensional sonography
aforementioned artifacts. The effective improve- allows a more accurate calculation of the uterine
ments of US imaging is due to accompanying volume. It also allows a more precise estimation
post-processing software. However, this techni- of endometrial morphology and volume.
cal processing cannot be regarded separately as Endometrial volume and morphology are the
these are integrated components of high-quality most crucial factors for IVF success. Nonoptimal
3D instruments. endometrial lining or a small endometrial volume
The rapidly increasing processing power was impacts embryo implantation. In these cases, it
also one basic requirement for the introduction of might be prudent to consider embryo cryopreser-
portable US systems. This innovation, together vation and opt for a cryocycle [38]. In addition,
with standardized higher image quality, standard- 3D techniques such as 3D Doppler enable the
ized image storage, and compression techniques visualization of endometrial blood flow and neo-
such as the Digital Imaging and Communications vascularization of cervical carcinomas, which are
in Medicine (DICOM) standard, enables a medi- completely beyond the scope of conventional
cal network and improved patient care. 2D US.
Imaging modes such as the glass-body mode
are the most optimal for the recognition of tumor-
Applications of 3D Ultrasound feeding vessels. The glass-body mode is a very
in ART good method for hysterosalpingo-contrast-
sonography (HyCoSy) to detect abnormal vari-
Several clinical trials have demonstrated the cosity in the adnexal region. The use of 3D US
superiority of 3D systems compared to conven- dramatically facilitates HyCoSy and provides a
tional 2D US. The images of the structure’s sur- better assessment of tubal patency [39].
faces become fully apparent (as a result of their Furthermore, 3D US techniques enable an
three-dimensional nature). The detailed advan- estimation of the ovarian reserve and can be
tages of the 3D sonography, especially for IVF, applied during follicle monitoring [40]. Thus,
are discussed within the Chap. 20. However, particular automated systems such as the
2 Principles of 3D Ultrasound 23
18. Ruano R. Recent advances in sonographic imaging 33. Bulletti C, DE Ziegler D, Levi Setti P, Cicinelli E,
of fetal thoracic structures. Expert Rev Med Devices. Polli V, Stefanetti M. Myomas, pregnancy outcome,
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Aubry MC, Benifla JL. Contribution of three- 34. Raga F, Bonilla-Musoles F, Blanes J, Osborne NG.
dimensional volume contrast imaging to the sono- Congenital Müllerian anomalies: diagnostic accuracy
graphic assessment of the fetal uterus. Ultrasound of three-dimensional ultrasound. Fertil Steril. 1996;
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21. Weber G, Merz E, Bahlmann F, Macchiella D. 36. Ghi T, Casadio P, Kuleva M, Perrone AM, Savelli L,
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Two-Dimensional
and Three-Dimensional Doppler 3
in Reproductive Medicine
Ernest Hung Yu Ng
on the right and left side of the cervix in a endometrial and subendometrial 3D Doppler flow
longitudinal plane before it enters the uterus. indices were similar among patients with aver-
The ‘gate’ of the Doppler is positioned when the aged uterine PI <2.0, 2.0–2.99 and ≥3.0. [14].
vessel with good colour signals is identified on
the screen. The PI and RI of the uterine arteries
were calculated electronically when three simi- Endometrial and Subendometrial
lar, consecutive waveforms of good quality were Blood Flow by 2D Doppler
obtained.
Good uterine blood flow as shown by low PI Endometrial and subendometrial blood flow
or RI is correlated with successful IVF out- examined by colour (Table 3.1) and power
comes [12, 13]. Steer et al. [12] classified PI Doppler (Table 3.2) was correlated with implan-
measured on the day of ET as low, medium and tation or pregnancy rates during IVF treatment.
high in the ranges of 0–1.99, 2.00–2.99 and 2D Doppler flow indices of spiral arteries such
≥3.00, respectively, and reported a 35 % implan- as PI and PSV are not predictive of pregnancy [8,
tation failure when PI was >3.0. Using a PI 19, 22], although Battaglia et al. [16] and
upper limit of 3.0 [12] or 3.3 [13], the uterine Kupesic et al. [23] found significantly lower spi-
Doppler flow indices have a high negative pre- ral artery PI in pregnant cycles than nonpregnant
dictive value and sensitivity (in the ranges of cycles.
88–100 % and 96–100 %, respectively) and a Yang et al. [18] used a computer software to
relatively higher range of positive predictive measure the area and intensity of colour signals
value and specificity (44–56 % and 13–35 %, present in the endometrium in a longitudinal axis,
respectively) when compared with endometrial i.e. intraendometrial power Doppler area (EDPA).
thickness and pattern [5]. Significantly higher EDPA was found in pregnant
Uterine artery Doppler study may not reflect cycles than nonpregnant cycles (8.8 mm2 vs.
the actual blood flow to the endometrium as the 5.8 mm2 respectively). Patients with EDPA
major compartment of the uterus is the myome- <5 mm2 had significantly lower pregnancy rate
trium and there is collateral circulation between (23.5 % vs. 47.5 %; P = 0.021) and implantation
uterine and ovarian vessels. I have shown 2D rate (8.1 % vs. 20.2 %; P = 0.003) than those
Doppler study of uterine vessels is a poor reflec- with ≥5 mm2. Contart et al. [20] graded endome-
tion of subendometrial blood flow by 3D power trial blood flow by the visualisation of power
Doppler in both stimulated and natural cycles as Doppler in the quadrants in the fundal region of
the transverse plane but could not demonstrate and this was expressed as a percentage (%) of the
any predictive value of such grading system. endometrial volume. Flow index (FI), the mean
Presence of endometrial and subendometrial power Doppler signal intensity inside the endome-
blood flow can be identified easily in 2D Doppler trium, is thought to express the average intensity
ultrasound. Absent endometrial and subendome- of flow. Vascularisation flow index (VFI) is a com-
trial blood flow has been shown to be associated bination of vascularity and flow intensity [24].
with no pregnancy [16, 22] or a significantly The subendometrium can be examined
lower pregnancy rate [17, 21]. through the application of ‘shell imaging’ which
allows the user to generate a variable contour that
parallels the originally defined surface contour.
Endometrial and Subendometrial The VI, FI and VFI of the subendometrial region
Blood Flow by 3D Doppler are obtained accordingly (Fig. 3.3). The intra-
observer reliability and interobserver reliability
3D power Doppler ultrasound with the aid of the of endometrial and subendometrial blood flow by
VOCAL® (Virtual Organ Computer-Aided 3D power Doppler have been confirmed to be
Analysis) imaging program for the 3D power high with all measurements obtaining an intra-
Doppler histogram can be used to measure the class correlation of above 0.9 [25, 26].
endometrial volume and indices of blood flow Studies addressing the role of endometrial
within the endometrium (Fig. 3.2). Vascularisation and subendometrial blood flow measured by
index (VI), which measures the ratio of the num- 3D Doppler in IVF treatment are summarised
ber of colour voxels to the number of all the in Table 3.3. Schild et al. [27] measured
voxels, is thought to represent the presence of the subendometrial blood flow after pituitary
blood vessels (vascularity) in the endometrium, downregulation but prior to ovarian stimulation
3 Two-Dimensional and Three-Dimensional Doppler in Reproductive Medicine 31
Fig. 3.2 Endometrial volume (a) and blood flow (b) measured by 3D Doppler ultrasound
32 E.H.Y. Ng
Fig. 3.3 Subendometrial volume (a) and blood flow (b) measured by 3D Doppler ultrasound
3
Table 3.3 Summary of studies of endometrial and subendometrial blood flow by 3D power Doppler ultrasound
Study IVF cycles Inclusion/exclusion criteria USS day Results
Schild et al. [27] 75 cycles using a long protocol Inclusion criteria Before stimulation Subendometrial VI, FI and VFI lower in
pregnant than nonpregnant cycles
ET 2 days after TUGOR Downregulation confirmed Subendometrial FI is the strongest predictive
(endometrium <5 mm, no ovarian factor for IVF in logistic regression analysis
cyst of >2.5 cm, serum oestradiol
<60 pg/mL)
Kupesic et al. [23] 89 cycles using a long protocol Inclusion criteria ET (hCG +7) Higher subendometrial FI in pregnant cycles
Blastocyst transfer 5 days after Serum FSH < 10 IU/L
TUGOR No fibroid, ovarian cysts and ovarian
endometriosis
Wu et al. [28] 54 cycles; first cycle only (details of Inclusion criteria hCG Subendometrial VFI higher in pregnant cycles
ovarian stimulation and ET not given) Age <38 years
Normal uterine cavity
Serum FSH <15 IU/L
≥2 good quality embryos
Dorn et al. [29] 42 cycles using a long protocol Exclusion criteria OR No difference in subendometrial VI, FI and VFI
Polycystic ovary syndrome between pregnant and nonpregnant cycles
Endometrium <6 mm
Gynaecological surgery
Järvelä et al. [30] 35 cycles using a long protocol Exclusion criteria After stimulation and No difference in endometrial and
ET 2 days after TUGOR Uterine fibroids OR subendometrial VI between pregnant and
Endometriosis nonpregnant cycles on both days
Two-Dimensional and Three-Dimensional Doppler in Reproductive Medicine
Single ovary
Previous operation on uterus or
salpingectomy
Ng et al. [31] 451 cycles using a long protocol; first Inclusion criteria OR Endometrial VI and VFI lower in pregnant
cycle only cycles
ET 2 days after TUGOR Normal uterine cavity on scanning
Ng et al. [32] 193 cycles Inclusion criteria LH + 1 No difference in endometrial and
Frozen-thawed embryo transfer Normal uterine cavity subendometrial 3D Doppler flow indices
cycles between pregnant and nonpregnant cycles
(continued)
33
34
USS ultrasound, VI vascularisation index, FI flow index, VFI vascularisation flow index, OR oocyte retrieval, ET embryo transfer
E.H.Y. Ng
3 Two-Dimensional and Three-Dimensional Doppler in Reproductive Medicine 35
and showed that subendometrial VI, FI and VFI the nonpregnant group. Endometrial thickness,
were significantly lower in pregnant cycles than endometrial volume, endometrial pattern, uterine
nonpregnant ones. Logistic regression analysis PI, endometrial FI and subendometrial VI, FI and
found that the subendometrial FI was the stron- VFI were similar between the nonpregnant and
gest predictive factor for the pregnancy outcome pregnant groups. The number of embryos
among other 3D Doppler flow indices. replaced and endometrial VI were the only two
Kupesic et al. [23] performed 3D ultrasound predictive factors for pregnancy in a logistic mul-
examination on the day of blastocyst transfer tiple regression analysis. ROC curve analysis
and found that subendometrial FI was signifi- revealed that the area under the curve was around
cantly higher in pregnant cycles. Subendometrial 0.5 for all ultrasound parameters for endometrial
VI and VFI were similar between pregnant and receptivity. Implantation and pregnancy rates
nonpregnant patients. Wu et al. [28] measured were comparable for patients with and without
subendometrial blood flow on the day of hCG endometrial and subendometrial blood flow [31].
and demonstrated that subendometrial VFI The age of women, their smoking habits, their
was significantly higher in the pregnant group. types of infertility and parity and causes of subfer-
Subendometrial VI and FI were also simi- tility had no effect on all endometrial and subendo-
lar between pregnant and nonpregnant cycles. metrial 3D Doppler flow indices [35]. Endometrial
Subendometrial VFI was superior to subendome- blood flow was negatively affected by serum oes-
trial VI, subendometrial FI and endometrial vol- tradiol concentration on the day of hCG. Indeed,
ume in predicting the successful outcome in the endometrial and subendometrial 3D Doppler flow
receiver-operating characteristics (ROC) curve indices in the stimulated cycles were significantly
analysis. lower than those in the natural cycles of the same
On the day of oocyte retrieval, Dorn et al. [29] patients undergoing IVF treatment [36].
compared the subendometrial blood flow before Uterine PI, uterine RI, endometrial and suben-
and after an intravenous administration of dometrial 3D Doppler flow indices were compa-
Levovist, which is a contrast agent and consists rable between the nonpregnant and pregnant
of 99.9 % of D-galactose. All subendometrial 3D groups’ frozen-thawed embryo transfer cycles
Doppler flow indices after the administration of using natural or clomiphene-induced cycles [32].
the contrast agent were significantly higher than On the other hand, endometrial and subendome-
those without the contrast agent. However, all trial blood flow was significantly higher in preg-
subendometrial 3D Doppler flow indices with nant patients with live birth following IVF and
and without the contrast agent were comparable frozen-thawed embryo transfer treatment [37].
between pregnant and nonpregnant cycles. The Mercè et al. [33] found that endometrial 3D
results of this study suggested that the use of 3D power Doppler flow indices were statistically sig-
power Doppler ultrasound under a contrast agent nificantly higher in the pregnant group. The area
during IVF treatment provided no additional under ROC curve was statistically significant for
advantage over the conventional 3D power endometrial VI, FI and VFI when no grade 1
Doppler ultrasound examination. embryos or only one was transferred, but not when
Järvelä et al. [30] determined endometrial and two or three grade 1 embryos were transferred.
subendometrial VI after gonadotrophin stimula-
tion but before hCG administration and again the
day of oocyte retrieval. There were no differ- Changes in Endometrial and
ences between the pregnant and nonpregnant Subendometrial Blood Flow
groups in endometrial and subendometrial VI on
either day examined. I have published the largest Ultrasound examination was performed on the
study involving 451 transfer cycles [31]. Patients day of hCG [28, 33], oocyte retrieval [29–31]
in the pregnant group had significantly lower and blastocyst transfer [23]. There is no
uterine RI, endometrial VI and VFI than those in consensus when the ultrasound examination for
36 E.H.Y. Ng
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Legal Aspects of Ultrasound
Imaging in Reproductive Medicine 4
James M. Shwayder
Medical liability concerns all providers and has Litigation in this area tends to focus on the
great impact on the health system. Recognizing following:
the prime areas of risk and proactively addressing 1. Inadequate training of the person performing
these issues can reduce the frequency and sever- the ultrasound study
ity of litigation. However, liability now extends 2. Inadequate and thus negligent performance of
to billing fraud, which can be even more finan- the study, with inadequate or incomplete images
cially devastating. 3. Inadequate supervision of the sonographer
The elements of malpractice include the fol- 4. Lost or misplaced images
lowing: (1) the duty to care for a patient; (2) a 5. Inadequate equipment maintenance
breach of that duty, i.e., a breach of the standard
of care; (3) that breach is the proximate cause of
an adverse outcome or complication; and (4) Personnel Performing Ultrasound
damages result that are compensable. If any one Examinations
of these elements is not met, then the action fails
or in other words defensible. Litigation in ultra- There are specific issues that are unique to
sound imaging focuses on two areas: (1) the ultrasound. Ultrasound performance is often
proper performance of the study with acquisition delegated to other personnel. The American
of images suitable to render a diagnosis and (2) Institute of Ultrasound in Medicine (AIUM)
errors surrounding study interpretation and accreditation guidelines require that all persons
reporting. who perform ultrasounds, other than physi-
cians, are either RDMS (Registered Diagnostic
Medical Sonographer) certified or eligible [1].
However, many reproductive medicine practices
J.M. Shwayder, MD, JD use nurses, nurse practitioners, or other person-
Department of Obstetrics and Gynecology, nel who do not meet these criteria to perform
University of Mississippi, 2500 North State Street,
ultrasound. In 2009, the American Institute
Room L305 (for FedEx or UPS), Jackson,
MS 39216, USA of Ultrasound in Medicine (AIUM) and the
e-mail: jshwayder@umc.edu American Society of Reproductive Medicine
(ASRM) issued a consensus statement regarding However, the training of the nonphysician
focused ultrasounds in reproductive medicine personnel who perform the diagnostic procedure
[2]. Ultrasounds for follicular monitoring are and equipment maintenance are the responsibil-
intended to provide specific diagnostic informa- ity of the physician [6]. Thus, any errors resulting
tion comprising the number and size of devel- from inadequately performed ultrasound studies
oping follicles, as well as uterine evaluation fall within legal concept of respondeat superior.
including endometrial thickness and morphology. This concept holds the employer, or physician,
These are considered limited ultrasounds, rather liable for the wrong of an employee if it was
than complete diagnostic sonographic studies. committed within the scope of employment [7].
The consensus is that such limited examinations The exception to this supervision level is in the
are within the scope of practice of a nurse with performance of sonohysterography that requires
specific training and with appropriate physician “personal supervision.” Personal supervision
supervision in an infertility practice. However, it requires the physician’s presence in the room
states that a comprehensive ultrasound examina- during the performance of the procedure. In most
tion should have been performed within the prior instances this requirement is met when the physi-
4–6 months to exclude significant gynecologic cian inserts the catheter and instills fluid while
pathology. the ultrasound is performed. Similar require-
A caution is that the position of AIUM and ments exist for sonosalpingography. If the physi-
ASRM on nurses performing ultrasound exami- cian is not available for immediate consultation,
nations pertains to the limited studies appropriate then guidelines should be established that address
for monitoring ovulation induction. If the prac- immediate communication with the supervising
tice performs comprehensive diagnostic studies, physician. In addition, callback mechanisms
according to AIUM guidelines, these should be should be established when further evaluation of
performed by physicians or appropriately trained the patient is required.
and qualified personnel. If not, the physician is at
increased legal risk in the event of misdiagnosis.
Image Acquisition and Retention
Adequacy of the Ultrasound Study Images obtained should conform with the guide-
lines set forth by AIUM [3–5]. Ideally, images
Images obtained should conform with the guide- should be retained in a digital format to maxi-
lines set forth by AIUM [3–5]. Incomplete stud- mize retention of image quality for a more
ies expose the physician to increased risk as the extended time. At a minimum, thermal print
lack of images supporting the reported diagnosis images of critical findings should remain in the
reduces defensibility. Also, the lack of a docu- medical record. The images, as well as the report,
mented complete study can expose the physician should be retained for the statute of limitations as
to a claim of insurance fraud specifically billing required in the applicable jurisdiction.
for a higher level of service than supported by
documentation.
Equipment Maintenance
Study Interpretation and Reporting the interpreting physician. The best defense is
available when the interpretation includes an
Ultrasound litigation surrounding ultrasound appropriate differential diagnosis, particularly if
remains most frequent with obstetrical ultra- it includes the correct diagnosis. As these cases
sound. However, gynecologic ultrasound is now are subject to interpretation, they tend to be more
the second most common cause of ultrasound- defensible, with 75 % won if the case goes to jury
related litigation [8]. The most common causes verdict [11].
of liability actions comprise the following: (1) Failing to suggest the next appropriate proce-
perception errors, (2) interpretation errors, (3) dure places the interpreting physician at risk of
failing to suggest the next appropriate procedure, litigation and liability. The prudent physician or
and (4) failure to communicate significant abnor- radiologist should suggest the next appropriate
mal findings [9]. study or procedure based upon the findings and
Perception errors occur when an abnormality clinical information. The recommended study
is seen in retrospect but it was missed when inter- should add meaningful information to clarify or
preting the initial study [10]. An example would confirm the diagnosis [12]. This is particularly
be an adnexal mass with a gestational sac, consis- apropos when performing and interpreting ultra-
tent with an ectopic pregnancy, which was not sound studies referred from outside physicians.
identified on the initial study but identified on An example is when a study is consistent with a
subsequent review. Although the error rate in pregnancy of unknown location. The appropriate
radiology is approximated at 30 % [10], this rate recommendation would be serial hCG levels and
is not accepted when errors occur. The critical a repeat ultrasound as clinically indicated.
question is: “Was it below the standard of care for Failure to communicate significant abnormal
the physician not to have seen the abnormality?” findings on an ultrasound again places the inter-
[11] These cases are difficult to defend with preting physician at risk for liability. Two exam-
almost 80 % of cases decided against the physi- ples are the diagnosis of an ectopic pregnancy or
cian if the case goes to jury verdict [11]. Thus, an ovarian malignancy without prompt notifica-
most of these suits are settled. The best defense is tion of the referring physician. These findings
(1) a complete examination performed in a sys- place the patient at significant risk and merely
tematic fashion, evaluating all appropriate struc- providing a written report is not adequate.
tures; (2) appropriate and adequate image Practices should have established protocols or
documentation; (3) appropriate and reasonable guidelines for notifying referring physicians of
interpretation of the findings; and (4) ongoing sonographic results, particularly for those cases
continuing education for the interpreting with critical findings. It is preferred that all stud-
physician. ies have a final reading and report issued within
Interpretation errors occur when the abnor- 24 h of the original procedure. Following these
mality is perceived but is incorrectly described protocols and guidelines provide the best defense
[9]. One example that is becoming a more fre- for the physician [9].
quent source of litigation is the misdiagnosis of
an “ectopic pregnancy.” In this instance an early
intrauterine pregnancy, with no visualized gesta- New Horizons in Ultrasound
tional sac, and a corpus luteum is diagnosed as an Liability
ectopic pregnancy, with subsequent administra-
tion of methotrexate. A more common error is First-Trimester Ultrasound
when a normal variant is called abnormal, such as
a corpus luteum diagnosed as a malignancy. The Identifying the early embryo and cardiac activity
converse is when a malignant lesion is called is an emotional event for patients. One should
benign, such as a complex ovarian mass diag- avoid the temptation to demonstrate the fetal
nosed as a benign lesion. These errors often occur heart rate with Doppler sonography as this
due to lack of knowledge or faulty judgment of exposes the early embryo to higher than ideal
44 J.M. Shwayder
energy. All ultrasound studies should be Intent to commit fraud is not necessary to
performed with the ALARA (as low as reason- face litigation and liability. However, compliance
ably achievable) principle as the standard. This programs can mitigate damages and penalties
minimizes fetal exposure and the potential risk to when in place and functioning. Guidance for
the developing fetus. even individual and small group practices has
Some physicians defer referral to an obstetri- been provided by the Office of the Inspector
cal or maternal-fetal medicine specialist until the General [14]. This includes the following
early second trimester. This habit should be care- recommendations:
fully scrutinized in light of advances in antenatal 1. Conduct internal monitoring and auditing.
diagnosis. ACOG recommends antenatal screen- Audits should be conducted at least every
ing for all patients prior to 20 weeks of gestation 6 months with a representative set of patient
[13]. First-trimester screening with nuchal trans- charts.
lucency, integrated and sequential testing in the 2. Implement compliance and practice stan-
first and second trimesters, and maternal blood dards. Practice standards should be adopted
screening for fetal cell-free DNA are all options and adhered to.
for earlier detection of chromosomal abnormali- 3. Designate a compliance officer or contact.
ties. However, counseling and appropriate refer- It is recommended that the compliance officer
ral are crucial to the effective use of these should not be the same person responsible for
diagnostic modalities. In addition, there is coding and bill submission. An “independent”
increasing evidence that screening for anatomic person is best suited to detect billing and
abnormalities may be feasible in the first trimes- coding irregularities.
ter. With this background, if one is not prepared 4. Conduct appropriate training and education.
to provide the necessary counseling and screen- The physicians and their staffs should receive
ing, it may be prudent to refer patients once car- ongoing education, with appropriate updates,
diac activity is demonstrated, such that appropriate to remain up-to-date on proper coding and
counseling and screening may be performed. billing practices.
5. Respond appropriately to detected offenses
and develop corrective action. If inappropri-
Healthcare Fraud ate payments are detected, the practice
should return these promptly. Further, edu-
Increasing liability exists related to inappropriate cation and actions to correct any detected
billing for ultrasound-related procedures. irregularities are to be instituted upon
Insurance fraud is assuming a greater role in lia- discovery.
bility in a physician’s practice. In reproductive 6. Develop open lines of communication. The
medicine, one must be cautious to avoid liability physician should maintain an environment
exposure for fraud. For example, infertility ser- that encourages compliance, open communi-
vices may not be covered by a patient’s insurance cation, and transparency.
plan. In such cases, patients may request a change 7. Enforce disciplinary standards through well-
in the diagnostic codes to gain insurance cover- publicized guidelines. Discipline for inten-
age. Pursuing such action, when not clinically tional coding or billing irregularities should
appropriate, exposes one to the claim of insur- be established, published, and enforced.
ance fraud, with devastating consequences, rang-
ing from monetary penalties (up to $11,000 per Conclusion
instance); exclusion from governmental payers, This chapter has addressed several areas of
such as Medicare, Medicaid, and Tri-Care; potential liability related to ultrasound imag-
closing of one’s office; and even prison sen- ing in reproductive medicine. Discussed are
tences. One must remind patients of these poten- strategies and practices that minimize liability
tial consequences and resist such actions. exposure and risk. Unfortunately, the potential
4 Legal Aspects of Ultrasound Imaging in Reproductive Medicine 45
for a liability action exists even if all of the 5. AIUM. Guidelines for performance of a focused
recommendations are followed. However, a reproductive endocrinology and infertility scan.
http://www.aium.org/resources/guidelines/reproduc-
case is more defensible when these best tiveEndo.pdf. 2012. Accessed 4 June 2012.
practices are followed. 6. CMS. Medicare requirements for physician supervi-
sion of sonographers. http://www.cms.gov/Medicare/
Medicare-Fee-for-Service-Payment/PhysicianFee
Sched/PFS-Relative-Value-Files.html. Accessed 12
References Mar 2012.
7. Garner BA, editor. Black’s law dictionary. 8th ed. St.
1. AIUM. Standards and guidelines for the accreditation Paul: West Group; 2004.
of ultrasound practices. AIUM Ultrasound Practice 8. Sanders RC. Changing patterns in ultrasound-related
Accreditation; December 17, 2010: http://www.aium. litigation. J Ultrasound Med. 2003;22:1009–15.
org/accreditation/accreditation.aspx. Accessed 11 9. Raskin MM. Liability of radiologists. Legal medicine.
July 2012. 6th ed. Philadelphia: Mosby; 2004. p. 456–60.
2. AIUM, ASRM. AIUM practice guideline for ultraso- 10. Berlin L, Hendrix R. Perceptual errors and negli-
nography in reproductive medicine. http://www.aium. gence. Am J Roentgenol. 1998;170(4):863–7.
org/accreditation/accreditation.aspx. 2009. Accessed 11. Berlin L. Malpractice issues in radiology: defending
6 July 2012. the “missed” radiographic diagnosis. Am J Roentgenol.
3. AIUM. AIUM practice guideline for the performance 2001;176:317–32.
of sonohysterography. http://www.aium.org/accredi- 12. Montgomery v. South County Radiologists, Inc., 49
tation/accreditation.aspx. 2007. Accessed 20 July S.W.2s 191 (2001).
2012 13. ACOG. Screening for fetal chromosomal abnormali-
4. AIUM. AIUM practice guideline for the performance ties. ACOG Practice Bull. 2007;77(January):1–11.
of pelvic ultrasound examinations. http://www.aium. 14. Foley & Lardner. OIG issues final compliance pro-
org/accreditation/accreditation.aspx. 2009. Accessed gram guidance for individual and small group physi-
19 July 2012. cian practices. Milwaukee: Foley & Lardner; 2000.
Part II
Ultrasound in Infertility Workup
The Normal Ovary (Changes
in the Menstrual Cycle) 5
Renato Bauman and Ursula Reš Muravec
probe with the visible angle of 240° that allowed and in postmenopausal women is 2.0 × 1.5 × 1.0 cm.
panoramic view of the genital organs was put in In order to measure, it is important to visualize the
market. The first meeting about endovaginal ovary in the frontal and sagittal plane. Three dimen-
ultrasound was organized in Hamburg, Germany, sions could be obtained, and the volume can be cal-
in 1985 by L. Popp [2]. First accepted with skep- culated using the ellipsoid formula (V = 4/3 × 3.14
ticism, the new technique was quickly adopted in × (D1/2 × D2/2 × D3/2)) [3] or the simplified ellip-
the majority of sonography centers, first in soid formula (V = 1/2 × length × height × width).
Germany and then all over the world. Because of Difficulties in the visualization of normal ovaries
the numerous advantages in pelvic sonography, can be caused by extreme cranial position of the
the endovaginal technique today is essential for ovary or in case of severe adhesions in the pelvis.
quality examination of the female pelvis.
Ovaries can be visualized with the probe
moved laterally of the uterus towards the pelvic Postmenopausal Ovaries
wall in the longitudinal or sagittal section. Ovaries
have ellipsoid shape, with relatively hypoecho- Ovarian volume and diameter decrease with age,
genic structure and homogenic echotexture, and consequently making postmenopausal ovaries
often are positioned near the iliac blood vessels appear small hypoechoic structures. The absence
(Fig. 5.1). Using probes with the wide angle of of follicles results in difficult sonographic visual-
insonation, it is possible to visualize in the same ization and often may not be detected.
frontal section of both ovaries if they are posi- Premenopausal ovaries can be visualized in 96 %
tioned in the same plane. Regularly each ovary is and postmenopausal in 62–65 % of cases [3, 4].
visualized separately. In order to compare the
ovaries, it is useful to divide the image in two
parts and then visualize both ovaries (Fig 5.2.). Premenarchal Ovaries
In fertile women ovaries are usually easily visu-
alized because they are relatively big and have fol- Before, sexarche ovaries can be visualized by
licles and/or corpus luteum, structures that are easy transabdominal ultrasound using the full blad-
to recognize using transvaginal ultrasound. The der technique or by transrectal approach using
average size of the ovaries in premenopausal the transvaginal probe. The images obtained
women is 3.5 × 2.5 × 1.5 cm (length × height × width) transrectally are quite similar to those obtained
5 The Normal Ovary (Changes in the Menstrual Cycle) 51
transvaginally. In children before 5 years of age, through the menstrual cycle, in which we distin-
ovaries have a volume of less than 1 cm. Before guish follicular phase, ovulation, and luteal phase.
puberty ovaries are small hypoechoic structures Ultrasound provides insight into the psychological
that measure less than 2 cm in diameter. Few changes during the ovarian cycle and allows accu-
years before menarche small anechoic structures rate and reproducible investigations of follicular
with sharp borders measuring 5–9 mm can be size, development, and growth during the follicular
visualized, indicating the start of folliculogenesis. phase [5].
In the years of adolescence, until the Newborn girl has two million follicles and
hypothalamus-hypophysis-ovary axis is not fully before puberty 300,000 follicles are still present.
mature, ovaries are visualized with the variety of For their development gonadotropins are not
growing follicles of different sizes. Anovulation required. Since the mid-fetal life until meno-
is common, and these large ovaries with a lot of pause, there is a permanent reduction in the num-
follicles can often be misdiagnosed as polycystic ber of follicles, and only 400 (100–1,000)
ovaries. follicles will achieve preovulatory maturation
and ovulate until menopause.
The majority of primordial of follicles will go
Reproductive Age Ovaries through the process of atresia.
In the first 5 days of the cycle, FSH levels are
Changes in the morphological appearance of high in order to stimulate the development of a pri-
the ovary which can be detected by ultrasound mary follicle in the ovary. A primary follicle mea-
come due to rhythmic changes in the secretion of sures 40 μm; it has one layer of granulosa cells and
female hormones FSH and LH. Ovaries pass an oocyte. By further growth and multiplication
52 R. Bauman and U. Reš Muravec
of cells, a preantral follicle is developed. Preantral This variety at the time of ovulation limits the
follicle has a diameter of only 150 μm, and it is use of follicle diameter for ovulation prediction.
not detectable by ultrasound. In order to predict ovulation serial follicle,
Between fifth and seventh day of the cycle, measurements have to be done in more than two
secondary antral follicles can be detected and are menstrual cycles in each patient. In the majority
presented as anechoic spheroid zones inside the of patients, a uniform pattern of morphologic
ovary, approximately 2–3 mm in diameter. These sonographic changes prior to ovulation can be
are the first follicular structures that may be visu- established, and the knowledge of follicle diam-
alized by common ultrasound devices [5]. eter and endometrial thickness and shape can
With further selection one dominant follicle is help in infertility procedures during the natural
being elected while other follicles go into atresia. cycle. Unfortunately not all patients have a uni-
The dominant follicle can be detected between form pattern and ovulate with different sizes of
8th and 12th day of the cycle when its size and dominant follicles.
growing pattern are clearly superior to other visu- Besides follicle diameter other sonographically
alized follicles (Fig. 5.3). The remaining follicles visualized morphologic changes could help in the
can continue with their growth but just up to detection of ovulation. In more than 20 % of folli-
14 mm in diameter. In up to 10 % of maturely cles >18 mm, a cumulus oophorus can be visualized
menstrual cycles, sonography can detect two and is seen as a small anechoic part in the lumen of
dominant follicles [6]. the dominant follicle that presents the detachment
The diameter is measured from one internal of granulosa cells containing the oocyte.
follicle wall to the other if the follicle is roundly Twenty-four hours before the ovulation,
shaped. If we are measuring an oval follicle, we a hypoechogenic line surrounding the preovula-
have to measure three distances (the longest, the tory follicle can be visualized; it presents the sepa-
shortest, and the oblique) and then calculate the ration of theca cells from internal granulosa cells.
median: DF = (D1 + D2 + D3)/3. The theca cells are at that time hypervascularized
The dominant follicle has a linear daily diam- and edematous, and these changes can be even
eter growth of 2–3 mm per day, and at the moment better visualized using color Doppler (Fig. 5.4).
of ovulation, the diameter of the dominant follicle Before ovulation the internal wall of the pre-
is 18–27 mm [7]. ovulatory follicle can be slightly hyperechoic
5 The Normal Ovary (Changes in the Menstrual Cycle) 53
with irregular internal borders. It is important to The corpus luteum vanishes before the start of
always check the endometrium because its thick- next menstrual cycle, and the presence of corpus
ness and shape correlates with the serum estra- luteum 12 or more days after ovulation can be a
diol level and endometrial findings can help in first sign of pregnancy.
predicting the ovulation.
The key sonographic markers of ovulation
are disappearance of or sudden decrease in folli- Color Doppler of the Normal Ovary
cle size (the most frequent sign of ovulation with
the sensitivity of 84 %), appearance of ultrasonic Transvaginal color Doppler (TVCD) plays an
echoes in the follicle, irregularity of follicle wall important role in better understanding the physi-
and free fluid in the pouch of Douglas (in 77 % of ology of the menstrual cycle. This technique was
cases on the day of ovulation) [5, 8], and secre- intensively studied in the beginning of the 1990s,
tory changes of the endometrium. and many studies proved the usefulness in detec-
After the ovulation the follicle is transformed tion of vascular changes in the uterus and the
in corpus hemorrhagicum with internal echoes. ovary [10–15].
The corpus luteum is afterwards created with the The blood supply of the ovary has two sources:
vascularization and luteinization of granulosa ovarian artery and the ovarian branch of the uter-
cells. Sonographic appearance can be variable in ine artery that anastomoses and forms an arch in
size and shape [9]. The size is generally reduced the ovarian hilus. Color Doppler signals of the
and is visualized as a structure with thick hyper- uterine artery can be found on the lateral border
echogenic walls enclosing the hypoechoic cen- of the ovary. The impedance indices found in the
ter (Fig. 5.1). It is well known that corpus luteum ovarian artery correlate with the menopausal sta-
can also look like many pathologic changes of tus. Before menarche and after menopause, the
the ovary (endometriosis, cystic teratoma, and ovarian artery is difficult to visualize because the
other benign or even malignant tumors), and ovaries are very poorly vascularized at that time.
sometimes it is absolutely necessary to perform The resistance to blood flow is high and so are the
an ultrasound examination after the menstrua- flow indices (RI = resistance index, PI = pulsatil-
tion in order to differentiate the possible ity index). During the reproductive age, there is a
pathology. difference in vascularization depending on which
54 R. Bauman and U. Reš Muravec
ovary is the dominant follicle growing and where oxygenation. Oocytes from severe hypoxic
the resistance to blood flow is lower in compari- follicles are associated with high frequency of
son to the non-dominant side. It is absolutely abnormalities in the organization of the chromo-
logic that a growing follicle or the corpus luteum somes. Color Doppler analysis of perifollicular
needs more vascularization, and so we register blood may provide an indirect sign of the devel-
lower flow indices. As ovarian arteries are not opmental competence of the oocyte [15]. In the
easy to find, in order to perform objective mea- stimulated cycles there is a correlation of higher
surements in practice, we estimate the intraovar- peak systolic velocity (PSV > 10 cm/s) in follicles
ian blood flow that changes during the age and with subsequent fertilized oocytes [16]. However,
the cycle. Before puberty and after menopause, in the natural cycles Doppler indices of perifol-
blood flow should not be detected in the ovaries licular blood flow as predictors of oocyte quality
using color Doppler. Any positive vascularization are still of limited value [17]. Three-dimensional
in that time of life in the ovaries has to raise sus- reconstruction of power Doppler perifollicular
picion about possible pathology of the vascular- vascular network could be a better predictor for
ized ovary [11, 12]. oocyte competence in natural cycles [18, 19].
TVCD is very reliable in confirming ovula-
tion. A marked drop in blood flow indices and
TVCD in Preovulatory Phase rise of blood flow velocities in the early luteal
phase are signs of prominent vascularization and
Perifollicular blood flow can be detected when a corpus luteum formation. Color Doppler findings
dominant follicle has a diameter of >10 mm. Few added to ovarian morphology changes mentioned
days prior to ovulation, the RI is around above accurately confirm ovulation.
0.54 ± 0.04. Two days before ovulation, the RI
starts to decline while at ovulation the RI is
0.44 ± 0.04. The flow velocity is increasing as the TVCD and the Corpus Luteum
RI gets lower, and even if the RI is not changing,
the peak systolic velocity rises on the onset of The formation of the corpus luteum is a key event
ovulation. Angiogenesis and dilatation of newly in the reproductive life and also plays an important
formed vessels between the theca and granulosa role in early pregnancy support. Immediately after
layer and changes in the follicular wall could be ovulation blood vessels of the theca layer invade
necessary for follicular rupture [13]. In case of the cavity of the ruptured follicle (Fig. 5.5). There
luteinized unruptured follicle, a failure of blood is a dramatic increase of the amount of blood flow
velocity to peak in the preovulatory period is with increased velocity and low impedance to
observed that proves that adequate vasculariza- blood flow. The RI is low (0.43 ± 0.04), remains
tion is necessary for achieving ovulation [14]. at the same level for 4–5 days, and then gradually
The vascularization in the polycystic ovaries rises to a level of 0.49 ± 0.04, which is still lower
is detected in the hyperechoic stroma, and wave- than in the follicular phase (Fig. 5.6).
forms showed mean RI = 0.54 but without cyclic If the pregnancy is achieved, corpus luteum
changes caused by hormonal steady state (anovu- has prominent blood flow with low Doppler indi-
lation). There are also no changes in the Doppler ces (RI = 0.45 ± 0.04) and similar vascularization is
indices in the uterine artery that are usually found detected during the 1st trimester. In cases of threat-
in regular menstrual cycles. The vascularization ened abortion (p < 0,01), missed abortion (p < 0,01),
of the uterus and the ovary is hormonally depen- and incomplete abortion (p < 0,01), the resistance
dent, and Doppler measurements reflect cyclic and pulsatility indices are significantly higher
hormonal changes in the female genital organs. than in the normal pregnancy. There is a correla-
The perifollicular vascularity is a constant chal- tion between vascularization indices of the corpus
lenge for clinicians and researchers. It is known luteum and hormonal levels of HCG, estradiol, and
that it correlates well with the level of follicular progesterone.
5 The Normal Ovary (Changes in the Menstrual Cycle) 55
After the 23rd day of cycle, if there is no preg- mean ovarian volume in nulliparous women in
nancy, the corpus luteum starts its regression. reproductive age is 7.8 cm3 (2.6 SD), and it
The color flow signals are poor, and the Doppler decreases to 3.4 cm3 (1.3 SD) in the first 5 years of
indices are getting higher until menstruation and menopause. After 5 years of menopause, it shrinks
the start of the new cycle. At that time there is no to mean volume of 2.5 cm3 (1.3 SD), and later in
color flow detected in the ovary. menopause it can become undetectable [3].
Luteal phase defect could be assessed nonin- Measurement of ovarian volume to predict
vasively by transvaginal color Doppler measure- ovarian reserve and responsiveness is limited and
ments of the blood flow in the corpus luteum. The it is useful only at the extremes of reproductive
mean RI in the defect luteal phase is significantly live. The novel ultrasound markers for the ovar-
higher (RI = 0.56 ± 0.04; p < 0,001) compared to ian reserve, such as AFC (antral follicle count),
controls [20]. AMH, and age, predict the responsiveness to
gonadotropins much better [24, 25].
Three-Dimensional Ultrasound
Visualization of the Normal Ovary Antral Follicle Count (AFC)
Volume of the Ovary AFC is one of the markers of the ovarian reserve.
Together with the AMH and age, it is considered
With the three-dimensional ultrasound (3D US), as the best marker for ovarian reserve [26]. AFC
the image of the ovary could be obtained in all is used to predict the response to the gonadotro-
three dimensions. Storage capacities, reconstruction pin stimulation during assisted reproductive tech-
of the volume images, and simultaneous viewing nology treatment.
of all three orthogonal planes are the main advan- AFC informs the clinician about quantitative
tages of this method. and not the qualitative ovarian reserve. AFC cor-
The volume of the ovary can be calculated relates well with the number of oocytes retrieved
using the simplified ellipsoid [3] formula (V = 1/ after gonadotropin stimulation and not so good
2 × length × height × width) or sonographic for- with the pregnancy results [26].
mula (ovary = length × height × width × 0.5236). With advanced reproductive age AFC
Volume of the ovary can be measured even decreases [27–31]. AFC declines progressively
more precisely with semiautomatic VOCAL over the time, with annual losses of 0.35–0.95
(virtual organ computer-aided analysis) tech- antral follicles per year [27, 31, 32]. The age-
nique (Fig. 5.7). VOCAL is a 3D software tech- related nomograms in infertile women for the
nology (General Electrics Healthcare, Kretz, 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percen-
Austria) program where the ovary is rotated tiles for AMH and AFC were produced [31].
around one axis from 6 to 30 times (every 30°, There is intra-cycle and inter-cycle variability,
15°, 9°, or 6° rotation angles), and in every step variability in the clinical definitions, and technical
it is required to outline the ovarian borders. If the methods used to count and measure the volume of
30° step is chosen, the ovary is rotated six times. antral follicles. The practical recommendations
The software estimates the volume from these for better standardization came out in 2010 [31].
six planes of the ovary. It is recommended to count the cohort of
The ovarian volume in the reproductive age of 2–10 mm follicles between day 2 and 4 of men-
the women inversely correlates with age, and a strual cycle [31].
statistically significant decrease in ovarian vol- The technique used for AFC can be as follows:
ume starts at 30 years of age [21, 22]. • 2D scrolling through each ovary (manual
It is reported that average volume of the ovary counting of all antral follicles in the scroll)
by the age of 1 year is 0.26 cm3 measured by • 2D counting of the antral follicles in one plane
transabdominal probe and increases steadily to an • 3D SonoAVC (sonography-based automated
average of 1 cm3 by 13 years of age [23]. The volume count) (Fig. 5.8)
5 The Normal Ovary (Changes in the Menstrual Cycle) 57
SonoAVC (General Electrics Healthcare, round to oval before the ovulation. More precise
Kretz, Austria) is a novel ultrasound technique measurement can be made with 3D ultrasound
which can be used for the ultrasonographically comparing to 2D US measurements. 3D mea-
hypoechogenic structures, such as the follicles. surement of the dominant follicle can be obtained
SonoAVC identifies hypoechogenic structures in three ways: first, classical with x, y, and z
and their approximate shape in the selected 3D diameters as described before; second, with
matrix and explorate the volume. It automatically semimanual technique VOCAL described before;
recognizes the follicular borders in 3D and does a and third by automated technique SonoAVC
follicle volume assessment for each follicle in a (Fig. 5.9).
selected volume box. The numbers and volumes The measurements of VOCAL, SonoAVC,
of antral follicles are reported. and actual volume of dominant follicle were
comparable – the median actual volume of domi-
nant follicle on the day of aspiration was 3.6 ml,
3D of the Dominant Follicle, with ranges from 2.9 to 8.0 ml [33]. SonoAVC is
Ovulation, and Formation of Corpus considered as a rapid and simple technique, with
Luteum a good reproducibility and reliability [33].
On the basis of the dominant follicle volume
The majority of small growing follicles are round measured with SonoAVC method, new criteria
and can be easily measured by 2D US, either with for timing hCG administration or planning the
one, two, or three perpendicular diameters. The oocyte retrieval can be established [34]. Follicles
dominant follicle usually changes the shape from with the measured volume ≥0.6 cm3 on the day
58 R. Bauman and U. Reš Muravec
the figure of total voxels minus the background follicle [35, 36]. In the late follicular phase,
voxels. Flow index (FI) measures the mean blood there is a short vascular depression in all indices.
flow intensity. The figure ranges from 0 to 100. FI After ovulation very important vascular changes
is calculated as the ratio of weighted color values take place in the ruptured follicle. There is an
(weighted by their amplitudes) to the number of increase vessel formation and blood supply and
the color values. The vascularization-flow index increase in velocities are noted. In a ruptured fol-
(VFI) gives combined information of vasculariza- licle (Fig. 5.12) increase in vascular index (VI),
tion and mean blood flow intensity. The figure of flow index (FI), and VFI (vascular flow index)
the VFI is also dimensionless and ranges from 0 to
100. It is calculated by dividing the weighted color
values (weighted by their amplitudes) by the total
voxels minus the background voxels.
3D vascular indices can be measured in the
selected volume (ovary, dominant follicle, corpus
luteum) in different phases of the menstrual cycle.
In the follicular phase, the vascularization around
the dominant follicle increases, the sonographic
angiogram of the dominant follicle shows the
angioarchitecture in the whole dominant follicle,
as shown schematically with the color Doppler
(Fig. 5.11). During the normal menstrual cycle,
typical changes in vascular indices were noted
[35–37]. Vascular indices (VI, FI, VFI) slowly Fig 5.11 3D color Doppler vascularization of dominant
increase during follicular phase in dominant follicle before ovulation
Fig. 5.12 3D vascularization of the corpus luteum with VI, FI, and VFI index
5 The Normal Ovary (Changes in the Menstrual Cycle) 61
can be noted in the first 7 days after ovulation 12. Kurjak A, Kupesic S. Ovarian senescence and its sig-
nificance on uterine and ovarian perfusion. Fertil
[35–37]. VFI in corpus luteum 7 days after ovu-
Steril. 1995;64:532–7.
lation is on average 3.1 times higher than 1 day 13. Bourne T, Jurkovic D, Waterstone J, Campbell S,
before the ovulation [35]. In the late luteal phase, Collins WP. Intrafollicular blood flow during human
the indices do not change significantly [35, 36]. ovulation. Ultrasound Obstet Gynecol. 1991;1:53–9.
14. Kupesic S, Kurjak A. Uterine and ovarian perfusion
The 3D sonographic angiogram is very useful
during the periovulatory period assessed by transvagi-
because it is relatively easy to obtain and it gives nal color Doppler. Fertil Steril. 1993;3:439–43.
a good impression on whole vascularization in 15. Van Blerkom J, Antczak M, Schrader R. The develop-
selected volume. 3D vascularization indices are mental potential of the human oocyte is related to the
dissolved oxygen content of follicular fluid: associa-
currently used mostly for research purposes, and
tion with vascular endothelial growth factor levels and
broad clinical use is still limited due to technical perifollicular blood flow characteristics. Hum Reprod.
problems, need for good equipment, and experi- 1997;12:1047–55.
ence of the clinicians. 16. Nargund G, Doyle PE, Bourne TH, Parsons JH,
Cheng WC, Campbell S, et al. Ultrasound derived
indices of follicular blood flow before hCG adminis-
tration and the prediction of oocyte recovery and pre-
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Ovarian Reserve and Ovarian Cysts
6
Laurel A. Stadtmauer, Alessandra Kovac,
and Ilan Tur-Kaspa
follicular phase for ovulation. The antral follicle signs occur relatively late much after changes in
count (AFC) is the total number of follicles the quantity and quality of the oocytes have
counted in 2D or 3D per ovary and correlates occurred.
well with the number of recruitable mature
oocytes for IVF. The recruitment process occurs
over 3 months. Antral Follicle Count and Ovarian
Before initiating ovarian stimulation, the Reserve
baseline day 3D US is a prerequisite for planning
the IVF therapy in detail; it can estimate the ovar- The estimation of antral follicle count and antral
ian reserve, which can be done most accurately follicle size performed by TVUS is currently the
by an AFC. During an IVF stimulation with most reliable method and gives the best correla-
gonadotropins, the largest follicles reach a diam- tion with retrieved oocytes [2–4]; moreover, it is
eter of 17–24 mm prior to human chorionic easy to perform and is noninvasive. The defini-
gonadotropin (hCG) trigger. The retrieval of a tion of AFC is the number of follicles in both
large number of good quality oocytes increases ovaries added up that can be recruited with the
the likelihood of a high fertilization rate and an threshold dose of gonadotropins for each particu-
adequate number of high quality embryos. lar patient. Therefore, the AFC determined by
Female reproductive ageing is a process that ultrasound on day 2 or 3 of the cycle, notably by
will reduce fecundity (the ability to have a via- 2D or 3D techniques, is the best predictor for
ble embryo implanted). The process of ageing poor ovarian response, ovarian hyperstimulation
involves decrease in both the quantity and qual- syndrome (OHSS), oocytes collected, and live
ity of the oocytes within the follicles. At birth rates [2–6]. Decreased AFC of 3 is shown in
4 months of fetal life, the germ cells are sur- Fig. 6.1. Only a small number of ovarian follicles
rounded by the somatic cells forming the pri- are highly responsive to FSH during an IVF stim-
mordial follicles, containing the peak number of ulation. The number of these antral follicles rep-
oocytes at six to seven million. At birth, there resents the “recruitable or selectable follicles.”
are one million oocytes, with loss by atresia. It The antral follicle count (AFC) reflects the ovar-
further decreases to 300,000–500,000 follicles ian reserve and is predictive of the IVF outcome
at menarche. Throughout life, follicles leave the in regard to the number of yielded oocytes in
primordial pool and enter the growing recruit- response to hormonal stimulation. Fratterelli and
able pool taking about 85 days or three men- colleagues correlated the AFC with the number
strual cycles to reach ovulation. The majority of of mature follicles (r = 0.52) and the number of
follicles undergo atresia, until rescued by the oocytes (r = 0.38) and found the AFC <4 was
FSH at puberty by the activation of the pituitary- associated with a high cancellation rate and poor
gonadal axis. Rate of decline of follicles during
the reproductive years is steady at approxi-
mately 1,000 follicles per month. The rate of
decline rapidly increases after 37 years of age.
The loss in the quality is due to increased rate of
meiotic nondisjunction leading to increased rate
of aneuploidy in early embryos at higher female
ages. At menopause of average age of 51, the
number of follicles remaining will be less than
1,000 [1].
The first noticeable sign of reproductive
ageing is shortening of the cycle by 2–3 days due
decrease in the follicular phase by early selection
and maturation of the dominant follicle. These Fig. 6.1 Decreased ovarian reserve with AFC of 3
6 Ovarian Reserve and Ovarian Cysts 65
pregnancy rates [7]. For the high responders the cancellation and lower chance of success.
cutoff level of >14 antral follicles has the best Pretreatment AFC and AMH were found to be the
combination of sensitivity and specificity for pre- most significant predictors of the number of
dicting a hyper-response with values close to oocytes retrieved especially for low and high
90 %. It is important in selection of the protocol responders in multiple studies including a meta-
and gonadotropin dosage which will lead to analysis by Hendricks et al. [2, 10–16]. These
decreasing OHSS and cancelled cycles. The studies showed that AFC and AMH demonstrated
accurate assessment of the ovarian reserve is a similar predictive power based on ROC area
way to individualize optimal therapy. Ovarian under the curve (AUC) analysis and correlated
volume also correlates with the AFC and can be with oocyte number better than other parameters
measured by TVS [8]. such as FSH or age. However, all these parame-
Standard AFC assessment was, and still is, ters correlate less well with pregnancy outcomes,
performed primarily with 2D US imaging. which is a more important outcome for the patient
Although this modality might be sufficient in than oocyte number. In addition, AMH and AFC
some cases, there might be some uncertainties have been shown to be the best predictors of
and disadvantages. OHSS in women undergoing ovarian stimulation
3D AFC is more reproducible and accurate but for IVF. The advantage of AMH is that it is not
the method is less standardized, and 3D technol- operator or cycle day dependent. A cutoff level of
ogy may not be freely available for all reproduc- >3.3 ng/mL determines the risk of OHSS with a
tive endocrinologists. Figure 6.2a, b shows 3D 90 % sensitivity,71 % specificity, and 61 % PPV,
antral follicle count. The 3D count can be per- and a cutoff value of AFC >8 predicts the risk of
formed in inverse mode as shown (Fig. 6.2a). It OHSS with a 78 % sensitivity, 65 % specificity,
should be noted that it is imperative to distin- and 53 % PPV [17].
guish between the total antral follicle count The validity of AFC for ovarian reserve comes
(TAFC), including follicles >6 mm in diameter; from studies showing a direct correlation with
however, the number of small antral follicles is the number of nongrowing follicles viewed on
more predictive of number of oocytes retrieved. histologic sections [18]. On the other hand, ovar-
AFC is also a predictor of pregnancy loss and ian volume, vascularity, and perfusion had no
low AFC correlates with 4× increase in early significant value in predicting poor ovarian
miscarriages [9]. response and all are inferior to AFC [19]. The
hypothesis that aneuploidy is negatively associ-
ated with the quantity of oocytes in the ovary is
Endocrine Markers of Ovarian supported by studies showing decrease AFC in
Reserve women with spontaneous abortions after IVF.
The conclusions are not supported by all studies
Endocrine markers of ovarian reserve are anti- possibly because some lack power and it may
müllerian hormone (AMH) and inhibin B which depend on the mechanism of diminished ovarian
are direct markers of quantity and follicular reserve. In many women with low AFC, espe-
cohort numbers. Indirect markers are basal day 3 cially at a young age, there is a decrease in quan-
FSH and estradiol (E2) levels [10–16], and high tity but not in quality of the oocytes.
levels indicate a decreased number of small antral
follicles. Both AFC and AMH predict similarly
the response to treatment, but ultrasound is the 3D Ultrasound and Ovarian Volume
only method so far that allows a direct assess-
ment of each ovary separately. Identification of Ovarian volume can be calculated by measur-
participants who are likely to respond poorly ing each ovary in three perpendicular direc-
during IVF treatment is clinically relevant as tions and applying the formula of the ellipsoid
the couple can be counseled regarding cycle (D1 × D2 × D3 × π/6). Ovarian volume can also
66 L.A. Stadtmauer et al.
Fig. 6.2 (a) 3D AFC in inverse mode (b) Multiplanar view of ovary with antral follicle count
6 Ovarian Reserve and Ovarian Cysts 67
Fig. 6.3 Ovarian volume with VOCAL program. (a–c) Multiplaner view of ovary with ovarian volume
be automatically calculated using the software the volume of aspirated follicular fluid than
called “virtual organ computer-aided analysis” 2D ultrasound measurements [22]. One of
or VOCAL (Fig. 6.3). This imaging program the most frequently employed applications is
calculates organ volume from the areas of the the sonography-based Automated Volume
three orthogonal sections, sagittal, transverse, Calculation (SONO-AVC; GE Medical Systems,
and coronal views, and allows very precise Zipf, Austria). The application of SonoAVC for
calculation of ovarian volumes. However, ovarian IVF was first described by Raine-Fenning et al.
volume can be affected by ovarian cysts. Ovarian [23]. Studies with SonoAVC have not shown a
volume and antral follicle volume can now be clear benefit in improving IVF outcomes [24].
automated. Three-dimensional US is an excel- Even if there is no clinical benefit, the advan-
lent technique for calculating ovarian volume tages of SonoAVC may be a time decrease dur-
very precisely using the VOCAL program and ing the ultrasound as the ovarian volumes are
observing the ovary with rotating angles. Low saved and can be calculated later. This may lead
ovarian reserve and poor response to controlled to less discomfort for the patients. However,
ovarian hyperstimulation in ART are associated there is time required for manual assessment of
with volumes <3 cm3 as seen by Lass and col- the 3D data which should be added to the time
leagues with increased cancellation rates [20]. in scanning and the technique needs to be
Polycystic ovaries are associated with volumes learned and reproducibility documented.
>6.6 cm3. Ovarian hyperstimulation syndrome Rodriguez Fuentes analyzed the impact of
( OHSS) is associated with increased ovarian SonoAVC on time and the clinical outcome of
volume [21, 22]. However, total volume of the IVF treatment. They found reduced time saving
ovaries detected by transvaginal ultrasound is not of 4 min per case after including the post-
better than the AFC in predicting parameters. processing time [24]. Their study has shown
The studies of IVF patients have demon- that SonoAVC provides different results from
strated that 3D ultrasound volume measure- those of 2D ultrasound imaging when the size of
ments for follicles correlate better with the follicle is considered.
68 L.A. Stadtmauer et al.
Fig. 6.6 Resolving hemorrhagic cyst Fig. 6.8 Dermoid cyst with hair
with tubal or male factor infertility and 10 PCOS automate the follicular measurements. Therefore,
women with chronic anovulation and clinical or our objective was to determine the accuracy,
biochemical hyperandrogenism. Mean follicle reproducibility, and efficiency of this novel
number/ovary (FNPO) as well as the maximal program. This will be discussed further in
number of follicles in a single sonographic plane another chapter.
(FSSP) were determined by 3D TVUS; simulta- One disadvantage of 2D for antral follicle
neously, the ovarian volume was determined by counts involves inter- and intra-observer repro-
2D TVUS. Interestingly, the authors postulated a ducibility. Of note, only a handful of studies
considerably higher threshold of antral follicles compare the accuracy of ultrasound in regard to
(20 or more) for PCOS patients, which is a con- AFC and inter- and intra-observer reliability.
siderably higher threshold than that of the Scheffer et al. [46] described the value of AFC
Rotterdam criteria. The authors explained this determined by AVC needed for the improvement
discrepancy by the identification of more folli- of standardization. They compared healthy vol-
cles by 3D US. The weakness of this study is the unteers with proven fertility to patients visiting
small number of patients, the missing direct an infertility clinic. For each patient, 2D or 3D
comparison to 2D US, and the low sensitivity TVS was conducted for AFC (2–10 mm) and
(true positive rate) using receiver-operating char- interobserver reliability was calculated. Both
acteristics (ROCs). According to most publica- techniques were adequate when only a few folli-
tions dealing with 3D US in PCOS patients, there cles were present; however, when higher AFCs
is a broad agreement about increased ovarian vol- occurred, the reproducibility decreased with the
ume of polycystic ovaries [42–45]. Nevertheless 2D technique. In addition to this report, studies
there is still disagreement regarding ovarian vas- by the group of Raine-Fenning [23, 47, 48] dem-
cularity, stromal changes, and cutoff values for onstrated an improvement of interobserver/intra-
antral follicles. observer reliability by the application of 3D
methods (in particular by automated systems,
such as SonoAVC).
Antral Follicle Count and SonoAVC The SonoAVC software is especially
designed for the automatic detection of mul-
The antral follicle count in 2D and 3D are gener- tifollicular growth and to overcome the afore-
ally similar although 3D ultrasound is superior mentioned problems of follicle observation
for the high antral follicle population. In the by 2D US [22, 24, 47, 49–55]. This software
inversion mode, follicles which appear white can allows not only the display of single follicles in
be counted easily. Image or volume rotation 3D but also automatically calculates the number
using the cine-loop facilitates the process and volume of hypoechoic structures in a 3D
(Fig. 6.2a). Assisted reproductive techniques echo-derived data set; furthermore, it provides
including in vitro fertilization (IVF) and ovula- estimations regarding the absolute dimensions
tion induction require close monitoring of follic- of follicles. The only necessary requirement
ular development. Follicular development is is adjustment of the ROI box over the entire
commonly assessed with transvaginal ultra- ovary to include only the information which is
sounds during which each follicle is measured in needed for calculation and to check during post-
2 or 3 dimensions. As there are often 10–20 fol- processing. Measurements are based on calcula-
licles, this is very time consuming. In addition tion of the largest diameters in three orthogonal
follicular boarders are irregular, and hence this planes: the mean follicle diameter, the follicular
method has poor reproducibility and is often an volume, and the volume-based diameter of the
inaccurate assessment of follicular volume. follicle. Thus, the volume is calculated via the
Recently a new software program, the automated voxel count within hypoechoic structures. The
follicular assessment using segmental topology true volume can be measured, and SonoAVC
or FAST program, was developed in order to calculates the follicle diameter by rendering
72 L.A. Stadtmauer et al.
Conclusions
AFC is highly predictive for the ovarian
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Ultrasound and PCOS
7
Nikolaos Prapas and Artemis Karkanaki
The Definition of Polycystic Ovary presupposes the existence of one more diagnostic
Syndrome criterion at least.
It should be emphasized that the diagnosis is
Polycystic ovary syndrome (PCOS) is a common posed after the exclusion of any other etiology
medical entity, of great scientific interest, affect- that mimics the clinical expression of PCOS, as
ing up to 10 % of women of reproductive age [1, thyroid dysfunction, hyperprolactinemia, con-
2]. Until 2003, when the presence of polycystic genital adrenal hyperplasia (including nonclassi-
ovarian morphology was included, the diagnosis cal), Cushing’s syndrome, androgen-secreting
of PCOS was based on the presence of clinical or tumors, and idiopathic hirsutism.
laboratory evidence of hyperandrogenemia and Thus, four distinct clinical phenotypes of
chronic oligo- or anovulation [3]. Despite the PCOS are recognized, according to the combina-
name of this syndrome, the polycystic ovarian tion of manifestations [6]. The distinct pheno-
morphology was not considered pathognomonic types are seen in Table 7.1. The first two
for the diagnosis until the Consensus Workshop phenotypes, already diagnosed by the old criteria
held in Rotterdam in 2003 [4, 5]. Thereafter, the of National Institutes of Health of 1990 [3], are
sonographic evidence of polycystic morphology widely characterized as the “classic PCOS.” The
was recognized as an equal diagnostic criterion last two groups, “newer PCOS,” comprise addi-
of the syndrome and was further defined and tional phenotypes that aroused after the new
simplified into the existence of either 12 or more diagnostic criteria of Rotterdam [4, 5], and both
follicles of 2–9 mm of diameter or an increased include the polycystic ovarian morphology as a
ovarian volume of more than 10 cm3 on both or feature in contrast to the classic PCOS pheno-
even one ovary. Importantly, the polycystic types. However, despite the consented criteria
ovarian morphology should not be confused with there is still uncertainty concerning the impor-
the syndrome, since the diagnosis of PCOS tance of each syndrome feature and the severity
N. Prapas, MD, MSc, PhD Table 7.1 The four phenotypes of PCOS
A. Karkanaki, MD, MSc, PhD (*)
Third Department of Obstetrics and Gynecology, Phenotypes 1 2 3 4
Hippokratio General Hospital of Thessaloniki, Anovulation + + − +
Greece, Aristotle University of Thessaloniki, Hyperandrogenemia + + + −
49 Str. Konstantinoupoleos, Thessaloniki,
Polycystic ovarian + − + +
54642, Greece
morphology
e-mail: nikos@iakentro.gr;
kartemis2004@hotmail.com Classic PCOS Newer PCOS
of the metabolic and reproductive dysfunction diurnal variation in uterine and ovarian blood
every phenotype implies [6, 7]. flow [13, 14].
The unstable and relatively common finding The current definition of polycystic ovarian
(20–25 %) of polycystic ovarian morphology in morphology makes no reference to the distribu-
the general population [8, 9] triggered the oppo- tion of the follicles, the stromal brightness (echo-
sition of Androgen Excess Society which stated genicity) and volume as well as to the uterine size
that PCOS is a primarily androgen excess disor- and its relationship to the ovarian size, and,
der and this feature should be a prerequisite for finally, to the blood flow through the uterine and
the diagnosis of the syndrome. Subsequently, ovarian arteries, including the intraovarian stro-
according to Androgen Excess Society, one of the mal blood flow.
two newer phenotypes with polycystic ovarian The typical polycystic ovary was initially
morphology and anovulation could not be described by Adams et al. as an enlarged ovary
defined as PCOS [10]. However, this opinion is with highly vascular and hyperechogenic stroma,
not widely accepted and is currently under compared to the cortex, and with many small fol-
investigation. licles arranged in the periphery [15]. The follicles
are at least ten and their diameter ranges between
2 and 8 mm, but are usually symmetrical and
The Polycystic Ovarian Morphology measure between 2 and 5 mm. The growth of
these gonadotropin-dependent antral follicles is
The polycystic ovarian morphology, as defined in halted due to the aberrant folliculogenesis of the
Rotterdam, is conditioned by two elements, the syndrome. Interestingly, the cohort of small fol-
presence of 12 or more follicles (2–9 mm of licles of 2–5 mm of diameter seems to be a better
diameter) and/or ovarian volume more than indicator of the ovarian reserve [16] and is nega-
10 cm3, in a single or both ovaries. This definition tively determined by the age [17].
leaves no margin for subjective assessments On the other hand, the term multifollicular
regarding the diagnosis which can be set even ovary refers to an ovary with many small follicles
with polycystic morphology in a single ovary. of variable size, scattered through an increased
Women taking an oral contraceptive pill cannot amount of stroma, but not in the classic type of
be diagnosed as the pill reduces the ovarian vol- “necklace” as in the polycystic ovary. The multi-
ume despite the possible persistence of polycystic cystic ovary may represent a milder disturbance
morphology [4, 5, 11]. In the case of a dominant of the ovary where normal folliculogenesis hap-
follicle (>10 mm) or a corpus luteum, the ultraso- pens to some degree [18]. Multicystic ovaries are
nography should be repeated in the next cycle common in early adolescence and in the majority
while an abnormal cyst or ovarian asymmetry regress without evolving to PCOS [19].
requires further investigation [4, 5, 12]. Asymptomatic women with only polycystic
The use of state-of-the-art equipment and ovarian morphology are commonly found in the
well-trained operators are some of the techni- general population up to 32 % of women [20].
cal requirements that should be met for success- These women may conceal some mild abnormal-
ful examination. Furthermore, the transvaginal ities of androgen secretion, insulin sensitivity,
approach, whenever possible, and especially and glucose metabolism [21–23], though the data
in obese women, is highly recommended. are still contradictory [20]. The sole presence of
Importantly, the scan should be performed dur- polycystic ovarian morphology seems to recede
ing the early follicular phase (days 3–5) of a with age, and especially after the age of 35 years
spontaneous cycle in women with regular cycles [20, 24]. However, when women with polycystic
and of a progesterone-induced bleeding episode ovarian morphology are subjected to controlled
or randomly in women with irregular cycles ovarian stimulation and ovulation, as an infertil-
[4, 5]. The time of the day is meaningful only ity treatment, they behave like women with
if Doppler examination is performed due to the PCOS and are faced with an increased risk of
7 Ultrasound and PCOS 77
follicles and, thus, the ovarian reserve [44]. measurement of the maximal diameter in the
Their number is also strongly correlated with longitudinal plane; the second includes an addi-
serum AMH levels [45]. The larger follicles tional measurement of a diameter at 90° to the
>6 mm are totally gonadotropin dependent and first; and the third is expanded to the measure-
one of them will evolve to dominant during the ment of a perpendicular to the previous two
next follicular phase, while the rest will become diameters in the transverse plane, after manual
atretic. So, in this phase, all other healthy folli- rotation of the transducer. In the latter two cases,
cles with granulosa cell activity tend not to the diameter is the mean of the two or three diam-
exceed 6 mm, suggesting that all larger follicles eters, respectively.
are possibly atretic and do not reflect the actual Alternatively, the size of a follicle could be
reproductive capability of the woman [46, 47]. defined by its volume. For optimal in vitro fertil-
Exogenous gonadotropin administration during ization (IVF) outcome, the follicular fluid vol-
IVF rescues these small antral follicles from atre- ume should be more than 1 and up to 7 mL, which
sia and promotes their growth. Eventually, the corresponds to a spheroid follicle of diameter of
retrieved oocytes by follicle aspiration come 12–24 mm [52]. The follicular volume can be
from this cohort of visible follicles. calculated by 2D ultrasound from the mean diam-
PCOS is related to an excess in small antral eter using the formula of a sphere: 4/3 × π × diam-
follicles of 2–5 mm [16]. Although the pool of eter [53]. When the mean diameter is estimated
growing primary and secondary follicles in by the three follicular diameters, as described
women with the syndrome is two- to threefold above, it is more accurate [51]. Follicles scarcely
that of normal ovaries, the pool of primordial fol- have the shape of a sphere; they usually are more
licles is normal [48]. This excess is drastically elliptical, and therefore, the formula of a sphere
involved in the follicular arrest of PCOS, pre- does not provide an accurate estimation of the
sumably through an auto-inhibiting effect that volume [54].
could involve AMH. Still, the 6–9 mm follicles This matter has been addressed by the three-
also appear to be affected by the unfavorable dimensional (3D) calculation of follicular vol-
environment of the syndrome [49]. ume which can be assessed by two ways:
The follicle number, using two-dimensional manually and automatically. The manual mea-
(2D) ultrasound, is estimated both in longitudinal surement is performed more often by the pro-
and anteroposterior cross sections of the ovaries, as gram Virtual Organ Computer-aided Analysis
the performer slowly moves the transducer from (VOCAL®). Initially, the data is acquired by an
one side of the ovary to the other. After the identifi- automatic mechanical sweep of the region ensur-
cation of the ovary, a scout sweep is performed in ing that the entire ovary is included. The process
the two planes and the largest follicle is localized. is repeated for the contralateral ovary and the
Then the counting is performed starting from the data are saved. The data are then processed using
outer ovarian margin to the opposite. The proce- VOCAL. Each follicle is delineated manually by
dure is repeated with the contralateral ovary [39]. It tracing around its perimeter and the volume of
has been observed that the number of follicles interest is calculated automatically.
counted by 2D is overestimated compared to The automatic technique is performed by
oocytes retrieved, and even more in ovaries with the program Automatic Volume Calculation
many follicles as the polycystic when they are stim- (SonoAVC®). The data are captured as described
ulated, possibly because of double counting (repe- above and then processed by SonoAVC after
titions) and inclusion of atretic follicles [39, 50]. right positioning. This program identifies every
The size of follicles in 2D ultrasonography is single follicle with a specific color and then auto-
expressed as the mean of the diameters measured matically calculates the mean diameter (relaxed
on the two aforementioned sections [4, 5]. sphere diameter), the maximum dimensions (x, y,
However, in clinical practice, three techniques z), and the follicle volume (Fig. 7.1). This later
are applied [51]. The first includes a single method is highly valid and provides more
7 Ultrasound and PCOS 79
Fig. 7.1 Multiplanar display of an ovarian three-dimen- right side (Reprinted from Deb et al. [47]. With permis-
sional ultrasound dataset by SonoAVC. Each follicle has a sion from John Wiley & Sons, Inc.)
specific color and its measurements are displayed on the
accurate values than those estimated from 2D 1–2 mm of diameter and provides the option of
measurements and automated measurements of post-procession where manually the observer
follicular diameter as well as calculated using picks any missed follicles or excludes any that
VOCAL [50, 51, 55]. has been included incorrectly. Post-procession
Antral follicle count can also be performed by seems necessary since SonoAVC misses follicles
3D ultrasound. Data are acquired as described of random sizes that are easily recognized in the
above. There are three ways to count the follicles. multiplanar view due to their specific color [57].
In the first, the observer counts manually the fol-
licles in a multiplanar view that is using all three
perpendicular planes simultaneously in order to Ovarian Volume
enhance the spatial awareness. In the second way,
the ovary is defined by VOCAL, inversion mode Women with PCOS have a larger ovarian volume
is applied and the follicles are displayed without [12, 15, 16, 58, 59]. The ovarian volume declines
the surrounding ovarian tissue, and, finally, the with age as the follicle both in women with PCOS
counting is performed in multiplanar view and controls, but this decline does not correlate
(Figs. 7.2 and 7.3). In the last way, SonoAVC dis- so well with age as the follicle number does [36,
plays every single follicle in a specific color in an 60, 61]. The pattern of the ovarian volume falling
inversion mode, again without the ovarian tissue in women with PCOS is different because
(Fig. 7.1). SonoAVC can distinguish follicles of declines less markedly than of controls despite
80 N. Prapas and A. Karkanaki
Fig. 7.2 Ovarian volume calculation using VOCAL before the application of inversion mode (Reprinted from
Jayaprakasan et al. [56]. With permission from Oxford University Press)
the similar decline in follicle number. This fact that investigated the sensitivity and specificity of
suggests that the stroma plays a significant role a diagnostic cutoff level [16, 58, 59]. However,
[61, 62] and also the size of the follicles, because other volume thresholds have been proposed sub-
the decrease with age affects mainly the number sequently [64, 65].
of small follicles (2–6 mm) but not of bigger fol- Again 3D ultrasound provides a more reliable,
licles (7–10 mm) in women with PCOS [63]. accurate, and reproducible assessment of ovarian
Alsamarai et al. demonstrated a linear decline in volume than the 2D-based methods, with better
ovarian volume and concluded that age-dependent spatial information and the ability to correct any
criteria for the diagnosis of PCOS are necessary shape irregularities [66–68]. 3D ultrasound also
[61]. This point could be of value in assisted confirmed the greater ovarian volume of women
reproduction field as the patients are very often with PCOS [69–72]. There two ways to calculate
more than 40 years old, but still in danger for the ovarian volume: the conventional full planar
OHSS. technique and the VOCAL program. During the
The calculation of the ovarian volume is per- conventional method, the observer scrolls
formed either using the formula for a prolate ellip- through one plane of the multiplanar display and
soid (0.5233 × length × width × thickness) [4, 5] or simultaneously delineates the ovary in a different
automatically by the software of the ultrasound plane [68, 72]. With VOCAL program, the
equipment just outlining the ovary. The simpli- observer manually defines the contour of the
fied formula, 0.5 × length × width × thickness, is ovary, while the dataset is rotated through 180°
practical and easy to use. The polycystic ovar- [72] (Fig. 7.4). Raine-Fenning et al. compared
ian morphology is diagnosed when the ovarian the two techniques and found that measurements
volume exceeds 10 cm3 [4, 5]. This consensus with VOCAL program are superior to conven-
definition was based on the findings of studies tional, though comparable [72, 74].
7 Ultrasound and PCOS 81
Fig. 7.3 Ovarian volume calculation using VOCAL after application of inversion mode (Reprinted from Jayaprakasan
et al. [56]. With permission from Oxford University Press)
Fig. 7.4 Calculation of stromal volume determining the stromal and follicular area by setting a threshold of voxels
(Reprinted from Lam et al. [73]. With permission from Oxford University Press)
82 N. Prapas and A. Karkanaki
Fig. 7.5 Mean gray value (MG) and 3D power Doppler indices within the ovarian volume delineated using VOCAL
(Reprinted from Deb et al. [89]. With permission from Elsevier)
flow rate. Vascularization flow index (VFI) [108]. Nevertheless, in a recent study, there
represents the ratio of the weighted color voxels was no difference in endometrial thickness and
to total voxels and gives a unified value for both volume between women with PCOS and
vascularity and volume flow reflecting the tissue controls [112].
perfusion [99]. The uterine and endometrial blood flow was
These indices are all significantly affected by found lower in women with PCOS [91, 92, 103,
volume flow, attenuation, vessel number, and 108, 113–117] with the exemption of a recent
erythrocyte density, but in different ways. The VI study [112]. The lower uterine and endometrial
and VFI seem to have a more predictable rela- blood perfusion is reflected in higher values of
tionship, whereas the FI often demonstrates a Doppler indices as PI and RI in PCOS and is cor-
more complex cubic relationship that is not related with obesity and hyperandrogenemia
always logical. Further work is required before a (higher levels of androstenedione, DHEAS, and
better understanding of 3D power Doppler ultra- LH/FSH) [91, 92, 116, 117]. Furthermore, uter-
sound imaging is achieved [100]. However, the ine perfusion increases with exogenous estrogen
findings are controversial even with 3D power and progesterone as well as antiandrogen admin-
Doppler. Some studies showed increased vascu- istration [113, 118], while there is a significant
larity and blood flow in the ovaries of women negative correlation between estrogens and uter-
with PCOS [88, 101–103] explained possibly by ine PI [119]. This impaired uterine perfusion was
the higher vascular endothelial growth factor associated with metabolic disorders and risk fac-
(VEGF), while others did not report any signifi- tors for cardiovascular events [114, 115]. The
cant difference [69, 77, 78, 87, 88]. Higher ovar- only study to investigate the endometrial blood
ian VFI was correlated with lower BMI, flow with 3D Doppler did not reveal any signifi-
hyperandrogenism, greater LH/FSH values, cant difference between PCOS and controls in
ovarian volumes, and follicle numbers [77, 78, 2D pulsed-wave (uterine arteries) and 3D power
103]. The 3D ultrasound approach is preferable Doppler (endometrial and subendometrial
because it provides the possibility to examine the blood flow) indices, apart from significantly dis-
blood flow and vascularization in the whole turbed endometrial perfusion in women with
ovary, avoiding the arbitrary selection of a single PCOS and clinical signs of hyperandrogenemia
vessel, or even to define a region and calculate diagnosed only by 3D Doppler [112].
separately the flow within and around this region
[71, 104].
Ultrasound and Assisted
Reproduction Outcome
Uterine Size and Perfusion
The poorer clinical outcome of assisted repro-
Literature references upon uterine ultrasound duction in women with PCOS has been associ-
characteristics in PCOS are scarce. The uterine ated with adverse factors interfering with every
volume has been found either smaller [105, stage of therapeutic process from impaired fol-
106] or bigger [15, 107] in women with PCOS liculogenesis and lower quality oocytes to higher
and lower in 40 % of adolescent with the syn- incidence of recurrent miscarriages. Despite the
drome [108], and also in correlation with LH importance, there are no sufficient knowledge
[107]. In few studies, a new criterion was sug- regarding the clinical outcome in women with
gested, the ratio of ovarian to uterine volume PCOS, and in some fields the data are contradic-
with an upper limit of 1.0 which was doubted tory. In general, ultrasound is considered helpful
and abandoned [106, 109]. Endometrial thick- to predict fertility outcome in PCOS [34]; how-
ness was diverse in women and adolescents ever, it seems that the most important contribu-
with PCOS [108, 110, 111] without correlation tion, currently, is the diagnosis of polycystic
with the time interval since the last period ovarian morphology.
7 Ultrasound and PCOS 85
Ovarian drilling is an effective, although uterine resistance and lower ovarian stromal
interventional, therapy of anovulatory infertility resistance, as reported in women with PCOS due
in women with PCOS. The success of ovarian to hyperandrogenemia and unopposed estrogens,
drilling could be estimated with ultrasound given are indicative of failure of conception in IVF and
that the ovarian volume reduces 3 weeks after recurrent miscarriage. Thus, further research and
intervention [120] and also the stromal blood maybe threshold value establishment, especially,
flow in the early follicular phase of the first post- in 3D power Doppler could contribute to a prog-
operative cycle or 3 months after drilling [101, nosis algorithm of failed implantation and mis-
102, 121]. The 3D Doppler assessment showed carriage in women with PCOS undergoing
significantly higher ovarian stromal VI, FI, and assisted reproduction.
VFI coexisting with higher AMH levels in PCOS
compared to controls before drilling and
decreased ovarian blood flow and AMH concen- Ultrasound and Prevention of OHSS
trations after drilling [101, 102]. Though, there
was no difference in stromal blood perfusion Ovarian hyperstimulation syndrome is a rare
between responders (spontaneous ovulation after (less than 5 %) but serious iatrogenic complica-
ovarian drilling) and nonresponders with PCOS tion of controlled ovarian hyperstimulation, con-
[102] and any clinical outcome report. cerning particularly patients with PCOS, with
The basal stromal flow measurement is con- significant health risk for the affected women
sidered to have no predictive value in PCOS with [132–135]. A great number of women undergo-
regard to pregnancy, since the flow indices ing controlled ovarian stimulation develop mild
between conception and non-conception cycles OHSS with symptoms such as abdominal bloat-
in women with PCOS undergoing IVF are similar ing and discomfort; however, the development of
[97, 122]. Nevertheless, the stromal blood perfu- moderate and severe OHSS could be fatal [133,
sion has been proven the most relevant predictor 136]. Therefore, the identification of women who
of ovarian response to controlled ovarian stimu- could manifest moderate or severe OHSS during
lation compared to ovarian or stromal volume ovarian stimulation is important, as would allow
[76, 122]. Jarvela et al. compared the vascular- adequate designing or modification of the stimu-
ization per follicle between women with PCOS lation protocol and dose of gonadotropin to
and controls, after pituitary suppression during reduce the risk. Currently, AMH and antral folli-
IVF. Women with PCOS had lower ovarian vas- cle count are the most prominent predictive fac-
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ambiguous and there was no report to clinical higher in women who developed OHSS [139].
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PCOS is also associated with recurrent mis- assessments showed that women who develop
carriages [123]. Likewise, hyperandrogenemia OHSS do not demonstrate increased ovarian
has been reported as a serious etiology of recur- blood flow and the only discriminative factor was
rent pregnancy loss, regardless of PCOS, possi- the significantly higher antral follicle count
bly due to lower endometrial and subendometrial [140]. A possible increase in blood flow in paral-
blood perfusion secondary to elevated uterine lel with higher VEGF and gonadotropin levels
arterial resistance [124–131]. Altogether, higher could trigger OHSS [101, 141], while a decrease
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The Normal Uterus
8
Khaled Sakhel and Alfred Z. Abuhamad
Fig. 8.3 The three orthogonal planes sagittal, transverse, and coronal planes as well as the rendered image. The coronal
image also portrays the hypoechoic junctional zone of the myometrium
of the cardinal ligaments and divide into ascend- postmenopausal bleeding is an important step in
ing and descending branches that travel within the overall evaluation process. It is important to
the layers of the broad ligament along the lateral know that a thin endometrium in that setting,
wall. Sonographically the normal myometrium typically at less than 5 mm, has been correlated in
has a medium echogenicity, less than the endo- multiple studies with the absence of endometrial
metrium, with a granular echotexture. The myo- cancer. When measuring endometrial thickness
metrium can be divided into three layers. The on ultrasound, it is critical to ensure that the
inner or junctional myometrium, which abuts the uterus is in a midsagittal plane, the whole endo-
endometrium, is thin and hypoechoic compared metrial stripe is seen from the fundus to the endo-
to the thicker homogeneous middle layer cervix, the thickest portion is measured, and the
(Fig. 8.3) [7, 8]. Thickening of this layer has been image is clear and magnified.
shown to be associated with adenomyosis [9]. Under the influence of increasing estradiol
The arcuate vessels separate the middle and outer hormone levels secreted by the growing ovarian
layer which is also thin and slightly less echo- follicles, endometrial proliferation occurs.
genic than the middle layer. The myometrium Sonographically this is seen as thickening of the
does not appear to change sonographically dur- lining into the so-called trilaminar layer (type B)
ing the course of the menstrual cycle. with an anterior and posterior hypoechoic layer
separated in the midline by a hyperechogenic cen-
tral line (Fig. 8.6). During the late proliferative
Endometrium period and near the time of ovulation, endometrial
lining is 8–12 mm in thickness with an accentu-
The uterine endometrium is the site of dynamic ated trilaminar appearance (type C, Fig. 8.7).
changes in response to ovarian hormones during The post-ovulatory endometrial lining, under
the menstrual cycle. It can be divided into the the influence of progesterone hormone secreted
inner functional layer that sloughs during menses by the corpus luteum, is characterized by loss of
and the outer basal layer which abuts the myome- the trilaminar appearance and the development of
trial junctional layer. The changes that occur dur- a uniformly hyperechoic stripe (type D, Fig. 8.8).
ing the menstrual cycle can be seen The implantation, pregnancy, and live birth
sonographically [7, 8, 10–17]. rates following in vitro fertilization (IVF) are
The immediate postmenstrual endometrium is affected by the midcycle endometrial thickness
a thin echogenic line (type A) at the intersection [14, 18–23]. Studies have shown that a midcy-
of anterior and posterior uterine walls and nor- cle endometrial thickness less than 8 mm was
mally measures 3–8 mm (Fig. 8.1). Assessing the associated with poor IVF outcome as compared
endometrial thickness in patients presenting with to at least 9 mm thickness. There is conflicting
8 The Normal Uterus 97
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Congenital Uterine Anomalies
9
Beth W. Rackow
development, at 6 weeks of gestation, the two tract development, unusual MA have been
processes are separate and distinct; females with documented that are exceptions to this order of
MA usually have normal ovaries and steroid progression. Examples include a complete septate
hormone production. uterus with a double cervix and vaginal septum,
Normal development of the female tract and a normal uterus and cervix with an isolated
involves a complex series of events, and failure of longitudinal vaginal septum [11–14]. Hence,
any part of this process can result in a Müllerian medial fusion of the Müllerian ducts can proceed
anomaly. Paired Müllerian ducts arise from coe- in a caudal or cranial direction or both [15].
lomic epithelium along the lateral walls of the
urogenital ridge, and these solid ducts are present
by week 6 of development. In the absence of Classification of Müllerian
Müllerian-inhibiting substance released from the Anomalies
male gonad, the Müllerian ducts proliferate while
the Wolffian ducts regress. The Müllerian ducts Müllerian anomalies are commonly classified
elongate caudally and cross the Wolffian ducts into three categories: agenesis and hypoplasia,
medially, and midline fusion of the ducts forms lateral fusion defects, and vertical fusion defects.
the primitive uterovaginal structure. By week 10 Reproductive tract abnormalities due to in utero
of development, fusion occurs between the exposure to diethylstilbestrol (DES) comprise a
caudal end of the joined Müllerian ducts and the fourth group of anomalies. Agenesis and hypo-
urogenital sinus. Subsequently, the unified plasia can occur for a portion of or an entire
Müllerian ducts undergo internal canalization Müllerian duct, or for both ducts, affecting one or
which results in two lumens divided by a midline multiple Müllerian structures. Lateral fusion
septum. Resorption of the septum commonly defects are the most common category of
occurs in a caudal to cranial direction. The fused Müllerian defects and originate due to failure of
caudal portion of the Müllerian ducts becomes migration of one or both ducts, midline fusion of
the uterus, cervix, and upper vagina, and the the ducts, or absorption of the midline septum
unfused cranial portion becomes the fallopian between the ducts. A range of anomalies can
tubes. Uterine development is completed by occur including symmetric or asymmetric and
week 20 of development. nonobstructed or obstructed Müllerian structures.
The lower vagina has a separate embryologic Vertical fusion defects occur due to disordered
origin. At week 10, when the fused Müllerian fusion of the Müllerian ducts with the urogenital
ducts connect with the urogenital sinus, the sino- sinus or abnormal vaginal canalization and may
vaginal bulbs develop and proliferate toward the present with menstrual flow obstruction.
caudal end of the uterovaginal canal, forming a Although there is no universally accepted
solid vaginal plate that elongates with time. The standard classification for Müllerian anomalies,
central cells of the vaginal plate degenerate in a the American Fertility Society classification sys-
caudal to cranial direction, forming a hollow tem from 1988 is commonly utilized and pro-
structure. Vaginal development is also complete vides a standardized nomenclature to describe
by week 20 of development. The hymenal mem- anomalies (Fig. 9.1) [4, 16]. This classification
brane originates from the sinus tubercle and sep- system focuses on the major categories of uterine
arates the vaginal lumen from the urogenital anomalies and describes them based on their
sinus. The central epithelial cells usually degen- embryologic etiology. Hypoplasia/agenesis (cat-
erate prior to birth, achieving a patent structure egory I) and unicornuate (category II) denote
with a thin fold of mucus membrane at the anomalies with developmental failure of one or
introitus. both Müllerian ducts; didelphys (category III)
Although the caudal-to-cranial direction and bicornuate (category IV) describe anomalies
of Müllerian duct fusion and septal resorption involving a varying degree of failure of midline
is the traditional theory of female reproductive fusion; septate (category V) and arcuate (category
9 Congenital Uterine Anomalies 103
Fig. 9.1 Classification of uterine anomalies according to the American Fertility Society [16]. DES, diethylstilbestrol
(Reprinted Bermejo et al. [17]. With permission from John Wiley & Sons, Inc.)
VI) identify anomalies with some degree of fallopian tube, and the contralateral side may
failure of resorption of the midline septum. DES have a variety of configurations: agenesis or a
drug-related anomalies (category VII) are a rudimentary horn in 74 % [6]. The rudimentary
separate category of anomalies and will not be horn can be noncommunicating (70 to 90 %) or
discussed in this chapter. With this classification communicating with the unicornuate uterus and
system, associated anomalies of the vagina, may contain functional endometrium [20].
cervix, fallopian tubes, and urinary system must Women with a rudimentary uterine horn contain-
be documented separately. Two additional issues ing functional endometrium may present with
with this classification system are the inability to cyclic or chronic pain, endometriosis, or a horn
fully describe a uterine anomaly when multiple gestation [20]. Nonfunctional rudimentary horns
abnormalities are present (i.e., septate uterus with are usually asymptomatic. Lastly, the unicornu-
duplicated cervix) and the lack of specific diag- ate uterus is associated with a 40 % incidence of
nostic criteria to enable differentiation between renal anomalies, usually ipsilateral to the anoma-
bicornuate, septate, and arcuate uteri [4, 11, 18, lous side [20–22].
19]. Hence, complex anomalies need to be
described according to the component parts.
Uterus Didelphys
Overview of the Uterine Anomalies The uterus didelphys results from complete
failure of lateral fusion of the two Müllerian
Unicornuate Uterus ducts; duplication of the Müllerian structures is
the result. Anatomically, these women have two
The unicornuate uterus arises due to agenesis or unicornuate uteri, two separate endometrial cavi-
hypoplasia of one of the two Müllerian ducts. ties, and two cervices. In the majority of women
The unicornuate uterus is a functional uterus with a uterus didelphys, vaginal duplication
with a normal-appearing cervix and a single also occurs and a longitudinal vaginal septum is
104 B.W. Rackow
present. Additionally, this anomaly can present septum [16], or a bicornuate uterus. Appropriate
with an obstructed hemivagina and associated imaging to define uterine anatomy is essential so
ipsilateral renal anomaly [23, 24]. as not to misclassify a uterus as arcuate instead of
partial septate or bicornuate, which have different
reproductive implications.
Bicornuate Uterus
Table 9.1 Clinical presentation of uterine anomalies size, insufficient musculature, impaired ability
Gynecology Obstetrics to distend, abnormal myometrial and cervical
Pelvic pain, cyclic or Pregnancy loss: first and function, inadequate vascularity, or abnormal
noncyclic second trimester endometrial development [1, 3, 8, 22, 41–46].
Dysmenorrhea Cervical incompetence Due to higher rates of malpresentation, an
Primary amenorrhea with Preterm labor and increased rate of cesarean delivery can be seen
pain delivery
with uterine anomalies. Additional obstetric
Primary amenorrhea Intrauterine growth
without pain restriction complications such as cervical incompetence
Hematometra Placental abruption [47], pregnancy-induced hypertension (due to
Abnormal uterine bleeding Intrauterine fetal demise renal anomalies), and antepartum and postpar-
Dyspareunia Malpresentation tum bleeding are also associated with congeni-
Cesarean delivery tal uterine anomalies. Lastly, pregnancy may
Pregnancy-induced occur in an obstructed or rudimentary uterine
hypertension (related to horn. These pregnancies are surgical emer-
renal abnormalities)
gencies due to an 89 % rate of rupture and the
Pregnancy in rudimentary
uterine horn
related morbidity and mortality [20].
will review all available imaging techniques Pelvic Magnetic Resonance Imaging
and will focus on the evolving technique of 3-D
ultrasonography. Pelvic MRI is a sensitive and specific imaging
modality for evaluating Müllerian anomalies [11,
54]. MRI provides detailed delineation of inter-
Hysterosalpingography nal and external uterine contours, can differenti-
ate between a myometrial and fibrous uterine
A common procedure for evaluation of tubal division, can differentiate between a septate cer-
patency in women with infertility, HSG can also vix and duplicated cervix, can diagnose vaginal
provide information about the contour of the uter- anomalies, and can identify if a rudimentary uter-
ine cavity. In a woman with a uterine anomaly, the ine horn contains functional endometrium [11,
HSG may identify patent canals and any complex 17]. Furthermore, MRI can also assess renal mor-
communications, but is unable to adequately eval- phology and location. Although costly, this non-
uate the external uterine contour and, hence, can- invasive imaging modality is less expensive than
not reliably differentiate between uterine anomalies surgery [18]. Pelvic MRI may not be necessary
[4, 11, 35]. When a uterine anomaly is identified, for every patient with a uterine anomaly and may
assessment of the external uterine contour can be be best utilized for the evaluation of complex
achieved with 2DUS, 3DUS, and/or SIS. In one Müllerian anomalies [17, 36].
study, HSG correctly diagnosed 55 % of septate A number of studies have evaluated the effi-
and bicornuate uteri, and the addition of ultraso- cacy of MRI to assess surgically confirmed uter-
nography improved this result to 90 % [50]. Since ine anomalies [18, 55–58]. A range of sensitivity
the HSG involves exposure to ionizing radiation, (29 to 100 %) and specificity (33 to 100 %) and
in young women with desired fertility, this test positive predictive value (83 to 100 %) and nega-
should only be ordered when clinically indicated. tive predictive value (25 to 100 %) was identified.
The ability of MRI to detect and correctly diag-
nose a uterine anomaly can be limited by the
Two-Dimensional Ultrasonography availability of technically adequate images which
may be influenced by the MRI machine and soft-
Two-dimensional transabdominal or transvaginal ware utilized and requires image interpretation
ultrasonography is a common initial technique by a practitioner with experience in the diagnosis
for assessing pelvic structures. It effectively visu- of uterine anomalies [18, 49].
alizes the uterine structure and endometrial con-
tour, can detect a pelvic mass or hematometra,
confirms the presence of ovaries, and can be used Three-Dimensional Ultrasonography
to evaluate the kidneys. When 2DUS is per-
formed in the secretory phase of the menstrual Three-dimensional ultrasonography (3DUS) is a
cycle, better visualization of the endometrium relatively new imaging technique that provides
and internal uterine contour can be achieved [51, detailed and highly accurate views of pelvic anat-
52]. A compilation of 2DUS studies for uterine omy; it constructs three-dimensional volumes
anomalies noted a pattern of low sensitivity and from a series of two-dimensional images [18,
high specificity; although 2DUS can only iden- 27]. After the volume is created, it can be stored
tify about half of the uterine anomalies present, and any section of a structure can be examined.
the diagnosis of an anomaly is highly likely to be With uterine anomalies, the ability to visualize
correct [4]. When indicated, saline infusion the coronal section of the uterus is invaluable
sonography can be employed to further assess the for assessing the architecture of the endometrial
internal and external uterine contours and can cavity and the uterine fundus (Fig. 9.2) [17, 27,
accurately diagnose uterine anomalies as well as 48, 59, 60]. Therefore, by evaluating the inter-
identify other intracavitary abnormalities such as nal and external uterine contours, 3DUS is able
polyps, myomas, or adhesions [4, 49, 53]. to reliably differentiate between various uterine
9 Congenital Uterine Anomalies 107
a b c d e
f g h i
Fig. 9.2 Three-dimensional rendered coronal ultrasound uterus; (f) complete septate uterus; (g) partial septate
images demonstrating different uterine anomalies using uterus; (h) arcuate uterus; (i) uterus with diethylstilbestrol
the American Fertility Society classification [16]: (a) nor- (DES) drug-related malformations (Reprinted Bermejo
mal uterus; (b) unicornuate uterus; (c) didelphic uterus; et al. [17]. With permission from John Wiley & Sons, Inc.)
(d) complete bicornuate uterus; (e) partial bicornuate
Table 9.2 Three-dimensional ultrasound criteria for classification of congenital uterine anomalies
Uterine morphology Fundal contour External contour
Normal Straight or convex Uniformly convex or with indentation
<10 mm
Arcuate Concave fundal indentation with central point Uniformly convex or with indentation
of indentation at obtuse angle (>90°) <10 mm
Partial septate Presence of septum (does not extend to Uniformly convex or with indentation
cervix) with central point of septum at an <10 mm
acute angle (<90 %)
Complete septate Presence of septum that completely divides Uniformly convex or with indentation
cavity from fundus to cervix <10 mm
Bicornuate Two well-formed uterine cornua Fundal indentation >10 mm dividing the two
cornua
Unicornuate uterus Single well-formed uterine cavity with a Fundal indentation >10 mm dividing the two
single interstitial portion of fallopian tube and cornua if a rudimentary horn is present
concave fundal contour
Adapted from Refs. [19, 61]
anomalies and can assess the often subtle dif- uterine anomalies (Fig. 9.1) does not provide
ferences between septate and bicornuate uteri dimensions or measurements to enable differen-
[17, 18, 27, 28, 59, 61]. However, distortion by tiation of uterine anomalies based on ultrasound
leiomyomas may make uterine assessment more findings, a modification of the AFS criteria based
challenging [7, 18, 59]. This modality is less on 3DUS landmarks has been utilized to facilitate
expensive and less time consuming than surgery the diagnosis of uterine anomalies (Table 9.2,
or pelvic MRI, is less invasive than surgery, and Fig. 9.3) [11, 16, 18, 19, 48, 61].
may be better tolerated [17, 18, 52]. Although When compared to HSG and 2DUS, 3DUS
the American Fertility Society classification for demonstrates high sensitivity and specificity
108 B.W. Rackow
a b
c d
Fig. 9.3 Three-dimensional rendered coronal ultrasound (c) Arcuate uterus: a normal external uterine contour is
images demonstrating ultrasound criteria for classifica- identified with a concave fundal indentation of the endo-
tion of congenital uterine anomalies. (a) Bicornuate metrial cavity at an obtuse angle. (d) Partial septate
uterus: two divergent cornua are noted, divided by a sagit- uterus: a normal external uterine contour is present, the
tal cleft >10 mm (arrow). (b) Complete septate uterus: septum does not extend to the cervix, and the central point
a normal external uterine contour is present, and a septum of the fundal indentation demonstrates an acute angle
divides the endometrial cavity and extends to the cervix. (Reprinted Ghi et al. [48]. With permission from Elsevier)
for the identification of a normal uterus (98 and (100 and 95 %). Hence, 2DUS may be best
100 %), arcuate uterus (100 and 100 %), or major utilized as a screening test for uterine anomalies,
uterine anomaly (100 and 100 %) [59]. In com- with 3DUS as the definitive diagnostic test [59].
parison, 2DUS has lower sensitivity and specific- Several studies investigated the accuracy of
ity for the diagnosis of a normal uterus (88 and 3DUS for the evaluation and diagnosis of uterine
94 %) or arcuate uterus (67 and 94 %), but is anomalies and confirmed the radiologic findings
similarly accurate with major uterine anomalies at surgery (laparoscopy and/or hysteroscopy).
9 Congenital Uterine Anomalies 109
In one study, 3DUS assessment of the uterine [49]. 3DUS correctly identified 31/31 uterine
fundus correlated 91.6 % with laparoscopic find- anomalies, and pelvic MRI correctly identified
ings, and evaluation of the uterine cavity corre- 24/31 uterine anomalies; five septate uteri were
lated 100 % with hysterosalpingography [62]. misclassified as bicornuate uteri, and 2 partial
Wu et al. compared 3DUS with laparoscopy for septate uteri as complete septate uteri. These dis-
the detection of uterine anomalies, and 3DUS crepancies were attributed to the lack of a coronal
demonstrated 100 % sensitivity and specificity uterine image and lack of familiarity with the
and correctly diagnosed 92 % (11/12) of septate evaluation of uterine anomalies.
uteri and 100 % (3/3) of bicornuate uteri [28]. 3DUS has been demonstrated to be at least as
A study of 3,850 infertile women who underwent accurate as pelvic MRI for diagnosing uterine
uterine evaluation with 3DUS and hysteroscopy anomalies. However, 3DUS is not a widely avail-
identified 689 (17.9 %) with septate uteri, and able imaging modality and requires a high level
3DUS demonstrated 99.27 % sensitivity and of practitioner skill and experience to achieve
100 % specificity for diagnosing a septate uterus high diagnostic accuracy [17, 18, 57]. Although
[7]. Another recent study investigated 254 nul- these studies have promising results, it must be
liparous women with recurrent pregnancy loss, emphasized that they were performed by practi-
and 3DUS findings were confirmed by office tioners with expertise in the performance and
hysteroscopy (for normal uteri) or laparoscopy/ interpretation of 3DUS and in the diagnosis of
hysteroscopy if a uterine anomaly was identified uterine anomalies.
[48]. Fifty-four subjects (19 %) were diagnosed
with a uterine anomaly, and 3DUS correctly
identified 52 (92.3 %) of the anomalies; two par- Urinary Tract Imaging
tial septate uteri were misclassified as bicornu-
ate and arcuate. When 3DUS and 2DUS were Lastly, since urinary tract anomalies are associ-
compared for the diagnosis of uterine anomalies ated with Müllerian anomalies, imaging of the
during different phases of the menstrual cycle, urinary tract needs to be considered when a uter-
both modalities had higher sensitivity and speci- ine anomaly is identified. Upper urinary tract
ficity during the luteal phase, but 3DUS demon- anomalies include renal agenesis, horseshoe or
strated greater sensitivity and specificity in both pelvic kidney, duplication of the collecting sys-
the follicular and luteal phases, and the diagnos- tem, or an ectopic ureter [10]. Renal anomalies
tic accuracy of 3DUS was comparable to HSG, most commonly occur with unicornuate and
hysteroscopy, and laparoscopy [52]. Lastly, the didelphic uteri and with Müllerian agenesis and
reproducibility of the interpretation of 3DUS are infrequently identified with bicornuate, sep-
volumes to diagnose uterine anomalies has been tate, and arcuate uteri [63]. If an obstructive
established [61]. Müllerian anomaly is identified such as a unicor-
Few studies have compared the diagnosis of nuate uterus with a rudimentary uterine horn or
uterine anomalies by 3DUS versus pelvic MRI. uterus didelphys with an obstructed hemivagina,
Bermejo et al. determined that in women with renal anomalies including renal agenesis are
uterine anomalies, 3DUS and MRI demonstrate a commonly identified ipsilateral to the obstruc-
high degree of concordance, with a kappa index tion. In more than 50 % of cases, renal agenesis is
of 0.880 (95 % CI, 0.77 to 0.99) [17]. predictive of an obstructive Müllerian anomaly
Discrepancies occurred in the diagnosis of 4 of [20].
65 anomalies; 3DUS misclassified one bicornu- Options for urinary tract imaging include
ate uterus as uterus didelphys, and 3 septate uteri renal ultrasound, intravenous pyelogram, com-
as bicornuate uteri. In contrast, Faivre et al. puted tomography (CT) scan, or magnetic reso-
investigated women with suspected septate and nance (MR) urogram. In women diagnosed with
bicornuate uteri; all 31 uterine anomalies were a Müllerian anomaly, the kidneys should be eval-
confirmed by hysteroscopy and/or laparoscopy uated with ultrasonography, and further imaging
110 B.W. Rackow
should be undertaken based on symptoms and the anomaly. Saravelos et al. report that the arcuate
extent of the malformation [10]. Due to a higher uterus is the most common uterine anomaly in the
risk of urinary tract anomalies, more detailed general (2.4 %) and recurrent miscarriage (12.0 %)
imaging is warranted in females with uterine populations, but the septate uterus is most com-
anomalies that may involve a unilateral obstruc- mon in the infertile population (3.9 %) [4]. A more
tion: unicornuate or uterus didelphys or Müllerian recent meta-analysis identified that the arcuate
agenesis [63]. uterus is the most common anomaly (3.9 %) in the
general population and its prevalence is not
increased in groups at high risk for poor reproduc-
Reproductive Outcomes tive outcomes, while the septate uterus is the most
with Uterine Anomalies common anomaly (3.0–15.4 %) in high-risk popu-
lations (women with infertility and a history of
Challenges with maintenance of pregnancy, not miscarriage) [5]. These data highlight the repro-
conception, are commonly associated with uter- ductive dysfunction associated with the septate
ine anomalies; uterine anomalies do not prevent uterus and raise questions about a possible rela-
conception and normal reproductive outcomes tionship between the septate uterus and infertility.
are possible. Infertile women have a 3.4 to 8 % The septate uterus contains a hypovascular
mean prevalence of uterine anomalies which is fibromuscular uterine septum, and this structural
comparable to that of the fertile population [3– abnormality as well as abnormalities in the endo-
5]. A higher prevalence of uterine anomalies metrium overlying the septum may predispose
(12.6 to 16.7 %) is seen in women with RPL this anomaly to the worst reproductive outcomes
[3–5]. These data suggest that uterine anoma- [42, 46, 66]. A compilation of studies investigat-
lies have a negligible effect on fertility, and ing pregnancy outcome in women with an
maintenance of pregnancy is the larger issue [3, untreated septate uterus identified a 44 % abor-
29]. Furthermore, women with uterine anoma- tion rate (range 23–67 %), 22 % preterm delivery
lies who undergo assisted reproductive technol- rate (range 8.6–33 %), 33 % term delivery rate
ogies have comparable pregnancy rates to (range 0–68 %), and 50 % live birth rate (range
infertile women with normal uteri, but a higher 28–68.5 %) (Table 9.3) [3]. Another study com-
rate of pregnancy loss and preterm delivery pared women with septate uteri to the general
[64]. These adverse reproductive outcomes are population and identified an increased rate of
attributed to deficient musculature and reduced early abortion (41.1 % versus 12.1 %) and late
cavity size, abnormal vascularity, and cervical abortion and preterm delivery (12.6 % versus
insufficiency [63]. 6.9 %) [7]. Due to variability in the pregnancy
Depending on the population studied and the outcomes reported in the included studies, these
accuracy of the imaging modalities in diagnosing data may overstate the degree of reproductive
uterine anomalies, the arcuate [4, 5] or septate compromise seen with this anomaly and repre-
uterus [3, 11, 65] is the most common uterine sent a “worst case scenario” [19]. Regardless,
Table 9.3 Reproductive outcomes in women with congenital uterine anomalies. Rates are averaged and presented as
a percentage
Uterine Number Number Number Abortion Preterm Term delivery Live birth
anomaly of studies of patients of pregnancies rate birth rate rate rate
Unicornuate 11 151 250 36.5 16.2 44.6 54.2
Didelphys 8 114 152 32.2 28.3 36.2 55.9
Bicornuate 4 261 627 36 23 40.6 55.2
Septate 4 198 499 44.3 22.4 33.1 50.1
Arcuate 3 102 241 25.7 7.5 62.7 66
Based on data from Ref. [3]
9 Congenital Uterine Anomalies 111
it is clear that the septate uterus may significantly infrequently necessary when diagnosing uterine
impact reproductive outcomes. Fortunately, it is anomalies.
the most treatable uterine anomaly and can be Surgical intervention is indicated for women
corrected with operative hysteroscopy, a mini- with obstructive anomalies, pelvic pain, endome-
mally invasive procedure. triosis, and poor obstetric outcomes such as RPL,
Unicornuate, didelphys, and bicornuate uteri second trimester loss, or preterm delivery. In
are implicated in adverse reproductive outcomes; women with RPL and preterm delivery, it is
live birth rates for women with these uterine important to rule out extrauterine causes of these
anomalies are at least 50–55 %, and miscarriage obstetric issues [8, 21]. Although certain uterine
rates are approximately 35 % (Table 9.3) [3, 63]. anomalies such as the septate uterus are amena-
These rates are somewhat better than those asso- ble to surgical correction, the unicornuate uterus
ciated with the septate uterus and, again, may is never considered operable (although rudimen-
represent a less optimistic statement of reproduc- tary horns may warrant surgical intervention),
tive outcomes. Additionally, overall obstetrical and bicornuate and didelphys uteri are consid-
outcomes may be somewhat better with the ered operable in select circumstances [21, 63, 65,
bicornuate uterus due to variability in the degree 68]. Abdominal metroplasty can be performed to
of cavity division; the rate of preterm delivery unify a bicornuate uterus or uterus didelphys but
differs between partial (29 %) and complete is only performed in select patients with poor
(66 %) bicornuate uteri [67]. obstetric outcomes [21, 65, 68]. The goals of sur-
By definition, the arcuate uterus deviates gery include treatment of pelvic pain and endo-
minimally from normal uterine anatomy, thus is metriosis, restoration of pelvic anatomy, and
traditionally considered benign and not associated preservation of fertility.
with an increased risk of adverse pregnancy out- Hysteroscopic metroplasty to correct a partial
comes [16, 27]. However, the arcuate uterus has or complete septate uterus can improve reproduc-
been associated with a range of reproductive out- tive outcomes and is indicated in women with
comes: live birth rates range from 48 to 82.7 % [1, recurrent pregnancy loss or second trimester
3, 38]. One concern is that when less accurate pregnancy loss [3, 41]. After the hysteroscopic
imaging techniques are utilized, a bicornuate or procedure, the risk of pregnancy loss or other
partial septate uterus may be misclassified as an adverse perinatal outcomes is dramatically
arcuate uterus and mistakenly associated with decreased; live birth and miscarriage rates are
worse reproductive outcomes [27]. Based on what improved to approximately 80 and 15 %, respec-
is known about arcuate uterine anatomy, the more tively [3, 7, 29, 41]. For surgical treatment of a
optimistic reproductive data are more believable, uterine septum, the hysteroscopic approach is
and surgical intervention is likely not warranted preferred due to its safety, simplicity, and excel-
unless poor reproductive outcomes occur. lent postoperative results [41, 65], and laparos-
copy can be utilized to assess the fundal contour
and guide the extent of septum resection but is
Indications for Surgical not mandatory [29, 41].
Intervention While hysteroscopic metroplasty for women
with RPL significantly improves the live birth
Historically, surgery was considered the gold rate, in women with unexplained infertility, sur-
standard for the evaluation and diagnosis of gery achieves modest improvements in pregnancy
Müllerian anomalies. However, due to the avail- and live birth rates [41, 65, 69, 70]. Furthermore,
ability of advanced imaging techniques that can a recent study identified that women with unex-
assess the uterine fundal contour and endometrial plained infertility and a septate uterus who under-
cavity architecture, diagnostic surgical proce- went hysteroscopic metroplasty had significantly
dures such as an exam under anesthesia, vaginos- improved rates of conception (38.6 % vs. 20.4 %)
copy, hysteroscopy, and laparoscopy are and live birth (34.1 % vs. 18.9 %) compared to
112 B.W. Rackow
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Uterine Fibroids
10
Bradley S. Hurst
higher incidence of transverse lie or breech pre- concluded that pregnancy outcomes are compro-
sentation (16.9 % vs. 2.4 %), a five times higher mised in women who have intramural fibroids
cesarean section rate (57.7 % vs. 10.8 %), 70 % [30].
higher risk of premature rupture of membranes Uterine fibroids tend to enlarge during preg-
(9.6 % vs. 5.5 %), and were three times more nancy, regardless of size and maternal age [31].
likely to receive transfusion (4.2 % vs. 1.4 %). Approximately 70 % of fibroids grow by a vol-
All of these outcomes were significant, with ume of 10 % or more between the first and sec-
p < 0.001. Adjusting for maternal age, parity, ges- ond, and second and third trimesters. As a fibroid
tational age, and malpresentation, pregnancies grows, masses located near the cavity have the
with fibroids still had a 6.7-times higher risk of potential to compress the cavity and cause a det-
cesarean delivery, with 95 % CI 5.5–8.1, p < 0.01). rimental effect.
Placental abruption and preterm deliveries It would appear that myomectomy could
remained significantly more common with be justified in some circumstances to reduce
fibroids. The size and locations of the fibroids the risk of adverse pregnancy outcomes [32].
were not assessed in this study, but other investi- Unfortunately, the benefit of myomectomy for
gators have found that fibroids adjacent to the intramural fibroids has not been definitively
placenta increase the risk of bleeding and prema- proven. The most compelling evidence for intra-
ture rupture of membranes [28]. mural myomas appears to be cases with large
A retrospective study in 2012 supports the fibroids, 4 cm or larger, and tumors close to the
hypothesis that fibroids have a detrimental impact uterine cavity. It is important to clarify this issue
on pregnancy, especially when the fibroids are since myomectomy for intramural fibroids has a
large [29]. The mean gestation age at delivery for risk of morbidity and adhesion formation, and
women with fibroids larger than 5 cm was surgery should not be considered unless the ben-
36.5 weeks, significantly earlier than women efits outweigh the risks.
with smaller fibroids or no fibroids. Other signifi- In spite of the limited data, myoma size, loca-
cant effects included shortened cervix, premature tion, and number are key factors when discuss-
preterm rupture of membranes, preterm delivery, ing the outcomes after myomectomy, and these
blood loss during delivery, and the need for post- are considered separately in this discussion.
partum transfusion. Considering these and other However, these factors are not separable for an
publications, authors of a literature review individual patient, and the surgeon must weigh
10 Uterine Fibroids 123
the cumulative impact of all three factors when follicular phase and after ovulation, when the
deciding to perform how and when to perform a endometrium is more homogeneous, endometrial
myomectomy. distortion is more difficult to assess and saline
infusion sonohysterography should be performed
if a submucous fibroid is suspected [33].
Diagnosis of Uterine Fibroids Uterine fibroids may appear to have sev-
eral variations in appearance using ultrasound,
A focused history and physical examination may depending on the characteristics of the mass. For
provide suspicion of uterine fibroids. Symptoms example, a calcified myoma has a bright echo-
related to fibroids may include menorrhagia, dys- genic pattern and distortion or “artifact” beyond
menorrhea, menstrual clotting, intermenstrual the mass (Fig. 10.5). Although calcified fibroids
bleeding, pelvic pain, pressure, progressive con- are easily identified, distortion that occurs
stipation or alternating constipation and diar- beyond the mass may “hide” the endometrium
rhea, abdominal distention, or urinary frequency. or other fibroids. Uterine fibroids are sometimes
However, other conditions can cause any of these visible as “hypoechogenic” oval masses in the
symptoms, and fibroids are often asymptomatic. myometrium. Less often, a fibroid may have the
On examination, the uterus is often enlarged and same echogenic pattern as the surrounding myo-
irregular with uterine fibroids due to the distor- metrium and be identified by finding a deflection
tion from the individual masses. A rectovaginal of the endometrial or the serosal surface of the
examination may be helpful to identify posterior uterus. Subtle or uncertain findings should be
fibroids. However, other conditions such as ade- cautiously interpreted, since normal physiologic
nomyosis can cause uterine enlargement, and a contractions of the myometrium can be con-
clinically significant fibroid may be present, even fused with an intramural fibroid. If an uncertain
if the examination is normal. Diagnostic testing abnormality is suspected, the sonographer should
with ultrasound is appropriate for any women reassess the area of interest after a few minutes
with infertility and is considered an important to allow a contracted area to change. Another
component of the infertility evaluation. method that may be helpful is the use of color
Doppler. Since the fibroid is surrounded by a rich
vascular supply, a myoma will usually demon-
Ultrasound strate a “ring of fire” [34]. In some cases, 3-D
ultrasound may also provide additional anatomic
Transvaginal ultrasound provides better image insight regarding the position of the myoma.
quality than abdominal ultrasound, but both Fibroids must be differentiated from adeno-
methods might be necessary in the uterus that is myosis, especially when surgery is considered,
markedly enlarged with uterine fibroids. Since since resection of adenomyosis and repair of the
overlying bowel may limit the visualization of defect can be difficult [33]. Adenomyosis may
the uterus, abdominal ultrasound is performed have several appearances by ultrasound, mak-
with the bladder full enough to provide a “win- ing the diagnosis uncertain in some cases. To
dow” for the uterus. Vaginal ultrasound studies add to the confusion, hormonal changes might
are performed with an empty bladder for patient cause variations in the appearance of an area
comfort. of adenomyosis throughout the cycle, since the
Careful examination of the endometrium and response of adenomyosis is similar to the nor-
myometrium is needed to assess anatomic abnor- mal endometrial response. Adenomyosis may
malities. A submucous myoma is easily identified appear hyperechoic, hypoechoic, or the signal
when the endometrium has a preovulatory “triple may be mixed. Adenomyosis can enlarge or
stripe” pattern. If there is no endometrial distor- shrink throughout a menstrual cycle, depend-
tion or deflection of trilaminar endometrium, ing on the hormonal response. In some cases,
a submucous fibroid is unlikely. In the early adenomyosis forms a nodular myometrial
124 B.S. Hurst
(frequency and/or obstruction), and (8) iron defi- losses and improves the term live birth rate [42]. In
ciency anemia secondary to chronic blood loss women with menorrhagia caused by a submucous
[40]. However, in women with otherwise unex- myoma who desire fertility preservation, hystero-
plained infertility, myomectomy may improve scopic myomectomy compares favorably to hyster-
pregnancy outcomes [39, 41]. Therefore, surgery ectomy [43].
should be recommended for infertile women with For optimal visualization during hysteroscopy,
submucous myomas and considered for women the procedure is either performed in the follicular
with a myoma, 4 cm or larger, or intramural myo- phase of the cycle to ensure a thin endometrial
mas within a few millimeters of the endometrial lining or after pretreatment with a GNRH ago-
cavity in women with otherwise unexplained nist or hormonal contraception for 1 or 2 months
infertility when appropriate fertility treatments before surgery. Hysteroscopic myomectomy
have been unsuccessful. can be performed concurrently with abdominal
Myomectomy is usually the best option for or laparoscopic myomectomy to reduce bulk
young women who desire preservation of the symptoms.
uterus. The type of myomectomy, hysteroscopic, During hysteroscopic myomectomy, the uter-
open, or laparoscopic, is chosen based on patient ine cavity is filled with distention media and the
symptoms, location, size and number of fibroids, fibroid is resected with monopolar or bipolar cau-
and the skill and experience of the surgeon. tery with the resectoscope. A bipolar instrument
Considerations to the route of surgery must include allows the use of saline for distention. It is impor-
selection of the approach that provides greatest tant to closely monitor fluid deficits during any
improvement in the prognosis, a high safety pro- hysteroscopic procedure as dangerous electrolyte
file. The decision should be made with the knowl- imbalances can occur. Typically hysteroscopic
edge of the length of patient recovery and cost of resection of myomas is appropriate for tumors
the procedure, but these should not be the deciding 6 cm or less, while larger masses may require a
factors for choosing the surgical route. 2-step surgery [44].
An appropriate preoperative evaluation is The hysteroscopic morcellator is a new tool
essential to prepare for surgery. In many cases, being used which breaks the myoma into small
ultrasound establishes the fibroid size and loca- chips and evacuates the fragments into a tissue
tion. SIS is beneficial to determine the relation- trap. This method appears to be safe and effective
ship of a submucous myoma to the myometrium [45], although intraoperative bleeding may be
for women with a submucosal myoma. MRI more problematic with this approach. In order to
should be considered if an atypical ultrasound minimize bleeding during hysteroscopic myo-
appearance is identified, if the ultrasound is not mectomy, the myoma base may be injected with
conclusive, or if adenomyosis is suspected. dilute vasopressin.
During hysteroscopic myomectomy of a ses-
sile myoma located partially within the myome-
Hysteroscopic Myomectomy trial wall, there tends to be a progressive
herniation of the intramural component of the
Hysteroscopic myomectomy is the most appro- myoma into the uterine cavity [46]. Movement of
priate approach when a submucous myoma has the fibroid into the cavity may allow for more
been identified, before initiating fertility treat- complete resection of the fibroid than would be
ment. Hysteroscopic myomectomy is appropri- expected based on the percentage of the fibroid in
ate for symptomatic submucous myomas and for the cavity as seen during SIS. However, contin-
infertile women with asymptomatic submucous ued resection into the myometrium may result in
myomas. uterine perforation and could cause injury to
Reproductive outcomes are improved following structures adjacent to the uterus, including bowel
hysteroscopic myomectomy [9]. Hysteroscopic and bladder. The use of concurrent abdominal
myomectomy lowers the incidence of first trimester ultrasound can provide additional safety during
126 B.S. Hurst
complex hysteroscopic procedures, allowing for compromise the results in some individuals.
better identification of the relationship of the sur- Myomectomy often reduces menorrhagia and
gical site and the myometrium [33]. improves fertility in women with excessive bleed-
ing or infertility primarily caused by endometrial
distortion from submucous myomas or large intra-
Abdominal Myomectomy mural myomas. Slightly more than 50 % of women
conceive after open myomectomy [52]. Adhesions
Although Washington Atlee reported his experi- form in more than 90 % of abdominal myomecto-
ence performing successful abdominal myomec- mies, with the incidence highest (94 %) with pos-
tomies in 1845 [47], the mortality rates were high terior incisions and lower (56 %) with fundal or
until Victor Bonney mastered the techniques of anterior uterine incisions [53]. When severe, adhe-
this procedure, after being inspired by his child- sions can result in bowel obstruction and require
less wife’s emotionally devastating hysterectomy additional intervention. Adhesion barriers are rec-
for a submucous leiomyoma in 1908. Bonney ommended to minimize the extent of adhesions,
introduced many surgical techniques still used and a Cochrane review concluded that Interceed is
today, including uterine artery compression with the most effective adhesion barrier for myomec-
his “Bonney clamp” to reduce bleeding and ele- tomy [54]. Growth of new fibroids is not uncom-
vation of the uterus to improve exposure during mon after myomectomy, but additional surgery is
myomectomy. He described an approach to oblit- required in a minority of patients.
erate the dead space from the myoma bed by
under-sewing the deeper tissue layers. In this
career, Bonney performed more than 700 myo- Laparoscopic Myomectomy
mectomies. His mortality rate was 1.1 %, remark-
ably low in an era before blood transfusions and Laparoscopic myomectomy provides several
antibiotics. By the 1930s, Bonney advocated advantages compared to laparotomy: postopera-
myomectomy for any woman wishing to have tive pain is reduced, recovery time is shorter,
children under the age of 41. postoperative febrile morbidity is less common,
Abdominal myomectomy is typically per- intraoperative blood loss is reduced, and adhe-
formed through a Pfannenstiel incision, although sion formation is less with laparoscopic myo-
a Maylard incision or vertical incision may be mectomy are the clear advantages seen in the
helpful for women with massive fibroids. The minimally invasive approach. Recurrence risks
fibroid pseudocapsule is injected with an agent to and pregnancy outcomes are comparable after
reduce intraoperative bleeding. A Cochrane resection of myomas from abdominal versus lap-
review found several interventions that reduce aroscopic route [39].
blood loss, including a pericervical tourniquet, Appropriate patient selection is important
vasopressin, gelatin-thrombin mix, tranexamic when considering laparoscopic myomectomy.
acid, and misoprostol, whereas bupivacaine with Optimal candidates have less than four fibroids
epinephrine was less effective, and oxytocin was and fibroid diameters less than 8–10 cm. Skilled
ineffective [48]. The surgeon should use a sys- surgeons may sometimes exceed these arbitrary
tematic approach and remove as many fibroids as limits, although operating time is longer with
possible through a single incision, with careful more extensive procedures [55].
dissection of the fibroid from the surrounding The pregnancy and obstetrical outcomes of
pseudocapsule [1]. Morbidity of abdominal myo- laparoscopic myomectomy are good when opti-
mectomy is comparable to abdominal hysterec- mal surgical techniques are used to perform the
tomy [49]. procedure. The importance of gentle dissec-
Long-term abdominal myomectomy outcomes tion of the fibroid from the pseudocapsule, with
are usually good and patient satisfaction is high preservation of the pseudocapsule, has been
[50, 51], but adhesions or recurrent fibroids may demonstrated, as 74 % of infertile women who
10 Uterine Fibroids 127
Fig. 10.7 Large fibroid demonstrated during laparoscopy Fig. 10.8 Incision into the same fibroid showing degen-
with prominent vessels erative changes and liquefaction during laparoscopic
myomectomy
MRgFUS
increasing evidence that fertility and preg- leiomyomas. J Minim Invasive Gynecol. 2012;19:
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Endometrial Polyps
11
Silvina M. Bocca
a b
c d
Fig. 11.1 Endometrial polyps. A single polyp located in (b). Multiple polyps and submucosal fibroids (by
a lateral wall at midcorpus, shown in two dimensional Pathology) shown by 2D US (c) and by 3D US (d)
transvaginal ultrasonographic view (a) and in 3D imaging
a b
Fig. 11.2 (a) Sessile polyps (arrow) shown in a transverse 2D view of the uterus distended by saline infusion.
(b) Coronal view (3D) of the uterus showing a pedunculated polyp (arrow)
11 Endometrial Polyps 135
a b c
Fig. 11.3 Large polyp (arrows) occupying the entire fundal area shown in a sagittal 2D view (a), in an HSG view (b)
giving a globular appearance of the uterus, and in a hysteroscopic view (c)
a b
c d
Fig. 11.4 Cornual polyps (arrows) clearly seen in HSG (a) and hysteroscopy (b, c) but not visualized in 2D US (d)
10 mg daily for 3–6 months, a levonorgestrel- The great majority of endometrial polyps are
releasing device), and another option is endo- benign, but malignancy occurs in some women.
metrial ablation for women who have completed A systematic review of 17 observational studies
their childbearing. including over 10,000 women reported that the
136 S.M. Bocca
a1 b1 c1 d
c2
a2 b2
c3
Fig. 11.6 Examples of different endometrial pathologies hysteroscopy); (c) retained products of conception (c1
presenting as endometrial thickening in TVUS. (a) HSG, c2 3D US, c3 3D SIS); (d) trophoblastic disease
Endometrial polyp (a1 2D US, a2 3D SIS); (b) complex (multivessel signal)
hyperplasia without atypia (b1 2D US, b2 flat lesions in
typically appears as a hyperechoic lesion with (Fig. 11.6), or submucosal leiomyoma (Fig. 11.1)
regular contours within the uterine lumen sur- [21]. If structural abnormalities are suspected on
rounded by a thin hyperechoic halo [24], occa- ultrasound examination, then these abnormali-
sionally cystic spaces corresponding to dilated ties can be further evaluated by saline infusion
glands filled with proteinaceous fluid may be sonography or hysteroscopy. In a retrospective
seen within the polyp [25], or the polyp may review of multiple studies, Salim and his group
appear as a nonspecific endometrial thickening or [23] report that for TVUS the sensitivity var-
focal mass within the endometrial cavity [26]. ies between 19 and 96 %, specificity of 53 and
None of these findings can reliably distinguish 100 %, positive predictive value (PPV) of 75 and
among polyps, submucous fibroids, adenomyo- 100 %, and negative predictive value (NPV) of
sis, and neoplastic change. 87 and 97 %, when compared with hysteroscopy
In premenopausal women, the TVUS exami- with guided biopsy. The ranges were tighter in
nation should be performed early in the prolifera- a single-large prospective study evaluating the
tive phase when the endometrium is at its thinnest causes of menorrhagia: 86 % sensitivity, 94 %
(4–8 mm) [27, 28] to minimize false-positive and specificity, 91 % PPV, and 90 % NPV [32].
negative findings [29]. Endometrial thickness There are limited data to support color-flow or
is associated with risk of endometrial cancer in power Doppler aiding in the differentiation of hyper-
menopausal women but not in premenopausal plasia and malignancy in polyps [33–35]. Color-
women [30, 31]. Endometrial thickening flow Doppler scanning identifies a single feeding
(Fig. 11.6) is a nonspecific finding of endome- vessel (Fig. 11.5) [11]. The use of power Doppler
trial hyperplasia as well as other causes such sonography with identification of a single-vessel
as polyp, endometrial cancer, trophoblastic dis- pattern improves diagnostic sensitivity to 89 % and
ease (Fig. 11.6), retained products of conception specificity to 87 % for an endometrial polyp [36], in
138 S.M. Bocca
Fig. 11.7 3D-rendered view of the uterus during sonohysterography. The arrow points to an endometrial polyp in the
left midcorpus
comparison to the multivessel (Fig. 11.6) or scat- outlined by fluid [26]. Differentiating endome-
tered pattern seen in malignant lesions or endome- trial polyps from submucosal fibroids can be dif-
trial hyperplasia [34]. At this time, sonographic ficult (Fig. 11.1), but examination of lesion
examination either with or without color-flow or echotexture and identification of overlying echo-
power Doppler sonography is not a substitute for genic endometrium are useful features to distin-
pathologic evaluation after surgical removal. guish the two [39]. SIS has relatively minor
disadvantages: it cannot provide definitive diag-
nosis of endometrial disease [40], a longer learn-
Sonohysterography ing curve compared with non-contrast TVUS
[41], and patient discomfort caused by fluid leak-
The use of saline infusion sonography (SIS), age or pain with the use of a balloon catheter
sonohysterography, or hydrosonogram involves [42]. Bingol et al. [43] selected a total of 346
injection of sterile saline into the endometrial patients for operative hysteroscopy, following
cavity followed by a transvaginal ultrasound SIS after TVUS. SIS seems to be superior to
examination (Figs. 11.2 and 11.7). This tech- TVS, for uterine pathologies, with respect to hys-
nique increases sonographic contrast of the endo- teroscopy as the gold standard.
metrial cavity, enabling delineation of the size, Kamel et al. [44] reported on 106 women with
number, and location of polyps that could have menometrorrhagia where sonohysterography
been missed on gray-scale TVUS, and is likely to was significantly more accurate than ultrasound
improve diagnostic accuracy [37, 38]. With SIS, alone in making a diagnosis, with a higher sensi-
polyps appear as echogenic, smooth, intracavi- tivity (93 % versus 65 %) and specificity (94 %
tary masses with either broad bases or thin stalks versus 76 %) than transvaginal ultrasonography.
11 Endometrial Polyps 139
a1 b1 b2 b3
a2
c1 c2
Fig. 11.8 Intrauterine lesions that may not be easily coronal view of the uterus. (b2) Thin, though multiple,
detected by TVUS. (a1) Apparently normal 2D sagittal bands of synechiae seen on 3D SIS and hysteroscopy
view of the uterus. (a2) Same uterus as in (a1), containing (b3). (c1) Synechiae not clearly visualized on 3D-SIS but
flat hyperemic lesions visualized directly by hysteroscopy more clearly identified upon evaluation of the multiplanar
(benign polyp on Pathology). (b1) Apparently normal 3D views (c2) of the uterus
a b
Fig. 11.9 Nonspecific endometrial US findings. An area of endometrial constrictions is shown by 2D US (a), by 3D
SIS (b), and by HSG (c). Arrows point to the area of narrowing representing synechiae
a1 b1 c
a2 d
b2
Fig. 11.10 Transient endometrial changes detected as blood flow in the hyperechoic mucus accumulation (b2).
morphological anomalies by US. Endometrial clots and Monoloculated (c) and multiloculated (d) cystic lesions
fluid seen on menstrual day 4 (a1) that spontaneously dis- observed by 3D US a few weeks after hysteroscopy that
appeared 1 day later (a2). (b1) Endometrial mucus seen spontaneously resolved within 2 months post op
during ovarian stimulation for IVF. Notice lack of internal
142 S.M. Bocca
a1 a2
Fig. 11.11 Artifacts created during SIS giving the false a 2D sagittal view (a1) and in a 3D coronal view (a2). Air
impression of intracavitary pathology. Endometrial tun- bubbles injected during SIS may resemble trophoblastic
neling created by the catheter used resembling a polyp in disease (b, 3D coronal view)
indicated when a uterine abnormality is found In a retrospective study from 2000 to 2005,
[57]. However, surgical correction should be Stamatellos et al. [73] reported on 83 subjects
considered when a submucous fibroid, endome- with endometrial polyps and no other cause for
trial polyp, septate uterus, or uterine synechiae their infertility subjected to hysteroscopic polyp-
are discovered in the setting of failure to conceive ectomy. The mean size of the endometrial polyps
or recurrent pregnancy loss, since there may be a was 1.9 +/− 1.4 cm. Following polypectomy,
causal association. menstrual pattern was normalized in 91.6 % of
Normal endometrial thickness, structure, and patients. Spontaneous pregnancy and delivery at
texture are crucial for uterine receptivity, and any term rates, in the total population of the study,
structural pathology in the uterine cavity may increased after the procedure and were 61.4 and
lead to subfertility or implantation failure [58]. 54.2 % respectively. There was no statistical dif-
Doldi et al. [59] reported endometrial polyps to ference in fertility rates between patients having
be the most common of the intrauterine lesions polyps ≤1 cm and patients having >1 cm polyps
interfering with the endometrial cavity. The exact or multiple polyps. Spontaneous abortion rate in
mechanism by which endometrial polyps cause the first trimester of pregnancy was 6 %, and
infertility is not known, but some proposed mech- there was no statistical difference between
anisms are induction of an inflammatory process patients with small or bigger/multiple polyps.
similar to an intrauterine device [60], mechanical They concluded that hysteroscopic polypectomy
interference with sperm and embryo transport, appeared to improve fertility and increase preg-
impairment of embryo implantation, or altered nancy rates in previous infertile women with no
endometrial receptivity such as abnormalities other reason to explain their infertility, irrespec-
in the expression of molecular markers such as tive of the size or number of the polyps.
HOXA 10 and HOXA 11 [61]. Regardless of the
mechanism of endometrial disturbance, uterine
polyps have been associated with decreased preg- Polyps and Assisted Reproductive
nancy rates both in natural conceptions [62–64] Technology
and in intrauterine insemination (IUI) cycles [65].
There are no data from randomized trials to Most of the data for polypectomy in subfertile
guide therapy of asymptomatic polyps, unless patients suggests that removal improves fertility,
there are risks for hyperplasia or carcinoma. For with reported pregnancy rates varying between
symptomatic patients, polypectomy results in the 43 and 90 % [23, 62, 68, 74]. Perez-Medina et al.
improvement of symptoms in 75 % of patients in [65] reported that both spontaneous pregnancy
studies with follow-up intervals of 2–52 months rates and those associated with assisted repro-
[66]. Lieng et al. [67] reported on 150 women ductive technology increased after polypectomy.
in a randomized clinical trial with an endome- Polyps were detected in 452 of 2,800 (16.1 %)
trial polyp allocated to hysteroscopic removal or consecutive patients scheduled for IUI, and after
observation. Although there was no improvement hysteroscopic removal of endometrial polyps,
in the volume of menstrual loss, a significant there was a 63 % cumulative pregnancy rate com-
improvement in other symptoms such as inter- pared with 28 % in the control group (relative risk
menstrual bleeding was significantly improved (RR) 2.3, 95 % confidence interval (CI) 1.6–3.2).
by removal at follow-up. Hysteroscopically Interestingly, 65 % of all pregnancies in the polyp-
guided polypectomy (with grasping forceps, ectomy group occurred before the first IUI cycle
suction curette, microscissors, a small electro- was started, resulting in a spontaneous pregnancy
surgical look, i.e., resectoscope, mechanical mor- rate of 29 % in the polypectomy group versus
cellation, or a bipolar electric probe [68–70]) is 3 % in the control group (RR 10, 95 % CI 3–30).
the most effective method of removal since small The pregnancy rate after surgery at the uterotubal
polyps and other structural abnormalities can be junction was significantly higher than that of
missed by blind curettage [68, 71, 72]. other locations [75]. Increased cumulative preg-
144 S.M. Bocca
nancy rates (76 % pregnancy rate in 1 year among [74] suggested that restoration of fertility was not
25 infertile patients) after hysteroscopic polypec- dependent on the size of lesion removed or that
tomy were also reported by Spiewankiewicz et al. there was no significant difference in the repro-
[74] and by Varasteh et al. [63] (78 % cumula- ductive outcome for patients with polyps ≤2.5 or
tive pregnancy rate after hysteroscopic polyp- >2.5 cm [68]. Even though Lass et al. [56] and
ectomy in cases of female infertility). Doubling Check et al. [83] reported no effect of endome-
of the pregnancy rates was reported by Bosteels trial polyps <2 cm discovered before or during
et al. [76] in a systematic review of the litera- IVF/ICSI on implantation rates, they also noted
ture for patients undergoing IUI who had hys- an increase, but not statistically significant, in
teroscopic removal of endometrial polyps with a miscarriage rates, making the recommendations
mean diameter of 16 mm detected by ultrasound for hysterosocpic polypectomy immediately fol-
when compared with diagnostic hysteroscopy and lowing oocyte retrieval and freezing all embryos
polyp biopsy (RR 2.3, 95 % CI 1.6–3.2). Given for embryo transfer in a subsequent cycle.
these data and additional evidence that cavitary Bulent Tiras’ group [58] presented probably
distortion by submucosal and possibly intramural the largest retrospective study on the impact of
fibroids decreases successful pregnancies, most endometrial polyps on pregnancy rates in 8,359
practitioners routinely remove polyps prior to an ICSI patients. The study included all fresh ICSI
IVF cycle. cycles performed in the Anatolia IVF Center
The appearance of polyps before or during IVF between 2005 and 2009. All patients diagnosed
or intracytoplasmic sperm injection (ICSI) cycles with an endometrial polyp by TVUS before the
is a very challenging situation, and the diversity ICSI cycle underwent hysteroscopic polyp resec-
of management options can be confusing: (1) tion. Localization of the polyp (upper, middle, or
cycle cancelation and polypectomy; (2) embryo lower third of the uterine cavity) or polyp size
freezing, removal of the endometrial polyp, and (4–14 mm) did not seem to affect pregnancy
embryo transfer after a few months; (3) ignoring rates. They concluded that endometrial polyps
the polyp and continuing treatment; and lastly, (4) <1.4 cm found during ovarian stimulation did not
hysteroscopic polypectomy during the IVF/ICSI affect pregnancy rates, miscarriage rates, and live
cycle before oocyte retrieval without cycle can- birth rates in ICSI cycles and that patients with
celation [77, 78]. There is lack of good evidence an endometrial polyp detected before ICSI treat-
on the impact of subtle intrauterine pathologies ment and resected by hysteroscopy had similar
on IVF outcome [79]. Hysteroscopic removal of pregnancy rates compared with patients with no
endometrial polyps appears to improve sponta- endometrial polyps.
neous pregnancy rates in women with otherwise However, the observation from non-controlled
unexplained infertility [63, 73, 80]. However, no trials that pregnancy rates are higher after
statistical difference in spontaneous fertility rates removal of tubocornual polyps than after removal
has been noted between patients undergoing hys- of polyps situated in other intrauterine locations
teroscopic removal of polyps <1 cm in diameter suggests that tubocornual polyps may have a dif-
and >1 cm in diameter or multiple polyps [72]. ferent effect on reproductive function regardless
In a recent study, excision of polyps located at of their size [75, 80, 84]. Besides, polyps in the
the uterotubal junction (Fig. 11.4) [65] was asso- istmocervical part of the uterus may preferen-
ciated with a significantly higher pregnancy rate tially interfere with sperm transport. These two
compared with localization to posterior, anterior, different mechanisms could explain the differ-
or lateral uterine walls [75]. ences in conception rates after hysteroscopic
There is conflict surrounding the size of polyp removal of polyps in different locations.
needed to be removed to achieve an improve- Recently, two studies suggested that hystero-
ment in ART. Some authors [56, 81, 82] reported scopic polypectomy before oocyte retrieval with-
that removal of polyps <2 cm has no impact on out cycle cancelation in IVF cycles might be
the outcome of fertility treatment, while others possible [77, 78]. Madani et al. [78] reported on
11 Endometrial Polyps 145
nine patients who were diagnosed with endome- In a prospective observational study, hystero-
trial polyps <1.5 cm by TVUS while undergoing scopic findings in 55 patients undergoing IVF
ART cycles and who underwent hysteroscopic who repeatedly failed to conceive despite trans-
polypectomy during ovarian stimulation in the fer of two good quality embryos were assessed
standard treatment cycles. The interval between [90]. All patients had a normal uterine cavity on
polyp resection and embryo transfer was 2–16 HSG performed within 1 year. In 25 patients
days. Four patients achieved pregnancy (two (45 %) an abnormality was noted at hysteros-
twins, two singletons), four patients were unsuc- copy: polyps (n = 10), endometritis (n = 7), adhe-
cessful, and one pregnancy was a blighted ovum. sions (n = 6), and submucous fibroid (n = 2).
Their trial proposes that hysteroscopic polypec- Significantly higher pregnancy (50 % versus
tomy during ovarian stimulation may be a harm- 20 %) and implantation (19 % versus 6 %) rates
less procedure. However, their series is too small were obtained after hysteroscopic surgical cor-
to be conclusive, with nine patients in one study rection of the abnormality.
and six patients in the other. The role of hysteroscopy in RIF was
Hysteroscopic polypectomy just before assessed in two randomized controlled trials
embryo transfer should be evaluated in detail, as [91, 92]. A total of 421 patients with normal
recent studies fail to prove any deleterious effect HSGs, who had two or more failed IVF cycles,
of endometrial polyps <1.5 cm on pregnancy were prospectively randomized to no-office
rates and pregnancy outcomes in ICSI cycles. In hysteroscopy (Group I) and office hysteros-
conclusion, further studies are required to iden- copy (Group II). Office hysteroscopy was nor-
tify the most appropriate management of endo- mal in 73 % of patients (Group IIa). An
metrial polyps found during IVF stimulation. abnormality was noted at hysteroscopy in 27 %
of patients (Group IIb), including endometrial
polyps (n = 33), filmy and mild adhesions
Intrauterine Lesions in Patients (n = 18), and cervical adhesions (n = 5). All
with Recurrent Implantation Failure intrauterine pathologies were corrected at the
time of hysteroscopy. After correction of uter-
Bozdag [85] emphasizes that recurrent implanta- ine anomaly, the clinical pregnancy rates sig-
tion failure (RIF) may be due to unrecognized nificantly increased (22 % for Group I, 33 %
uterine pathology which varies, based on hys- for Group IIa, and 30 % for Group IIb) with
teroscopic findings, between 18 and 50 % and 40 similar miscarriage rates in all groups.
and 43 % in patients undergoing IVF with or In summary, due to the high incidence of
without RIF, respectively, and that endometrial pathologic findings in infertile patients and the
polyps may be associated with increased miscar- improvement in pregnancy rates after treatment,
riage rate [86–92]. it seems prudent to perform a diagnostic hyster-
Doldi et al. [59] found 40 % of 300 patients oscopy before the first IVF-ET in all patients,
scheduled to undergo IVF, with normal HSG thereby reducing the failures and then the cost of
within the previous year and normal US within IVF.
the previous 2 months, had subtle intracavitary
uterine pathologies: endometrial polyps in 78 Conclusion
(65 %), endometrial hyperplasia in 20 (17 %), Endometrial polyps are a common gyneco-
endometrial hypotrophia in 16 (13 %), and others logic disease that increases with age and are
(endometritis, adhesions) in 6 (5 %). In another rarely associated with malignancy. They are
study, despite normal HSG, an abnormality found in 10 % of women with abnormal uter-
was also noted in 43 % (12/28) of the patients ine bleeding, in 36 % of women taking tamox-
at hysteroscopy before IVF [93] including small ifen, and in up to 50 % of women with
uterine septa, small submucous fibroids, uterine recurrent implantation failure despite normal
hypoplasia, and cervical ridges. screening with TVUS and HSG.
146 S.M. Bocca
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Intrauterine Adhesions
12
Gautam N. Allahbadia
Causes
G.N. Allahbadia, MD, DNB, FNAMS
Rotunda-The Center for Human Reproduction,
Intrauterine adhesions or synechiae evolve after
36 Turner Road, 201 Second Floor, B Wing,
Bandra (W), Mumbai, Maharashtra 4400 050, India trauma to the endometrium from surgical proce-
e-mail: drallah@gmail.com dures usually secondary to curettage of a recently
pregnant uterus in the context of missed abortion open ostia. On laparoscopy performed on 18
or pregnancy-related hemorrhage [1–3], follow- women, there were varying grades of adhesions
ing hysteroscopic myomectomy (10 %) and trans- in 16 (88.8 %) women, with beading (33.3 %),
mural myomectomies, especially when combined tubercles (33.3 %), caseation (11.1 %), and tubo-
with uterine ischemia [9]. Previous curettage on a ovarian masses (11.1 %) [13].
gravid uterus has been reported as the possible
cause of Asherman’s syndrome in the majority
(64 %) of patients [10]. In a prospective, random- Risk Factors
ized, controlled trial in 82 women, Tam et al. [11]
reported that conservative management and medi- In women with menstrual disorders, a statisti-
cal evacuation for spontaneous abortion are both cally significant 12-fold increased risk for
acceptable alternatives to standard surgical evacu- Asherman’s syndrome grades I–IV was found,
ation, which resulted in a prevalence of 7.7 % previous abortion, as well as infection during sur-
filmy IUA at hysteroscopic diagnosis of IUA, 6 gery being associated with a mildly but nonsig-
months after initial treatment [11]. nificant increased risk [6]. Myomectomy for
Dawood et al. [12] evaluated the predisposing multiple, apposing fibroids is reported to have a
factors and treatment outcomes of different stages higher incidence of IUA [9]. Uterine arteries
of intrauterine adhesions over a 7-year period in embolization also carries a risk of intracavitary
65 patients. They identified stage I intrauterine adhesions. Poujade et al. [14] reported a signifi-
adhesions in 36.9 %, stage II in 46.2 %, and stage cant risk of uterine synechiae after placement of
III in 16.9 % of patients, the main reasons for uterine compression sutures [(Hackethal tech-
referral being infertility (stage I 75 %, stage II nique) that transverse the uterine cavity for con-
73.3 %, stage III 27.3 %) and amenorrhea (stage I trolling postpartum hemorrhage (PPH)], with the
25 %, stage II 23.3 %, stage III 72.7 %). The main development of uterine synechiae on explorative
predisposing factor was dilatation and curettage, hysteroscopy or HSG in 26.7 % of women [14].
with 40 patients reporting IUA related to early
pregnancy curettage; 45 % had stage I adhesions,
42.5 % had stage II, and 12.5 % had stage III in Effects
contrast with 10 patients who had peripartum
curettage, in whom 60 % developed stage III In addition to abnormal menses, infertility and
adhesions (p = 0.004) [12]. recurrent spontaneous abortion are common com-
Genital tuberculosis has been reported as an plaints of IUA, and the accompanying retrograde
important and common cause of Asherman’s syn- menstruation may lead to endometriosis [2, 15].
drome in India, causing oligomenorrhea or amen- Adhesions are a significant source of impaired
orrhoea with infertility. Sharma et al. [13] studied organ functioning, decreased fertility, bowel
28 women with positive evidence of genital obstruction, difficult reoperation, and possibly,
tuberculosis on endometrial biopsy (histopathol- pain with consequent financial sequelae [16].
ogy or culture) or positive polymerase chain
reaction (PCR) on endometrial aspirate or posi-
tive findings of tuberculosis on laparoscopy or Diagnosis
hysteroscopy who underwent hysteroscopy with
or without laparoscopy for suspected Asherman’s History and a high index of suspicion contribute
syndrome. They reported various grades of adhe- significantly to the diagnosis of IUA. Several con-
sions (grade I in 17.8 %, grade II in 28.5 %, grade firmatory tests, such as hysteroscopy, ultrasound-
III in 28.5 %, and grade IV in 17.5 %) at hyster- guided techniques-3D hysterosonography (3D
oscopy in all women, bilateral (28.5 %) or unilat- HS), 2-dimensional (2D) and 3-dimensional
eral (21.3 %) blocked ostia, or inability to see the (3D) transvaginal ultrasonography (TVS), hydro-
ostia (28.5 %). Only four women (14.3 %) had sonography, minimal invasive saline contrast
12 Intrauterine Adhesions 153
hysterosonography (SCHS), saline infusion hys- HSG and/or TVS and especially in patients with
terography (SIS), sonohysterosalpingography], prior failed ART cycles who reported a signifi-
radiographic techniques [hysterosalpingography cantly higher incidence of abnormal hystero-
(HSG)], and rarely magnetic resonance imag- scopic findings. The procedure was acceptable in
ing have been used for the diagnosis of IUA. almost all patients with no reported complica-
However, hysteroscopy has been documented as tions [18].
the gold standard for the diagnosis and treatment Fedele et al. [19] performed transvaginal US
of IUA, and the several comparative studies eval- before hysteroscopy as part of the routine diag-
uating these techniques have used hysteroscopy nostic workup in 77 women who had repeated
as the reference standard to evaluate the effi- spontaneous abortions. They were able to cor-
ciency of a particular technique against the other. rectly identify uterine adhesions (minimal in ten
Hysteroscopy may be recommended in patients instances and moderate in one) with TVS in
who develop menstrual disorders, either after 90.0 % (10/11) of the women in whom this find-
secondary intervention for placental remnants ing was subsequently confirmed at hysteroscopy.
after delivery or after a repeat curettage [6]. The sensitivity, specificity, PPV, and NPV of
transvaginal US were 91, 100, 100, and 98.5 %,
respectively. Hysteroscopic findings were con-
The Role of Ultrasound sidered the reference. They concluded that TVS,
in the Diagnosis which is a noninvasive and relatively inexpen-
sive procedure, seems to be effective in screening
Several ultrasound techniques, such as trans- for uterine adhesions in a population at risk [19].
vaginal color Doppler sonography (TCDS), Narayan and Goswamy [20] correlated pre-
sonohysterosalpingography (SHSG), and three- operative TVS (performed on days 7, 14, and
dimensional sonography (3DS), are capable of 21 in spontaneous ovulatory cycles) with hys-
providing diagnostic information that, in some teroscopic findings (performed in the subsequent
cases, is equivalent to the information afforded cycle) in 200 patients being investigated for
by established techniques that require exposure infertility. A total of 182 patients were diagnosed
to radiation, such as hysterosalpingography correctly to have an abnormality by TVS giving
(HSG), or that are more invasive, such as hys- a false-positive rate of 5.5 %. The sensitivity and
teroscopy or diagnostic laparoscopy [17], tissue PPV of TVS in detecting endometrial pathol-
biopsies, and dilation and curettage (D&C). The ogy were 98.9 and 94.3 %, respectively, with a
role of ultrasonography for the diagnosis of IUA PPV of 98.5 % for the detection of intrauterine
has been studied by several authors with mixed adhesions and a strong correlation between find-
opinions, and all these studies used hysteroscopy ings from transvaginal sonography and hysteros-
as the most reliable reference standard. copy. The authors concluded that TVS may be
El-Mazny et al. [18] reported abnormal hys- used to detect intrauterine pathology and iden-
teroscopic findings, including IUA, in 33.1 % of tify patients in whom hysteroscopy and hystero-
patients with reported normal uterine findings on scopic surgery are indicated [20]. With further
HSG who were scheduled for assisted reproduc- advance in ultrasound technology, Knopman and
tive techniques (ART) [in vitro fertilization Copperman [21] assessed the value of 3-dimen-
(IVF)/intracytoplasmic sperm injection (ICSI)] sional (3D) ultrasound in the management of
investigations [1]. patients with suspected Asherman’s syndrome
Transvaginal sonography (TVS) has been in a case series of 54 infertile patients who pre-
reported to be specific (100 %), but not sensitive sented with suspected Asherman’s syndrome.
(41.7 %) compared with outpatient hysteroscopy, Intrauterine adhesions (IUAs) were demonstrated
which leads the authors to suggest that outpatient on 3D ultrasound and HSG in all cases and con-
hysteroscopy should be part of the infertility firmed by hysteroscopy. They reported 100 %
workup before ART even in patients with normal sensitivity with 3D ultrasound for correctly
154 G.N. Allahbadia
grading the extent of IUAs compared to only and enables examination of endometrial lesions
66.7 % for HSG. In 61.1 % of cases in which with a sensitivity and specificity of 83 and 99 %,
HSG results were inconsistent with hysteroscopy, respectively and a diagnostic precision similar to
lower uterine segment outflow obstruction was the results achieved by hysteroscopy [26].
present, and HSG misclassified findings as severe In a prospective study on 65 infertile women 19
Asherman’s with complete cavity obstruction. to 43 years of age, Soares et al. [27] compared the
With a postoperative conception rate of 90 %, the diagnostic accuracy of sonohysterography (SHG)
authors concluded that 3D ultrasound provides a in uterine cavity diseases in infertile patients with
more accurate depiction of adhesions and extent that of HSG and TVS, using hysteroscopy as the
of cavity damage than HSG in patients with sus- gold standard. Sonohysterography and HSG had
pected Asherman’s syndrome, particularly when a sensitivity of 75 % in the detection of intrauter-
differentiating severe IUAs from lower uterine ine adhesions and respective PPVs of 42.9 and
segment outflow obstruction. Therefore, grading 50 %, while TVS showed a sensitivity and PPV
systems utilizing HSG to classify severity of dis- of 0 % for this diagnosis. The authors concluded
ease should be revised to include 3D ultrasound that, while sonohysterography was in general the
findings [21]. most accurate test with a markedly superior diag-
Sonohysterography, a simple ultrasound nostic accuracy for polypoid lesions and endo-
(US) procedure technique, involves placement metrial hyperplasia (EH), with total agreement
of a 5-F catheter into the endometrial canal with with the gold standard, however, in diagnosis of
subsequent instillation of sterile saline solu- intrauterine adhesions, SHG had limited accu-
tion under US guidance. Saline infusion offers racy, similar to that obtained by HSG, with a high
a good contrast, enabling improved visualiza- false-positive diagnosis rate [27]. Makris et al.
tion and distinction between diffuse and focal [28] compared 3D hysterosonography (3D HS)
abnormalities. Sonohysterography has been and diagnostic hysteroscopy in 242 women with
shown to be a safe, simple, and cost-effective abnormal uterine bleeding. They reported a simi-
outpatient method for evaluating the potentially lar specificity (99.4 %), but a higher sensitivity
abnormal endometrium using transvaginal ultra- for hysteroscopy compared to 3D HS (98.7 % vs.
sound (US) in an outpatient setting and to plan 93.5 %, respectively). The PPV and NPV of 3D
the next step in case management [22]. Besides HS were 98.6 and 97 %, respectively, compared
the cost-related issues, it has been indicated as to 98.7 and 99.4 % for hysteroscopy, respectively.
a well-tolerated technique with a short learn- The two techniques were in agreement for eight
ing curve in the diagnosis of abnormal uterine cases of adhesions and in 165 cases of normal
bleeding (premenopausal and postmenopausal), endometrium [28].
bleeding while using tamoxifen, suspected con- de Kroon et al. [23] evaluated the accuracy of
genital uterine abnormality, and Asherman’s syn- minimal invasive saline contrast hysterosonogra-
drome [23]. According to Badu-Peprah et al. [24] phy (SCHS) in the diagnosis of uterine pathology.
sonohysterography is an affordable and feasible They reported that this technique can detect intra-
diagnostic modality in developing nations for cavity abnormalities (with a prevalence of 54 %)
evaluating the endometrial cavity that should be with a sensitivity, specificity, PPV, and NPV of 94,
used more often where equipment and skill per- 89, 91, and 92 %, respectively, and in combination
mit [24], thereby obviating the need for laparos- with endometrial sampling, whenever indicated, it
copy and hysteroscopy in the majority of cases might be able to replace diagnostic hysteroscopy
[25]. In a very recent study, Kowalczyk et al. as the gold standard in the evaluation of the uterine
[26] reported real-time 3D sonohysterography cavity in 84 % of the diagnostic hysteroscopies as
(SIS 3D) to be a minimally invasive advance to SCHS is two to nine times cheaper than diagnostic
conventional 2D sonohysterography (sensitiv- hysteroscopy. However, SCHS fails more fre-
ity 72 % and specificity 96 %) that enables a quently in postmenopausal women than premeno-
three-dimensional image of the uterine cavity pausal women (12.5 % vs. 4.7 %; p = 0.03), and the
12 Intrauterine Adhesions 155
Management of IUA
and its precise localization and control endocavi- sharp dissection [32, 34]. Various techniques for
tary surgeries such as hysteroscopic adhesiolysis adhesiolysis and for prevention of scar reforma-
for uterine synechiae [35]. Though sonohysterog- tion have been advocated. According to March,
raphy and hysterosalpingography are useful as [2] the use of miniature scissors for adhesioly-
screening tests of intrauterine adhesions [15], sis and the placement of a balloon stent inside
hysteroscopy has been considered the mainstay the uterus immediately after surgery appear to
of diagnosis, classification, and treatment of the be the most efficacious [2]. Patients with more
intrauterine adhesions, with medical treatments severe adhesions, in whom the uterine fundus is
having no role in management [1, 2, 4, 15, 32, 36]. completely obscured, and those with a greatly
Diagnostic and therapeutic hysteroscopy is a sim- narrowed fibrotic cavity present the greatest
ple, feasible, safe, reproducible, effective, quick, therapeutic challenge. Several techniques have
well-tolerated, and low-cost surgical procedure been described for these difficult cases, but the
that is highly successful in an outpatient setting, outcome is far worse than in patients with mild,
offering a see-and-treat approach in majority of endometrial-type adhesions [4, 34]. A signifi-
the subjects with intrauterine adhesions [37, 38]. cantly obliterated cavity may require multiple
Hysteroscopy has also become accepted as the hysteroscopic adhesiolysis to achieve a satisfac-
optimum route of surgery, the aim being to restore tory anatomical and functional result [15, 36],
the size and shape of the uterine cavity, normal while laparoscopic or ultrasound guidance may
endometrial function, and fertility [15, 16]. Lysis aid in the hysteroscopic lysis of dense scar tissue
of intrauterine adhesions, for the treatment of and difficult entry into the cervix [1].
infertility and recurrent pregnancy loss, results in
improved fecundability and decreased pregnancy
loss. Though adhesiolysis for pain relief appears Treatment Outcome
efficacious in certain subsets of women, unfortu-
nately, even when lysed, adhesions have a great Treatment outcomes are difficult to assess as
propensity to reform [16]. According to Bettocchi there is no universally agreed upon classification
et al. [38] there is no consensus on the effective- system [1]. Anatomic, but most of all functional
ness of hysteroscopic surgery in improving the prognosis, is directly correlated to the severity of
prognosis of subfertile women. However, office adhesions, and the number of surgical procedures
hysteroscopy is a powerful tool for the diagno- required to complete treatment [40].
sis, and treatment of intrauterine benign patholo- Restoration of menstruation is highly success-
gies and in patients with at least two failed cycles ful (more than 90 %), and pregnancy rates around
of assisted reproductive technology, diagnostic 50–60 % with live birth rates around 40–50 % can
hysteroscopy and, if necessary, operative hys- be achieved [32]. The risk of complications for
teroscopy is mandatory to improve reproductive those that achieve pregnancy is significant with
outcome [38]. A descriptive study (Canadian Task a significant risk for placenta accreta and subse-
Force classification II-2) concluded that hystero- quent blood loss, transfusion, and hysterectomy
scopic adhesiolysis is an effective and safe option [12]. In perhaps the largest study, involving 6,680
even for postmenopausal women with intrauterine hysteroscopies with hysteroscopic adhesiolysis
lesions adhesions on hysteroscopy or ultrasound. in 75 patients, 94.6 % functional restoration and
It allows the correct diagnosis to be made, reduces 93.3 % anatomic resolution, with pregnancy rates
the need for major and unnecessary surgery, and ranging from 28.7 to 53.6 %, were achieved. At
is therapeutic in most patients [39]. 2-month follow-up, the uterine cavity was com-
Treatment can range from simple cervical pletely regular in 70 cases, while in four cases,
dilatation in the case of cervical stenosis, but an a second surgical treatment was necessary [41].
intact uterine cavity, to extensive adhesiolysis of Using a standard technique with a loop elec-
dense intrauterine adhesions using scissors, elec- trode and glycine 1.5 % as distension medium,
tro- or laser energy, or a combination of blunt and Dawood et al. [12] reported an improvement in
12 Intrauterine Adhesions 157
the rate of amenorrhea from 32.3 % before adhe- Roy et al. [10] reported an overall conception
siolysis to 9.2 % after the procedure with an over- rate of 40.4 %, live birth rate of 86.1 % and a mis-
all pregnancy rate of 51.2 % and the live birth rate carriage rate of 11.1 % in a mean conception time
32.6 % among women who wished to conceive. after surgery of 12.8 months following hystero-
Severe intrauterine adhesions were managed scopic adhesiolysis with the monopolar electrode
with the assistance of abdominal ultrasound to knife in 89 infertile patients with Asherman’s syn-
ensure that the uterine cavity was not breached, drome. The cumulative pregnancy rate showed
and the rates of pregnancy and term pregnancy that 97.2 % of patients conceived within 24
among this selected group of women were simi- months. The conception rate was higher (58 %)
lar regardless of the severity of adhesions [12]. in mild Asherman’s syndrome compared to 30 %
Yu et al. [42] evaluated the outcome of hys- conception rate in moderate and 33.3 % concep-
teroscopic adhesiolysis with electrode needle tion rate in severe cases. There was a significantly
or loop under direct vision in 85 women with higher likelihood of conception (44.3 %) in those
Asherman’s syndrome who presented with a his- who continued to have improved menstrual pattern
tory of infertility or recurrent pregnancy loss. compared to only 10 % likelihood of conception
After hysteroscopic adhesiolysis, the chances in those who continued to have amenorrhea after
of conception among the 18.2 % of women who adhesiolysis. A second-look office hysteroscopy,
remained amenorrheic were significantly lower performed after 2 months, showed reformation of
than those who continued to have menses (50 %). adhesions in12 patients that needed a repeat adhe-
The conception rate in women who had reforma- siolysis with no conception in these patients. The
tion of intrauterine adhesions at second look hys- authors concluded that hysteroscopic adhesiolysis
teroscopy (11.8 %) was significantly lower than for Asherman’s syndrome is a safe and effective
that of women who had a normal cavity (59.1 %), method of choice for restoring menstrual function
suggesting that the outcome of hysteroscopic and fertility [10].
adhesiolysis for Asherman’s syndrome is sig- Shokeir et al. [45] attempted to analyze the
nificantly affected by recurrence of intrauterine adhesion grade in multiple hysteroscopic-guided
adhesions [42]. biopsies from IUA following the initial hystero-
Hysteroscopic adhesiolysis with monopolar scopic adhesiolysis at a follow-up diagnostic
or bipolar energy can be performed safely and hysteroscopy, performed early (2–4 weeks) after
effectively for severe stage 3 and 4 adhesions the initial operation or late, about 12 months
with a 97 % restoration of menses, 43.8 % PR, (8–16 months). They observed that at follow-
and 32.8 % LBR. The pregnancy rate was signifi- up hysteroscopy, 25 % of both groups had no
cantly higher in patients ≤35 years compared to significant adhesions. Grade I adhesions (thin,
patients older than 35 years (66.6 % vs. 23.5 %, filmy) occurred in 60 % of the early hysteros-
respectively; p = 0.01), suggesting that age is the copy patients and in only 12 % of the late group
main predictive factor of success: the pregnancies (P < 0.05). Grade II adhesions were present in
were at risk of abnormal placentation [43]. The 10 % of the early group and in up to 41 % in the
impact of age on the outcome of hysteroscopic late group (P < 0.05), whereas grade III adhesions
adhesiolysis is in agreement with a previous were present in only 5 % of the early hysteros-
study by Capella-Allouc et al. [44] that reported copy group, but in 22 % of the late one (P < 0.05).
a pregnancy rate of 42.8 %, live birth rate of Correlation between hysteroscopic and his-
32.1 %, the pregnancy rate being much higher tologic findings were good in most of cases in
in patients ≤35 years compared to patients older both groups. The follow-up to determine the
than 35 years (62.5 % vs.16.6 %, respectively; subsequent reproductive outcome revealed simi-
p = 0.01) following hysteroscopic adhesiolysis in lar conception rates in both groups. The authors
31 patients with severe Asherman’s syndrome. suggested that the IUA that might be formed
However, these pregnancies were at risk for hem- immediately following hysteroscopic reproduc-
orrhage with abnormal placentation [44]. tive surgery is histologically different from those
158 G.N. Allahbadia
appearing a longer time after the original opera- ine adhesions with sharp adhesiolysis has been
tion. Routine early follow-up hysteroscopy can suggested as an effective technique for the main-
influence the prognosis resulting from the origi- tenance of cavity patency with an improvement
nal surgery [45]. in menstrual flow in 95 % of the patients, relief of
Having excluded hormonal imbalances, pre- dysmenorrhea in 92 %, 92 % improvement in
mature ovarian failure, and congenital uterine disease staging over the treatment interval, and a
abnormalities Yasmin et al. [46] reported thick pregnancy rate of 46 %. Initially, 50 % had severe
fibrous adhesions in 45 % of patients, flimsy adhesions, 46 % had moderate, and 4 % had min-
adhesions in 40 %, and muscular adhesions in imal disease according to the March criteria [48].
15 % at hysteroscopy, with 65 % adhesions in the Colacurci et al. [49] analyzed the reproduc-
body of uterus, 25 % at the site of internal os, and tive outcome in 53 women undergoing hystero-
1 % had adhesions in the cervical canal as well as scopic lysis of intrauterine adhesions, according
the body of the uterus. Following diagnostic hys- to their localization and severity. Hysteroscopic
teroscopy and resection of adhesions in 20 surgery restored an acceptable menstrual cycle
patients (median age 26 years), presenting with in almost all the patients affected by intrauterine
scanty menses and secondary infertility (65 %), isolated adhesions in 52 % of women with com-
secondary amenorrhoea (20 %), or with primary plex incomplete adhesions, and in none of the
infertility alone (15 %), they reported a restora- patients with an entirely obliterated cavity. In
tion of menses in 95 % of the patients and con- isolated, isthmic, central, or marginal synechiae,
ception in 10 % of the patients. Though the a pregnancy rate of 73.3 % was observed with
patient number was small, the authors suggested a pregnancy rate to term, respectively, of 63.3 %
that hysteroscopy is an effective procedure for and of 86.3 %, while in case of complex but not
not only diagnosing Asherman’s syndrome, but is complete adhesions, the pregnancy rate was 25 %
equally effective for treating it [46]. with only two term pregnancies. There were no
Hysteroscopic adhesiolysis in women with pregnancies in three cases of complex synechiae.
Asherman’s syndrome and poor reproductive per- The authors concluded that the basic parameter
formance (previous spontaneous abortions or a to define the functional and reproductive prog-
premature delivery) contributes significantly to a nosis of the hysteroscopic lysis of intrauterine
successful reproductive outcome. Whereas preg- adhesions is not the menstrual profile or the his-
nancy outcome prior to the hysteroscopic adhe- tological characteristic of the lesions, but rather
siolysis was 18.3 % term deliveries, 3.3 % their extension [49].
premature deliveries, 62.4 % first-trimester abor- Hysteroscopy and hysteroscopic surgery have
tions, and 16.0 % late abortions, after hystero- been the gold standard of diagnosis and treat-
scopic adhesiolysis, the pregnancy outcome was ment, respectively, for patients with Asherman’s
68.6 % term deliveries, 9.3 % premature deliver- syndrome who presented with amenorrhea or
ies, 17.4 % first-trimester abortions, and 4.7 % hypomenorrhea, infertility, or recurrent preg-
late abortions. The operative success rate, mea- nancy loss. However, according to most authors,
sured by delivering a healthy newborn, improved despite the advances in hysteroscopic surgery,
from 18.3 % preoperatively to 64 % postopera- the treatment of moderate to severe Asherman’s
tively in women with two previous unsuccessful syndrome still presents a challenge [40, 50].
pregnancies [47], whereas in women with three or Furthermore, pregnancy after treatment remains
more unsuccessful pregnancies, the success rate high risk with complications including spontane-
improved from 18.3 to 75 %. Successful outcome ous abortion, preterm delivery, intrauterine
of adhesiolysis was observed in 61.9 % of mild growth restriction, placenta accreta or previa, or
(stage I) and in 70.6 % of moderate to severe cases even uterine rupture, that necessitate close ante-
(stages II and III) of intrauterine adhesions [47]. natal surveillance and monitoring for women
Blunt adhesiolysis with a flexible hystero- who conceive after treatment [50]. According to
scope, following primary treatment of intrauter- Piketty et al. [40] despite the infrequent but well-
12 Intrauterine Adhesions 159
known complications during surgery and the less Coccia et al. [53] described a new therapeutic
frequent but often severe obstetrical complica- procedure called pressure lavage under ultrasound
tions, the benefit gained by the recovery of fertil- guidance (PLUG) for selected cases of IUA. This
ity (either spontaneous or not) remains superior technique is based on sonohysterography to mon-
to the risks of the surgical management [40]. itor the effects of intrauterine injections of saline
solution on the continuous accumulation of saline
in the uterine cavity for the mechanical disruption
Role of Ultrasonography of IUA. In an open clinical investigation with no
in the Treatment control group, they reported satisfactory lysis of
adhesions and restoration of menses in 71.4 % of
Serial intrauterine device-guided hystero- the patients with mild IUA with a pregnancy rate
scopic adhesiolysis of intrauterine synechiae, of 66.63 % following the use of the PLUG tech-
especially for early intervention, may prevent nique. A second-look hysteroscopy after 1 month
complications during the treatment of severe showed the persistence of filmy adhesions in two
intrauterine adhesions and may present a secure patients with moderate IUA that were removed
and effective alternative for constructive clinical successfully during hysteroscopy. The authors
outcomes with spontaneous pregnancy rates of suggested that PLUG is a safe and ideal in-office
47.2 and 30 % and live birth rates of 28 and 20 % procedure that allows complete lysis in mild IUA
in patients who did and did not undergo early cases avoiding the need for therapeutic, and pos-
intervention of office hysteroscopy, 1 week after sibly, follow-up hysteroscopy, and may represent
insertion of the IUD at hysteroscopic adhesioly- a useful initial step in moderate IUA cases reduc-
sis, respectively [51]. Following echo-controlled ing the need for operative hysteroscopy [53]. In
hysteroscopic surgical cure of complex and/ a recent study, Taniguchi and Suginami [54] also
or recurrent uterine synechiae in 11 patients, suggested that sonohysterographic (SHG) lysis
Salat-Baroux et al. [35] concluded that intraop- for recurrent adhesions following hysteroscopic
erative echography allowed hysteroscopic adhe- lysis may be a treatment option for recurrent
siolysis of intrauterine adhesions at a controlled adhesions in infertile patients, with improved
and equivalent distance from the uterine walls, menstrual cycles and restored tubal patency [54].
enabling better treatment of the uterine cornua Tiras et al. [55] demonstrated the value of
since the operator is informed when to limit pro- laparoscopic intracorporeal ultrasound (LIU)-
gression to avoid massive fluid infusion into the guided hysteroscopic adhesiolysis in a patient
abdominal cavity and perforation of the uterus. with amenorrhea and infertility with total intra-
The intraoperative echographic control was vali- uterine synechiae. Adequate intrauterine adhe-
dated in the operating theater radiographically. siolysis was performed by a resectoscope with a
With this technique normal cavities with bilat- wire loop, suggesting that complex intrauterine
eral tube permeability were obtained in 72.72 % procedures can be easily performed by the guid-
of the patients and normal cycles in 90.9 % of ance of endoscopic ultrasonography to avoid the
the patients [35]. Following hysteroscopic lysis possibility of inadvertent uterine perforation [55].
under ultrasound control for significant intra- Schlaff and Hurst [56] evaluated the predictive
uterine synechiae, Bellingham [52] reported nor- value of preoperative endometrial sonography in
mal menstruation in 61 % of the patients and live the diagnosis and surgical treatment of women
births in 80 % of the patients, of whom 50 % had with amenorrhea due to severe Asherman’s syn-
had severe adhesions. They reported that ultra- drome, characterized by complete obstruction of
sound control is ideally essential if the adhe- the cavity at hysterosalpingogram. They sug-
sions are extensive [52]. However, in both these gested that an endometrial pattern, demonstrating
studies, the number of patients was very small a well-developed endometrial stripe on transvagi-
to effectively document the role of ultrasound in nal sonography is highly predictive of a positive
the treatment of IUA. surgical and clinical outcome in women with
160 G.N. Allahbadia
severe Asherman’s syndrome with resumption of in assisted reproductive technology cycles war-
normal menses and normalization of the cavity rants further investigation [58]. In a 5-year ret-
after hysteroscopy in contrast to women with rospective, uncontrolled cohort study, Thomson
minimal endometrium who had no cavity identi- et al. [59] conducted fluoroscopically-guided
fied and derived no benefit from surgery [56]. hysteroscopic synechiolysis for Asherman’s syn-
However, this study was limited to just seven drome in 30 patients (13 % AFS grade I, 43 %
patients and hence, substantial evidence in this AFS grade II, and 43 % AFS grade III), 60 %
direction is lacking. of whom were amenorrheic. They reported a
96 % restoration of regular menses with a 53 %
pregnancy rate among patients who attempted to
Radiographic Methods conceive and concluded that hysteroscopic syn-
echiolysis, performed by injecting radiographic
In a small but significant study, Karande et al. contrast medium and visualized under image-
[57] demonstrated that in-office lysis of intrauter- intensifier control, followed by cyclic high-
ine adhesions, under fluoroscopic control, using dose estrogen therapy to stimulate endometrial
a specially designed catheter (gynecoradiologic proliferation, appears to be an effective treatment
control) can be carried out safely in the majority for Asherman’s syndrome. Repeat procedures
of patients, using minimally invasive techniques. were performed monthly until the endometrial
They could successfully lyse adhesions in 76 % cavity was re-established [59].
(13/17) of the patients (9 mild, 3 moderate, and 1
severe), while in remaining 4 patients (2 moder-
ate and 2 severe), lysis was only partially suc- Prevention of IUA
cessful. Nine procedures were performed with
the catheter’s balloon tip and four with hystero- One of the most important features of treatment
scopic scissors. Procedure complications result- for intrauterine synechiae is the prevention of
ing in the abandoning of the procedure included recurrence [4]. Follow-up studies to assure reso-
patient discomfort before attempting the use lution of the scarring are mandatory before the
of scissors (n = 1), extravasation of dye into patient attempts to conceive as is careful moni-
the myometrium making visualization difficult toring of pregnancies for cervical incompetence,
(n = 1), and thick, fibrotic adhesions that were placenta accreta, and intrauterine growth retar-
resistant to scissors (n = 2). They opined that dation [2]. The best available evidence demon-
the potential cost savings with this technique in strates that the newly developed adhesion
comparison with endoscopic procedures, which barriers, such as hyaluronic acid, show promise
require utilization of expensive operating room for preventing new adhesions [4, 15].
time, are especially relevant in a cost-conscious Postoperative mechanical distention of the
managed care environment and only failures of endometrial cavity with the use of intrauterine
in-office procedures would reach the operating contraceptive devices and postoperative hor-
room. [57] The fluoroscopic approach to adhe- monal treatment with estrogen +/− progestogen
sions was further evaluated a decade later by to facilitate endometrial regrowth are important
Chason et al. [58] who used hysteroplasty with in the prevention of recurrence [15, 32].
fluoroscopic cannulation and balloon uterine With regard to primary adhesion formation, a
dilation to treat intrauterine adhesions and cervi- recent study by Rein et al. [60] demonstrated
cal stenosis and lower uterine defects in select that selective hysteroscopic resection (HR) of
cases. They concluded that while the treatment residual trophoblastic tissue after first- or
of intrauterine adhesions resulted in an improved second-trimester miscarriage or term delivery
pregnancy outcome, albeit in a case study, the significantly reduces the incidence of intrauter-
effect of lower uterine segment-filling defects ine adhesions and increases pregnancy rates
from cesarean deliveries on pregnancy outcome compared to ultrasound-guided evacuation with
12 Intrauterine Adhesions 161
a curette (D&E). They reported mild adhesion the Foley catheter group compared to the IUCD
in 4.2 % of the patients after selective HR com- group, respectively. They concluded that the
pared to an incidence of 30.8 % after D&E, of Foley catheter is a safer and more effective
which 17.9 % were mild, 7.7 % single dense adjunctive method of treatment of IUA compared
adhesions, and 2.6 % with extensive endome- with the IUCD [61].
trial fibrosis. Conception rates were signifi-
cantly higher in the HR patients compared to
Fluid Barriers
curetted patients (68.8 % vs. 59.9 %, respec-
tively; p < 0.05) and 78.1 % vs. 66.6 %, respec-
The application of auto-cross-linked hyaluronic
tively; p < 0.05 in patients younger than 35 years
acid (ACP) gel has been reported to significantly
of age with a significantly (p < .05) shorter time
reduce the incidence and severity of de novo for-
to conception (11.5 months vs. 14.5 months)
mation of intrauterine adhesions after hystero-
[60]. Operative hysteroscopy for selective curet-
scopic surgery, with a significant decrease in
tage of residual trophoblastic tissue instead of
adhesion severity on staging of adhesions [62].
nonselective conventional curettage may pre-
vent intrauterine adhesions [36].
Tissue Barriers
2 weeks. Diagnostic hysteroscopy, performed ate injured endometrium. These cells could be
at 2 to 4 months postoperatively, revealed isolated from adult autologous stem cells isolated
significant improvement in adhesion grade from a patient’s own bone marrow using immu-
with the amnion graft versus intrauterine bal- nomagnetic isolation [65]. Gargett and Healy
loon alone (p = 0.003) and significant improve- [66] also reported regeneration of thin endome-
ment with fresh compared to dried amnion graft trium refractory to estrogen stimulation follow-
(p = 0.01). Restoration of normal menstruation ing intrauterine administration of bone marrow
(46.7 % in group 3, 35.7 % in group 2, 28.6 % stem/progenitor cells sufficiently to support a
in group 1) and the conception rate (80 % after pregnancy in a case study. However, whether its
amnion graft and 20 % without amnion) was local endometrial damage is induced by concur-
higher in patients with the graft compared to the rent curettage that stimulated endogenous endo-
balloon. The overall conception rate was 23.3 % metrial stem/progenitor cells into action, or both,
with a miscarriage rate of 60 %. The authors con- is open to question [66].
cluded that hysteroscopic lysis of severe intra-
uterine adhesions with grafting of either fresh or Conclusion
dried amnion is a promising adjunctive proce- Intrauterine adhesions are a significant gyne-
dure for decreasing recurrence of adhesions and cological complication that require prompt
encouraging endometrial regeneration [64]. and accurate diagnosis and treatment. Despite
Prevention strategies, including bipolar resec- its invasiveness, cost issues and the techni-
tion, barrier gel, or postoperative estradiol, might cal skill required, hysteroscopy is recog-
be useful, but stronger evidence is needed and nized as the gold standard for the diagnosis,
there is a need for other randomized controlled classification, and treatment of adhesions with
trials to fully justify the use of adhesion barri- an encouraging restoration of fertility in terms
ers for clinical use [5, 9]. In view of the current of menstruation, pregnancy rates, and live
knowledge, Gambadauro et al. [9] recommend birth rates in patients with mild, moderate,
a prevention strategy based on a combination and severe IUA, including postmenopausal
of surgical trauma minimization and identifica- women. Moreover, it offers a see-and-treat
tion of high-risk cases, with early hysteroscopic approach in majority of the patients where
diagnosis and lysis possibly representing the therapy is required, thus obviating the need
best means of secondary prevention and treat- for a second intervention. Though ultrasonog-
ment of postoperative intrauterine adhesions [9]. raphy is gradually gaining acceptance in the
Considering the decreased pregnancy outcome diagnosis of IUA, particularly in economi-
in patient with recurrence of adhesions, further cally compromised settings, with the pur-
research in Asherman’s syndrome should be pose of avoiding costly invasive techniques,
directed toward reduction of adhesion reforma- it has limited accuracy and sensitivity in the
tion with a view to improving outcome [42]. diagnosis of IUA compared to hysteroscopy.
The addition of 3D ultrasound is reported
to have improved accuracy in the diagnosis,
Recent Advances but consistent large-scale studies are lacking.
However, with regard to treatment, ultrasound
In an effort to treat injured endometrium may have a significant role in controlling hys-
nonresponsive to conventional treatment for teroscopic surgery, especially in patients with
Asherman’s syndrome (IUCD) with cyclical hor- complex severe adhesions, to avoid inadver-
monal therapy for 6 months, Nagori et al. [65] tent uterine perforation. More large-scale
demonstrated that placement of endometrial randomized trials will be required before
angiogenic stem cells in the endometrial cavity ultrasonography can be established as a more
under ultrasound guidance after curettage fol- functionally effective alternative to hysteros-
lowed by cyclical hormonal therapy can regener- copy in the diagnosis and treatment of IUA.
12 Intrauterine Adhesions 163
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Sonohysterography
in Reproductive Medicine 13
Ilan Tur-Kaspa and Laurel A. Stadtmauer
The existing practice guidelines, indications, and Sonohysterography (SHG) was first described in
contraindications and the optimal technique for 1986 by Randolph et al. [1]. Randolph et al.
Sonohysterography (SHG) are reviewed. This instilled saline into the uterus to provide contrast
will include a discussion on how to make the pro- during transabdominal US and compared the
cedure pain free for women by using flexible SHG findings in 61 women to hysterosalpingog-
catheters and gentle movements, inflating the raphy (HSG) and laparoscopy/hysteroscopy.
balloon inside the cervix rather than inside the They concluded that real-time US with fluid
uterine cavity, and injecting the saline slowly. installation provides an accurate alternative to
The main focus will be on diagnosis of intrauter- HSG in screening for uterine abnormalities and
ine abnormalities through SHG rather than their tubal patency. Syrop and Sahakian were the first
treatment thereafter. We conclude that SHG is a to describe transvaginal SHG in 1992, followed
safe, accurate, cost-effective, and easy-to- by Parsons and Lense in 1993 [2, 3].
perform procedure, for patients as well as for For a long time hysteroscopy with direct
physicians, to evaluate intrauterine pathology visualization of the intrauterine cavity was con-
and can be used as the primary diagnostic tool for sidered the gold standard for diagnosing uterine
the evaluation of infertility and before ART. abnormalities [4–13]. The percentage of intra-
cavitary abnormalities in women screened by
SHG or hysteroscopy for infertility range from
11 to 45 %, with polyps range between 6 and
25 % [5, 14]. In the last 15 years, accumulating
evidence-based data, including randomized con-
trol trials, systematic reviews, and meta-analyses,
I. Tur-Kaspa, MD (*) has demonstrated that SHG has comparable sen-
Institute for Human Reproduction (IHR),
Department of Obstetrics and Gynecology,
sitivity, specificity, and accuracy in diagnosing
The University of Chicago, 409 W. Huron St., intrauterine abnormalities as hysteroscopy [7–13,
Chicago, IL 60654, USA 15–21]. Therefore, SHG and other ultrasonog-
e-mail: drtk@infertilityihr.com raphy techniques may be used as effectively as
L.A. Stadtmauer, MD, PhD hysteroscopy for diagnosing intracavitary abnor-
Department of Obstetrics and Gynecology, malities [8, 10, 11]. Pre-IVF SHG was shown to
Eastern Virginia Medical School, Jones Institute for
Reproductive Medicine, 601 Colley Avenue,
be effective at limiting cycle cancellations caused
Norfolk, VA 23507, USA by endometrial polyps [22], and it was shown to
e-mail: stadtmla@evms.edu be highly valuable as the first line of office-based
diagnostic tool for patients with recurrent IVF postmenopausal abnormal uterine bleeding [29,
implantation failure [23]. These data may explain 30]. Screening of the uterine cavity prior to ART
why most of the high-performing IVF programs and for the evaluation of infertility and habitual
in the US use SHG for the evaluation of uterine abortions is the second most common indication.
cavity before ART [24]. SHG may be performed for the evaluation of con-
In addition, cost analysis comparing SHG vs. genital or acquired (fibroids, polyps, and syn-
hysteroscopy screening prior to IVF showed that echiae) uterine anomalies and preoperative and
using SHG is more cost-effective. While hystero- postoperative evaluations of the uterine cavities.
scopic screening is cost-effective [25], Kim and SHG may also be performed for further diagnosis
Rone [26] have shown that SHG is more cost- of any suboptimal imaging of the endometrium
effective than hysteroscopy. They calculated the and when focal or diffuse endometrial thickening
average cost per patient (n = 229) of SHG screening or abnormalities are seen on a regular TVUS.
and hysteroscopy in the subset of patients who had The two main contraindications for SHG is
significant and/or correctable abnormalities (n = 35, pregnancy and pelvic infection or unexplained
15.3 %). The cost per patient using SHG screening pelvic tenderness. Abnormal uterine bleeding
with additional hysteroscopy as needed was $645. (AUB) is not a contraindication, though it may
If hysteroscopy would have been used to screen the make the interpretation of the findings more chal-
same group of patients instead of SHG, the cost per lenging [20]. Tur-Kaspa et al. [14] have prospec-
patient would have been $1281. tively analyzed SHG of 409 consecutive patients
with AUB and have found 37.2 % of intracavitary
abnormalities, mainly polyps and submucosal
Practice Guidelines for SHG fibroids. Goldstein [30] has suggested “ultrasound
first” as an approach to women with postmeno-
The American Institute of Ultrasound in Medicine pausal bleeding. SHG may be used for triage by
(AIUM) has published in March 2008 [27] a prac- identifying patients with no disease vs. those with
tice guideline for ultrasonography in reproductive focal or global abnormalities. Furthermore,
medicine. In the same year, the American College patient acceptability and diagnostic capability of
of Obstetrics and Gynecology (ACOG) published a SHG is high, and it reduces demand for hysteros-
technology assessment on SHG, in collaboration copy [29]. SHG-guided endometrial biopsy pro-
with AIUM; the Society for Reproductive vided an accurate pathological diagnosis in 89 %
Endocrinology and Infertility (SREI), an affiliate of patients compared to 52 % with blind endome-
of the American Society for Reproductive Medicine trial sampling [29, 31].
(ASRM); and the American College of Radiology
(updated in 2012) [28]. The reader is highly encour-
aged to review these guidelines. They describe the SHG Procedure [14, 27, 28, 32]
technique, the indications and contraindications,
and the qualifications and responsibilities of the Menstrual dating should be documented and
physician performing the SHG. The authors of this pregnancy should be ruled out before performing
chapter have found it easy to adhere and to comply SHG. The best timing for performing SHG is
with the above guidelines in their practices and after the menstrual flow and prior to ovulation, in
have incorporated them into this review. cycle days 5–10. This is when the endometrial
lining is most symmetrical and precludes the
chance for an early pregnancy. During the luteal
Indication and Contraindication phase, the lining is thickened and more echo-
genic and may be associated with a higher false-
The AIUM and ACOG guidelines [27, 28] describe positive rate of polyps. Using birth control pills
the indications and contraindications for SHG. may assist in scheduling this test at any day of the
The most common indication for SHG is pre- and menstrual cycle.
13 Sonohysterography in Reproductive Medicine 169
Patients should be informed of alternative such as endometrial polyp. Next, the speculum is
procedures and the possible risks and complica- removed and the TVUS probe is inserted into the
tions of SHG (mainly discomfort, low risk of vagina. Physiological saline solution is then
infection, and bleeding) and then sign a consent slowly injected to distend the endometrial lumen
form. Pretreatment antibiotic is not recom- under direct real-time visualization. Injecting the
mended routinely unless the patient has a history fluid slowly is mandatory to avoid abrupt uterine
of gynecological infections or tubal factor infer- distension and pain. Documentation should
tility [33]. Several RCTs, using different analge- include images of the endometrial cavity, includ-
sics, have failed to demonstrate benefits of using ing the lower segment and the upper cervical
any drug to significantly reduce pain during or canal in at least two planes, longitudinal and
after SHG [34–36]. Unless indicated, no analge- transverse (Fig. 13.1). The reader is encouraged to
sics or sedatives are routinely needed before, dur- read the official guidelines set by ACOG and
ing, or after SHG, since it may be considered as a AIUM [27, 28].
pain-free procedure [14, 37].
Prior to SHG, TVUS is performed with rou-
tine evaluation and measurement of the uterus, SHG for Congenital Uterine
endometrium, and ovaries. The presence of fluid Anomalies
in the cul-de-sac should be noted, and any pelvic
abnormal findings such as hydrosalpinges should SHG is a cost-effective method available in an
be documented. If a patient had a baseline TVUS outpatient setting which is highly accurate in
on day 3 of her period and returns for SHG a few identifying uterine anomalies, especially septate
days later, then a quick scan for the evaluation of and bicornuate uterus [44]. Mullerian anomalies
the uterine cavity and of fluid in the cul-de-sac are congenital defects in the development of the
may be performed after the insertion of the cath- uterus and the upper vagina. The ability of 2D
eter before the injection of the saline. US to distinguish between different types of
A speculum is placed in the vagina to visualize uterine anomalies is limited and operator depen-
the cervix. After cleansing the external os with dent. The finding of a uterine anomaly may
betadine or equivalent solution, the SHG catheter affect the management of the infertile and/or
is inserted into the cervical canal. The SHG cath- pregnant woman and the pregnancy outcome. In
eter should be prefilled with saline in order to a recent meta-analysis [39], including 94 obser-
avoid infusing air bubbles into the uterine cavity. vational studies comprising 89,861 women, the
There are many catheter options, including HSG/ prevalence of uterine anomalies diagnosed by
SHG curved catheters, intrauterine insemination optimal tests was 5.5 % (95 % CI, 3.5–8.5) in
catheters, and balloon SHG/HSG catheters. Any unselected population, 8.0 % (95% CI, 5.3–12)
rigid catheter, which requires grasping the cervix in infertile women, 13.3 % (95 % CI, 8.9–20.0)
with a tenaculum, may induce significant pain for in women with a history of miscarriage, and
the patient. If a balloon catheter is used, it is pre- 24.5 % (95 % CI, 18.3–32.8) in women with
ferred to inflate the balloon intracervically rather miscarriage and infertility.
than intrauterine, and the appropriate position of Congenital uterine anomalies are associated
the catheter may be confirmed by pulling it with poor reproductive outcome [40]. All uterine
slightly. An RCT recently showed a significantly anomalies are associated with an increase inci-
less fluid used for SHG and significantly less pain dence of fetal malpresentations at delivery.
felt by patients when the balloon was inflated Unification defects do not reduce fertility but
inside the cervix rather than in the lower uterine some defect, in particular bicornuate uteri, are
segment [38]. Furthermore, by inflating the bal- associated with aberrant outcomes throughout the
loon intracervically, one may avoid balloon course of pregnancy. Canalization defects appear
hyperinflation inside the uterine cavity, which to reduce the chance of clinical pregnancy and to
may displace and obscure a pathological finding, increase risk of preterm delivery. These are more
170 I. Tur-Kaspa and L.A. Stadtmauer
profound in cases of septate uteri. Arcuate uteri, et al. [14] studied prospectively the prevalence
while previously considered to have no reproduc- of uterine anomalies diagnosed by SHG in 600
tive sequelae, are specifically associated with consecutive infertile patients compared to 409
poor outcomes in late pregnancy, i.e., second-tri- patients with AUB. While the prevalence of
mester miscarriage and malpresentation [40]. septate uterus was 3 % in each group, arcuate
Uterine anomalies are defined by the cri- uterus was significantly more common among
teria outlined by the American Society of the infertile patients (15 % vs. 6 %, respec-
Reproductive Medicine [41]. The visualiza- tively). All other anomalies had <1 % frequency
tion of the uterine fundus at the coronal plane in either group. Tur-Kaspa et al. [14], as well as
is necessary for classifying uterine shape. SHG others [7–11], concluded that SHG is an excel-
has been shown to have superior diagnostic abil- lent method for the evaluation of congenital uter-
ity with compared with HSG and 2D US for the ine anomalies. 3D SHG may be needed in some
evaluation of uterine malformation. Tur-Kaspa cases to assist in the final diagnosis.
13 Sonohysterography in Reproductive Medicine 171
SHG for Acquired Uterine abnormal finding among patients with AUB or
Abnormalities infertile women (30 and 13 %, respectively) [14].
Submucosal fibroids were found in 9 % of the
SHG can serve as a first-line test for the evalua- AUB group and 3 % among infertile women [14].
tion of acquired intrauterine abnormalities such Submucosal fibroids have been shown by meta-
as adhesions (Fig. 13.2), polyps (Fig. 13.3), and analysis to significantly lower pregnancy rates in
fibroids. Tur-Kaspa et al. [14] have documented ART and should be removed by operative hyster-
that intracavitary abnormalities are significantly oscopy [4, 6]. Besides infertility, the submucosal
more frequent among patients with AUB than fibroids may cause bleeding and miscarriages. The
with infertility. Polyps were the most common European Society of Hysteroscopy has developed
172 I. Tur-Kaspa and L.A. Stadtmauer
Fig. 13.4 3D SHG images of a uterine polyp. They are able to show the size and location of the stalk of the polyp more
accurately in preparation for operative hysteroscopy and for consulting the patient
a classification system for fibroids which can also the evaluation of postmenopausal bleeding, 2D
assist in the surgical approach. A Type 0 submu- and 3D SHG have similar diagnostic accuracy
cosal fibroid has no myometrial invasion, while as hysteroscopy with higher patient acceptabil-
a T1 has <50 % extension and T2 has more than ity of SHG [45, 46].
50 % extension into the myometrium. The TO and A 3D US, in comparison to a 2D US, allows
T1 are appropriate for the hysteroscopic approach, for the visualization of the entire uterine cavity in
while the T2 may require more than one procedure the coronal view; it can detect the exact place-
or be removed laparoscopically. ment of uterine fibroids, polyps, and synechiae in
the cavity, as well as the mean diameter of differ-
ent tissues. A 3D US examination comprises
2D vs. 3D SHG approximately four steps: (1) data acquisition, (2)
volume calculation, (3) image animation, and (4)
When the option of having a 3D SHG scan is data storage and transfer. The scans can be
available, it may shorten the procedure and the obtained either by freehand, by manual move-
volume of the saline used [42]. 3D SHG vs. 2D ment through the region of interest (ROI), or,
SHG is more accurate for diagnosing congeni- automatically, by sweeping through the ROI. 3D
tal uterine anomalies. For acquired uterine US needs post-processing of the received data.
anomalies, in experienced hands, 3D will not Data can be stored and visualized in various
improve the accuracy, but may assist it for bet- displays such as multiplanar with navigation
ter imaging (Figs. 13.4 and 13.5) [43, 44]. For through the planes or surface rendering mode.
13 Sonohysterography in Reproductive Medicine 173
Fig. 13.6 3D SHG demonstrating an arcuate uterus. The visualization of the fundal area at the coronal plane and the
ability to measure the depth of the anomaly can easily define arcuate uterus and rule out a septum
174 I. Tur-Kaspa and L.A. Stadtmauer
Fig. 13.7 3D SHG demonstrating a completely septated assisting in planning the surgical treatment needed as well
uterus. The 3D reconstruction at the coronal plane leaves as consulting with the patient
no space for imagination, providing definite diagnosis and
Gel Instillation SHG media that significantly reduced pain during and
after HSG [56–60] was unable to affect signifi-
Gel SHG uses hydroxyethylcellulose gel instead cantly HSG’s “reputation.” SHG and HyCoSy,
of saline as its medium. This is done in order to the modern ultrasound-based procedures that are
try to simplify the technique of artificial uterine currently used instead of HSG for the evaluation
cavity distension for SHG [49]. The gel provides of the uterine cavity and/or the fallopian tubes,
a more stable filling of the uterine cavity, allowing “inherited” this high level of fear of pain. It is
a high-quality ultrasonographic visualization of possible that this stigma discourages patients and
intrauterine pathology by 2D and 3D US [50– 55]. makes them believe that the procedure should be
Still, most centers will use saline for SHG. painful when it does not have to be. Several recent
randomized controlled trials (RCT) have failed to
demonstrate a significant benefit of various phar-
No Pain with SHG macological strategies available to reduce pain
during these procedures, suggesting that the pain
Tur-Kaspa [37] has recently summarized is more psychological than physical [34–36]. It is
data supporting that SHG, as well as HSG the author’s opinion, based on evidence data and
and HysteroContrastSonography (HyCoSy), the experience of performing thousands of these
should be considered pain-free procedures. tests, that they can be pain free for women.
Hysterosalpingography (HSG) has a long- One of the primary ways to make SHG a pain-
standing reputation of being a painful procedure. free procedure is using gentle movements with a
The use of modern thin catheters and nonionic thin flexible catheter. Using a rigid catheter,
13 Sonohysterography in Reproductive Medicine 175
which requires grasping the cervix with a tenacu- 4. Bozdag G, Aksan G, Esinler I, Yarali H. What is the
role of office hysteroscopy in women with failed IVF
lum, will promote pain. If a balloon catheter is
cycles? Reprod Biomed Online. 2008;17:410–5.
used, it is preferred to inflate the balloon intracer- 5. Fatemi HM, Kasius JC, Timmermans A, van
vically rather than intrauterine, and the appropri- Disseldorp J, Fauser BC, Devroey P, Broekmans FJ.
ate position of the catheter may be confirmed by Prevalence of unsuspected uterine cavity abnormali-
ties diagnosed by office hysteroscopy prior to in vitro
pulling it slightly. An RCT recently showed a
fertilization. Hum Reprod. 2010;25(8):1959–65.
significantly less fluid used for SHG and signifi- 6. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BW,
cantly less pain felt by patients when the balloon D’Hooghe TM. Hysteroscopy for treating subfertility
was inflated inside the cervix rather than in the associated with suspected major uterine cavity abnormali-
ties. Cochrane Database Syst Rev. 2013;(1):CD009461.
lower uterine segment [38]. Warming the saline
doi:10.1002/14651858.CD009461.pub2.
solutions to body temperature before instillation 7. van Dongen H, de Kroon CD, Jacobi CE, Trimbos JB,
is another way of reducing patients’ discomfort. Jansen FW. Diagnostic hysteroscopy in abnormal
It is crucial to introduce the saline solution slowly uterine bleeding: a systematic review and meta-
analysis. BJOG. 2007;114(6):664–75.
into the cavity to prevent abrupt overdistention of
8. Saunders RD, Shwayder JM, Nakajima ST. Current
the uterus, which would induce immediate pain. methods of tubal patency assessment. Fertil Steril.
While women naturally may feel embarrassed, 2011;95:2171–9.
stressed, and discomfort, as with any medical and 9. Taylor E, Gomel V. The uterus and fertility. Fertil
Steril. 2008;89:1–16.
gynecological examinations, there should be no
10. Van Voorhis BJ. Ultrasound assessment of the uterus
more fear of pain from procedures such as SHG, and fallopian tube in infertile women. Semin Reprod
HyCoSy, and HSG [37]. Med. 2008;26:232–40.
11. Devroey P, Fauser BCJM, Diedrich K, and on behalf
of the Evian Annual Reproduction (EVAR) Workshop
Conclusions
Group 2008. Approaches to improve the diagnosis
SHG is a simple, cost-effective, safe, and and management of infertility. Hum Reprod Update.
easy-to-perform procedure for the evaluation 2009;15:391–408.
of congenital and acquired uterine abnormali- 12. Grimbizis GF, Tsolakidis D, Mikos T, Anagnostou E,
Asimakopoulos E, Stamatopoulos P, et al. A prospec-
ties. Published guidelines by AIUM and
tive comparison of transvaginal ultrasound, saline
ACOG are easy to implement in routine gyne- infusion sonohysterography, and diagnostic hysteros-
cological and reproductive medicine practice. copy in the evaluation of endometrial pathology.
While using thin flexible catheters, placing Fertil Steril. 2010;94:2720–5.
13. Brown SE, Coddington CC, Schnorr J, Toner JP,
them inside the cervix, and injecting the saline
Gibbons W, Oehninger S. Evaluation of outpatient
slowly, this procedure can be pain free. SHG hysteroscopy, saline infusion hysterosonography, and
can serve as a first-line test for screening and hysterosalpingography in infertile women: a prospec-
evaluation of the uterine cavity for the diagno- tive, randomized study. Fertil Steril. 2000;74(5):
1029–34.
sis of infertility and before ART.
14. Tur-Kaspa I, Gal M, Hartman M, Hartman J, Hartman
A. A prospective evaluation of uterine abnormalities
by saline infusion sonohysterography (SIS) in 1009
women with infertility or abnormal uterine bleeding.
Fertil Steril. 2006;86:1731–5.
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13 Sonohysterography in Reproductive Medicine 177
captured either on still photographs or on video. (often metal) is inserted transcervically, and
Although laparoscopy is now a routine operation, a radio-opaque dye (e.g. Urografin) is passed
it is still associated with risks. These include through the cannula. X-ray images are then
bleeding, infection, vascular damage as well as obtained and patency is confirmed by visualis-
visceral injuries to other organs (bowel and blad- ing the bilateral peritoneal spillage of the dye.
der). Should complications at laparoscopy occur, Following the procedure, patients should be
then a laparotomy may be required. The use of a advised about pelvic pain, which will be similar
general anaesthetic poses risks, and the possibil- to dysmenorrhoea. Prophylactic antibiotics are
ity of subsequent venous thromboembolism must also usually prescribed.
not be overlooked. Facilities to perform laparos- In comparison to laparoscopy, HSG is more
copy may not be readily available in all fertility cost-effective, can be performed in a low-
clinic settings. resource setting and does not require as much
Laparoscopy is an expensive and invasive operator expertise. In addition, HSG can delin-
procedure when used in this context, and appro- eate uterine cavity abnormalities as well as tubal
priately trained clinical and auxiliary staff are blockage. The passage of dye through the tubes
required to perform this. can sometimes inadvertently cure the blockage
Although this procedure is the gold standard and therefore HSG can, on occasions, be thera-
method for evaluating tubal patency, it shouldn’t peutic. A meta-analyses of over 4,000 subjects
be the first-line screening method employed on a concluded that HSG has a sensitivity of 53 % and
large scale. Patients should be appropriately a specificity of 87 % for any tubal pathology and
selected for this procedure. One possible way of 46 and 95 % for bilateral tubal pathology [6, 9].
risk assessing women would be to perform the Both oil-soluble and water-soluble contrast
inexpensive chlamydia antibody titre (CAT) media have been employed in HSG. Oil-soluble
blood test, and if positive, these women should media are associated with risk of oil emboli as
be offered laparoscopy as the possibility of well as inducing inflammatory reactions within
encountering pelvic pathology is higher in this the diseased fallopian tubes. The more commonly
group of patients [2]. This is already occurring in used water-soluble agents have been shown to
some parts of Europe where CAT testing is used result in increased bleeding post HSG; however,
as a first-line test in subfertility workup, and they do produce superior radiographic images. A
those above a fixed cut-off level have post- randomised controlled trial did not show any sta-
infectious pelvic disease excluded by means of tistically significant difference in the live birth
laparoscopy and chromopertubation, rather than rates following oil- or water-soluble contrast
having HSG [5, 6]. In patients who are CAT posi- media [10].
tive, HSG should be omitted in order to avoid the Disadvantages of HSG include the radiation
potential of infectious complications [7]. Patients exposure to the pelvis. The mean dose-area prod-
with a high-risk history (e.g. known endometrio- uct (DAP) for HSG is 2.05 Gy cm2 versus 0.09 Gy
sis and previous pelvic surgery) should have their cm2 for a chest X-ray [11]. The use of iodine-
pelvis assessed by means of a laparoscopy and based contrast media can result in hypersensitiv-
dye test [8]. ity reactions and should be avoided in patients
known to be sensitive to iodine-containing com-
pounds. HSG requires the services of the radiol-
Hysterosalpingography (HSG) ogy department for interpretation of the images
produced. The procedure is associated with
HSG is an outpatient X-ray examination of the patient discomfort during and after the proce-
uterine cavity and fallopian tubes using con- dure. The use of thinner, non-metal cervical cath-
trast media. This procedure is performed in eters may reduce the discomfort experienced by
the follicular phase of the menstrual cycle so the patient. A study comparing HSG using a
as to not disrupt an early pregnancy. A cannula rigid, metal cannula with a balloon catheter
14 Evaluation of Tubal Patency (HyCoSy, Doppler) 181
Hysterosalpingo-Contrast- Fig. 14.1 HyCoSy with water and air: this image
Sonography (HyCoSy) demonstrates air echogenic areas with a background of
echo-free areas. The air bubbles are seen to move through
the tube to demonstrate patency
Hysterosalpingo-contrast-sonography is an out-
patient transvaginal ultrasound procedure that
visualises the uterine cavity and observes spill
from the fimbrial ends of the fallopian tubes.
The technique of HyCoSy was founded upon
two independent observations. The initial obser-
vation, published over 30 years ago, was that
saline could be injected into the uterine cavity to
delineate endometrial structures using a trans-
vaginal ultrasound probe [13]. The same investi-
gators noted that saline would then be present in
the pouch of Douglas, indicating spill of saline
had occurred through patent fallopian tubes. Fig. 14.2 HyCoSy with SonoVue® dye showing dye in
Normal fallopian tubes are rarely visualised on the uterine cavity and the right tube
ultrasound; however, diseased tubes (e.g. hydro-
salpinx) are more readily apparent due to the echogenic properties, Echovist® revolutionised
presence of fluid. The notion that a fluid-filled the visualisation of the fallopian tubes using
intrauterine cavity/fallopian tubes could enhance HyCoSy. Echovist® consists of galactose parti-
visual diagnosis leads to the idea that injecting cles suspended in an aqueous galactase solution.
fluid into the uterus could be used to detect both Echovist is no longer available, and SonoVue®, a
intrauterine anomalies and tubal patency at ultra- second-generation agent, is now commonly used.
sound. Although saline was the first fluid agent to The SonoVue® kit consists of a lyophilised pow-
be used, its use was reported with varying degrees der which is mixed vigorously with normal saline
of success. There were limitations in observing to form the injectable contrast media. SonoVue
the flow through the entire tube as well as unpre- consists of microbubbles of sulphur hexafluo-
dictable and not easily reproducible results. Air ride. The interface between the sulphur hexafluo-
has also been described as a contrast agent that ride bubble and aqueous medium acts as a
can be used at HyCoSy. Although it has obvious reflector of the ultrasound beam, thus enhancing
cost benefits, visualisation of the tubal course blood echogenicity and increasing contrast
may be more challenging. This, in part, may be between the blood and the surrounding tissues
due to the similar echogenicities of air and the (Fig. 14.2).
surrounding structures (e.g. bowel gas) (Fig. 14.1). The contrast agent produces a hyperechoic
In the mid-1980s, an ultrasound contrast appearance on transvaginal ultrasonography. The
agent named Echovist® was being trialled contrast media are detected first in the uterine
for use in echocardiography. Due to its cavity, proximal and then distal fallopian tubes
182 D. Vinayagam and K. Ojha
gently removed, ensuring the catheter is not 13. This could be followed by assessment of the
dislodged. The patient is then forewarned uterine cavity with normal saline to exclude
that the transvaginal ultrasound probe will be endometrial polyp or submucous fibroids.
inserted. HyCoSy (and HSG) has the significant advan-
7. At this stage, the authors perform a conven- tage over laparoscopy of being outpatient-based
tional B-mode transvaginal scan to assess (office) investigations without a need for general
the uterus, ovaries and pouch of Douglas. anaesthesia. There is no risk of visceral or vascu-
The correct placement of the catheter bal- lar injuries. Patients do not need to be fasted for
loon can also be checked at this point. either procedure, and both the patient and her
Alternatively, a conventional scan can be partner can be present whilst the investigation is
performed after step 1(before the catheter is being performed.
introduced). Unlike HSG, HyCoSy does not involve the
8. After warning the patient, the contrast use of ionising radiation and iodine-based con-
medium can be injected slowly and steadily. trast media or the use of radiology services – it
It is important to remember that the uterus is can be performed by a gynaecologist/specialist in
pressure sensitive, and as such, excessive reproductive medicine, obviating the need for a
rates and/or volumes of injecting will result radiologist. As an ultrasound-based investiga-
in unnecessary patient discomfort. Beware tion, other pelvic structures can be assessed
that blocked fallopian tubes may increase the simultaneously. HSG may preclude the need for
pain experienced by the patient. The authors laparoscopy in some cases, thereby improving
suggest using no more than 10 ml of contrast patient satisfaction and preventing the need for
media. If the balloon has been inflated cor- invasive investigations.
rectly, there should be no leakage, and evalu- HyCoSy has been shown to be at least as
ation of the uterus and both tubes should be effective as hysterosalpingography at detecting
possible using less than 10 ml. In the author’s tubal blockage. When compared with the gold
experience, 2–5 ml is sufficient for demon- standard of laparoscopy and dye testing, reported
strating tubal patency. rates for sensitivity and specificity are 80 and
9. Tubal patency is assessed by demonstrating 84 %, respectively [17]. The use of HyCoSy is
flow along the entire length of the tube or by superior to hysterosalpingography in detecting
streaming at the cornual end for at least 10 s intrauterine anomalies such as leiomyoma, pol-
with spill into the pouch of Douglas [16]. yps, septae and hydrosalpinx.
10. A detailed examination of the uterus is Two-dimensional transvaginal HyCoSy as
performed by scanning slowly and system- described above, although in many ways superior
atically from the cervix to fundus. Any rele- to HSG, does have its limitations. Due to the tor-
vant lesions (e.g. submucous leiomyoma) tuous course of the fallopian tubes, the entire tube
can be closely analysed and relevant images will not be visualised in one scanning plane.
produced. Visualisation of the tubal course can be further
11. Each tube is followed, in turn, until spill is limited by tubal spasms. As a result, the false-
visualised adjacent to the ovary. positive rate for tubal occlusion is 5–10 % [18].
12. Strict criteria must be adhered to in order to Due to the echogenicity of bowel, distal spill from
ensure that the fallopian tube is followed in the tubes may be difficult to distinguish from sur-
its entirety, before it is considered to be pat- rounding bowel and therefore relies on a certain
ent. Any delay in tubal fill and/or spill must level of operator expertise. Interpretation can
be appropriately documented. Any apparent therefore be slightly more challenging as com-
distortion of the tubal diameter or tubal pared to hysterosalpingography. As the procedure
course must also be documented and prefer- does rely on the technical ability of the clinician
able supplemented with the use of images/ performing the procedure, there can be consider-
videography. able inter- and intra-observer variability.
184 D. Vinayagam and K. Ojha
Three-Dimensional Coded Contrast is combined with CCI, the tubal course and
Imaging (3D CCI) During HyCoSy structure can be studied in much greater detail.
Software packages that provide the volume
Coded contrast imaging (CCI) comprises of dedi- acquisition images are available, and when this is
cated computer software, designed to enhance combined with 3D CCI, then a 3D image with the
the view of the fallopian tubes whilst filtering out uterus and tubes, showing the tubal course in its
signals from other tissues. The image which is entirety and tubal spill (if patent), is seen as a
produced is based on ultrasound signals produced hyperechoic image in a completely anechoic
by the contrast media and not by surrounding pelvis (i.e. no other structures are seen).
tissues. Volume acquisition performed during
Coded contrast imaging enhances the use of HyCoSy is a static procedure and as such requires
contrast media by means of low acoustic pres- less challenging probe movements and therefore
sure, thereby enhancing visualisation of the requires less operator experience and expertise as
fallopian tube by enabling the clinician to differ- compared to conventional 2D TVS HyCoSy [18].
entiate between the harmonic response of the As 3D CCI visualises both fallopian tubes, less
contrast medium and signals from other sur- contrast media are required – this is beneficial
rounding organs such as bowel [18]. The soft- both to the patient and also from a cost perspec-
ware is able to filter out ultrasound signals tive. Another advantage of 3D CCI at HyCoSy is
produced by the organs and thereby display an that the images can be stored (similar to Doppler
image which is solely based on harmonic signals imaging and HSG) and viewed by clinical col-
produced by the contrast media. leagues, unlike conventional 2D HyCoSy which
This technology has been applied in other is a dynamic procedure that only the operator
fields including studying the microvasculature of can interpret. However, 3D imaging requires
the liver, breast lesions as well has myocardial greater funding and therefore is not accessible in
perfusion function. resource poor settings. A recent study [19] com-
In order to further enhance the technology, paring 3D HyCoSy in 150 tubes to laparoscopy
second-generation contrast media are used. The and dye testing demonstrated a sensitivity and
first-generation contrast media (Echovist®) con- specificity of 93.5 and 86.3 %, respectively. The
tain microbubbles that have rigid membranes and authors reported a positive predictive value of
are therefore unable to respond with harmonic 87.8 % and negative predictive value of 92.6 %.
signals at low acoustic pressures. However, These values compare favourably with previ-
second-generation agents, such as SonoVue®, ously reported sensitivities and specificities of
provide a substantial harmonic response at low 2D HyCoSy.
acoustic pressure. The use of a second-generation Although more work is required to assess the
contrast medium with CCI technology enables diagnostic accuracy and feasibility of 3D CCI
the operator to view the hyperechoic fluid firstly HyCoSy, it appears that this novel method of
in the uterus and then the proximal tube and lastly evaluating tubal patency will become widespread
spill into the abdominal cavity. Due to the detect- in the future and an integral part of the subfertil-
able differences between the harmonic response ity workup (Fig. 14.4).
between the contrast media and that of the sur-
rounding tissue, there is a clear distinction
between the contrast media and the surrounding Blood-Flow and Doppler Imaging
structures.
The use of 3D imaging (without CCI) using Blood flow and Doppler are additional modalities
saline-air contrast has been reported; however, that can be employed in conjunction with
the resulting image may not necessarily be clear HyCoSy.
enough to make a conclusion regarding tubal Blood flow is a relatively new technique
patency. However, when 3-dimensional imaging which has been employed in other medical
14 Evaluation of Tubal Patency (HyCoSy, Doppler) 185
HyCoSy, it allows visualisation of contrast media function. Best Pract Res Clin Obstet Gynaecol.
2003;17(2):187–209.
throughout the entire tubal length. The use of
4. Lanzani C, Savasi V, Leone FP, Ratti M, Ferrazzi E.
3D-PDI has clear advantages over the use of Two-dimensional HyCoSy with contrast tuned imag-
HyCoSy alone. It has been shown that visualisa- ing technology and a second-generation contrast
tion of distal tubal spill occurs twice as often media for the assessment of tubal patency in an infer-
tility program. Fertil Steril. 2009;92:1158–61.
when 3D-PDI is employed [21]. As the procedure
5. Coppus SFPJ, Opmeer BC, Logan S, Van der Veen F,
does rely on the technical ability of the clinician Bhattacharya S, Mol BWJ. The predictive value of
performing the procedure and, in the case of medical history taking and Chlamydia IgG ELISA
3D-PDI, time for analysis, this has not been rou- antibody testing (CAT) in the selection of subfertile
women for diagnostic laparoscopy: a clinical predic-
tinely implemented in clinical practice.
tion model approach. Hum Reprod. 2007;22:1353–8.
6. Swart P, et al. The accuracy of hysterosalpingography
Conclusion in the diagnosis of tubal pathology: a meta-analysis.
Being one of the commonest causes of subfer- Fertil Steril. 1995;64(3):486–91.
7. den Hartog JE, Lardenoije CM, Severens JL, Land JA,
tility, tubal patency is an essential component
Evers JL, Kessels AG. Screening strategies for tubal
of the subfertility workup. In this chapter, we factor subfertility. Hum Reprod. 2008;23:1840–8.
have provided an overview of the gold stan- 8. National Collaboratry Centre for Women’s and
dard technique of chromopertubation and clas- Children’s Health. Fertility: Assessment and
Treatment for People with Fertility Problems.
sical methods such as the hysterosalpingogram
Commissioned by the National Institute for Clinical
and then covered the use of ultrasound in Excellence (NICE). London: RCOG Press 2004.
slightly more detail. We hope we have pro- ISBN 1-900364-97-2.
vided the reader with a good understanding of 9. Broeze KA, Opmeer BC, Van Geloven N, Coppus
SFPJ, Collins JA, den Hartog JE, et al. Are patient
these newer techniques involving ultrasound
characteristics associated with the accuracy of
as well as a foundation for a technique that we hysterosalpingography in diagnosing tubal pathol-
employ. The methods we have outlined above ogy? An individual patient data meta-analysis. Hum
are by no means exclusive, and the readers are Reprod. 2011;17:293–300.
10. Spring DB, et al. Potential therapeutic effects of
encouraged to develop their own techniques
contrast materials in hysterosalpingography: a pro-
when carrying out the procedures discussed. spective randomised controlled trial. Radiology.
As the boundaries of investigative medicine 2000;214:53–7.
continue to be expanded, there will be further 11. Hart D, Hillier MC, Wall BF. HPA-RPD-029-doses to
patients from radiographic and fluoroscopic X-ray imag-
development of the above employed methods
ing procedures in the UK – 2005. Review. 2009;2010:95.
as well as newer modalities. What is certain is 12. Tur-Kaspa I, Seidman DS, Soriano D, Greenberg I,
that ultrasound does and will continue to play Dor J, Bider D. Hysterosalpingography with a balloon
a pivotal role in the armamentarium we have at catheter versus a metal cannula: a prospective, ran-
domized, blinded comparative study. Hum Reprod.
our disposal in the investigation of our patients.
1998;13:75–7.
13. Nanini R, Chelo E, Branconi F, Tantini C, Scarselli
GF. Dynamic echohysteroscopy: a new diagnostic
technique in the study of female infertility. Acta Eur
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1. Steinkeler JA, Woodfield CA, Lazarus E, Hillstrom Hysterosalpingo-contrast-sonography (HyCoSy) and
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assessing the use of hysterosalpingo-contrast sonog- 19. Zhou L, Zhang X, Chen X, Liao L, Pan R, Zhou N,
raphy and magnetic resonance imaging. Hum Reprod. Di N. Value of three-dimensional hysterosalpingo-
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Hydrosalpinx
15
Dale W. Stovall and Mark W. Austin
the fallopian tube can be divided into distinct by the fimbriated end of the fallopian tube.
segments. The most proximal portion of the fal- Assisted by tubal contractions and the tubal epi-
lopian tube, which is connected to the lateral sur- thelial lining, the oocyte migrates to the ampul-
face of the fundus of the uterus, is called the lary portion of the tube. There, the oocyte is
interstitial segment. This segment of tube primar- fertilized. For spermatozoa to reach the ovulated
ily functions as the tubal lumen’s entry into the oocyte, they must travel from the vagina, through
uterine cavity. For all practical purposes, this seg- the cervical os, into the uterus, through the small
ment of the fallopian tube is contained within the tubal ostea, and finally to the ampullary segment
wall of the uterus. As the uterus contains several of the tube. Once fertilized, the embryo migrates
smooth muscle layers, this portion of the fallopian through the fallopian tube in the opposite direc-
tubes’ lumen is surrounded by a thick smooth tion of the aforementioned spermatozoa into the
muscle lining. The opening of the interstitial seg- intrauterine cavity where it subsequently
ment into the uterus is called the tubal ostea, and implants. The secretory cells within the fallopian
it can be seen from inside the uterine cavity via tube secrete electrolytes, calcium, glucose, and
hysteroscopy. Moving distally from the uterus, protein that serve as nutrients for the spermato-
the next tubal segment is called the isthmic por- zoa, oocyte, and the developing embryo. The
tion of the fallopian tube. It is approximately fluid within the fallopian tube also assists in the
2 cm in length. This segment is completely clear transport of both gametes and embryos.
from the serosal and muscular layers of the uterus
and contains the second thickest muscular layer
of the tube. However, the lumen of the isthmic Definition, Prevalence, and Etiology
portion of the fallopian tube, like that of the inter-
stitial segment, is very narrow. The next segment Injury to the distal end of the fallopian tube can
of the tube is called the ampullary segment. The result in either a hydrosalpinx or fimbrial phimo-
ampula is approximately 7 mm in length and has sis. Hydrosalpinges are fallopian tubes that are
a relatively thin muscularis layer and a wide completely occluded at their distal end and are
internal lumen as compared to isthmic portion of dilated with fluid. In this case, the secretions
the tube. The mucosal lining of the ampullary from within the fallopian tube accumulate within
portion of the tube contains more pronounced the tube, distending primarily the ampullary por-
mucosal folds also known as rugal folds. The tion of the fallopian tube. This occurs despite the
next tubal segment is known as the infundibulum. fact that the proximal portion of the tube remains
It is approximately 1 cm in length and is the wid- patent. Fimbrial phimosis results from a partial
est portion of the fallopian tube. Extending off obstruction of the distal end of the fallopian tube.
the end of the tube are feather-like projections In this case the distal end of the fallopian tube is
known as the fimbriae. These projections are still patent, but there is agglutination of the fim-
thought to assist in oocyte pickup after ovulation. bria and adhesive bands that surround the termi-
A long projection of the fimbria, the fimbria ovar- nal end of the tube yielding a narrow phimotic
ica, is commonly connected to the ovarian sur- tubal opening.
face to maintain the fimbria in close proximity to The incidence and prevalence of hydrosalpin-
the ovarian surface. ges is unknown. However, it is known that
approximately 25–35 % of female factor infertil-
ity is caused by tubal disease. Furthermore, more
Tubal Function than half of the cases of tubal disease arise from
salpingitis [1]. Salpingitis is part of the more gen-
The fallopian tube is an integral part of the repro- eral process known as pelvic inflammatory dis-
ductive process. Beyond reproduction, however, ease or PID. PID is an acute infection of the
the fallopian tubes serve no further physiologic upper genital tract which includes the uterus, fal-
function. After ovulation, the oocyte is picked up lopian tubes, and ovaries. The two most common
15 Hydrosalpinx 191
organisms associated with salpingitis are factor infertility) but heterogeneity in regard to
Chlamydia trachomatis and Neisseria gonor- the contents within their hydrosalpinx, the condi-
rhoeae [2]. In general, the longer salpingitis is tion of their contralateral tube, and adhesions
allowed to go untreated, and the greater the num- within the pelvis. It has been well documented
ber of infections, the greater the damage to the that the fluid within a hydrosalpinx may contain
fallopian tube and the greater the likelihood of microorganisms, debris, toxins, cytokines, and
developing a hydrosalpinx. Therefore, patients prostaglandins. Furthermore, it is known that
with a history of pelvic inflammatory disease are even though a fallopian tube may be completely
at risk for distal tubal occlusion and hydrosal- occluded distally and contain a significant collec-
pinx. Other risk factors for tubal occlusion and tion of fluid within its ampullary region, its prox-
hydrosalpinx include a history of endometriosis, imal end may still be patent, allowing for drainage
ectopic pregnancy, and prior pelvic surgery. For of fluid into the uterine cavity. Thus, tubal fluid
patients with no risk factors, a negative chla- contents may come into direct contact with the
mydia antibody test indicates that there is less endometrium, gametes, and embryos.
than a 15 % likelihood of tubal pathology [3]. To better assess these contents and to deter-
mine their effects on fertility, Beyer et al. studied
the contents of tubal fluid from infertile women
Signs and Symptoms with hydrosalpinges and the effects of this fluid on
murine embryonic development. They found that
The natural history of hydrosalpinges is not well as compared to values for normal human tubal
studied. In other words, it is not well known how fluid, fluid from hydrosalpinges tended to be nor-
rapidly they develop from a given insult or how mal with respect to components such as sodium,
commonly they resolve or recur. Furthermore, no chloride, and bicarbonate and with respect to pH
selected population of patients has been screened and osmolarity. However, they found that hydro-
by ultrasound or any other imaging method to salpinx was relatively low in regard to the con-
determine the incidence of the disease. Therefore, centrations of potassium, calcium, phosphate,
the percentage of women with a hydrosalpinx glucose, and protein. Although there was some
who are symptomatic is unknown. Clearly, some variability within the biochemical components of
women with hydrosalpinges do suffer from inter- the hydrosalpinx fluid, murine embryonic devel-
mittent or constant lower abdominal pain and a opment was inhibited by this fluid [4]. These
bothersome vaginal discharge. However, it is investigators concluded, however, that it was
possible that the majority either are asymptom- likely a lipophilic embryotoxic factor(s) and not
atic or have infertility as their only clinical prob- the differences in the biochemical components
lem associated with their hydrosalpinges. found between “normal” and hydrosalpinx-
derived tubal fluid that was responsible for the
reduction in embryonic development. To date,
Effects on Pregnancy the embryotoxic effects of hydrosalpinx fluid
have not been documented in human embryos.
Complete bilateral distal tubal occlusion pro- Other studies have evaluated the effects of
duces sterility. However, even the presence of a hydrosalpinges on endometrial receptivity. Meyer
unilateral hydrosalpinx can have a significant et al. prospectively studied the endometrium of
effect on fertility. In this regard, one must realize 103 women with hydrosalpinges for three integ-
that there are numerous causes for infertility, and rin markers of endometrial receptivity and com-
therefore, it is very likely that patients with a uni- pared those results to 55 infertile and 44 fertile
lateral hydrosalpinx and infertility are likely to controls. They also looked at the effects of tubal
be a very heterogeneous group. This heterogene- occlusion or resection on endometrial receptivity
ity may involve not only multiple causes for markers. These investigators found that women
infertility (e.g., endometriosis, PCOS, and male with hydrosalpinges expressed significantly less
192 D.W. Stovall and M.W. Austin
αvβ1 integrin as compared to controls. Based is placed in the dorsal lithotomy position on the
on these data, they concluded that hydrosalpin- examination table in the fluoroscopy suite, and a
ges may have a direct impact on endometrial bimanual pelvic examination is performed. In the
receptivity [5]. Subsequently, these investigators absence of any evidence of acute pelvic or cervi-
demonstrated a restoration of αvβ1 integrin fol- cal infection, the procedure can commence. The
lowing surgical treatment for hydrosalpinx. In patient’s perineum is draped with sterile cloth
addition, other investigators have found potential or paper, the uterine cervix is visualized using a
defects in embryo implantation that are associ- sterile speculum, and the cervix is cleaned with
ated with hydrosalpinges. In this regard, the an iodine solution. If the Jarcho cannula is to be
expression of HOXA10, a transcription factor for used, the cervix is grasped with a tenaculum. The
embryo implantation, was shown to be decreased cannula is filled with an iodinated, radio-opaque,
in women with hydrosalpinges and the expres- water-soluble contrast medium, taking care to
sion of this transcript was restored after salpin- expel any trapped air. The prefilled cannula is
gectomy [6]. Finally, the effects of hydrosalpinx placed into the cervical os and held in place by a
fluid on sperm motility and velocity have been spring-loaded mechanism. If a balloon HSG cath-
studied. These investigators found that sperm eter is used, one may be able to dispense with the
motility and velocities remained unchanged after tenaculum; however, the filled balloon may cause
a 5-h incubation period with various concentra- discomfort to the patient as well. A randomized
tions of hydrosalpinx fluid but that the percentage trial failed to demonstrate the efficacy of the intra-
of motile spermatozoa were significantly reduced uterine instillation of 2 % lidocaine prior to HSG
after 24 h of incubation [7]. Therefore, it appears for the relief of pain [9]. Typically, a scout film
that there are several possible etiologies for the is taken prior to the instillation of dye to look for
negative effects of hydrosalpinx-derived fluid pelvic calcifications. Contrast media are slowly
on reproduction beyond simple tubal occlusion. injected under fluoroscopic control, and an image
Whether unilateral salpingectomy is appropriate is taken during this filling phase to look for intra-
for women with infertility who have a unilateral uterine cavity filling defects. A second image is
hydrosalpinx and are undergoing infertility ther- taken when the uterus appears to be distended,
apy with induction of ovulation with or without and a third documents the dye filling the fallopian
insemination has not been well studied. tubes. Lastly, an image of the contrast media spill-
ing from the tubes and flowing freely in the pelvis
is obtained. At the conclusion of the procedure,
Imaging the cannula or catheter is withdrawn, the tenacu-
lum is removed, and the speculum is withdrawn.
Hysterosalpingogram (HSG) Normal tubes appear thin, with a smooth con-
tour. Rugae are often visible. Hydrosalpinges
Hysterosalpingography is a well-established appear enlarged and irregular, with absent rugae,
method used for imaging of the intrauterine cavity and contrast medium is most often not vis-
and the fallopian tubes. The technique utilized is ible spilling from the tubes into the pelvis. In a
oft published and well known [8]. Briefly, the pro- meta-analysis of studies that evaluated HSG and
cedure is performed between menstrual cycle days laparoscopy findings independently, the authors
5 and 12, that is, after the cessation of menses, but calculated a point estimate of 0.65 for sensitiv-
before ovulation and thus the possibility of preg- ity and 0.83 for specificity [10]. The authors
nancy. An NSAID such as ibuprofen is commonly concluded that although HSG is of limited use
prescribed to be taken approximately 1 h before for detecting tubal patency because of its low
the procedure to ameliorate cramping. A prophy- sensitivity, its high specificity made it a useful
lactic antibiotic such as doxycycline may be given test for detecting tubal obstruction. Of more rel-
to those patients with a history of PID or evidence evance, Mol et al. studied the reproducibility and
of same at the time of the procedure. The patient accuracy of hysterosalpingography in diagnosing
15 Hydrosalpinx 193
Contrast Medium
3-D ultrasonography is a useful tool for the fluid into their uterine cavities with adverse
diagnosis of hydrosalpinges and may be utilized reproductive consequences. In fact, this phenom-
initially, or in addition to 2-D ultrasound imaging enon has been widely studied. A meta-analysis
when the results from 2-D images are equivocal. of 6713 IVF cycles compared the pregnancy
outcomes of women with and without a hydro-
salpinx. This study found that the presence of a
Utility of Tubal Surgery hydrosalpinx was associated with approximately
a 50 % reduction in pregnancy rates and a two-
In regard to tubal surgery, patients with a good fold increase in the risk for spontaneous abortion
prognosis are those who have no more than lim- [21]. Another large study of women with tubal
ited filmy adnexal adhesions, mildly dilated tubes disease who either did or did not have a hydro-
(<3 cm) with thin and pliable walls, and a lush salpinx revealed similar results [22]. Therefore,
endosalpinx with preservation of the mucosal it seems clear that the presence of a hydrosalpinx
folds [18]. The mean cumulative pregnancy rates has a significant negative impact on both preg-
reported after terminal salpingostomy overall is nancy and live birth rates after IVF.
approximately 30 %, with an ectopic pregnancy Numerous procedural methods used to treat
rate of 5 %. However, in poor prognosis patients unilateral or bilateral hydrosalpinges either
with large hydrosalpinges, thick non-pliable before an anticipated IVF cycle or during an
walls, and loss of luminal rugae, the cumula- ongoing IVF cycle have been studied. Included
tive pregnancy rate may be as low as zero. In are laparoscopic salpingectomy, proximal tubal
comparison, the pregnancy rates following ter- occlusion via either laparoscopy or hysteros-
minal salpingostomy in good prognosis patients copy, salpingostomy, and ultrasound-guided
who are younger and have a more conserved needle aspiration. A Cochrane review, using
tubal anatomy may be as high as 80 % [19, 20]. data from several randomized trials, evaluated
Unfortunately, it is difficult to determine the the utility of laparoscopic salpingectomy, lapa-
presence of rugal folds with ultrasonography. roscopic proximal tubal occlusion, and ultra-
This is better evaluated via hysterosalpingo- sound-guided aspiration of hydrosalpinges on
gram. Nevertheless, an increased tubal diameter pregnancy rates with IVF [23]. These data
is associated with a greater destruction of tubal revealed that ongoing pregnancy rates were
rugae and a more rigid tube. Therefore, ultraso- increased by an odds ratio (OR) of 2.14 (95 %
nography is a reasonable tool for the assessment CI, 1.23–3.73) after laparoscopic salpingec-
of patients for tubal surgery with a hydrosalpinx. tomy, that clinical pregnancy rates were
However, pregnancy rates with IVF exceed the increased by an OR of 4.66 (95 % CI, 2.47–
chances for pregnancy with tubal surgery except 10.01) after proximal tubal occlusion, and that
for the patients with the best prognosis after the clinical pregnancy rates were not signifi-
surgery. cantly increased (OR = 1.97, 95 % CI, 0.62–
6.29) after ultrasound-guided aspiration. Two
small reports have evaluated the use of hystero-
Assisted Reproduction scopic-guided proximal tubal occlusion using
the Essure® device [24, 25]. Although these data
Hydrosalpinges have been shown to have an are very promising, the technique cannot be rec-
adverse effect on both pregnancy and deliv- ommended at this time. However, it may be an
ery rates in women undergoing IVF. Similar option for patients who are not candidates for
to women with a unilateral hydrosalpinx and a laparoscopy secondary to known extensive pel-
contralateral patent tube who are trying to con- vic adhesion disease. Other data regarding the
ceive without IVF, women with either unilateral effectiveness of laparoscopic salpingectomy on
or bilateral hydrosalpinges who are undergoing IVF pregnancy rates has demonstrated that the
IVF may experience drainage of hydrosalpinx effectiveness of this procedure is greatest with
196 D.W. Stovall and M.W. Austin
adversely affect markers of endometrial receptivity. 17. Timor-Tritsch IE. Three-dimensional ultrasound
Hum Reprod. 1997;12(7):1393–8. inversion rendering technique facilitates the diagnosis
6. Daftary GS, Kayisli U, Seli E, Bukulmez O, Arici A, of hydrosalpinx. J Clin Ultrasound. 2010;38(7):
Taylor HS. Salpingectomy increases peri-implantation 372–6.
endometrial HOXA10 expression in women with 18. American Fertility Society. The American Fertility
hydrosalpinx. Fertil Steril. 2007;87(2):367–72. Society classifications of adnexal adhesions, distal
7. Ng EH, Ajonuma LC, Lau EY, Yeung WS, Ho PC. tubal occlusion, tubal occlusion secondary to tubal
Adverse effects of hydrosalpinx fluid on sperm motil- ligation, tubal pregnancies, Mullerian anomalies and
ity and survival. Hum Reprod. 2000;15(4):772–7. intrauterine adhesions. Fertil Steril. 1988;49:944–55.
8. Baramki T. Hysterosalpingography. Fertil Steril. 19. Schlaff WD, Hassiakos DK, Damewood MD, Rock
2005;83:1595–606. JA. Neosalpingostomy for distal tubal obstruction:
9. Frishman GN. The use of intrauterine lidocaine to prognostic factors and impact of surgical technique.
minimize pain during hysterosalpingography: a ran- Fertil Steril. 1990;54:984–90.
domized trial. Obstet Gynecol. 2004;103:1261–6. 20. Rock JA, Katayama KP, Martin EJ, et al. Factors
10. Swart P. The accuracy of hysterosalpingography in influencing the success of salpingostomy techniques
the diagnosis of tubal pathology: a meta-analysis. for distal fimbrial obstruction. Obstet Gynecol.
Fertil Steril. 1995;64(3):486–91. 1978;52:591–6.
11. Mol BWJ. Reproducibility of the interpretation of 21. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of
hysterosalpingography in the diagnosis of tubal hydrosalpinx on pregnancy rates after in vitro fertilization-
pathology. Hum Reprod. 1996;11:1204–8. embryo transfer. Fertil Steril. 1998;70:492–9.
12. Patel MD. Likelihood ratio of sonographic findings in 22. Camus E, Poncelet C, Aucouturier JS, et al.
discriminating hydrosalpinx from other adnexal Hydrosalpinx and fertilization in vitro-embryo trans-
masses. AJR Am J Roentgenol. 2006;186:1033–8. fer abstention or salpingectomy? Abstention, salpin-
13. Guerriero S. Transvaginal ultrasonography associated gectomy, or salpingostomy? Gynecol Obstet Fertil.
with color Doppler energy it the diagnosis of hydro- 2000;29:466–73.
salpinx. Hum Reprod. 2000;15:1568–72. 23. Johnson N, van Voorst S, Sowter MC, et al. Surgical
14. Exacoustos C. Hysterosalpingo-contrast sonog- treatment for tubal disease in women due to undergo
raphy compared with hysterosalpingography and in vitro fertilization. Cochrane Database Syst Rev.
laparoscopic dye perturbation to evaluate tubal 2010;(3):CD002125.
patency. J Am Assoc Gynecol Laparosc. 2003;10(3): 24. Mijatovic V, Veersema S, Emanuel MH, et al. Essure
367–72. hysteroscopic tubal occlusion device for the treatment
15. Strandell A. The assessment of endometrial pathology of hydrosalpinx prior to in vitro fertilization-embryo
and tubal patency: a comparison between the use of transfer in patients with a contraindication for lapa-
ultrasonography and X-ray hysterosalpingography for roscopy. Fertil Steril. 2010;93:1338–42.
the investigation of infertility patients. Ultrasound 25. Galen DI, Khan N, Richter KS. Essure multicenter off-
Obstet Gynecol. 1999;14:200–4. label treatment for hydrosalpinx before in vitro fertil-
16. Chan CC. Comparison of three-dimensional ization. J Minim Invasive Gynecol. 2011;18:338–42.
hysterosalpingo-contrast-sonography and diagnostic 26. Murray DL, Sagoskin AW, Widra EA, Levy MJ. The
laparoscopy with chromopertubation in the assessment adverse effect of hydrosalpinges on in vitro fertiliza-
of tubal patency for the investigation of subfertility. tion pregnancy rates and the benefit of surgical correc-
Acta Obstet Gynecol Scand. 2005;84(9):909–13. tion. Fertil Steril. 1998;69:41–5.
Virtual Hysterosalpingography:
A New Diagnostic Technique 16
for the Study of the Female
Reproductive Tract
information similar to a conventional hysteros- one patient had an allergic reaction requiring
copy and falloposcopy (Figs. 16.7 and 16.8). medical treatment that improved all symptoms
The rate of complications with VHSG in in a very short time.
our experience is extremely low; in over 7,000 In known cases of allergy to iodine, we use
VHSG studies performed since 2006, we did gadolinium [6], a nonallergenic paramagnetic
not find any cases of infection, bleeding, or contrast with a much higher cost (3×) than the
other significant complications requiring hos- iodine contrast and therefore should not be
pitalization. In a few cases we observed intra- used routinely. We recently performed a com-
vascular passage of contrast, of which only parative study between iodine and gadolinium
202 P. Carrascosa and C.E. Sueldo
a b
Fig. 16.14 Submucous myoma seen by (a) endoscopic and (b) volume rendering views
removal and the possible success of the proce- insufficient amount (or pressure) of the contrast
dure. The use of VHSG permits the identification injected transcervically to complete the study.
of submucous myomas and determines the size Recently, the introduction of VHSG, as a new
and at times the percentage of intramural exten- diagnostic modality based on computer tomogra-
sion. We determined that the sensitivity and spec- phy, appears to be a step forward in the diagnosis
ificity of VHSG for the detection of submucous of fallopian tube pathology. Initially in our expe-
myomas are 91.7 and 100 %, respectively. The rience with this technique, using older CT equip-
volume rendering and endoscopic views clearly ment, we were not able to clearly visualize the
distinguish the endometrial-myometrial line and fallopian tubes. More recently, the use of 256-
localize the myoma and its relation with the row MDCT allows the study to be completed in
endometrial cavity (Fig. 16.14a, b). only 1.5 s, capturing the images in real time
while the filling material is still present in the
tubes or as it escapes through the fimbriated
Evaluation of the Fallopian Tubes ends. Through the filling of the fallopian tubes,
one is able to obtain volumetric images of high
Hysterosalpingography (HSG) has been the tra- resolution, which allows high image quality and
ditional method of evaluation of the fallopian virtual endoscopic navigation, similar to the
tubes for the last several decades; tubal patency visualization of the inner tubal lumen as
is clearly established as the dye injected passes described by conventional falloposcopy. Also,
through the fimbriated ends and disperses around the projection of volume rendering (VR) pro-
the peritoneal cavity near the adnexa. The diag- vides excellent definition of the fallopian tubes,
nosis of tubal obstruction when a hydrosalpinx is detecting the presence of hydrosalpinx
present is fairly certain; on the other hand the (Fig. 16.15), tubal obstructions (Fig. 16.5), etc.
lack of passage of dye into the fallopian tube may making VHSG a valuable diagnostic tool for the
represent a cornual spasm, a mucus plug, or assessment of tubal pathology.
206 P. Carrascosa and C.E. Sueldo
References
1. Carrascosa P, Capunay C, Sangster D, Carrascosa J.
Virtual colonoscopy: experience in 500 patients. Acta
Gastroenterol Latinoam. 2003;33(3):145–9.
2. Carrascosa P, Capunay C, Baronio M, Lopez EM,
Borghi M, Sueldo C, Papier S. Virtual hysteroscopy
by multidetector computed tomography. Abdom
Imaging. 2008;33(4):381–7.
3. Carrascosa P, Baronio M, Capunay C, Lopez E,
Borghi M, Sueldo C, Papier S. Multidetector CT vir-
tual hysterosalpingography in the investigation of the
uterus and fallopian tubes. Eur J Radiol. 2008;67(3):
531–35.
4. Carrascosa P, Baronio M, Capunay C, Lopez EM,
Sueldo C, Papier S. Clinical use of 64-row multislice
CT hysterosalpingography in the evaluation of female
factor infertility. Fertil Steril. 2008;90(5):1953–58.
5. Carrascosa P, Capunay C, Vallejos J, Baronio M,
Fig. 16.15 Bilateral hydrosalpinges
Lopez EM, Borghi M, Sueldo C, Papier S. 64 Row
multidetector CT virtual HSG. Abdom Imaging.
2009;34(1):121–33.
6. Carrascosa P, Capunay C, Vallejos J, Baronio M.
Conclusions Gadolinium vs iodine virtual HSG: an alternative for
patients allergic to iodine 64 row multidetector CT
VHSG should be considered a new and virtual HSG. Fertil Steril. 2008;90:S157.
improved diagnostic technique for the evalua- 7. Carrascosa P, Capunay C, Vallejos J, Lopez EM,
tion of the female reproductive tract over other Carrascosa J. Virtual HSG: a new multidetector CT
technique for evaluating the female reproductive sys-
existing diagnostic modalities, as it provides tem. Radiographics. 2010;30(3):643–61.
high-quality images of the cervix, uterine cav- 8. Celik O, Karkas H, Hascalik S, Tagluk M. Virtual
ity, and fallopian tubes. The versatility of the hysterosalpingography and hysteroscopy: assessment
image reconstructions allows for accurate of uterine cavity and fallopian tubes using 64-detector
CT data sets. Fertil Steril. 2010;93(7):2383–84.
visualization and diagnosis of diverse patho- 9. Carrascosa P, Capunay C, Vallejos J, Baronio M,
logic processes in the female reproductive Carrascosa J. Virtual hysterosalpingography: experi-
tract, many of them of high significance in ence with over 1000 consecutive patients. Abdom
infertility. The study is completed in a short Imaging. 2011;36(1):1–14.
10. Carrascosa P, Sueldo C, Capunay C, Baronio M,
amount of time, well tolerated, and with mini- Papier S. Virtual HSG in the diagnosis of bicornuate
mal radiation exposure as compared to con- vs septate uterus. Fertil Steril. 2011;96(5):
ventional HSG. The cost-benefit ratio, which 1190–92.
Ultrasound in Male Infertility
17
Landon W. Trost, David D. Casalino,
and Robert E. Brannigan
including patient assistance in localization of men, approximately 60–70 % of which were not
findings (e.g., pain), advancements in technology found clinically on physical examination alone
permit increasing resolution of underlying struc- [15, 16]. In reporting scrotal ultrasound findings
tures, assessments of vascular flow, and tissue in 545 infertile males with a mean age of 36 years,
characteristics (elastosonography). As the scro- Sakamoto and colleagues identified left varico-
tum typically does not consist of gas-containing celes in 313 (57.4 %), testicular microlithiasis in
or large calcified structures, a complete visualiza- 30 (5.5 %), epididymal cysts in 21 (3.9 %), right
tion of anatomy is available in multiple planes of varicoceles in 4 (0.8 %), testicular cysts in 3
imaging. (0.6 %), and a testicular tumor, intrascrotal hem-
The role for scrotal ultrasonography in the angioma, and hydrocele of the spermatic cord in
evaluation of the infertile male has been previ- 1 (0.2 %) patient each [16]. When compared to
ously established. Scrotal abnormalities have normospermic men, males with infertility have
been reported to occur in 38–65 % of infertile been confirmed to have significantly increased
Table 17.1 Ultrasound findings associated with male infertility
210
CBAVD congenital bilateral absence of the vas deferens, EDO ejaculatory duct obstruction, MAGI male accessory gland infections, SV seminal vesicles
17 Ultrasound in Male Infertility 211
rates of scrotal findings including varicocele epididymis measuring 7–8 mm in diameter, with
(35.5 % vs. 16 %), hydrocele (16.7 % vs. 8.7 %), increasing diameter associated with infectious
testicular microlithiasis (9.8 % vs. 2 %), processes [19]. Epididymitis as a clinical diagno-
epididymal enlargement (9 % vs. 2.6 %), and sis may be confirmed with ultrasound findings,
epididymal cysts (7.7 % vs. 2 %) [17]. which include an enlarged or thickened epididy-
Color flow Doppler adds further value to scro- mis with decreased echogenicity.
tal ultrasonography as it provides real-time assess- Infectious processes associated with infertility
ments with increased sensitivity to testicular are more broadly categorized as male accessory
blood flow. This is particularly useful in cases of gland infections (MAGI), which include infections
testicular ischemia, trauma, differentiation of tes- of the epididymis, seminal vesicles, prostate, or
ticular/paratesticular lesions, and infectious pro- bladder. Organisms commonly identified include
cesses. Elastosonography, which further assesses Chlamydia, Mycoplasma, and E. coli, although
tissue firmness, has also been reported to improve organisms such as tuberculosis have also been
characterization of testicular lesions <1 cm [18]. directly associated with infertility [20]. Although
Given the high rate of intrascrotal findings in relatively limited data exist and vary by region, the
infertile men, particularly the increased risk of sig- prevalence of MAGI and infertility have been
nificant pathology such as testicular tumors, scrotal reported to occur in up to 12 % of cases [21]. Several
ultrasound is becoming increasingly utilized in the studies have identified abnormal semen parameters
assessment of males presenting with infertility. in patients with MAGI including decreased motil-
ity, increased abnormal forms, and a higher rate of
DNA fragmentation [22, 23]. Despite these find-
Paratesticular Structures ings, the etiologic role of MAGI with male-factor
infertility remains unclear, as reports have failed to
Epididymis demonstrate consistent findings [24, 25].
Ultrasound evaluation of the epididymis is per- Epididymal masses may be further defined as
formed to assess for the presence of infectious being solid versus cystic. Solid masses are most
findings, masses or lesions, or evidence of epi- commonly benign adenomatoid tumors with
didymal obstruction. Measurements of the epi- additional lesions encountered including cystad-
didymis are obtained at the caput with a normal enoma, mesothelioma, or sarcomas (Fig. 17.3).
212 L.W. Trost et al.
Cysts of the epididymis are benign lesions congenital etiology were found to have higher
commonly located at the head of the epididymis rates of ectasia in the epididymal head with taper-
and may represent simple cysts (no sperm in ing and absence of the epididymal body and tail
fluid) or spermatoceles (sperm in fluid) (Fig. 17.4). [28]. Acquired azoospermia, in contrast, exhib-
Although epididymal cysts are found more com- ited increased rates of epididymal body and tail
monly among men with infertility than those duct ectasia and an epididymal inflammatory
without, they have not been shown to result in mass.
epididymal obstruction or infertility [17]. In per-
forming surgical resection of spermatoceles and Varicocele
hydroceles, epididymal injury has been reported Varicoceles are reported to occur in approxi-
to occur in 17 and 6 % of cases, respectively [26]. mately 15–25 and 35–60 % of fertile and infertile
A more recent report by Kauffman and colleagues males, respectively, and remain the most com-
describing a microsurgical technique of sper- mon, reversible cause of male-factor infertility
matocelectomy demonstrated no changes in [16, 17, 29]. Clinical varicoceles are more com-
sperm count among patients with pre- and post- mon on the left and are graded on a scale of I–III
operative semen analyses, suggesting the absence with grade I varicoceles palpable in the standing
of iatrogenic epididymal obstruction [27]. position with Valsalva maneuver, grade II palpa-
In addition to identifying paratesticular masses ble in the standing position without Valsalva
and infectious processes, improvements in ultra- maneuver, and grade III in the standing position
sound resolution have led to its utility in grossly visible. Intratesticular varicoceles identi-
diagnosing epididymal obstruction. Clinical and fied on ultrasonography are relatively uncommon
laboratory findings of epididymal obstruction and are likely of minimal significance for male-
include normal volume ejaculate with oligo- or factor infertility [30].
azoospermia. Imaging findings may demonstrate Ultrasonography is able to detect varicoceles
epididymal enlargement with prominence of with a 97 % sensitivity and 94 % specificity [31]
the rete testis and a hypoechoic appearance. (Fig. 17.5). When using the commonly accepted
Epididymal findings have further been described definition of internal spermatic veins measuring
to help delineate between congenital and acquired ≥3 mm in diameter, ultrasound has been demon-
causes of obstructive azoospermia. In a report of strated to have 53 % sensitivity and 91 % speci-
211 infertile males undergoing scrotal ultrasonog- ficity in identifying varicoceles when compared
raphy for obstructive azoospermia, men with a to physical examination [32].
17 Ultrasound in Male Infertility 213
oligospermia in patients with testicular volumes associated with impaired future fertility [70].
<10 mL (normal 15–20 mL), including length Although there is ongoing debate as to the optimal
<3.5 cm, depth <1.75 cm, and width <2.5 cm time for orchiopexy, there is increasing consensus
with direct correlations noted with sperm density, that earlier repair (at 6–12 months of age) results
total sperm count, motility, and FSH and LH lev- in improved long-term fertility potential [71].
els [62]. Diminished testicular volume may be In evaluating future paternity in males previ-
secondary to several etiologies including varico- ously undergoing orchiopexy for undescended
celes, current or previous cryptorchidism, post- testes, Lee and colleagues observed successful
pubertal mumps, Klinefelter’s syndrome, or paternity within 12 months in 90 and 65 % of
hormonal abnormalities, among others. patients with prior unilateral or bilateral cryptor-
In addition to estimating testicular volume, chidism, respectively [72]. This was compared
Doppler ultrasound may be utilized to identify and against control subjects who demonstrated a
assess testicular microcirculation. As spermato- 93 % rate of successful paternity. The author con-
genesis is dependent upon microcirculatory perfu- cluded that patients with unilateral cryptorchi-
sion, diminished testicular blood flow as visualized dism have equal rates of paternity to controls,
on ultrasound directly correlates with elevated while patients with repaired bilateral cryptorchi-
FSH levels and decreased sperm quality [63–65]. dism continue to have impairments in paternity
Resistive indices may be obtained to further quan- lifelong. Further findings indicated that although
tify testicular tissue perfusion and are commonly patients with unilateral cryptorchidism demon-
obtained at the level of the testicular artery and via strated equal rates of paternity, they exhibited
intratesticular branches near the rete testis. elevated levels of FSH, decreased inhibin B, and
Intratesticular branch resistive indices less than preserved levels of LH/testosterone compared to
0.6 have been suggested as a threshold level of controls, suggesting subclinical impairments in
normal tissue perfusion, with elevated levels spermatogenesis.
indicative of impaired microcirculation [66, 67]. To further evaluate the effect of timing of
Testicular ultrasound may assist in differenti- orchiopexy on paternity outcomes among azo-
ating between obstructive and nonobstructive ospermic patients undergoing IVF, Wiser and
etiologies for infertility. Moon and colleagues colleagues found no difference in rates of sperm
demonstrated a reduced median testicular vol- retrieval, fertilization, implantation, pregnancy,
ume in patients with nonobstructive (8.3 mL, or live birth rates among men with a history of
range 1.2–16.4) versus obstructive (11.6 mL, unilateral (2 patients) or bilateral (40 patients)
range 7.7–25.8) azoospermia [68]. Similarly, orchiopexy at ≤10 years of age versus >10 years
patients with azoospermia secondary to obstruc- [73]. Despite the late repairs performed, 60 % of
tion were shown to have dilation of the mediasti- patients were found to have sperm at the time of
num testis, epididymis, and intrascrotal portion testicular sperm extraction (TESE).
of the vas deferens. The sensitivity, specificity, The role for ultrasonography is likely limited
and accuracy for differentiating obstructive ver- in the initial evaluation of patients presenting
sus nonobstructive azoospermia were noted to be with cryptorchidism (Fig. 17.6). Tasian and
82.1, 100, and 87.5 %, respectively. Further find- colleagues performed a meta-analysis to review
ings which suggest a nonobstructive etiology the diagnostic performance of ultrasonography
include reduced or absent testicular vessels, with among patients with non-palpable cryptorchi-
isolated regions of visualized blood flow poten- dism with results demonstrating a sensitivity of
tially indicative of residual spermatogenic pro- 45 % and specificity of 78 % in localizing non-
duction [69]. palpable testes [74]. These findings increased or
decreased in the probability of actually finding
Cryptorchidism an intra-abdominal testicle based on imaging
Cryptorchidism is estimated to occur in approxi- from 55 to 64 % and 49 %, respectively. Given
mately 2–5 % of boys born at term and is these low rates of precision, the authors indicated
216 L.W. Trost et al.
that abdominal-scrotal ultrasonography did not reported to occur in 1.2 % of infertile men and
reliably assist in the management decision tree are of unclear significance [81].
for patients with non-palpable testes and was Scrotal hydroceles represent accumulation of
therefore of limited utility. Older patients pre- fluid within the tunica vaginalis and are com-
senting with non-palpable testes may more reli- monly the result of prior trauma, inflammatory,
ably undergo MRI in lieu of ultrasound to further or infectious processes. Although there is a
assist in localization of intra-abdominal testes. known increased prevalence of hydroceles in
Although there is likely limited utility for infertile males (17 % vs. 9 %), it is unclear if
ultrasound during the initial evaluation of unde- treatment of the hydrocele results in improved
scended testes, patients with a history of cryptor- semen parameters or fertility [17]. Epididymal
chidism have a known two- to eightfold increased injury has been reported to occur in up to 6 % of
risk of testicular cancer, with 5–10 % of men patients undergoing hydrocelectomy, and this
with testicular cancer having a prior history of injury may result in impaired fertility, including
cryptorchidism [70, 75]. This finding has led azoospermia [26, 82]. A long-term follow-up
some authors to advocate for the routine use of study of children undergoing inguinal hernia
scrotal ultrasonography as a screening tool for repairs demonstrated a 5 % infertility rate, with
testicular malignancy among patients presenting 15 % of patients previously undergoing hydroce-
with infertility, particularly those with a history lectomy at the time of herniorrhaphy [83]. To our
of cryptorchidism [76–78]. knowledge, no study has thus far examined the
impact of hydrocelectomy on semen parameters
Cysts, Hydrocele, Infectious Processes in infertile males.
Testicular ultrasonography is an excellent modal- Infectious processes of the testicles visualized
ity for identifying benign testicular structures on ultrasonography may frequently demonstrate
including cysts, hydroceles, and infectious pro- decreased echogenicity, increased heterogene-
cesses. Intratesticular cysts are identified as ity, hypervascularity, and testicular enlargement
hypoechoic/anechoic regions, can represent cys- (Fig. 17.7). Similar to MAGI, orchitis may be
tic dilation of the rete testes, and may be a result secondary to infectious (E. coli, Chlamydia,
of postinfectious or posttraumatic epididymal Mycobacterium, mumps, among others) or non-
obstruction [79, 80]. Testicular cysts have been infectious etiologies. Although there remains
17 Ultrasound in Male Infertility 217
limited epidemiological data on the impact of mumps, with 16–65 % occurring bilaterally [86].
orchitis on overall infertility, previous reports Among patients with a history of mumps orchitis,
have demonstrated oligospermia and azoosper- approximately 50 % will demonstrate some
mia occurring at follow-up among 15–33 % and degree of testicular atrophy with one study dem-
8–27 % of males with unilateral epididymo- onstrating complete atrophy of seminiferous
orchitis, respectively [84, 85]. Subsequent tubules in 38 % of biopsies obtained [24, 87, 88].
pathologic analysis of patients with prior epi- These findings may be persistent, even in the set-
didymo-orchitis has demonstrated scarring of ting of appropriate acute phase treatment [88].
the seminiferous tubules involving both the ipsi-
lateral and contralateral testicles with chronic Testicular Masses
inflammatory changes noted [84]. Males presenting with infertility are at increased
Mumps orchitis is the most common compli- risk for both immediate and subsequent develop-
cation of pubertal and postpubertal mumps and is ment of testicular malignancy (Fig. 17.8). The
reported to occur in 5–37 % of patients with reported incidence of testicular malignancy in
218 L.W. Trost et al.
infertile males ranges from 0.2 to 1 % and is esti- Of interest, testicular ultrasound findings fol-
mated to be 20–100-fold more common than in the lowing sperm retrievals including PESA, TESA,
general population [15, 19, 77, 89–92]. Men with and TESE demonstrate focal abnormalities which
abnormal semen parameters are also at an increased persist in 77 and 54 % of patients at 5 days and
risk of testicular malignancy with an incidence 6 months, respectively [98]. These findings are
ratio of 1.6 [93]. Additionally, infertile men con- not to be misinterpreted as concerning for malig-
tinue to be at risk for malignancy following sterility nancy in this otherwise at-risk population.
with one report of subsequent development of tes-
ticular cancer occurring 14 years after initial evalu- Microlithiasis
ation [78]. These findings have led some authors to Microlithiasis is identified on testicular ultraso-
advocate for the routine use of ultrasound during nography as hyperechoic regions measuring
the initial infertility evaluation [76, 77]. 3 mm or smaller without definitive shadowing
The increasing utilization and improved reso- present (Fig. 17.9). Among asymptomatic
lution of scrotal ultrasonography have addition- patients undergoing screening scrotal sonogra-
ally resulted in an increased rate of detection of phy, testicular microlithiasis is reported in
testicular lesions with series reporting incidental 2.4–6 % of individuals with a higher frequency
testicular masses in 1–6 % of infertile patients of testicular microlithiasis present in infertile
[77, 91, 94, 95]. When the criteria for an inciden- males (10 % vs. 2 % in controls) [99–101].
tal testicular lesion are broadened to include Despite the known association between testicular
hypoechoic/hyperechoic regions, 34 % (49/145) microlithiasis and infertility, Yee and colleagues
of azoospermic patients are found to have focal reported no differences noted in semen analyses
abnormalities, with only one of the 49 cases sub- between infertile males with microlithiasis ver-
sequently found to represent malignancy [92]. sus those without microlithiasis [100].
This increased rate of detection has also led to Microlithiasis has additionally been associ-
an altered ratio of benign versus malignant ated with a relative risk of testicular malignancy
lesions [96]. Carmignani and colleagues reported of 21.6, with testicular tumors occurring in
on a series of patients undergoing scrotal ultraso- approximately 6 % of patients with microlithiasis
nography for infertility evaluations as well as [102, 103]. Patients with microlithiasis and uni-
multiple causes (varicoceles, testicular pain) with lateral testicular germ cell tumors have an
benign pathology found at surgical excision in increased incidence of carcinoma in situ in the
75–80 % of incidentally discovered testicular contralateral testicle, with some authors recom-
lesions [91, 94]. Other groups have reported mending routine biopsy of the contralateral testi-
higher ratios of malignancies occurring in 50 % cle [104, 105]. However, subsequent surveillance
(2/4)–71 % (7/9) of incidental lesions, albeit of patients with isolated testicular microlithiasis
these series were comprised of relatively small followed over a period of 7 years has not been
numbers [77, 89]. When benign findings are shown to develop malignancy [104].
reported on frozen section with later determina- Given the increased incidence of testicular
tion of malignancy on final pathology, subse- microlithiasis with malignancy and indetermi-
quent orchiectomy specimens were found to have nate clinical relevance of carcinoma in situ, rou-
no residual malignancy detected [89]. tine surveillance is commonly recommended
Given the higher rate of incidental, benign with repeat self-testicular exams with or without
lesions, close observation with repeat physical serial scrotal ultrasonography [102, 103].
examinations and ultrasonography has been pro-
posed for non-palpable testicular lesions, particu- Testicular Torsion/Trauma
larly those <1 cm [97]. Despite the increasing Scrotal ultrasonography is an excellent imaging
rate of detection of benign testicular lesions, the modality for the rapid assessment and triage of
decision as to perform radical excision, testicular testicular injuries. In the case of testicular trauma,
sparing surgery, or active surveillance remains an ultrasonography provides visualization of the
area of active debate. tunica albuginea and assessment of rupture of
17 Ultrasound in Male Infertility 219
seminiferous tubules, scrotal and testicular or straightened spermatic cord. In contrast, early
hematomas, and incidental testicular lesions or partial testicular torsion may present with
[106]. In patients with an acute scrotum, Doppler venous congestion and preserved arterial inflow.
ultrasonography is able to differentiate between Complete torsion is characterized by the absence
infectious processes and testicular torsion [107]. of testicular blood flow, frequently with a proxi-
Epididymitis and/or orchitis may present with mal “whirlpool” sign (Fig. 17.10). Given the
various imaging findings including diffuse occasional difficulty in identifying early ischemic
hypoechogenicity, enlarged epididymis/testicle, injuries, alternative imaging techniques includ-
increased heterogeneity, increased Doppler flow, ing pulse inversion ultrasound may eventually
220 L.W. Trost et al.
offer a superior assessment in cases of acute isch- infertility including prostatic cysts and ejacula-
emia [108]. tory duct obstruction (EDO) and may be used as
Multiple studies have examined hormonal and an adjunctive measure in cases of suspected pros-
semen profiles following unilateral testicular tatic infections or abscesses. Infertile males with
loss. In patients undergoing orchiectomy second- EDO or prostatic cysts may present with varied
ary to testicular trauma, impaired hormonal and accompanying symptoms including perineal
semen characteristics were identified including pain, low-volume ejaculate, hematospermia,
decreased sperm density and elevated FSH/LH painful ejaculation, or epididymal tenderness,
compared to fertile controls [109]. Studies com- among others [6, 23, 24].
paring outcomes following orchiectomy versus
orchiopexy for acute testicular torsion have Cysts
reported varied results. Arap and colleagues Prostatic cysts are frequently identified in cases
reported decreased sperm counts and morphol- of obstructive azoospermia/severe low-volume
ogy with preserved hormonal levels in patients oligospermia and may be further classified based
undergoing either orchiectomy or orchiopexy on location including peripheral/parenchymal,
while a second study noted decreased inhibin B midline, or paramedian. Midline cysts are typi-
levels in both groups, indicating possible persis- cally of a Mullerian embryologic origin and usu-
tent subclinical gonadal dysfunction [110, 111]. ally do not contain sperm, while paramedian
Other studies demonstrate decreased inhibin B cysts are typically of Wolffian duct origin and
levels, elevated FSH, and impaired sperm density may contain sperm upon aspiration [115, 116].
in patients undergoing orchiectomy compared to Midline cysts may further be differentiated into
orchiopexy [112, 113]. utricular cysts which are typically 15 mm in
diameter or true Mullerian cysts which may be
larger and extend posteriorly beyond the prostatic
Transrectal Ultrasonography base (Fig. 17.11). Peripheral cysts may be
acquired following infectious processes or rarely
Transrectal ultrasonography (TRUS) is fre- may represent benign or malignant processes
quently utilized during the evaluation of male including multilocular cystadenoma/cystadeno-
infertility in cases of low-volume ejaculate, azo- carcinoma [117, 118].
ospermia on semen analysis, or palpable asym-
metry on digital rectal exam in order to rule out Ejaculatory Duct Obstruction
ejaculatory duct obstruction or to evaluate for the The ejaculatory duct is minimally visualized on
presence/absence of seminal vesicles. TRUS ultrasonography in the absence of obstruction
identifies pathologic findings (hypoplastic/atro- and enters the urethra at the level of the verumon-
phic SVs, vasal agenesis, among others) in 75 % tanum with standard lengths of approximately
of azoospermic males, compared to no pathology 4–8 mm and a lumen of 2 mm. In contrast, ejacu-
in 65 % of non-azoospermic males [114]. latory duct obstruction (EDO) is often well dem-
TRUS is frequently performed with a 6.5– onstrated in the sagittal view and is commonly
7.5 MHz probe with the bladder partially filled. associated with dilation of the ejaculatory duct,
Patients are placed in the lateral decubitus and seminal vesicles, and occasional ejaculatory duc-
knee-to-chest position and may alternatively be tal calcifications.
placed in the prone jackknife or dorsolithotomy Ejaculatory duct obstruction may occur sec-
positions depending on the surgical scenario. ondary to congenital processes including com-
pression by prostatic cysts or ejaculatory duct
atresia/stenosis or may be acquired from infec-
Prostate tions (UTI, sexually transmitted diseases, tuber-
culosis), inflammatory conditions, traumatic
Transrectal ultrasonography is an excellent strictures, or stone formation or following prior
modality to assess obstructive etiologies of surgical procedures (transurethral resection of
17 Ultrasound in Male Infertility 221
a a
b b
includes ejaculatory ductal dilation utilizing ARTs. Several studies have examined the use of
seminal vesicoscopy, with one study demonstrat- power Doppler at the time of TESE to identify
ing equal efficacy and fewer complications com- regions with increased sperm density to improve
pared to TURED [136]. the likelihood of sperm retrieval.
Calcifications of the prostate are commonly Herwig and colleagues reported on the use of
visualized on transrectal ultrasonography and are a laser Doppler scanner to determine perfusion
of unlikely significance in regards to infertility. rates and noted higher sperm quality and quantity
Increasing calcifications are associated with age based on underlying tissue perfusion. In patients
and are present in 23 % of asymptomatic males with at least 70 tissue perfusion units (TPU),
aged 20–29 versus 83 % in males 60–69 years 72.3 % of biopsies identified progressive sperm
old [137]. compared to 13.3 % among those with ten or
fewer TPUs [65, 144]. A similar study performed
Seminal Vesicles in patients with nonobstructive azoospermia
The SVs are clearly visualized on TRUS cepha- demonstrated successful sperm extractions in 38
lad to the prostate and posterior to the bladder and 14 % of patients with subjective good versus
and may result in decreases to semen volume, poor vascularity, respectively [145]. A more
pH, and fructose concentration when abnormali- recent Cochrane review evaluating the efficacy
ties are present. Although there is variability in of various techniques for sperm aspiration dem-
reported standard SV lengths, normal, hypoplas- onstrated no statistically significant improvement
tic, and atrophic are commonly classified as in ultrasound-guided testicular sperm aspiration
occurring at >24, 17–24, and <17 mm, respec- versus aspirations performed without ultrasound
tively, without significant change following ejac- [146]. It is not clear, however, how these tech-
ulation [137–139] niques compare to the results reported by Herwig
Dilation of the SVs resulting from mechanical and colleagues, and therefore the role for ultra-
obstruction, particularly when >15 mm, is most sound at the time of sperm extraction remains
commonly associated with EDO as described unclear.
previously. Dilation may also be seen in patients Further techniques to enhance extraction of
with adult polycystic disease and infertility, ipsi- sperm at the time of TESE are being developed
lateral upper urinary tract agenesis (Zinner syn- with Ramkumar and colleagues recently report-
drome), or diabetes mellitus and is felt to be ing their initial experience with microdissection
secondary in these cases to SV hypotonicity probe-TESE (MP-TESE) [147]. The procedure
rather than anatomic obstruction [140–142]. utilizes a microfabricated silicon microprobe
Absence of the SVs is associated with cystic with an ultrasonic horn actuator and strain gauges
fibrosis and unilateral/bilateral absence of the vas to detect tissue interface boundaries between
deferens as well as renal anomalies including seminiferous tubules. This reportedly improves
renal agenesis, ectopia, and horseshoe, among size discrimination of seminiferous tubules with
others [49, 51, 54, 55]. Infections of the seminal the average diameter of sperm containing tubules
vesicles may also be visualized on ultrasound and noted to be 41.2 +/− 1.6 μm per report. Although
have been reported to impact fertility with this technology reports intriguing findings, it has
improved semen parameters following antibiotic yet to be validated by other groups and remains
therapy [143]. experimental at the present time.
Conclusion
Assisted Reproductive Techniques Ultrasonography, including adjunctive tech-
niques of power and duplex Doppler, is
In addition to the initial evaluation of the infertile increasingly utilized in the evaluation and
male, ultrasound has been increasingly utilized in management of male-factor infertility. Scrotal
the performance of sperm retrieval for use in and transrectal ultrasonographies provide
17 Ultrasound in Male Infertility 223
both anatomic and functional information to of the American Society for Reproductive Medicine.
assist in identifying underlying etiologies for Report on optimal evaluation of the infertile male.
Fertil Steril. 2006;86(5 Suppl 1):S202–9.
infertility including infectious processes and 11. Male Infertility Best Practice Policy Committee
varicoceles as well as differentiating between of the American Urological Association; Practice
obstructive (EDO, epididymal obstruction, Committee of the American Society for Reproductive
absence of the vas deferens) and nonobstruc- Medicine. Report on evaluation of the azoospermic
male. Fertil Steril. 2006;86(5 Suppl 1):S210–5.
tive causes. Ultrasonography may additionally 12. Practice Committee of the American Society for
detect associated findings including testicular/ Reproductive Medicine. Report on management
paratesticular lesions, upper tract renal anom- of obstructive azoospermia. Fertil Steril. 2006;86
alies, testicular microlithiasis, hydroceles, (5 Suppl 1):S259–63.
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a limited role with ARTs, an emerging body S247–249.
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inversion US imaging of testicular ischemia: quanti- obstruction. BJU Int. 1999;84:1050.
tative and qualitative analyses in a rabbit model. 127. Jarow JP. Seminal vesicle aspiration of fertile men.
Radiology. 2006;239:718. J Urol. 1996;156:1005.
109. Lin WW, Kim ED, Quesada ET, et al. Unilateral tes- 128. Purohit RS, Wu DS, Shinohara K, et al. A prospec-
ticular injury from external trauma: evaluation of tive comparison of 3 diagnostic methods to evaluate
semen quality and endocrine parameters. J Urol. ejaculatory duct obstruction. J Urol. 2004;171:232.
1998;159:841. 129. Eisenberg ML, Walsh TJ, Garcia MM, et al.
110. Arap MA, Vicentini FC, Cocuzza M, et al. Late hor- Ejaculatory duct manometry in normal men and in
monal levels, semen parameters, and presence of patients with ejaculatory duct obstruction. J Urol.
antisperm antibodies in patients treated for testicular 2008;180:255.
torsion. J Androl. 2007;28:528. 130. Stricker HJ, Kunin JR, Faerber GJ. Congenital pros-
111. Romeo C, Impellizzeri P, Arrigo T, et al. Late hor- tatic cyst causing ejaculatory duct obstruction: man-
monal function after testicular torsion. J Pediatr agement by transrectal cyst aspiration. J Urol. 1993;
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112. Anderson MJ, Dunn JK, Lipshultz LI, et al. Semen 131. Heshmat S, Lo KC. Evaluation and treatment of
quality and endocrine parameters after acute testicu- ejaculatory duct obstruction in infertile men. Can J
lar torsion. J Urol. 1992;147:1545. Urol. 2006;13 Suppl 1:18.
113. Taskinen S, Taskinen M, Rintala R. Testicular tor- 132. Schroeder-Printzen I, Ludwig M, Kohn F, et al.
sion: orchiectomy or orchiopexy? J Pediatr Urol. Surgical therapy in infertile men with ejaculatory duct
2008;4:210. obstruction: technique and outcome of a standardized
114. Engin G, Kadioglu A, Orhan I, et al. Transrectal US surgical approach. Hum Reprod. 2000;15:1364.
and endorectal MR imaging in partial and complete 133. Meacham RB, Hellerstein DK, Lipshultz LI.
obstruction of the seminal duct system. A compara- Evaluation and treatment of ejaculatory duct obstruc-
tive study. Acta Radiol. 2000;41:288. tion in the infertile male. Fertil Steril. 1993;59:393.
115. Parsons RB, Fisher AM, Bar-Chama N, et al. MR 134. Kadioglu A, Cayan S, Tefekli A, et al. Does response
imaging in male infertility. Radiographics. 1997;17: to treatment of ejaculatory duct obstruction in
627. infertile men vary with pathology? Fertil Steril.
116. Jarow JP. Transrectal ultrasonography of infertile 2001;76:138.
men. Fertil Steril. 1993;60:1035. 135. Yurdakul T, Gokce G, Kilic O, et al. Transurethral
117. Tuziak T, Spiess PE, Abrahams NA, et al. resection of ejaculatory ducts in the treatment of
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118. Park JP, Cho NH, Oh YT, et al. Giant multilocular 136. Xu B, Niu X, Wang Z, et al. Novel methods for the
prostatic cystadenoma presenting with obstructive diagnosis and treatment of ejaculatory duct obstruc-
aspermia. Yonsei Med J. 2007;48:554. tion. BJU Int. 2011;108:263.
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137. Zackrisson B, Hugosson J, Aus G. Transrectal ultra- 143. Andrade-Rocha FT. Unusual presentation of seminal
sound anatomy of the prostate and seminal vesicles vesiculitis in an infertile man. Can J Urol. 2007;14:
in healthy men. Scand J Urol Nephrol. 2000;34:175. 3750.
138. Hernandez AD, Urry RL, Smith Jr JA. Ultrasono- 144. Herwig R, Tosun K, Pinggera GM, et al. Tissue
graphic characteristics of the seminal vesicles after perfusion essential for spermatogenesis and out-
ejaculation. J Urol. 1990;144:1380. come of testicular sperm extraction (TESE) for
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estimation of the seminal vesicles by means of tran- 21:175.
srectal ultrasonotomography: a preliminary report. 145. Tunc L, Alkibay T, Kupeli B, et al. Power Doppler
Br J Urol. 1975;47:695. ultrasound mapping in nonobstructive azoospermic
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141. Pace G, Galatioto GP, Guala L, et al. Ejaculatory duct Techniques for surgical retrieval of sperm prior to
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Part III
Ultrasound in Infertility Treatment
Ultrasound in Follicle Monitoring
for Ovulation Induction/IUI 18
Josef Blankstein, Shumal Malepati, and Joel Brasch
Estrogen
is characterized by relatively elevated levels of Cohort of Maturation
growing
FSH and low levels of LH, estrogens, and proges- follicles
terone. During this early cycle phase, the growth DF
of a number of follicles, referred to as a cohort of
follicles, is initiated. It has been demonstrated DF
that this oocyte selection process involves two N-1 N-1
N N-1
main processes. First, a number of follicles are Atresia
recruited, and second, a number of growing fol-
licles are selected out of the recruited group to 1 – 3 5 – 7 9 – 11 13 – 15
continue towards maturation. Studies supporting Days of the menstrual cycle
the “dominant follicle theory” support that new
follicular growth is arrested in the presence of a Fig. 18.1 Cyclic ovarian changes: time course for
single dominant follicle. Provision of more recruitment, selection, and ovulation of the dominant
ovarian follicle, with onset at atresia among other follicles
gonadotropins in stimulated or induced cycles by
of the cohort (Adapted from Hodgen [40])
clomiphene citrate or human menopausal gonad-
otropins or both will violate the normal mono-
ovular quota. Moreover, the responsiveness of The dominant follicle is selected due to its
other follicles to human menopausal gonadotro- responsiveness to elevated circulatory FSH lev-
pin (hMG) therapy was found to be suppressed in els. It is not uncommon to observe two, or more,
the presence of the overt dominant follicle, while follicles developing to approximately 10 mm,
the same dose of hMG early in the follicular with one achieving dominance and growing,
cycle increased the number of follicles recruited while the others regress. LH reinitiates meiosis of
and/or selected for maturation (Fig. 18.1). the oocyte, and typically, ovulation occurs within
In the normal ovulatory cycle, the dominant 36 h of its “surge.”
follicle steadily increases in size, while the accom- Small follicles can be visualized easily as
panying smaller follicles are not observed to show echo-free, smooth-walled, structures and usually
a similar increase. Thus, while one or more folli- lie towards the periphery of the more echogenic
cles will grow to full maturity and ovulate, others ovarian tissue. As the follicle matures, more fluid
are destined to atresia and degeneration. This fol- is released and accumulates into its center. The
licular atresia appears to involve genetically pro- granulosa cell mass, lining the inner of the folli-
grammed cell death within the oocyte – a nuclear cle, increases. Microscopically the oocyte itself,
cell death referred to as apoptosis. which is less than one-tenth of 1 mm, is sur-
Ovarian secretion of estradiol (E2) and estrone, rounded by a cluster of granulosa cells. This
from the granulosa cells, promotes follicular mat- complex surrounding the oocyte is termed the
uration by increasing follicular sensitivity to cumulus oophorus. It measures approximately
gonadotropin stimulation. This is accepted to be 1 mm and can occasionally be depicted by trans-
a gonadotropin receptor-mediated process. vaginal scan (TVS) adjacent to the wall of a
The temporal relationship between hormonal mature follicle. Immediately prior to ovulation
profile and follicular development with respect to the cumulus separates from the wall and floats
ovulation is summarized in Fig. 18.2. freely within the follicle’s center. Today, even
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 233
15
FSH
32
21
LH
24
Estrogens 82
8
Progesterone
10
0
12 10 8 6 4 2 0 2 4 6 8 10 12
Fig. 18.2 Temporal relationships between hormonal peaks are given in hours prior to ovulation (circled num-
profile and follicular development with respect to ovula- bers) (Courtesy of Dr. Josef Blankstein)
tion. Significant hormone levels and their preovulatory
with the enhanced resolution afforded by TVS, insemination cycles with clomiphene citrate or
the attached or floating cumulus is only rarely letrozole was found to be in the 23–28 mm
seen. However, new technological developments, range. The optimal size of the leading follicle
mainly high-resolution probes (40 MHz), have was not statistically significantly different
enabled clinical researchers to clearly visualize between cycles using letrozole or clomiphene
the antrum, the granulosa (GC), and the theca citrate and was closely related to the endometrial
cells (TC) in a preovulatory follicle (Fig. 18.3). thickness [5]. Intrafollicular echoes may be
Monitoring ovarian response to ovulation observed with mature follicles, probably arising
induction can be achieved by ultrasonography from clusters of granulosa cells that shear off the
alone. The dimensions of the growing follicles wall near the time of ovulation. After ovulation,
are plotted from around day 8 of stimulation the follicular wall becomes irregular as the fol-
together with a measurement of endometrial licle becomes “deflated.” The fresh corpus
thickness. The mean follicular growth rate is luteum usually appears as a hypoechoic struc-
1.4 mm/day in spontaneous menstrual cycle and ture with an irregular internal wall and may con-
1.7 mm during ovarian stimulation cycles [4]. tain some internal free-floating or fixed echoes
Mature follicles, those containing a mature that correspond to hemorrhage. As the corpus
oocyte, typically measure from 17 to 25 mm in luteum develops 4–8 days after ovulation, it
average inner dimension. The optimal follicular appears as an echogenic structure of approxi-
size before triggering ovulation in intrauterine mately 15 mm in size. Its wall is thickened due
234 J. Blankstein et al.
Fig. 18.3 Antrum, granulosa (GC), and the theca cells (TC) in a preovulatory follicle (Reprinted from Palleres et al.
[41]. With permission from Elsevier)
The formation of new blood vessels is taking vascular morphology showed that the capillary
place in the ovary during folliculogenesis and network of preovulatory follicles was more
corpus luteum formation, as well in the endome- extensive than that of other follicles, conse-
trium mainly during the follicular phase. It was quently proposing that initiation and maintenance
already recognized as early as in 1926 that neo- of follicular growth depends on development of
vascularization may be of prime importance in the follicular microvasculature.
the growth and selection of ovulatory follicles, in A study done by Shrestha et al. [6] to deter-
addition to the subsequent development and mine whether ovarian perifollicular blood flow
function of the corpus luteum. Studies of ovarian (PFBF) in the early follicular phase (EFP) is
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 235
associated with treatment outcome of IVF their implications on the health service is also
showed high-grade ovarian PFBF in the EFP well recognized. Since there were higher multi-
during IVF to be associated with a higher clinical ple pregnancy rates in stimulated intrauterine
pregnancy rate. Coulam et al. [7] correlated peak insemination (IUI) cycles with uniformly high-
systolic velocity (PSV) of individual follicles grade follicular vascularity, perhaps these cycles
with oocyte recovery, fertilization rate, and in particular should be considered for follicle
embryo quality in women undergoing in vitro reduction or even cancellation. This may poten-
fertilization (IVF) and embryo transfer. They tially reduce the number of developmentally
assessed the role of quantitative and qualitative competent oocytes that have a higher capability
indices of follicular vascularity in predicting of producing more viable embryos for implanta-
pregnancy after IVF and embryo transfer. Women tion [10].
who had PSV ≥10 cm/s in at least one follicle on In a recent prospective study by Ivanovsky
the day of hCG administration more often et al. [11], vascular impedance was calculated
became pregnant than those with PSV <10 cm/s using the uterine artery and arcuate artery pulsa-
(P = 0.05). Nargund et al. [8] demonstrated that tility resistance and velocity on the day of hCG
there was a 70 % chance of producing a grade I administration. It was found that optimal uterine
or II embryo if the follicular blood velocity was receptivity can be accomplished by reduced vas-
>10 cm/s, compared with 14 % if the PSV was cular resistance and increased blood flow.
<10 cm/s. This study concluded that there is a Obviously more studies are needed to confirm
physiological relationship between follicular their results.
blood velocity, oocyte recovery, and the produc- The relationship between endometrial and
tion of a high-grade preimplantation embryo, subendometrial blood flow and pregnancy after
which may form the basis of a useful clinical intrauterine insemination was examined in a pro-
test. Jayaprakasan et al. [9] on the other hand spective study. The main outcome measured were
concluded that ovarian vascularity as measured vascularization index (VI), flow index (FI), and
by 3D ultrasound is not decreased in women who vascularization flow index (VFI) of the endome-
demonstrate poor ovarian response to controlled trium as well as those of the subendometrial
ovarian stimulation as part of assisted reproduc- region. These measurements were analyzed in
tion treatment. relation to IUI outcome, pregnant versus non-
Perifollicular vascular perfusion appears to be pregnant. It was found that the pregnant group
an important factor in determining the outcome had higher endometrium VI, FI, and VFI scores
of stimulated cycles, and may have clinical impli- than the nonpregnant group. The subendometrial
cations in assisted reproduction therapy. As there region VI, FI, and VFI scores did not differ
were low pregnancy rates and oocyte retrieval in between the groups [12] (Fig. 18.5).
the group of women with uniformly low-grade
vascularity, the identification of these cycles
would be valuable in terms of counseling with Ovulation Induction and
regard to the potential outcome in that cycle. Intrauterine Insemination (IUI)
Ideally, the identification of these women (who
may also be “low recruiters”) earlier in the cycle In conjunction with ovulation induction, IUI is a
would be helpful. This could allow the cancella- way to potentially overcome various fertility
tion of treatment after careful counseling, on the problems such as oligospermia, i.e., low sperm
basis of perifollicular vascular perfusion, and count, low sperm motility, cervical factor infertil-
could be cost-effective, both financially and emo- ity (cervical mucus inactivates sperm motility),
tionally. However, further longitudinal data sexual dysfunction, and unexplained infertility.
would be needed before this form of prospective By placing sperm directly into the uterine cav-
management of treatment cycles could be applied ity, the greatest barrier, the mucus in the cervix, is
clinically. The risk of multiple pregnancies and bypassed; therefore, more sperm reaches the egg,
236 J. Blankstein et al.
creating a better chance of fertilization for the treatment schemes, unfortunately this therapy
egg. IUI is usually combined with ovulation may be complicated by premature luteinization
induction. Optimal timing of insemination is and hyperstimulation.
achieved either by the detection of a luteinizing Premature Luteinization: Premature LH surge
hormone (LH) surge through urinary LH testing will luteinize the follicle which is too small and
(uLH) or by ultrasound monitoring of follicular not ready to ovulate. Cantineau et al. [13] studied
growth followed by the administration of human the prevalence of premature LH surges in an IUI
chorionic gonadotropin (hCG). In most centers, program. It has been concluded that 24 % of IUI
when the leading follicle reached >18 mm cycles suffer from premature LH surge and this
diameter, 10,000 IU hCG was given to trigger can result in IUI procedure cancellation.
ovulation and IUI is timed 36 + or – 2 h later. Obviously, this represents economic and psycho-
While IUI is a natural starting point for many logical stress for the patients.
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 237
Manzi et al. [14] showed that patients who Assisted Reproductive Technologies). In the
underwent controlled ovarian stimulation (COS)/ USA such regulations remain voluntary, while in
IUI treatment and had premature LH surge dem- many other countries, such guidelines are legis-
onstrated much better pregnancy rates in the sub- lated and strictly enforced.
sequent cycle when a GnRH analogue was added, Low-dose stimulation and careful follicular
thus avoiding premature LH surge. monitoring may help to reduce the risk of multi-
GnRH agonist has been, in the past, the stan- ple pregnancies. The risk of multiple pregnancies
dard of care in reducing the incidence of prema- after IUI is dependent on the type of stimulation
ture LH surge by reversibly blocking pituitary (clomiphene citrate vs. gonadotropins) and on the
gonadotropin secretion in IUI-stimulated cycles size and number of follicles. Dickey et al. [17]
[15]. These drugs are nowadays completely reported a positive correlation of multiple preg-
abandoned in IUI cycles because of their stimula- nancies with the number of follicles 12 and
tory effect, with consequent higher incidence of 15 mm or larger. Offering oocyte aspiration of
multiple pregnancy and OHSS and the long pre- excess follicles in an effort to reduce multiple
treatment period required. gestations has been proposed by many research-
An alternative to GnRH agonists, GnRH ers, and this method has shown to reduce the risk
antagonists have been proposed to prevent pre- of multiple pregnancies.
mature LH surge [16]. These drugs do not pro- Stoop et al. [18] concluded that aspiration of
duce flare-up effect, reducing synchronous excess oocytes in stimulated IUI cycles reduced
follicular pool recruitment. Moreover, the poten- cancellation rates and further reduced multiple
tial advantage of a GnRH antagonist is that pitu- pregnancy rates. Additional studies are needed to
itary gonadotropin secretion is suppressed better define the criteria and methods for oocyte
immediately after the start of the therapy. aspiration of preovulatory follicles prior to hCG
Therefore, co-treatment with GnRH antagonists administration.
can be restricted to the time in the cycle where
there is a risk of premature LH rise.
Polycystic Ovarian Syndrome (PCOS)
Ultrasound Diagnosis
of pregnancy. Commonly used ovulation induc- was significantly greater, i.e., 1.7 mm per day.
tion medications include clomiphene citrate, Continued research on the effect of greater fol-
human menopausal gonadotropin, purified FSH, licular growth rates and shorter intervals to ovu-
and recombinant gonadotropins. Although all of lation is being conducted (Fig. 18.7).
these medications result in the development of The baseline scan of the pelvis is mandatory
multiple follicles, they act via different to rule out ovarian or uterine pathology and
mechanisms. assess the ovarian reserve: moreover one needs to
Transvaginal sonography has a vital role in rule out the presence of ovarian cysts [3].
monitoring the follicular growth rate in women The objectives of a baseline scan are:
receiving ovulation induction medications. A. To rule out ovarian or uterine pathology
In an elegant prospective study, Baerwold requiring attention prior to beginning infertil-
et al. [4] compared the growth rate of ovarian fol- ity treatment (see Table 18.1)
licles during natural cycle and ovarian stimula- A common adnexal finding, endometrosis
tion cycles using standardized techniques. [20], can be seen in over 30 % of women with
While the growth rate in natural cycles was clinically defined infertility. Endometriosis is
1.42 mm per day, the growth in stimulated cycles defined as the extrauterine presence of endo-
a b
c d
Fig. 18.7 Serial transvaginal ultrasonographic images of throughout the growth phase in (a–e). The corresponding
the right ovary of a research participant on days 1 (a), 4 corpus luteum on the day of ovulation is shown in (e)
(b), 7 (c), 11 (d), 16 (e), and 17 (f) of a spontaneous men- (Reprinted from Baerwald et al. [4]. With permission
strual cycle. The same ovarian follicle is identified from Elsevier)
240 J. Blankstein et al.
e f
The ovulatory treatment options are based on Technical Tips on How to Scan
WHO classification with patients separated into 3 the Ovaries and Follicular Growth
main groups (see Table 18.2):
Group I: Hypothalamic-pituitary failure included Ovaries: The ovaries are located posterior to the
women with primary or secondary amenorrhea, broad ligament and anteromedial to the internal
low levels of endogenous gonadotropins, and iliac vessels which are easily located and can be
lack of endogenous estrogen activity. The used as a land mark for ovarian localization;
treatment of choice for this group of patients moving laterally from the endometrial canal will
is gonadotropic therapy. produce the image of the ovary adjacent to the
Group II: Hypothalamic-pituitary dysfunction iliac vessels.
included patients with anovulation associated The pelvic organs may be scanned either
with a variety of menstrual disorders whose transabdominally or transvaginally. In most
serum gonadotropin levels were within the infertility units, transvaginal ultrasound has
normal range and who had evidence of endog- become the routine method since it improves
enous estrogen activity. spatial resolution; however, it has a smaller field
The treatment of choice for patients belonging of view. During the transvaginal approach, only a
to Group II is a chlorotrianisene analogue, few centimeters separate the probe from the
such as clomiphene citrate. ovaries.
Group III: Includes patients with high FSH levels The best way to locate the ovaries is to scan
and the only viable option for them is ovum along the lateral margin of the uterus in trans-
donation. verse plane from the fundus to the cervix. In
cases where you cannot locate the ovaries, look
for them adjacent to the iliac vessels, which are
Table 18.2 Anovulation treatment options (based on
WHO classifications) usually easily identified, or try to follow the fal-
lopian tube laterally.
Group I Option I Option II
In cases when the ovary is high in the pelvis, a
Low FSH GnRH (pulsatile)
Gonadotropins
transabdominal scan is also necessary; in these
Bromocriptine Gonadotropins, situations begin with the abdominal transducer
bromocriptine, and perpendicular at the midline just superior to the
clomiphene citrate symphysis pubis. Once you locate the long axis
Group II Clomiphene Gonadotropins of the uterus, move the transducer lateral until the
Normal FSH citrate Surgical approach ovary is located. Again remember that the inter-
Group III Ovum donation nal iliac vessels are located immediately poste-
High FSH rior to the ovary.
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 243
Follicle: The spatial resolution of transvaginal by rotating the transducers. If the structure is a
scans is 2–3 mm, so small follicles can be visual- vessel, it will appear tubular following rotation.
ized easily as echo-free structures which usually A baseline scan should always be done to
lie towards the periphery of the more echogenic identify cystic structures which could later be
ovarian tissue. Since the follicles may be flat- misinterpreted as follicles.
tened in one plane or have their shape altered due Sono AVC (Automatic Volume Calculation):
to pressure, the internal diameter of the follicle Recently a new software program (GE) with 3D
should be measured in three planes and the mean data set, which can automatically estimate the
value calculated. The intra-observer standard diameter and volume of each follicle, has been
deviation of transabdominal follicular measure- developed; this ultrasound program will automat-
ment was reported in one study to be 0.6 mm, and ically identify the ovarian follicle and the volume
the inter-observer standard deviation is 1.2 mm, for each follicle (Fig. 18.10).
irrespective of the follicular diameter. Thus, the Raine-Fenning et al. [29] compared automatic
95 % confidence limits for any particular mea- volume measurement of each follicle to manual
surement should be 2.4 mm [3, 28], and one measurements from 2D and 3D ultrasound; Sono
would expect transvaginal measurements to con- AVC provided measurements that were more
fer even greater accuracy [16]. accurate than manual measurements, and obvi-
Follicles can be confused with blood vessels ously the time taken for measurements was sig-
(hypogastric vein), and they can be differentiated nificantly shorter.
Fig. 18.10 Sono AVC ultrasound study: automatic estimation of diameter and volume. Each volume is separately
color coded (see text)
244 J. Blankstein et al.
6
Clomid
FSH
5
4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Cycle day
a b
Fig. 18.12 (a) Cervical canal measurement near ovulation and (b) after ovulation (Reprinted from Wolman et al. [31].
With permission from Elsevier)
discrepancy between the ovulation rate (85 %) Treatment Schema and Monitoring
and the pregnancy rate (43 %) of women receiv- of Clomiphene Citrate Therapy
ing CC treatment. Jirge and Patil [30] have dem-
onstrated in a prospective crossover study that the Clomiphene citrate is administered orally in
number of follicles at the assumed time of ovula- 50-mg tablets. Therapy should be initiated with
tion is significantly higher in patients treated with 50 mg of CC over a period of 5 days, usually
clomiphene citrate; moreover, the endometrial starting on the fifth day after the first appearance
thickness on the same day was significantly of spontaneous or progestin-induced menstrual
smaller (7.6 mm vs. 8.5 mm). Most investigators bleeding. Clomiphene citrate dosage is typically
report decreased secretion of mucus from the cer- increased in subsequent months until ovulatory
vical glands caused by antiestrogenic agents such cycles become evident. Clomiphene-citrate-
as CC. The antiestrogenic effect on the cervical induced ovarian cysts often resolve spontane-
mucus, when present, is expressed by a decreased ously and typically do not require intervention.
amount of mucus, which occurs despite the rela- In addition to the baseline scan, we advocate
tively high levels of estrogen in the circulation. cycle monitoring via ultrasonographic evaluation
Wollman et al. [31] demonstrated that the cervi- of follicular size, endometrial thickness, and cer-
cal mucus can be visualized in many patients vical mucus observation. Ultrasound monitoring
around the time of ovulation using pelvic ultra- of patients undergoing ovulation induction cycles
sound (see Fig. 18.5). In many patients given CC, will ensure adequate follicular recruitment and
the cervical mucus does not exhibit any depressed identify those patients not responding or have
effects. To understand this phenomenon, we must delayed endometrial thickening. In cases where
remember that the antiestrogenic effect on the there is concern that cervical mucus is insuffi-
hypothalamus will result in elevated circulating cient, often due to the antiestrogenic effect of
FSH and LH levels. The elevated gonadotropin Clomid, intrauterine insemination (bypassing the
levels may cause multifollicular development, cervix) is probably the best solution. Whenever
which in turn enhances estrogen production. The the endogenous feedback mechanism responsi-
elevated estrogen levels, five to ten times higher ble for the preovulatory LH surge is not properly
than in normal cycles, sometimes mask the anti- activated, the midcycle LH peak may conse-
estrogenic effect of CC and tamoxifen citrate in quently be inadequate, ill-timed, or entirely
the cervix and uterus (Fig. 18.12). absent. In such instances hCG should be
246 J. Blankstein et al.
administered to induce ovulation. Optimal timing disorders. The treatment of choice for patients
for hCG ovulation trigger injections includes belonging to Group II is a clomiphene citrate
ultrasonographic measurement of mean follicular alone or in conjunction with estrogen and/or
diameter ranging 19–20 mm. Ovulation will hCG. Patients who fail to ovulate or conceive
occur 34–36 h following hCG injection, so the within a reasonable time are considered “clomi-
IUI is often performed 34 h later. Recently Paltnik phene failures” and can be considered for hMG
et al. [5] have shown that higher pregnancy rates therapy.
were achieved when the leading follicle was in Monitoring of Therapy: Gonadotropins are
the 23–28 mm range. given daily by injection in order to stimulate fol-
Universal agreement is lacking as to when to licular development; ovulation is actually induced
introduce ultrasonographic cycle monitoring ver- by hCG. The daily dose of gonadotropins given
sus less complicated or costly alternatives. in a particular cycle depends upon the ovarian
However, we agree with the predominant opinion response of the patient in that particular cycle.
that the additional ultrasound expense is justified The response is reflected by a growth of follicles
by the prevention of protracted periods of inef- accompanied by biochemical changes mainly
fective therapy [32]; moreover it has been shown with respect to increased synthesis and secretion
that a significant number of women (14 %) devel- of steroidal hormones. The follicular enlarge-
oped 3 or more follicles, despite receiving low ment can be visualized by ultrasonographic mea-
doses of clomiphene citrate [33]. surement, while estrogen secretion values can be
estimated directly by blood measurement.
Ultrasonographic monitoring of treatment
Gonadotropins cycles serves to assess the effective dose required
to evoke an ovarian response, the length of time
Principles of Gonadotrophic Therapy: In order to required for follicular maturation, and the appro-
optimally stimulate follicular maturation, both priate time for induction of ovulation.
FSH and LH are required. While FSH content of Furthermore, such monitoring should aim to pre-
the pharmacologic preparation is essential for vent ovarian hyperstimulation syndrome (OHSS),
follicular development, final maturation of the or at least lead to early detection. For these pur-
follicles and subsequent ovulation are brought poses, a combination of ultrasonography and
about by a pituitary release and circulatory surge estrogen determination was advocated. Given
of LH. Thus two gonadotropins are required for that exogenous gonadotropic stimulation usually
induction of ovulation: one providing the required induces the development and growth of several
amount of FSH and another providing LH or follicles, ultrasonographic monitoring is particu-
LH-like material (hCG) of sufficient quantity to larly advisable for these treatment cycles.
provoke ovulation and corpus luteum formation. Sonographic visualization may thus dis-
Well accepted ovulation induction protocols criminate between single and multiple follicular
include alterations in the precise ratio of FSH growths, and their measurement may aid in the
to LH. interpretation of the meaning of the estrogen
Selection of Patients: Ideal candidates for levels. Evidence is accumulating that follicles
ovulation induction with gonadotropins are of diameters greater than 18–19 mm should be
patients who have low endogenous gonadotropin “ovulated.” Thus, sonography can be a more pre-
secretion and are amenorrheic or anovulatory cise indicator for the determination of the opti-
(Group I—WHO). This treatment can also be mal ovulatory timing. Gonadotropin treatment
given to patients with hypothalamic-pituitary is often started on the fifth day of spontaneous
dysfunction (Group II), including anovulatory or induced bleeding. It is safe to start with low
patients associated with a variety of menstrual doses of gonadotropins with close ultrasonic
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 247
Clomiphene Citrate and hMG Table 18.3 Complications associated with twin pregnancy
Maternal complications Fetal complications
The rationale of clomiphene citrate followed by Anemia Premature delivery
hMG is the utilization of the former to increase Preeclampsia/eclampsia Difficult delivery
FSH in the initial phase (recruitment and selec- Pre-/postpartum hemorrhage Prolapse of an umbilical
tion) and maintain adequate FSH levels by admin- cord
istration of hMG during follicular growth phase. Hypoxia of second twin
It has been shown that by using the combined
clomiphene citrate/hMG protocol in normogo- epidemics. Table 18.3 summarizes the clinical
nadotropic patients, they could reduce the neces- complication associated with twin pregnancies. It
sary hMG requirement by 50 %. Abdelazim and is important to diagnose multiple pregnancies
Makhlouf [37] compared sequential clomiphene early, in the first trimester, so women who con-
citrate/hMG regimen to hMG regimen for ovula- ceive with high-order multiple pregnancies may
tion induction in clomiphene citrate-resistant consider multiple pregnancy reduction.
women. They found that the sequential CC/hMG In cases of twin pregnancy, it is recommended
regimen is as effective as hMG regimen for ovu- by the AIUM to document amnionicity and cho-
lation induction, produces satisfactory preg- rionicity in the early first trimester, so one can
nancy results, and reduces treatment cost. prepare for high-risk situations such as a mono-
The clomiphene citrate/hMG treatment scheme chorionic twin gestation.
is as follows: on the fifth through the ninth days In many countries, triggering of ovulation
after induced or spontaneous bleeding, the nor- with hCG is only done if there are no more than
mogonadotropic patient receives 100 mg of clo- two mature follicles around the assumed time of
miphene citrate daily. From the eighth day ovulation.
onwards, hMG is administered. The patient is Adhering to strict guidelines involving ultra-
carefully monitored by estrogen determination sound monitoring will definitely reduce the inci-
and ultrasound visualization of the growing dence of multiples.
follicle(s). This will help to determine if and when Ovarian hyperstimulation is the most serious
the ovulatory dose of hCG should be administered complication which in extreme situations is
and to prevent hyperstimulation and multiple potentially life threatening and the reader is
pregnancies. referred to Chap. 23.
It is important to understand the risk factors
that can be identified in high-risk patients before
The Help of Ultrasound: Assessing ovulation is being induced. The presence of poly-
Complications cystic ovaries put the patient at increased risk; we
have shown that a decrease in the fraction of the
Multiple Pregnancies: The major adverse effects mature follicles and an increase in the fraction of
of induction of ovulation are multiple pregnan- the very small follicles around the assumed time
cies and OHSS. of ovulation correlated with an augmented risk
Five to eight percent of clomiphene-induced for the development of severe stimulation of the
pregnancies and 15–25 % of all pregnancies fol- ovaries. Our data suggest [38] that ultrasonogra-
lowing gonadotropin-induced ovulation are mul- phy is of good predictive value in the occurrence
tiple gestations. of clinically moderate to severe OHS in women
While almost all of the multiple gestations treated by hMG and hCG. Even with estrogen
conceived on clomiphene will be twins, 30 % of levels within accepted normal limits, it is sug-
multiple gestations following gonadotropin ther- gested that hMG/hCG administration should be
apy will be triplets. interrupted in the presence of 11 or more preovu-
Poorly monitored ovulation induction is prob- latory follicles, especially if most of them are
ably the major cause of the multiple pregnancy immature (<9 mm).
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI 249
Devroey P. Profound LH suppression after GnRH 28. Eissa MK, Hudson K, Docker MF, Sawers RS,
antagonist administration is associated with a signifi- Newton JR. Ultrasound follicular diameter measure-
cantly higher ongoing pregnancy rate in IVF. Hum ment: and assessment of inter-observer and intra-
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17. Dickey RP, Olar TT, Taylor SN, Curol DN, Rye PH, 29. Raine-Fenning NJ, Jayaprakasan K, Chamberlain S,
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89–92. ultrasound profiles during ovulation induction with
18. Stoop D, Van Landuyt L, Paquay R, Fatemi H, clomiphene citrate and letrozole in ovulatory volun-
Blockeel C, De Vos M, Camus M, Van den Abbeel E, teer women. Fertil Steril. 2010;93(1):174–83.
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2D Ultrasound in Follicle
Monitoring for ART 19
Mette Toftager and David P. Cohen
In addition 2D ultrasound with power Doppler At the beginning of an ovarian cycle, in prepa-
has made it possible to study ovarian and endo- ration to monitor follicular growth and develop-
metrial blood flow. By monitoring perifollicular ment (with or without added ovulation induction
blood flow, the physician can identify follicles medications), the 2D ultrasound assessment of
with oocytes that may have a better chance of the antral follicle count (AFC) is simple, mini-
pregnancy (see Chap. 5). mally invasive, and a beneficial information.
Ben-Haroush et al. [3] assessed the correlation
between AFC and IVF cycle success. In their
Why Monitor the Follicular Phase? study of 115 women, 33 % achieved a preg-
nancy, and AFC was significantly higher in the
During in vitro fertilization (IVF), gonadotropins successful IVF group. Furthermore, and perhaps
cause growth of the cohort of ovarian follicles, more interestingly, the subgroup of women with
and monitoring at various stages is essential in high AFC values of smaller follicles (2–5 mm)
order to optimize and individualize IVF treat- did best compared to those with larger follicles
ments. Ultrasound monitoring during the follicu- (5–10 mm). A subsequent study by the same
lar phase has many useful attributes. authors [4] documented better outcomes after
It can identify the quiescent ovary and avoid IVF among women with higher AFC values, and
initiating ovulation induction if there is any ovar- higher AFC values correlated positively with age,
ian abnormality. For example, it may be that a ovarian volume, number of oocytes retrieved, and
follicular cyst remains from a recent ovulatory the number of highest quality embryos.
cycle or there may be an as yet identified ovar-
ian pathologic cyst or adnexal mass that needs
to be addressed. Next, a baseline count of antral Normal Folliculogenesis
follicles provides a hint into the probable suc-
cess of the cycle, predicting ovarian response to Before reviewing the details of the parameters
identify the optimal starting dose of gonadotro- of follicular growth studied with 2D ultra-
pin and decide upon the type of stimulation pro- sound imaging, it is helpful to summarize
tocol. Third is to verify pituitary downregulation; normal folliculogenesis, in order to be able to
before gonadotropin stimulation is started (when correlate imaging findings with physiologic
GnRH analogs are used to suppress ovulation), it expectations. Follicles grow in two stages: the
is imperative to determine whether the initially gonadotropin-independent and gonadotropin-
suggested gonadotropin stimulation dosing is dependent stages. Primordial follicles consist
ideal or needs to be adjusted. Fourth, evaluating of an oocyte with a thin layer of granulosa and
the ease with which the ovaries will be acces- stromal cells and cannot be seen on ultrasound.
sible for transvaginal needle aspiration is crucial, By the time follicles develop a fluid antrum,
and this information is easily obtained again, just they are ultrasonographically identifiable, and
prior to initiating gonadotropin stimulation. Fifth, they have reached the gonadotropin-dependent
ultrasound scanning conveniently estimates folli- stage of the 3-month maturation process. These
cle size and number to predict how many oocytes antral follicles measure between 2 and 10 mm
will be mature and ready to aspirate after gonad- and represent the pool of follicles that may be
otropin stimulation is complete. Sixth is avoid- recruited in the ensuing follicular phase. In a
ing ovarian hyperstimulation syndrome (OHSS). natural cycle, one is ultimately selected for
When OHSS is evolving, free fluid is identified ovulation, and that selection process occurs
in the peritoneal cavity and clearly recognized during the latter half of the follicular phase of
with 2D ultrasound imaging. Finally, ultrasound the ovarian cycle when the endogenous pitu-
monitoring is critical to determine the optimal itary follicle-stimulating hormone (FSH) level
time to provoke ovulation; most clinicians agree is falling in response to the increasing ovarian
that given only one modality to monitor ovulation estradiol production. Falling FSH promotes a
induction, they would select ultrasound first. selection process in which each of the follicular
19 2D Ultrasound in Follicle Monitoring for ART 253
microenvironments competes for the diminish- superior to the other is questionable, but it has
ing FSH needed to stimulate granulosa cells in been shown that ultrasound imaging of follicular
the follicle to produce aromatase. Aromatase, growth and endometrial thickness is sufficient to
in turn, is necessary to convert testosterone and monitor follicular maturation [8, 9].
androstenedione produced in the peripheral Which approach, when to adjust the gonado-
theca cells into estradiol and estrone, respec- tropin dose up or down, and how often monitor-
tively. Failure of this conversion leads to an ele- ing should be done is dependent on the individual
vated androgen to estrogen ratio, which leads clinician, the experience, and the routine at each
to follicular atresia. From this cursory review individual clinic. Some monitoring methods are
of the anatomy and physiology of oocyte matu- very complex, whereas other methods are rather
ration, it is easy to see how ovulation-inducing simple; however, the outcomes of IVF cycles
agents that either indirectly increase endoge- seem to be the same, regardless of the chosen
nous FSH (e.g., clomiphene citrate) or directly method [10].
add FSH to the system diminish the competi- When viewed on ultrasound, follicles appear
tion between the follicles and permit the devel- as echo-free structures within the more echo-
opment of multiple dominant follicles [5, 6]. genic ovarian tissue. By convention, follicle size
in 2D is estimated by calculating the mean of
the maximum follicular internal diameter in two
Monitoring Follicular Maturation perpendicular planes [11]. Alternatively, the fol-
licle size can be estimated in three dimensions,
Methods for Monitoring the x, y, and z planes. Using this technique, it
is possible to calculate volumes for each fol-
It is difficult to predict the optimal number of licle. Most recently, 3-dimensional software
growing ovarian follicles in an IVF cycle, since programs that distinguish the echogenicity of
there is considerable variation in ovarian response the well-circumscribed, sharp-edged, echolu-
among women undergoing ovulation induction cent follicular fluid from the surrounding greater
therapy. The ovarian response depends on age, echogenicity of the ovarian cortical parenchyma
ovarian reserve, how the hypothalamic-ovarian have automated this process and permitted fol-
axis is manipulated exogenously (the stimulation licular volume calculations from data derived
protocol), FSH dose, cause of infertility, ethnic- from 2D-derived images. The technician can now
ity, etc. simply sweep through the ovarian tissue, and the
Follicular maturation in IVF cycles can be stored image data is analyzed, reducing the time
monitored clinically in different ways, either by: needed to separately measure each follicle’s mul-
• Serum estradiol value alone tiple axes. Particularly in busy practices perform-
• 2D ultrasound alone ing dozens of follicular monitoring scans daily,
• 3D ultrasound alone this is a valuable asset.
• Serum estradiol and ultrasound combined
• Supplemental power Doppler imaging
There are numerous studies on the use of these Standard Ultrasound Monitoring
different methods for monitoring follicular matu- Program
ration. Traditional monitoring of an IVF treat-
ment cycle includes a combination of regular Follicular growth can be directly monitored
ultrasonography and serum estradiol concentra- with 2D ultrasound, since the follicular diam-
tions and has long been accepted as the gold stan- eter increases during the gonadotropin-sensitive
dard. However, the need for estradiol monitoring stage of development. Most practices measure
remains controversial [7]. Ultrasound provides the follicles at baseline (Fig. 19.1), prior to ini-
more accurate measurement of follicle number tiating gonadotropin stimulation and then again
and size than can be obtained by serum estradiol after approximately 5 days of gonadotropin
alone. Whether serum estradiol or ultrasound is stimulation, and then every 24–48 h depending
254 M. Toftager and D.P. Cohen
on the rate of development (Figs. 19.2, 19.3, progesterone production. This is accompanied
19.4, and 19.5). Once the mature follicle mea- by a dramatic loss of the concentric architec-
sures 18–21 mm, the practitioner can trigger ture of the preovulatory follicle and an increase
ovulation with human chorionic gonadotropin in blood supply, presumably designed to chan-
(hCG, a luteinizing hormone (LH) surrogate) nel progesterone from the corpus luteum to the
(Fig. 19.6), and confirmation of ovulation can endometrium. A very specific, nearly pathogno-
be demonstrated with ultrasound as well. The monic “ring of fire” ultrasound finding is easily
sudden change from an intact follicle, made up discerned around each corpus luteum at this time
of concentric layers of theca cells surrounding (Fig. 19.7). Doppler technology added to the 2D
granulosa cells enclosing the follicular fluid image enables observation of this flow pattern
and the oocyte, is suddenly lost at ovulation. so it is nearly impossible to mistake. Combining
Physiologically it is at this moment that both the classic echogenicity of the corpus luteum
testosterone-secreting theca cells and estradiol- with the Doppler low impedance flow charac-
secreting granulosa cells convert intracellu- teristics surrounding the corpus luteum confirms
lar steroid production to preferentially favor the structure [5].
19 2D Ultrasound in Follicle Monitoring for ART 255
Follicular Size and Volume follicular maturation at 18–21 mm, and at that
point the oocyte inside is ready to ovulate, that is,
During ovulation induction it is realistic to recruit complete meiosis, and be released in preparation
five to ten ovarian follicles in each ovary; how- for fertilization.
ever, the number, rate of growth of each follicle,
and the number of stimulation days can vary
greatly. Criteria Used for Triggering
After 6–7 days of gonadotropin stimula- Ovulation
tion, follicles measuring more than 10 mm are
expected. The criteria used for triggering ovulation-inducing
Once a dominant follicle measures greater final oocyte maturation vary between protocols,
than 12 mm, follicular growth of 2 mm (1–3 mm) but all aim to produce mature oocytes to be fertil-
per day is expected [12]. Growth continues until ized; it is important to keep in mind that mature
256 M. Toftager and D.P. Cohen
oocytes are those that have completed meiosis I, when ≥1 follicle of ≥18 mm and three follicles
extruded the first polar body, and rearrested in of ≥15 mm are identified. More complex crite-
metaphase of meiosis II. Most commonly hCG is ria have taken into consideration serum estradiol
administered to mimic the endogenous LH surge levels; hCG is administered when the leading
to provoke meiotic re-initiation from the oocyte’s follicle reaches 18–20 mm and the coincident
prophase I resting state. As noted, protocols vary serum estradiol level suggests satisfactory follic-
and are often altered, but most commonly ovu- ular development. In addition, induction of final
lation is provoked when ≥3 follicles ≥17 mm oocyte maturation has been performed in the
are identified on ultrasound. Another approach presence of at least one follicle ≥20 mm and a
many clinicians employ is to trigger final oocyte serum estradiol level ≥1,200 pg/ml. Finally, hCG
maturation when ≥3 follicles is observed, each has been administered in the presence of at least
with a maximum diameter of 18 mm, or, finally, one follicle ≥20 mm or a serum estradiol level
19 2D Ultrasound in Follicle Monitoring for ART 257
≥1,200 pg/ml [13]. There are no data to sug- rate, and the number and morphological quality
gest that any one protocol is significantly supe- of the embryos developed [17].
rior to any other, and protocols will vary based Attempts to find a universally accepted thresh-
on individual physician preferences and patient old of a worth-to-be-punctured follicle size, how-
responses to stimulation. ever, has been disappointing due to conflicting
In summary, for timing of hCG administration, outcomes. What is accepted is that a large fol-
the number of adequate size follicles (12–24 mm) licle is more likely to lead to the retrieval of a
appears to be more important than the size of the mature oocyte than a smaller follicle. The cor-
leading follicle [14]. It has been shown that when relation between the follicle size and the likeli-
hCG is administered in the presence of a leading hood of retrieving a mature oocyte may be the
follicle >20 mm, the fertilization rate is greater observable physical manifestation of the idea
and the embryo implantation rate higher than that larger follicles have completed the matura-
when hCG is given with a leading follicle of tion process and released the oocyte-cumulus
smaller size [15]. cell mass as a free-floating structure in the antral
fluid just before follicle rupture [18]. According
to Teissier [19], 14 mm diameter should be
How to Predict Retrieval considered the threshold follicle size to get an
of Mature Oocytes? acceptable chance of finding meiotically com-
petent oocytes at retrieval, both in normal and
Follicular size and the volume of follicular fluid polycystic ovaries. For IVF patients, Bergh et al.
have always been recognized as possible predic- found oocytes in follicles with a mean diameter
tors of oocyte quality, specifically, oocytes that >16 mm to have a significantly higher fertiliza-
will be fertilized and result in embryos that tion rate (71.4 %) compared to oocytes from
implant and result in a live-born infant. In one smaller follicles (58.1 %). Interestingly, in that
study, embryo quality, defined as decreased same study, the authors note that once an oocyte
embryo fragmentation and increased cleavage is fertilized, embryo cleavage rates were similar
rate, and the implantation rate was higher, and (95.4 and 93.9, respectively), but pregnancy rates
clinical and ongoing pregnancy rates tended to be for the two groups were dramatically different,
higher when hCG was administered after a larger 47 and 15 %, respectively. For intracytoplasmic
follicle size was observed [16]. The follicular sperm injection (ICSI) patients, the fertilization
volume together with follicle number are the only rate was 72.0 and 71.1 % for oocytes from large
two independent predictors of the number of and small follicles, respectively; the correspond-
oocytes that will be retrieved, the fertilization ing cleavage rate was 93.0 and 91.1 %, and the
258 M. Toftager and D.P. Cohen
pregnancy rate for the two groups was 41 and comparable morphologic scores and/or to the
42 % [20]. Follicles measuring 11–15 mm were fact that the male gamete contributes to embryo
observed to have a 50 % chance of yielding a quality as well and needs to be considered along
mature oocyte [21]. with the oocyte.
Mature metaphase II (MII) oocytes are more Importantly, follicular size, volume, morphol-
frequently retrieved from 16 to 22 mm diameter ogy, or vascularity does not provide enough
(2–5 ml volume) follicles, and MII oocytes tend information to ascertain oocyte quality when
to develop the best morphologically scored quality is defined as the conception of a euploid
embryos. On the contrary, follicles with a mean child. The best approximation of quality, how-
diameter above 22 mm result in lower recovery ever, is that a follicle with at least a diameter of
of mature, fertilizable oocytes as they often con- 14 mm, more than 0.6 ml volume, and well-
tain postmature eggs, postulated to result from developed vascularity houses an oocyte more
the development of intrafollicular atresia and likely to be successfully fertilized.
degenerative phenomena [22].
Other investigators have also observed a cor-
relation between oocyte fitness and ultrasound- Monitoring of Endometrial
measured size prior to retrieval. A higher Proliferation
proportion of immature germinal vesicle (GV)
stage oocytes, for example, are found in smaller During the proliferative phase of the menstrual
follicles, particularly follicles below 12 mm of cycle, many factors have been studied and identi-
mean diameter. This is not a universal finding, fied to contribute to a successful pregnancy
however, since even small follicles can generate among patients undergoing assisted reproduc-
mature MII oocytes [20, 23]. Wittmaack et al. tion. The aim of 2D monitoring of the follicular
[14] found the optimal follicle volume to be phase in ART is not solely to monitor follicular
>1 ml, which corresponds to ≥12 mm, and the development, but also to monitor endometrial
maximum volume to be 6–7 ml, corresponding to development. Predicting the probability of preg-
a 24 mm follicle. They observed a higher oocyte nancy by assessing the degree of endometrial
recovery rate, higher fertilization rate, and higher development on sonography has been the objec-
cleavage rate for follicles in this interval. Oocytes tive of numerous studies.
from larger follicles are reported to allow higher Endometrial thickness and pattern, in response
fertilization rates and generate better embryos. to estrogen secretion by the ovarian follicles, var-
Conversely, in a prospective study including ies throughout the menstrual cycle. The endome-
9,933 follicles from 535 IVF cycles, it was trium is thin immediately after menstruation
observed that oocytes from follicles with volume (2–5 mm), thickens during the proliferative
<1 ml (<12 mm diameter) had a significantly phase, is trilaminar before ovulation, and is thick
lower fertilization rate than oocytes from larger and echogenic in the secretory phase of the cycle.
follicles, but when fertilized they yielded A small amount of endometrial fluid (0.5–1.0 mm
embryos of comparable quality; in fact, no sig- film in the middle of the cavity), thought to be
nificant differences in the implantation, clinical mucus, can be seen before ovulation, is consid-
pregnancy, or live birth rates per cycle were ered normal, and rapidly disappears. However,
detectable from embryos derived from oocytes significant endometrial fluid at the time of an
measured in small or large follicles [24]. embryo transfer (ET), often visible in the pres-
In these studies, however, it was not possible ence of hydrosalpinges, is associated with a
to identify a clear relationship between follicle poorer prognosis. When this observation is made,
size and morphological quality of the in vitro- freezing of all the embryos is frequently consid-
produced embryos. This may be due to the fact ered to provide time to optimize management.
that follicles with a volume within a certain With respect to endometrial differentiation,
interval contain oocytes that lead to embryos of sonography predictors that are often studied
19 2D Ultrasound in Follicle Monitoring for ART 259
include endometrial blood flow, endometrial for higher pregnancy rates in controlled ovarian
echo pattern, and endometrial thickness. stimulation cycles with triple-line isoechogenic
The thickened endometrium provides the crit- patterns observed in the late follicular phase [31].
ical site for embryo attachment. Controversies Although there may be a relationship between
exist, however, regarding the clinical signifi- endometrial differentiation and pregnancy,
cance of observed variations in endometrial implantation potential is probably more complex
thickness in relation to pregnancy rates (PR) than a few ultrasound measurements can deter-
during IVF. Some studies reported no correlation mine. De Geyter concludes that pregnancy rates
between endometrial thickness and PR, while of assisted reproductive procedures are influ-
others suggest a positive correlation between enced only marginally by the degree of endo-
endometrial thickness and PR, reporting signifi- metrial proliferation, and treatment should not
cantly greater endometrial thicknesses occur in be canceled because of inadequate endometrial
successful IVF cycles compared to unsuccessful thickness [26, 32]. At this point there is no con-
cycles. Possible reasons for this observed dis- sensus to resolve this question.
cordancy in results may be attributed to different
treatment protocols and/or the different etiolo-
gies of infertility. All studies, however, seem to Monitoring with 2D Versus 3D
agree that a “thin” endometrium is detrimental
to the implantation and development of a preg- Three-dimensional follicular volume measure-
nancy [25]. Patients with a thin endometrium ments have a stronger correlation with the num-
present the clinician with a dilemma, therefore, ber of mature oocytes retrieved than 2D
whether to continue the cycle despite a possibly measurements. As 3D technology improves, this
reduced chance of pregnancy or to cancel the parameter may replace 2D measurements in the
cycle and cryopreserve the embryos [26]. Most optimal timing of hCG before oocyte retrieval
recently a meta-analysis from 2011 found a sig- [21].
nificant difference in mean endometrial thick- Most recently 3D power Doppler angiography
ness on the day of hCG administration between has been introduced for the study of perifollicular
IVF patients achieving pregnancy versus those blood flow, and this technique enables the study
failing to achieve a pregnancy; a difference of of all the ovarian and follicular blood vessels. It
0.4 mm (95 % CI 0.22–0.58) and an odds ratio can be used to calculate both the vascularization
for pregnancy of 1.40 (95 % CI 1.24–1.58) were index (VI) and the flow index (FI) from the whole
reported [27]. ovary [33].
The use of endometrial blood flow in predict-
ing endometrial receptivity has also been studied.
Presence of both endometrial and subendome- Monitoring with Power Doppler
trial blood flow correlates with higher implanta- (In Relation to 2D)
tion and pregnancy rates, and the absence of
endometrial and subendometrial blood flow is Under physiological gonadotropin stimulation,
associated with a thinner endometrium and is granulosa cells produce angiogenesis factors
associated with higher uterine artery resistance which contribute to the increasing vasculariza-
[28, 29]. tion needed for follicle development, ovulation,
Studies indicate that echogenic patterns of the and optimal function of the corpus luteum (CL).
endometrium reflect histologic processes that are Around the dominant follicle, neovascularization
believed to be involved in the establishment of can be detected by Doppler ultrasound both dur-
receptivity as well. This may explain the reported ing spontaneous ovulation and during ovulation
association between premature hyperechogenic induction. This phenomenon allows measure-
patterns of the endometrium and poor implanta- ment of the increased perifollicular blood fluxes,
tion rates [30]. Check et al. demonstrated a trend and the associated decreased vascular resistance
260 M. Toftager and D.P. Cohen
6. Verberg MF, Macklon NS, Nargund G, Frydman R, 19. Teissier MP, Chable H, Paulhac S, Aubard Y.
Devroey P, Broekmans FJ, et al. Mild ovarian stimula- Comparison of follicle steroidogenesis from normal
tion for IVF. Hum Reprod Update. 2009;15(1):13–29. and polycystic ovaries in women undergoing IVF: rela-
7. Thomas K, Searle T, Quinn A, Wood S, Lewis-Jones tionship between steroid concentrations, follicle size,
I, Kingsland C. The value of routine estradiol moni- oocyte quality and fecundability. Hum Reprod. 2000;
toring in assisted conception cycles. Acta Obstet 15(12):2471–7.
Gynecol Scand. 2002;81(6):551–4. 20. Bergh C, Broden H, Lundin K, Hamberger L.
8. Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz Comparison of fertilization, cleavage and pregnancy
A, Shulman A. Monitoring stimulated cycles during rates of oocytes from large and small follicles. Hum
in vitro fertilization treatment with ultrasound only– Reprod. 1998;13(7):1912–5.
preliminary results. Gynecol Endocrinol. 2012;28(6): 21. Shmorgun D, Hughes E, Mohide P, Roberts R.
429–31. Prospective cohort study of three- versus two-
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Monitoring of stimulated cycles in assisted reproduc- rity. Fertil Steril. 2010;93(4):1333–7.
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3D Ultrasound for Follicle
Monitoring in ART 20
Maximilian Murtinger and Nicolas Herbert Zech
was first described almost 30 years ago in 1984 subcutaneous injection. These agonists do not
[1]. Even though several infertility clinics apply quickly dissociate from the GnRH receptor and
generally the two other protocols, short and block the GnRH function by reversibly binding
antagonist protocols were designed for distinct to the GnRH receptor of the pituitary gland (also
medical indications such as low responders or known as competitive inhibition). As a result, the
patients at high risk for ovarian hyperstimulation release of FSH and LH from the pituitary gland is
syndrome (OHSS) syndrome [2, 3]. suppressed.
Before initiating follicular growth using the This physiological state, also called downregu-
long protocol, the first step after the medical lation, is usually confirmed by two main criteria:
examination is the downregulation of the pitu- (1) the determination of blood hormone levels
itary gland by supraphysiological doses of GnRH (serum estradiol <200 pmol/l) by a clinical labo-
agonists. These pharmaceutical peptides (i.e., ratory and (2) transvaginal ultrasound (TVUS) by
triptorelin, ganirelix, cetrorelix, and buserelin) a physician. The pituitary downregulation should
prevent a premature LH surge. Indeed, in almost be confirmed by a hypoestrogenic state, and addi-
one-fourth of all cycles, such an LH surge occurs tionally, the endometrial thickness (ETS) should
only when gonadotropins are used [4]. Provided be <5 mm. Measurement of the ETS diameter per-
the menstrual cycle is regular, the initiation of formed by 3D TVUS can be a highly predictive
GnRH agonists in the long protocol is normally method to determine the state of hypoestrogen-
between days 18 and 22 of the menstrual cycle. ism [5]. It should also be noted that an endome-
GNRH agonists are usually administered via a trial morphology examination is also necessary to
20 3D Ultrasound for Follicle Monitoring in ART 265
determine whether the embryos can be transferred fer. In regard to the mode of data acquisition, US
in a fresh cycle or it is advisable to cryopreserve scans can be obtained either freehand, by manual
them in order to perform a transfer in a subsequent movement through the region of interest (ROI),
cryo-cycle (this will be further discussed later in or automatically, by sweeping through the ROI.
this chapter). Examinations of the endometrial It is indisputable that the former modality is more
volume and the endometrial morphology are cru- subjective and is more susceptible to inter- and
cial to estimate the implantation success, the risk intraobserver reliability, while the latter is more
of spontaneous abortion, or other risks. standardized and accurate. However, it should be
In a subsequent step, ovarian stimulation is per- noted that 3D US needs post-processing of the
formed by FSH (i.e., Puregon®, Gonal-F®, received data. Data can be stored and visualized
Altermon®, or Bravelle®) or combinations of LH in various displays such as multi-planar with
and FSH (i.e., Pergoveris®, Merional®, or navigation through the planes or surface render-
Menopur®); these are administered by subcutane- ing mode. The 3D US technique allows for an
ous or intramuscular injections. The administration easy volume calculation of the examined objects,
of such high, ultra-physiological doses of human which is one of its greatest fortitudes in contrast
FSH triggers the stimulation, growth, and retrieval to 2D imaging; furthermore, the determination of
of multiple follicles, thus increasing the number of the mean diameter of the analyzed object can be
mature oocytes [6]. The retrieval of good quality determined. Additionally, post-processing soft-
oocytes increases the likelihood of a high fertiliza- ware allows the presentation of 3-dimensional
tion rate and an adequate number of high-quality structures of the examined object in the so-called
embryos. Before initiating ovarian stimulation, an inversion mode [7]. According to differences
US is a prerequisite for planning the IVF therapy in in density of tissues or structures, there are dif-
detail; it can estimate the ovarian reserve, which can ferences in ultrasound reflection and scattering,
be done most accurately by an antral follicle count. which is also referred as echogenicity. Normally,
To date, as previously mentioned, there are the degree of echogenicity can be visualized by a
many applications of US for gynecology and gray scale. Minor echogenicity is represented by
reproductive biology; furthermore, a variety of black voxels, while regions of high echogenicity
US equipment and techniques are available to are pictured by white voxels. The gray-scale
perform US scans. However, as a matter of prin- voxels of volume data sets can be inverted; this
ciple, US techniques can be differentiated by 2- sometimes allows a better illustration of anechoic
or 3-dimensional techniques. Very recently, 4D structures such as cysts. Inversion mode can be
US has emerged. With 4D US, only 3D data can used for a better determination of tissue boundar-
be acquired in real-time mode. ies and efficient volume calculation. Some soft-
Conventional 2D US instruments are based on ware programs also picture the captured objects
cross-sectional scans, where only a single focus in different colors and, therefore, enable a clear
is visualized. In contrast, 3D US is based on a overview. This is needed when many objects are
series of 2D images, received either by manual or scanned and counted (i.e., follicles).
automatic systems; the 3D image is then calcu- One of the major advantages of US is that it is
lated and generated. In 3D mode, several scans a noninvasive, painless, and harmless procedure.
are assembled into a 3-dimensional structure; In contrast to X-ray, US scans are not hazardous
therefore, the limitation of 3D US quality depends either to the patients or to the follicles; further-
on the quality of the initial 2D imaging. Thus, it more, US radiation does not impair the devel-
must be kept in mind that when the original 2D opmental potential of implanted embryos [8, 9].
quality is low, there might be a loss of spatial Portable magnetic resonance tomography (MRT)
resolution in the reconstructed 3D image also. instruments are now available; however, the
A 3D US examination comprises four steps: advantage of US over other imaging techniques
(1) data acquisition, (2) volume calculation, (3) such as MRT is that US equipment is less expen-
image animation, and (4) data storage and trans- sive and easier to operate. Examination with MRT
266 M. Murtinger and N.H. Zech
is more time-consuming than US; furthermore, uterine anomalies [15]. The use of 3D ultrasound
it requires contrast agents. Moreover, regarding techniques is superior to other modalities for the
imaging and velocity, 3D Doppler sonography detection of uterine malformations. The correct
is the only established imaging method for ART diagnosis of malformations is crucial for deciding
that can display liquid flow such as blood circula- whether to correct them i.e., by hysteroscopy or to
tion; this is accomplished by calculating the fre- refrain from surgical intervention.
quency shift within the analyzed sample volume. Although 3D US can confirm the status of a
Due to these various options, Doppler sonogra- woman’s reproductive system, the medical litera-
phy is applicable to a broad field of diagnostic ture contains only a handful of studies in this
applications. regard. A prospective study encompassing 284
Interestingly, the principle of 3D US is not women demonstrated the reliability of 3D US for
a new innovation; the technique itself has been the detection of Müllerian anomalies [16]. The
in existence for almost three decades [10]. This accuracy was verified by endoscopy, and the
fact might be quite astonishing; however, it must authors noted that the scan could be performed in
be kept in mind that in the past its application a brief period of time. Their findings confirmed
was limited because of the restricted calcula- previous studies by other investigators [17, 18].
tion and memory capacity of computer systems Furthermore, the high intra- and interobserver
at that time. With the tremendous acceleration reliability for 3D sonography has been reported
of technical advancements in this field, instru- [15]. In view of this, it must be kept in mind that
ments also became available at an affordable 2D US of the pelvic organs cannot achieve this
price for medical applications. Fast computers degree of accuracy. Rosendahl et al. demon-
now enable 3D ultrasound picture construction, strated this feature by comparing the true ovarian
and the Digital Imaging and Communications in volume and the volume determined by 2D US;
Medicine (DICOM) specification has facilitated they reported a discrepancy of approximately
the full integration of ultrasound into the picture 30 % [19].
archiving and communication system (PACS). Ultrasound not only allows the imaging of the
major organs but also the detection of small histo-
logical abnormalities. For example, a recent study
Use of 3D Ultrasound of the Female evaluated 275 consecutive women undergoing an
Reproductive System Before IVF cycle in which TVUS was applied; it showed
and During IVF in Regard that the clinical and ongoing pregnancy rates
to Endometrial Receptivity drastically decreased when women had adenomy-
osis [20]. The authors pointed out that the diag-
On occasion, ultrasound can help determine fac- nosis of adenomyosis could be promptly made
tors involved in female infertility. Three- with high-resolution transvaginal ultrasound. The
dimensional TVUS allows evaluation of the finding that adenomyosis can impair pregnancy is
pelvic organs, and it is useful for the detection of also supported by a former retrospective study of
pelvic pathologies such as myomata, polyps, or 748 IVF patients who underwent a TVUS to iden-
cysts, which can have detrimental effects on a tify possible pelvic pathology before starting IVF
patient’s health, fertility, and pregnancy outcome. therapy with the GnRH antagonist protocol. The
US aids in the identification of malformations of investigators found that the clinical pregnancy rate
the uterus such as unicornuate uterus, bicornuate was reduced by 50 % in patients with adenomyo-
uterus, or uterine septae. Patients with these mal- sis, compared to women without the condition
formations require intense pregnancy surveillance [21]. Nevertheless, these authors correctly stated
because pregnancy loss, premature birth, and that “there is no consensus regarding the impact
other complications are more common [11–14]. of adenomyosis on implantation potential.” This
Furthermore, approximately about one-fourth of finding is quite remarkable because the worldwide
patients with recurrent pregnancy loss may have IVF success rates are still unsatisfactorily low and
20 3D Ultrasound for Follicle Monitoring in ART 267
assisted reproduction facilities are still facing the by Yaman et al. [5]. They first examined endo-
challenge of pregnancy rate improvement. This metrial volume by 3D ultrasound in the case of
situation might be explained by the fact that US pituitary downregulation. They found that 3D
advancements, especially the 3D techniques, have measurements of the endometrial volume were
only recently appeared; thus, IVF pregnancy rates highly accurate; however, the authors reported
may increase in the near future. no additional benefits of the endometrial vol-
The endometrium is the innermost glandular ume measurement. The endometrial receptivity
layer of the uterus and the location for embryo for embryo implantation is characterized by cer-
implantation. Morphology and thickness (vol- tain morphological and biochemical alternations
ume) of the endometrium can be visualized by and is also called the “window of implantation.”
US. This technique is widely used because patho- These alternations include an increase in the pro-
logical alternations of the endometrium can dras- liferation and thickness of the endometrium.
tically impair female fertility. Endometrial polyps According to the application of high, supra-
might affect embryo implantation (depending on physiological hormone dosages during stimula-
their size, position, and number). Therefore, tion, it is sometimes difficult to simultaneously
detection of these polyps is relevant for IVF suc- achieve both perfect development of multiple
cess. Either subsequent removal by polypectomy follicles and optimal endometrium buildup.
or the application of IVF cryo-cycles is the Therefore, characteristics of the human endome-
method of choice. Nevertheless, to date only lim- trium, including thickness (volume), morphol-
ited data is available, and only a few studies have ogy, endometrial blood flow, and vascularization,
demonstrated the superiority of 3D techniques in can be readily and noninvasively monitored by
the diagnosis of endometrial polyps compared to US monitoring. Nevertheless, a direct correlation
2D US [22]. A study of 103 patients with post- between endometrium buildup and implantation
menopausal bleeding revealed the advantages of rates as well as pregnancy rates is still to be con-
3D techniques for the diagnosis of endometrial firmed. Although endometrial patterns have been
pathologies [23]. Therefore, the application of reported to correlate with endometrial stages for
3D US allows a conceivably better discrimina- the past 15 years [24], large discrepancies have
tion between benign and malignant endometrial been reported in regard to correlations between
pathologies with less false-positive results; fur- the foregoing and endometrial thickness neces-
thermore, endometrial volume calculation with sary for successful implantation. Some studies
3D US was found to be superior to 2D US for the have reported correlations between endometrial
measurement of endometrial thickness. The thickness, endometrial morphology, and preg-
advantage of 3D US to discriminate between dif- nancy outcome; however, others do not address
ferent uterine anomalies was also demonstrated those factors [25, 26].
by two other studies [17, 18]. Currently, there is still no consensus regarding
In addition to correctly diagnosing endome- the endometrial thickness and endometrial vol-
trial pathology, a second crucial point is that fol- ume necessary for successful implantation.
licular maturation needs to be synchronized with However, most physicians agree that a certain
endometrial receptivity in order to achieve and degree of buildup is crucial. Several studies have
sustain a pregnancy. Endometrial morphology, suggested that pregnancy rates dramatically
thickness, and perfusion are subjected to hor- decrease when the endometrial thickness is
monal alterations, which are reflected by a shift <5–7 mm or the endometrial volume is <2.5 or
in morphology and function. Beginning in the 1 ml, respectively [5, 27–30].
1990s, the relationship between serum estradiol In a 2001 study, it was reported that implanta-
levels and endometrial thickness during down- tion is unlikely when the endometrial thickness
regulation has been demonstrated by multiple is <5 mm [31]. Other investigators report no cor-
studies; however, the first study of the new 3D relation of endometrial thickness and patterns
US that imaged the endometrium was published to implantation rates [32]. The reason for these
268 M. Murtinger and N.H. Zech
discrepancies might be based on the application ever, four defined criteria have broad acceptance
of different stimulation protocols, the various as symptomatic of the disease: (1) chronic irregu-
sonographic instruments and techniques (primar- lar ovulation or anovulation (therefore oligomen-
ily 2D US) employed, and especially on the dif- orrhea, might be an early clinical symptom for
ferent patient subgroups analyzed. Therefore, the PCOS), (2) hyperandrogenism diagnosed clini-
outcome cannot be directly compared. It must be cally (expressed by alopecia, hirsutism, and/or
noted, however, that there are application limi- acne) or by laboratory findings (serum testoster-
tations of 2D US for this procedure. Measuring one >1.4 nmol/l), and (3) the exclusion of other
the endometrial volume by this technique yields endocrine disorders. The fourth criterion can only
limited accuracy and requires significant time. be defined by ultrasound examination. Polycystic
Even for endometrial thickness, there is cur- ovaries are defined as those which contain ten or
rently no general consensus of a cutoff value more cysts with a maximum diameter of 10 mm
[30]. However, some authors have proposed a arranged either peripherally around a dense core
minimum of 5–8 mm. Despite this situation, of stroma and/or scattered throughout an increased
there might be a higher consensus to recommend amount of stroma [40]. Moreover, PCOS patients
embryo cryopreservation in cases of thin and are more likely to have larger ovarian volumes
non-trilaminar endometrium because the likeli- (>10 cm3) and ovarian stroma with increased
hood of implantation is low with this finding. volume and increased numbers of antral follicles
One study directly compared 2D and 3D US (12 or more follicles, according to the Rotterdam
applications in US scans of the endometrium [30]; criteria) [41]. Therefore, US scans play a crucial
in addition, several studies have reported the role in diagnosing this disease. The new auto-
advantages of 3D US in analyzing the endome- mated 3D US techniques facilitate the exclusion
trium. The major advantage of 3D US over 2D US of a false-positive PCOS diagnosis and reflect
is that it is a simple method of measuring the endo- pathophysiological changes in these patients in
metrial volume. The morphology of the endome- a more accurate manner. An early detection of
trium can be readily determined when it appears as PCOS is highly recommended for women under-
trilaminar (with a central echogenic line, inner going IVF treatment, due to the elevated risk for
hypoechoic regions, and hyperechogenic outer OHSS. Unfortunately, because 3D ultrasound is a
walls) or non-trilaminar (as a homogenous layer). relatively new imaging modality, the Rotterdam
Additionally the advantage of 3D US for calcula- criteria only take 2D US sonography into account.
tion of the endometrial volume is its low deviation At present, only a few studies have evaluated
of inter- and intraobserver reliability [33, 34]. the use of 3D US for PCOS patients [42]; further-
However, these parameters might not in them- more, to date, only one study has addressed auto-
selves be adequate for the prediction of successful mated 3D US (SONO-AVC) [43]. In a
implantation [35, 36]; thus, other factors that can retrospective cohort study, Allemand et al. ana-
influence the success rate have to be considered. lyzed 29 normoandrogenic, ovulatory women
with tubal or male factor infertility and 10 PCOS
women with chronic anovulation and clinical or
US Monitoring of Polycystic Ovary biochemical hyperandrogenism [42]. Mean folli-
Syndrome (PCOS) Patients cle number/ovary (FNPO) as well as the maximal
number of follicles in a single sonographic plane
Polycystic ovary syndrome (PCOS) is one of the (FSSP) was determined by 3D TVUS; simultane-
most common endocrine disorders impairing female ously, the ovarian volume was determined by 2D
fertility; it has been reported to occur in about 20 % TVUS. Interestingly, the authors postulated a
of the general female population and in up to 50 % considerably higher threshold of antral follicles
of women undergoing IVF therapy [37–39]. (20 or more) for PCOS patients, which is a con-
A number of symptoms have been associated siderably higher threshold than that of the
with PCOS that are subject to controversy; how- Rotterdam criteria. The authors explained this
20 3D Ultrasound for Follicle Monitoring in ART 269
discrepancy by the identification of more follicles Graafian) follicles represents the “for stimula-
by 3D US. The weakness of this study is the tion selectable follicles.” The antral follicle count
small number of patients, the missing direct com- (AFC) reflects the ovarian reserve and is predic-
parison to 2D US, and the low sensitivity (true tive of the IVF outcome in regard to the num-
positive rate) using receiver operating character- ber of yielded oocytes in response to hormonal
istics (ROCs). According to most publications stimulation [45, 52, 53]. This allows the classi-
dealing with 3D US in PCOS patients, there is a fication from very low (≤6) to high responding
broad agreement about increased ovarian volume patients (≥12 up to 30), the calculation of risks
of polycystic ovaries [43–48]. Nevertheless there for ovarian hyperstimulation syndrome or poly-
is still disagreement regarding ovarian vascular- cystic ovaries (PCO), and, most importantly,
ity, stromal changes, and cutoff values for antral the adaption of gonadotropin dosage during the
follicles [41, 44, 48, 49]. stimulation schedule [41, 54–57]. Inappropriate
In most PCOS studies where 3D techniques stimulation with subsequent excessive response
were applied, the numbers of analyzed patients increases the risk of OHSS; however, inadequate
were low; therefore, further studies are neces- stimulation might result in cancellation of an
sary. However, it should be noted that a major IVF cycle. It should also be noted that antral
advantage of 3D US imaging of female pelvic follicles of different sizes respond differently to
organs when a hydrosalpinx or cyst is noted is the gonadotropin stimulation. Furthermore, follicles
aforementioned inversion mode. Such structures that are >9 mm are more likely to become atretic
might not be displayed by a single slice; how- (apoptosis-induced degeneration and the fol-
ever, they may be recognized at full scale by lowing reabsorption process) [58]. The accurate
viewing multiple planes. In 2006, Benaceraf [50] assessment of the ovarian reserve is therefore a
noted that the transformation of voxels within a prerequisite for planning the optimal therapy for
volume to echogenic structures and voxels of each patient and an individualized management
solid structures to radiolucent images is one protocol. Various clinical, endocrinologic, and
method that can facilitate the acquisition of the other parameters (i.e., estradiol, the basal FSH,
total volume of a hydrosalpinx or cyst without the declining levels of anti-Müllerian hormone
being hampered by the gray-scale portion of the (AMH), or inhibin B levels) have been suggested
image. as predictive indicators for ovarian reserve and
COH response [59–64]; however, their validity is
extremely limited, and hormonal assays are cur-
Ultrasound in Estimation rently expensive [65, 66]. Additionally, there are
of the Ovarian Reserve several markers that significantly correlate with
the ovarian reserve such as age or ovarian vol-
Before initiating an ART cycle, it is crucial to ume; however, these markers are less predictive
estimate the ovarian response to stimulation. The [67, 68]. It is widely accepted that age is strongly
latest time for this estimation should be the cycle associated with ovarian reserve; however, there
prior controlled ovarian hyperstimulation (COH) is a high variability even among women of the
cycle; moreover, it is the last possible opportu- same age [69].
nity to determine any pelvic organ abnormalities The estimation of antral follicle count and
before stimulation. antral follicle size performed by TVUS is
The ovaries contain several subtypes of fol- currently the most reliable method and gives the
licles: the primordial follicles (≤0.05 mm diam- best correlation with retrieved oocytes [64, 68,
eter), primary follicles, secondary follicles, 70, 71]; moreover, it is easy to perform and is
pre-antral follicles, and antral follicles (>2 mm noninvasive. Therefore, the AFC determined by
diameter). However, only a small number of ultrasound, notably by 3D techniques, is the best
ovarian follicles are highly responsive to FSH predictor for poor ovarian response, OHSS,
[51]. The number of these so-called antral (or oocytes collected, and live birth rates [72].
270 M. Murtinger and N.H. Zech
It should be noted that it is imperative to distin- finding was contradicted by the same research-
guish between the total antral follicle count ers in a second study, in which they measured the
(TAFC), including follicles >6 mm in diameter examination time instead of including time for
and the number of small antral follicles which post-processing of the US scans [79].
better reflects the ovarian reserve [73] and pre- Interestingly, in several studies the TAFC was
dicts the COH response [74]. found to differ between 2D and 3D techniques
AFC can even be obtained on day 2 of the [78, 79]. This might be explained by the fact that
menstrual cycle [71]; however, the best time for when the follicle number increases, the accuracy
estimation of antral follicles is the middle to late of 2D techniques decreases because of losing
phase of folliculogenesis. Currently, the AFC is track of counted follicles and multiple counting
determined by 2D as well as 3D US, with pre- of the same follicles [81, 82]. In conclusion AFC
dominance of the 2-dimensional techniques. In is highly predictive for the ovarian reserve and
regard to 3D ultrasound, we must distinguish strongly associated with the serum AMH level
between manual and automatic systems (such as [74]. The estimation of the ovarian response by
Voluson e in combination with SONO-AVC soft- US is simple and noninvasive; thus, it is an advis-
ware); this will be discussed later in this chapter. able procedure. The reliability of this method is
Nevertheless, there is the question regarding the probably increased with 3D instruments.
reliability of AFC determined by different US
techniques as well as which current methods are
the best. Of note, only a handful of studies com- Follicle Tracking During Controlled
pare the accuracy of ultrasound in regard to AFC Ovarian Hyperstimulation
and inter- /intraobserver reliability. Broekmans
et al. described the value of AFC determined by The consistent aim of controlled ovarian hyper-
AVC needed for the improvement of standardiza- stimulation during an IVF is to obtain the maxi-
tion and presented a tutorial on clinical and tech- mum number of mature and good quality oocytes.
nical requirements [52]. This increases the chance for having an adequate
Standard AFC assessment was, and still is, per- number of high-quality embryos, which rises the
formed primarily with 2D US imaging. Although likelihood of achieving a viable pregnancy.
this modality might be sufficient in some cases, Therefore, oocyte maturity is a critical factor.
there might be some uncertainties and disadvan- The cytoplasmic as well as nuclear maturity,
tages. One disadvantage of 2D involves inter- and defined as oocytes that have completed their first
intraobserver reproducibility. Scheffer et al. [75] meiotic division and reside in metaphase II (MII),
compared healthy volunteers with proven fertil- is required for a high fertilization rate and opti-
ity to patients visiting an infertility clinic. For mal embryo development. According to the clas-
each patient, 2D or 3D TVS was conducted for sical IVF protocols, GnRH analogues and hCG
AFC (2–10 mm), and interobserver reliability are administered to trigger the ovulation process
was calculated. Both techniques were adequate when the dominant follicle reaches a diameter
when only a few follicles were present; however, between 18 and 20 mm or the follicle volume has
when higher AFCs occurred, the reproducibil- reached 3–4 ml [83]. The timing for hCG admin-
ity decreased with the 2D technique. In addition istration is the most critical step of an IVF cycle.
to this report, studies by the group of Raine- During COH, follicle growth occurs at different
Fenning [76–80] demonstrated an improvement rates; thus, follicles of varying sizes are present.
of interobserver/intraobserver reliability by the Therefore, the best method to obtain a maximal
application of 3D methods (in particular by auto- yield of MII oocytes is to obtain a maximal num-
mated systems, such as SONO-AVC). One of ber of follicles of large diameter or volume.
the disadvantages of manual 3D US AVC is the Nevertheless it should be also considered that in
greater examination time that occurred in a study the case of an extended stimulation period, folli-
comprising 55 women [78]. Nevertheless, this cles might become atretic and oocyte quality
20 3D Ultrasound for Follicle Monitoring in ART 271
3D US was reported to be superior for the identi- in three orthogonal planes: the mean follicle
fication of the cumulus oophorus complex [98]. diameter, the follicular volume, and the volume-
Nevertheless, it must be kept in mind that 3D US based diameter of the follicle [82]. Thus, the
only differs in capturing volume while 2D pro- volume is calculated via the voxel count within
duces slices. hypoechoic structures. The true volume can be
From the 3D ultrasound data set, the exact measured, and SONO-AVC calculates the fol-
volume of a clearly defined object is calculated. licle diameter by rendering the follicle as a per-
The basic principle of volume calculation is fect sphere. This results in the visualization of
based on the combination of shape information sono-anatomic details, which could not previ-
from different image planes. The automatic sys- ously be recognized. A major advantage of this
tems significantly facilitate volume calculation. sono-anatomic rendering is that individual struc-
tures are color-coded (Figs. 20.2, 20.3, and 20.4)
allowing the exact count, which is needed for the
New Applications of 3D US determination of factors such as ovarian reserve.
Several studies have demonstrated the advan-
The application of 3D US technologies in medi- tages and validity of SONO-AVC in vitro and in
cine is rapidly evolving. Promising new appli- vivo. In this report, we focus only on studies and
cations in ultrasound technology have been reviews concerning the application of SONO-
developed during recent years and have been AVC related to assisted reproduction. Most
successfully introduced in the field of IVF. These importantly, 3D SONO-AVC yields high reliabil-
new applications facilitate ultrasound examina- ity for volume and diameter calculations.
tions by automatic measurements and calculation; In a 2008 study by Raine-Fenning et al. [76],
thus, they markedly increase the reproducibil- which comprised 51 women undergoing con-
ity of the results. Several new software pro- trolled ovarian stimulation, 200 follicles were
grams support this: VOCAL, STIC, TUI, VCI, analyzed. Measurements were performed in six
and SONO-AVC. One of the most frequently different ways, including manual 2D US, manual
employed applications is the sonography-based 3D US, and automatic measurements with
automated volume calculation (SONO-AVC; GE SONO-AVC. Ultrasound data were analyzed by a
Medical Systems, Zipf, Austria). The application single observer, and diameters of each follicle
of SONO-AVC for IVF was first described by were estimated. The true volumes were deter-
Raine-Fenning et al. in 2007 [99]. Furthermore, mined by manual measurement of the follicle
SONO-AVC is not only used in ART but also in aspirate. The true diameter was estimated by the
pregnancy and for examinations of the bladder sphere formula. The researchers concluded that
[100, 101]. the automatic system provides more accurate
Nevertheless, SONO-AVC is a software espe- measurements of follicle diameter than manual
cially designed for the automatic detection of measurements. SONO-AVC perfectly reflects not
multifollicular growth and to overcome the afore- only the true follicular diameter but also follicu-
mentioned problems of follicle observation by lar volume. Most studies addressing these topics
2D US. This software allows not only the display confirmed a high accuracy [102–107], and most
of single follicles in 3D but also automatically importantly, this accuracy was also maintained
calculates the number and volume of hypoechoic with follicles of different size [108]. Additionally,
structures in a 3D echo-derived data set; further- using the automatic system, the measurement
more, it provides estimations regarding the abso- time was significantly curtailed [109]. The time-
lute dimensions of follicles. The only necessary saving feature of the SONO-AVC was also
requirement is adjustment of the ROI box over reported and acknowledged by numerous other
the entire ovary to include only the information studies [77, 103, 110]. The time-saving aspect
which is needed for calculation. Measurements was also highlighted by Sherbahn and Deutch in
are based on calculation of the largest diameters 2009 [110]. By comparing two groups of patients,
274 M. Murtinger and N.H. Zech
Fig. 20.2 Imaging of a cyst as a scan and in 3D reconstruction. US scans of a cyst performed with E8 Voluson and 3D
imaging by SONO-AVC software
either using SONO-AVC or traditional 2D-US, comprised of 40 IVF patients between 25 and
they reported that less time was required for per- 35 years of age, Murtinger et al. compared the
forming the scans, data analysis, and chart outcome of follicle monitoring and the calculated
recording. day of hCG administration in regard to the num-
Raine-Fenning et al. [76] described the superi- ber of mature oocyte retrieved, mature oocytes
ority of another 3D imaging software product, per oocytes recovered, embryo development to
3D VOCALTM (Virtual Organ Computer-aided day 5, and pregnancy rate. For 20 patients, fol-
AnaLysis, Kretz Technik, Zipf, Austria), for vol- licle monitoring was proceed by 2D US; hCG
umes, which had been estimated from 2D US was administered when a cohort of follicles
measurements. The basic principle of 3D reached a diameter between 16 and 24 mm. For
VOCAL is the combination of 3D ultrasound tis- the other 20 patients, the day of hCG adminis-
sue presented as voxels and the geometric infor- tration was estimated by the same criteria; how-
mation regarding surfaces in a 3D data set. The ever, follicle diameter was processed by 3D
main advantage of VOCAL is the surface charac- US, and subsequent volume was calculated by
terization. This software enables the determina- the SONO-AVC software. In this group, more
tion of volumes by the virtual plane rotation oocytes were retrieved, and significantly more
around a fixed axis, calculating the contours of oocytes were found to have been fertilized on
each 2D plane. day one [109]. Rodriguez-Fuentes et al. [107]
Another useful application of SONO-AVC elucidated a correlation between follicular vol-
might be for hCG administration. In a study ume (determined by SONO-AVC), day of hCG
20 3D Ultrasound for Follicle Monitoring in ART 275
Fig. 20.3 Antral follicle count performed by 3D US right: color-encoded 3-dimensional reconstruction of fol-
SONO-AVC. Automatically identified antral follicles by licles enables the accurate determination of the number of
E8 Voluson in combination with SONO-AVC software. follicles
Follicle boundaries are marked by different colors. Lower
Fig. 20.4 Representation of a stimulated ovary generated colored line corresponds to a follicle. The lines are coded
via 3D TVUS scanning plus SONO-AVC software 1 day with the same colors as the corresponding follicles; dx,
before OPU. Follicle boundaries are marked by colors. dy, and dz diameters; mean diameter; and volumes are
Lower right: color-encoded 3-dimensional reconstruc- automatically provided
tion of follicles. Left: detailed SONO-AVC report. Each
276 M. Murtinger and N.H. Zech
administration, and retrieval of mature oocytes. the number of follicles is high. In contrast the
They postulated that there is a higher likelihood SONO-AVC color coding prevents counting one
of obtaining mature oocytes when the follicular follicle twice. Moreover the received data still
volume is ≥0.6 ml. In contrast to these results, requires post-processing [82].
in a randomized study, no difference in the COH
outcome in terms of mature oocytes, fertilized
oocytes, embryo development, and pregnancy Optimal Outpatient Monitoring
rate were observed by Raine-Fenning et al. [111].
However, it should be noted that they used diam- There are several advantages of the new 3D US
eter rather than volume-based criteria for deter- techniques. New software systems such as
mining the timing of hCG injection. However, due SONO-AVC allow a smooth, facilitated work-
to the paucity of studies concerning SONO-AVC flow with a shorter examination time. This pro-
and timing of final follicle maturation, there is a vides an advantage for physicians in busy IVF
need for larger studies. The time-saving aspects centers as well as patient-friendly therapy [103].
of these new techniques might decrease patient Another problem, which can now be avoided, is
anxiety, physician stress, and facilitate a smooth the already mentioned inter- and intrapersonal
work outflow. SONO-AVC allows automated variability in the processing, readout, and inter-
volume calculation without the need for separate pretation of ultrasound scans. When manual post-
measurement of each follicle. To date, studies processing of US scans is required, there is a
addressing AFC estimation by SONO-AVC are natural maximal interpersonal variability and
limited. In a study comprised of 55 patients under error source when the attending physicians are
age 40 years, Deb et al. [79] estimated the TAFC from different institutions and differ in their rou-
by SONO-AVC and compared the results to tines, experience, handling, and knowledge.
these obtained by 2D and manual 3D techniques. The complexity of assisted reproductive tech-
Antral follicle volumes were analyzed automati- nologies has increased markedly during recent
cally by SONO-AVC or manual via longitudinal decades due to the rise of scientific and medical
or transversal planes. The initial automated count data as well as the statutory requirements of the
was recorded and post-processed. The median effort to improve the safety and the outcome of an
AFC by SONO-AVC was significantly less than IVF therapy. Therefore, it is essential that therapy
2D, and SONO-AVC measurements took longer planning and ART processing be conducted at
than 2D. In contrast, in a subsequent study in highly specialized IVF units. As a result of this
2010 conducted by the same investigators [79], increasing complexity, it is likely that the number
the required measurement time using SONO- of IVF centers will decrease rather than increase.
AVC was less than that of 2D US. The first study Not all centers will be able to keep pace with the
was not performed in real time and included the increasing technical requirements and the appear-
time for post-processing; however, the second ance of new (and sometime cost-intensive) appli-
study focused on real-time count. cations. Currently, gynecologists who practice
Moreover, SONO-AVC was demonstrated to apart from infertility clinics are involved in patient
be time-saving, compared to manual applications care during the IVF therapy, especially for the
[103, 109]. However, as the manufacturers noted, monitoring of follicle growth. Results are rou-
the focus for the automatic detection is mainly on tinely communicated to the IVF clinic so that
follicles ≥12 mm diameter. In regard to antral physicians there can determine how to proceed
follicle imaging, the algorithm is not adequate for with the therapy in terms of further dosing of fol-
optimal imaging regarding the true size and vol- licle-stimulating hormone, the adaption of hor-
ume [112]. Nevertheless, it should be noted that monal stimulation, the duration of stimulation,
not the exact diameter but the correct number of and the time of initiating final oocyte maturation.
antral follicles is crucial. The repeated observa- These challenges were previously reported by
tion of fewer antral follicles in several studies Murtinger et al. in 2010 [113]. The difference in
might be explained by the inaccuracy of 2D when operative experience and handling, distinct ways
20 3D Ultrasound for Follicle Monitoring in ART 277
Patient
management VPN tunnel
system
Internet
Fig. 20.5 Scheme of patient data transmission between clinic is done by VPN (virtual private network) tunneling.
local gynecologist and IVF center. The ultrasound device All data is encrypted and safe from unauthorized access.
(USD) transmits the results of the medical examination IPsec (Internet Protocol Security) with encryption key
(follicle volumes and endometrium measurements) to the length of approximately 2,048 bits allows the secure
PACS server. The USD queries work lists and patients Internet protocol by data, authentication, and integrity
data from the PACS server. All data transmission between validation. Data is encrypted during the communication
USD of the referring physician and PACS server in the and the encryption key changes every second
of interpretation of ultrasound scans, and the device is connected via a DSL modem to the
interobserver variability can lead to too early or Internet. All communication takes place through a
too late hCG administration, thus negatively secured connection (virtual private network
affecting the IVF outcome. Currently, there is an (VPN)) tunneling to ensure that non-authorized
enormous need for an unobstructed interaction individuals cannot gain access to sensitive data.
between the IVF centers and the referring physi- The requested ultrasound examinations and struc-
cians who might be separated by a distance of tured reports are performed by the gynecologist,
hundreds of kilometers. Additionally, in large IVF and if necessary, the images are sent via DICOM
centers, which comprise several subunits or satel- standard back to the center. There, medical soft-
lite clinics, an unobstructed data transfer must be ware such as DynaMed® (IMA Systems, Bregenz,
guaranteed. In 1995, Roest et al. [114] noted, Austria) allows the seamless integration of all
“Travelling time and inconvenience for the processes needed for an accurate and precise
patients is limited since the monitoring of ovarian workflow (Fig. 20.5). The technical advances in
stimulation is carried out in their local hospital by ultrasound will play a crucial role for more patient
their own gynecologist.” However, this situation and practitioner-friendly therapies in the future.
brings up a counter-argument that, when satellite Two major benefits can be attained. First, the
physicians monitor ovarian stimulation for their establishment of standards in the application of
own patients, quality assurance is necessary. ultrasound in assisted reproduction. This is a pre-
Additionally, regarding patient subgroups, which requisite to fulfill the regulatory requirements
are at high risk of OHSS (primarily PCOS such as those given by the EU Directive on tissue
patients), it is commonly accepted that short mon- and cells (2004/23/EC) [115]. Moreover, a smooth
itoring intervals are crucial to detect OHSS. clinical workflow can be guaranteed. In fact, the
Therefore, accurate and complete transmission of objective and standardized information exchanges
US data is crucial. The introduction of new US and documentation allow more legal certainty in
techniques such as Voluson I ultrasound system cases of legal disputes between IVF centers, phy-
(GE Medical Systems, Kretztechnik, Zipf, sicians, and patients.
Austria) combined with the SonoAVC® software
(General Electric Company, New York, USA) Conclusions
now allows optimal digital data transfer. The During the last two decades, 2D US was one
results can be communicated via DICOM. The of the key modes employed for IVF; however,
IVF centers now have the ability to transfer patient 3D US is increasingly being employed for
data via a PACS server to the ultrasound machine reproductive medicine. There are several
of the gynecologist. The firewall prevents unau- advantages of 3D-based US instruments.
thorized access to the PACS server. The ultrasonic Examination time is reduced because the US
278 M. Murtinger and N.H. Zech
scan data are stored and can be analyzed in hyperstimulation before in vitro fertilization. Acta
detail at a later time. These data can be recon- Obstet Gynecol Scand. 2005;84:812–26.
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Ultrasound-Guided Surgical
Procedures 21
Donna R. Session and Jennifer F. Kawwass
potential risks. An abdominal ultrasound cov- is hypothesized that implantation on a poorly vas-
ered with a sterile sheath can be used to visualize cularized septum may contribute to this increased
boundaries of the uterine cavity, the instrument’s risk of miscarriage. After resection, spontaneous
location within the cavity, and the extent of miscarriage rates return to the baseline rate of
resection/depth of remaining myometrium (see approximately 15 %; 80 % of pregnancies post-
Fig. 21.1). The ultrasonographic operator may resection result in term delivery [7, 8].
provide a narrative of position of the instru- The high degree of accuracy of magnetic res-
ments and depth of the uterine wall at the opera- onance imaging (MRI) and three-dimensional
tive site. Alternatively, the surgeon may view (3D) ultrasound in the diagnosis of congenital
the ultrasonographic and hysteroscopic images anomalies has decreased the previous need for
simultaneously. diagnostic laparoscopy at the time of surgery to
aid in characterization of the type of anomaly.
Three-dimensional ultrasound has been shown
Uterine Septum to have 98 % specificity and 100 % sensitivity
of accurate septum diagnosis [10]. Although
The incidence of congenital uterine anoma- diagnostic hysteroscopy/laparoscopy is still
lies is estimated to be 3–4 % of reproductive considered the gold standard, MRI and 3D
age women and 5–10 % in women with recur- ultrasound are accepted alternatives with both
rent miscarriages [5, 6]. The anomalies may be lower risk and cost.
asymptomatic or result in infertility, recurrent Upon diagnosis, a uterine septum is treated
pregnancy loss, intrauterine growth retardation, by noninvasive outpatient hysteroscopic sur-
or endometriosis when obstruction is present. gical resection which results in significant
Uterine septum, which results from incomplete improvement in subsequent pregnancy outcomes
resorption of the medial septum between two [5, 7, 11]. Ultrasonographic guidance without the
normally fused hemi-uteri, is not only the most aid of hysteroscopy has also been described; 11
common uterine anomaly but also is the mal- patients had postprocedural evaluation of the uter-
formation most highly associated with poor ine cavity, 2 patients had a residual septum, and
pregnancy outcomes [5, 7]. Case series report a 1 patient had extensive synechiae [12]. Although
spontaneous miscarriage rate ranging from 65 to the number of cases is limited, the results with
88 % in the presence of a uterine septum [8, 9]. It ultrasonographically guided hysteroscopy appear
21 Ultrasound-Guided Surgical Procedures 285
better than metroplasty without the use of hys- IVF [18]. Several recent studies evaluated the
teroscopy. Hysteroscopic metroplasty can be suc- effect of fibroids on in vitro fertilization cycles;
cessfully performed using microscissors, laser, or the balance of data suggests that pregnancy
electrocautery with comparable improvements in outcomes and implantation rates are adversely
future pregnancy outcomes [7]. The procedure is affected by submucosal myomas that enter the
complete once both ostia are visible simultane- uterine cavity but not by subserosal or intramural
ously and when less than 1 cm of myometrium fibroids that are less than 5–7 cm in size [19–22].
remains [13]. Discontinuing the procedure once Resection of submucosal fibroids clearly within
a fundal thickness of 8–10 mm is obtained was the uterine cavity is likely warranted in patients
associated with a normal intrauterine contour on with dysfunctional uterine bleeding, infertility,
hysterosalpingography [14]. Postoperative hys- or pregnancy loss who desire to optimize future
terosalpingography revealed incomplete resec- fertility. A hysteroscopic approach is reasonable
tion of the septum when thicknesses of 11–16 mm if the majority of the fibroid is within the cav-
were used [14]. ity or if subtotal hysteroscopic myomectomy is
A prospective, open study including 81 deemed preferable to abdominal myomectomy.
patients undergoing ultrasound-guided operative Hysteroscopic resection may be performed using
hysteroscopy for uterine septum or submucosal a hysteroscopic morcellator or resectoscope.
myoma compared outcomes to that of a historical A resectoscope allows for the use of electrocau-
control group of 45 patients who underwent the tery at time of resection but, as a result, requires
same procedure under laparoscopic guidance electrolyte-poor distending media such as man-
[15]. All patients in the ultrasound group were nitol, sorbitol, or glycine. Morcellating devices
successfully treated with a single surgery, and resect using a rotating blade rather than electro-
none required conversion to laparoscopy. In con- cautery and allow for use of isotonic distending
trast, four of the control group patients required media such as normal saline or lactated ringers
additional surgery to resect residual fibroid or which have lower risk for fluid overload and sub-
septum. Ultrasound guidance allowed the sur- sequent electrolyte imbalance. The avoidance of
geon to accurately determine depth of remaining electrocautery also has a theoretical benefit of
septum and the outer limit of uterine fundus. avoiding thermal damage to the myometrium and
decreasing chance of future uterine rupture at time
of pregnancy. Both methods incur a risk of pro-
Submucosal Fibroids cedure abortion secondary to bleeding. Prior to
starting the hysteroscopy, injection of vasopres-
Uterine fibroids, the most common benign tumors sin into the cervical stroma can be used to help
in females, have a prevalence of 8–18 % in the decrease myoma bleeding. If bleeding is encoun-
general population and are often asymptomatic tered intraoperatively, conversion from morcella-
[16, 17]. Symptomatic fibroids can cause pelvic tor to electrocautery or use of uterine balloon for
pain, menorrhagia, abdominal fullness, and occa- tamponade and uterine compression can be used
sional urinary and bowel symptoms. Fibroid size to help achieve hemostasis. Lin et al. resected
and location affect the type and degree of patient six submucosal myomas under ultrasonographic
symptoms and may also have reproductive conse- guidance [23]. All cases were completed in less
quences including pregnancy loss and infertility. than 1 h. There were no traumatic complica-
As with uterine septa, resection of submuco- tions. None of the patients required laparotomy
sal fibroids benefits from ultrasound guidance or blood transfusion. Postoperative electrolyte
at time of hysteroscopy. The extent of uterine values revealed no significant change from pre-
fibroids’ effect on pregnancy rates and outcomes operative values. Menorrhagia and metrorrhagia
remains controversial. However, submucosal improved. Postoperative hysteroscopy revealed
myomas that significantly distort or encroach on no intrauterine adhesions, and the endometrium
the uterine cavity may lower implantation and at the operative site appeared normal. Wortman
pregnancy rates in infertile women undergoing and Dagget used ultrasonographic control to
286 D.R. Session and J.F. Kawwass
remove large submucosal myomas [24]. These received a nonhormonal copper intrauterine device
authors claimed that ultrasonography may help for 3 months [27]. More recently, investigators are
prevent perforation and obviate laparoscopy [24]. comparing the effectiveness of newer synthetic
barrier methods such as Seprafilm and hyaluronic
acid gel compounds [30, 31]. Preliminary results
Synechiae are promising; however, larger randomized studies
have not yet been performed. Of note, antibiotic
Asherman’s syndrome, scarring of the endome- prophylaxis is recommended for as long as a for-
trial cavity that may have resulted from preexist- eign intrauterine device remains in place.
ing infection or uterine instrumentation, may be The exact regimen and dose of oral estrogen
manifested as hypomenorrhea, amenorrhea, infer- remains unclear. Accepted supplementation
tility, or recurrent pregnancy loss. Hysteroscopic ranges from 4 to 6 mg daily (often dosed bi-daily)
lysis of adhesions remains the treatment of for 4–10 weeks duration.
choice. In severe cases of intrauterine adhesions,
it is difficult to determine, without ultrasonogra-
phy, which part of the cavity is being observed Intrauterine Foreign Bodies
during hysteroscopy. Shalev et al. performed hys-
teroscopic lysis of intrauterine adhesions using The use of ultrasonographic guidance for the
ultrasound (rather than laparoscopic) guidance in retrieval of an intrauterine foreign body has
106 women with varying degrees of Asherman’s been described [32]. Retained bony fragments
syndrome. Adhesiolysis was successful in all after a therapeutic abortion were removed suc-
cases; there were no complications [25]. In cases cessfully with the use of an ultrasonographi-
of moderate-to-severe intrauterine synechiae, cally guided resectoscope [3]. Ultrasonography
ultrasonographic guidance permits the accurate allowed visualization of bone embedded in the
localization of the instruments within the uterus myometrium.
and of myometrial depth. This may result in a
greater chance of success in a single surgical pro-
cedure with a lower perforation rate. A recent ret- Hematometra
rospective cohort study including 159 procedures
affirms a lower uterine perforation rate for ultra- As in the case of intrauterine foreign body, ultra-
sound-guided (1.9 %) compared to laparoscopic sonography can direct the surgeon to the patho-
(8.7 %) or blind (5.3 %) hysteroscopic uterine logic site within the uterus when this is not
septum resection [17]. Cost was also significantly evident by direct hysteroscopic vision, as in
less for the ultrasound- rather than laparoscopic- hematometra. Kohlenberg et al. described five
guided resections [17]. cases of hematometra following endometrial
After significant adhesiolysis, the placement of ablation [33]. Ultrasonography was used to guide
an intrauterine balloon stent to provide mechanical the hysteroscope to the cornua where these col-
separation and administration of estrogen to pro- lections were located. Similarly, Goudas and
mote endometrial proliferation have been shown Session described a case of successful treatment
to decrease postoperative synechiae formation of cervical stenosis and hematometra with ultra-
[19, 26–28]. Initial extent of adhesions has been sonographically guided hysteroscopy [34].
shown to correlate with adhesion reformation [29].
Both uterine balloons and intrauterine devices
have been evaluated for postoperative Asherman’s Limitations of the Technique
management. A 1993 study revealed signifi-
cantly improved outcomes (resumption of men- Replacing laparoscopy with ultrasound at time
ses, increased conception, and decreased need for of hysteroscopic resection of a uterine septum,
reoperation) in patients for whom a uterine balloon myoma, or adhesive disease usually decreases
was placed for 10 days as compared to those who potential risk while shortening operative time
21 Ultrasound-Guided Surgical Procedures 287
and maintaining optimal surgical results [25, 35]. interfere with subsequent stimulation. Usually,
However, in a limited number of patients in cysts rupture or are reabsorbed within 6 months
whom abdominal pathology is suspected, lapa- without need for intervention; a recent meta-
roscopy concurrent with hysteroscopy may analysis including eight randomized controlled
reveal an intra-abdominal abnormality that can trials found no benefit to oral contraceptive use
be treated laparoscopically. Additionally, severe to hasten cyst resolution [36]. However, if a cyst
retroversion and cul-de-sac adhesions may hinder is causing significant pain, persists for several
clear transabdominal ultrasound visualization. months, and grows large enough to pose a signifi-
Furthermore, diathermy heat may alter tissue cant bleeding or torsion risk, or if time constraints
or distending fluid by creating microbubbles or exist for a subsequent cycle, a role remains for
produce electrical interference that appears as cyst aspiration. Cysts may be either functional
a “snowstorm” that impedes ultrasonographic (hormone-secreting) or nonfunctional. Small
imaging [33]. Nonetheless, it is still usually pos- (<15–20 mm), nonfunctional (<50 pg/mL estra-
sible to measure myometrial depth, although diol) cysts likely have little effect on fertility treat-
hysteroscopic localization within the area may be ment; however, functional cysts can deleteriously
difficult. Additionally, the majority of hystero- affect number and quality of retrieved oocytes,
scopic procedures can now be performed without fertilization rates, implantation rates, miscarriage
cautery using new hysteroscopic morcellating rates, and cycle continuation rates [37, 38].
devices. Small, nonfunctional cysts usually do not
require intervention. Larger, functional cysts may
be managed conservatively either by prolonging
Summary downregulation with GnRH agonist prior to stim-
ulation start or by surgical aspiration. In this situ-
For uterine septa, submucosal fibroids, and uter- ation, no clear benefit to surgical aspiration exists
ine synechiae, ultrasound guidance helps obtain [39]. In fact, even for larger (>15 mm), estrogen-
complete resection while minimizing risk of uter- producing (>50 pg/mL estradiol) cysts, the
ine perforation [24]. majority of evidence suggests no improvement in
number of retrieved oocytes, embryo quality, fer-
tilization rate, and implantation and pregnancy
Ovarian Cyst and Hydrosalpinx rates between women whose cysts were aspirated
Aspiration and those whose cysts were not [39–42]. The del-
eterious impact of functional cysts on in vitro fer-
Both ovarian cysts and tubal fluid can be easily tilization cycles persists and, unfortunately, has
aspirated while using transvaginal ultrasound not been shown to be blunted by cyst aspiration.
guidance. A needle guide fits on the superior Occasionally, however, time pressure, inabil-
aspect of a standard transvaginal ultrasound ity to prolong stimulation start, or patient
allowing the sonographer/surgeon to advance discomfort drive the need for surgical cyst aspi-
the needle in a predictable, visible plane. ration. Aspirated fluid may be collected and sent
Ultrasound color Doppler can be used to confirm to pathology for further cytologic evaluation.
an avascular path from the vagina to the ovary or A 1992 study including 1,544 oocyte retrievals
tube. sent aspirated follicular fluid for cytologic evalu-
ation and found no cases of malignancy [43].
result from a direct embryo toxic effect of the approaches using sterile-draped abdominal ultra-
hydrosalpinx fluid on inhibition of implantation sound and either a guided or freehand needle.
or from a more direct mechanical flushing effect. The procedure may be performed using mineral
Implantation rates have been improved by aspi- oil rather than potentially oocyte-toxic ultrasound
ration of hydrosalpinges during the IVF cycle gel in a manner similar to amniocentesis [51].
following oocyte aspiration, by salpingectomy Transvaginal aspiration, first described by
or tubal occlusion prior to the IVF cycle, and Gleicher in 1983, has replaced other routes of
by extended antibiotic treatment during the IVF aspiration, except when the ovary is not accessi-
cycle [44–46]. Diagnosed hydrosalpinx is usually ble vaginally such as in some cases of Mullerian
treated (excised or occluded) prior to initiation of anomalies [52, 53]. As with all surgical interven-
IVF. However, the size of a hydrosalpinges var- tion, oocyte retrieval incurs a risk of infection,
ies during the menstrual cycle [47]. As a result, bleeding, and damage to nearby structures. Such
patients may not have a visible hydrosalpinx risks are <1 % and are minimized by adequate
prior to stimulation but may accumulate fluid visualization and proper surgical technique [54].
during an IVF cycle. In such situations, mixed For transvaginal aspiration, the patient is placed
evidence exists regarding benefit of aspiration in the dorsal lithotomy position. After sedation is
at time of retrieval. A controlled retrospective obtained by either a local, regional, or intrave-
analysis of 151 women compared implanta- nous route, the vagina is prepped with saline
tion rates in patients with hydrosalpinx at time lavage or antiseptic to decrease bacterial counts.
of retrieval and found no benefit to drainage at Prophylactic antibiotics may be given to reduce
time of retrieval but confirmed overall reduction the occurrence of possible pelvic inflammatory
in implantation rates in the presence of hydro- disease particularly in patients with endometrio-
salpinx compared to patients without tubal dis- sis [55]; however, peri-retrieval antibiotics have
ease [48]. However, a smaller retrospective study not been shown to affect clinical pregnancy
(n = 34) reported significantly improved implan- rates [56]. As with cyst and hydrosalpinx aspira-
tation rates (14 % versus 1 % p = .015) with trans- tion, a transvaginal ultrasound probe is placed in
vaginal aspiration of the hydrosalpinges at time a sterile sheath and fitted with a needle guide
of oocyte retrieval [45]. Possible concerns with through which a single- or double-lumen 16–17
this approach include the rapid re-accumulation gauge needle is passed to sharply puncture ovar-
of hydrosalpinx fluid and risk of pelvic infec- ian follicles and aspirate (at 100–200 mmHg) fol-
tion caused by the aspiration of the hydrosalpinx. licular fluid and oocytes. The tip of the needle is
Nonetheless, aspiration of tubal fluid rather than etched to increase echogenicity.
cryopreservation of all embryos may be useful Puncture site is determined by visual observa-
when hydrosalpinges become evident during an tion and use of color Doppler for avoidance of
IVF cycle as a significant decrease in chance of vaginal and pelvic blood vessels. The planned
pregnancy was found only when the hydrosal- course of the needle can be clearly visualized
pinx was evident on ultrasound [49]. with the biopsy line setting on the ultrasound
machine and the probe rotated in such a manner
as to avoid blood vessels (see Fig. 21.2). Absence
Oocyte Retrieval of vasculature in the needle’s course can be con-
firmed with color Doppler. Additionally, if an
Although initially performed laparoscopically, ovary is malpositioned, its location can be
oocyte retrieval is now routinely performed using improved with abdominal pressure or by rotation
ultrasound guidance due decreased operative risk of the surgical table.
and a higher rate of oocytes retrieved. Ultrasound- The decision to use a single- or double-lumen
guided aspiration was first described by Lenz in needle depends on the physicians desire to flush
1981 [50]. Aspiration techniques have included aspirated follicles with culture media to attempt
transabdominal, transvesical, and transurethral to increase oocyte yield. Flushing requires a
21 Ultrasound-Guided Surgical Procedures 289
on embryo placement was once controversial. In Similarly, Hurley et al. found tactile feedback
1985, Strickler et al. reported ultrasound-guided unreliable; they identified 19 of 94 cases of
embryo transfer in 16 patients. It was noted ultrasound-guided embryo transfer where the
that the transfer catheter tip could be accurately physician unknowingly misplaced the catheter
positioned in the uterine cavity and ejection (6 in the cervix, 12 in the lower uterine segment,
of the transfer media and air bubble could be and 1 in a false passage). However, they did not
documented [67] (see Fig. 21.5). Woolcott and find a significant difference in implantation rate
Stranger suggest that blind tactile feedback is with and without ultrasound, 20.2 and 17.5 %,
unreliable for ascertaining proper embryo place- respectively [69]. A randomized controlled trial
ment [68]. They describe abnormal placement by Kan et al. also found no significant difference
near the internal tubal ostia in 9 of 121 transfers in implantation rate in the ultrasound-guided
of the embryo transfer catheter documented by group (20.4 %) compared to the control (16.2 %)
ultrasound [68]. The authors suggest that ultra- [70]. This study controlled for the pregnancy
sound guidance may decrease ectopic pregnancy rate of the physician performing the procedure
rate by avoiding transfer near the tubal ostia. and day of the procedure (the control patient was
21 Ultrasound-Guided Surgical Procedures 291
selected on the same day as the study patient). Cochrane review comparing ultrasound-guided
Although not significant, the implantation rate versus “clinical touch” embryo transfer [76].
of difficult transfers was 54.5 % in the study Although initially controversial, ultrasound
group and 10.0 % in the control group [70]. guidance appears to play a beneficial role in
This group suggested that ultrasound guidance embryo transfer. While the only disadvantages
may be useful in patients with difficult trans- include the need for additional time, equip-
fers. In contrast, Coroleu performed a random- ment, and skilled personnel, ultrasonography
ized trial in 362 patients and found a significant has the potential to aid in ideal embryo place-
difference in implantation rate: 25.3 % in the ment 15–20 mm from the fundus, to decrease
ultrasound-guided group compared to 18.1 % in uterine contractions, to increase the frequency of
the control group [71]. However, they failed to “easy” atraumatic transfers, and most important
control for the pregnancy rate of the physician to improve implantation and pregnancy rates.
performing the procedure. In addition, the loca-
tion of embryo transfer differed between the
two groups. In the ultrasound-guided group, the Intrauterine Device Placement
embryos were transferred to within 1.5 cm of and Removal
the fundus, while the control group had embryos
transferred as close to the fundus as possible The intrauterine device (IUD) is one of the most
without touching. Coroleu et al. in 2002 pro- effective forms of reversible contraception; the
spectively randomized 180 consecutive patients failure rate is 0.1–0.8 % in the first year of use and
to embryo transfer at 10 mm from the fundus, risk of complications such as perforation or expul-
15 mm from the fundus, and 20 mm from the sion is extremely low, 0–2 % and 2–3 %, respec-
fundus [72]. All groups were equal in regard to tively [77, 78]. Occasionally, a tortuous cervical
patient age, BMI, diagnosis, duration of infer- canal may make insertion difficult. In such
tility, number of embryos transferred, and the instances, using the aforementioned techniques to
degree of difficulty with transfers. Implantation obtain visualization of the cervical path and uter-
rates were 26 % if transferred 10 mm from the ine contour, transabdominal ultrasound can
fundus, 31.3 % at 15 mm, and 33.3 % at 20 mm. be used to help with difficult intrauterine device
The benefit of ultrasound guidance appears to insertion. In addition, the use of misoprostol before
occur by placing embryos in the thickest portion the procedure may soften the cervix and make
of endometrium at a distance of at least 15 mm the procedure easier to perform [2]. Similarly,
from the fundus [72]. ultrasound can be used to confirm appropriate IUD
Additionally, it is generally well accepted that placement and also can be used to help with device
an easy, atraumatic bloodless transfer improves localization if IUD strings are not visible at time of
implantation rates [65]. Trauma and bleeding desired removal (see Fig. 21.6). A role for ultra-
increase the likelihood of uterine contractions sound guidance has also been reported for imme-
and increase embryo expulsion [73]. Blood on diate postpartum IUD placement at which time
the tip of the embryo catheter has been associated theoretical risk of uterine perforation or IUD
with a six- to seven-fold decrease in clinical preg- expulsion is greater [79]. Routine transvaginal
nancy rate [74]. ultrasound use has not been shown to be beneficial
A 2003 meta-analysis including eight ran- at time of IUD insertion [80].
domized controlled trials revealed improved
implantation (OR 1.39) and clinical pregnancy Conclusion
rates (OR 1.44) in the ultrasound compared to The use of ultrasonography at the time of intra-
“clinical touch” groups [75]. The group attri- uterine procedures provides visualization of
butes previously reported insignificance to lack the intrauterine instruments as well as the myo-
of power [75]. These significant findings favor- metrium. Therefore, ultrasonographic guid-
ing ultrasound use were affirmed by a 2010 ance may decrease the risk of perforation and
292 D.R. Session and J.F. Kawwass
increase the chance of a successful procedure. 6. Acien P. Incidence of Mullerian defects in fertile and
As an alternative to laparoscopy, ultrasono- infertile women. Hum Reprod. 1997;12(7):1372–6.
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Ultrasound Role in Embryo
Transfers 22
Edmond Confino, Roohi Jeelani,
and Ilan Tur-Kaspa
E. Confino, MD (*)
Repro/Endo, Infertility, Feinberg School of Medicine,
Northwestern University, 675 N. St. Clair St.,
Chicago, IL 60611, USA
e-mail: e-confino@northwestern.edu
R. Jeelani, MD
Department of Obstetrics and Gynecology,
Wayne State University, Detroit, MI, USA
I. Tur-Kaspa, MD
Institute for Human Reproduction (IHR),
Department of Obstetrics and Gynecology, Fig. 22.1 A short, thin-lumen, T-shaped uterus. Saline
The University of Chicago, 409 W. Huron St., 3D US may replace the radiologic hysterography in simi-
Chicago, IL 60654, USA lar cases. 2D US may be difficult to measure and interpret
e-mail: drtk@infertilityihr.com because of thin lumen cavity
does not reduce ectopic pregnancy or miscarriage in easier ETs and significantly improve ART out-
rates. This chapter will review the data available come [11–14]. These RCTs and meta-analysis
today on the important role of US in ET. compared the main outcomes of clinical touch
ETs versus ultrasound-guided ETs: implantation,
clinical pregnancies, and live birth rates. In addi-
Tactile ET Versus Ultrasound- tion, other parameters were investigated: miscar-
Guided ET riage rate, multiple and ectopic pregnancies rate,
difficult or failed transfers, the need for instru-
The optimal area of embryo deposition in the uter- mental assistance during the transfer (e.g., sty-
ine cavity is probably 1–1.5 cm from the fundus lette, tenaculum, dilatation), signs of cervical or
resulting in higher PR [15, 16]. Evidence-based endometrial trauma (e.g., presence of blood,
data demonstrated that US-guided ET will result mucus, or both), and percentage of retained
embryos. While few studies have found no signifi-
cance in ART outcomes, most RCTs and the
meta-analysis concluded that ultrasound guidance
improves the chances of clinical pregnancies and
live birth compared to the clinical touch method.
A recent analysis showed that blood on the cathe-
ter is associated with decreased implantation rates,
clinical pregnancy rates, and live birth rates when
compared to no blood, which is easier to attain
when performing US-guided ET [17]. Further-
more, it increases the ease of transfer rate and sig-
nificantly decreases the chance of a difficult
transfer [18], the need for instrumental assistance,
and the failure to transfer with the assigned cath-
eter. The incidence of finding blood on the cathe-
Fig. 22.2 A very anteverted 3 cm deep uterine cavity
depicted on MRI. A skilled vaginal US may replace the ter tips after US-guided ET was significantly
MRI and result in a significant cost savings lower. Adding ultrasound had no significant effect
on finding mucus on the catheter tips, percentage US-guided transmyometrial ET (Fig. 22.4)
of transfer with retained embryos, and the rate of can be easily performed in the rare occasion
multiple pregnancies, ectopic pregnancies, and when catheter access into the uterus is impossible
spontaneous miscarriages. [20, 21]. This alternative US-guided approach
Routine US use before, during, and post-ET eliminates an unplanned laparoscopic intratubal
has largely eliminated the discordance between ET. This technique is usually performed under
mock ET and live ET [19]. US guidance has conscious sedation using a coaxial needle outfit-
reduced unrecognized events such as 180° curl- ted with a matching ET catheter.
ing of the inner catheter and cervical deposition There are several mechanisms by which
of the embryos. US prevents inadvertent embryo ultrasound-guided ET may improve ART out-
injection into the fallopian tube and directly into come. The full bladder needed for transabdomi-
the uterine wall. nal US straightens the angle between the cervix
298 E. Confino et al.
and the uterus. Avoiding endometrial indentation more difficult to perform. It needs to be placed in
and uterine contractions as well as confirming the the vagina, in addition to a speculum and catheter
position of the tip of the catheter at the desirable for ET. Several RCTs demonstrated no difference
site for embryo deposition seems to be the pre- in overall pregnancy, live birth, or implantation
dominant mechanism by which US guidance rate when comparing a transabdominal to trans-
improves ART outcomes. vaginal US [22, 23]. While the duration of the
procedure is significantly longer with the TVUS,
it was associated with increased patient comfort
Transvaginal Versus due to the absence of bladder distension [23].
Transabdominal Ultrasound for ET
factor in obtaining high ET success rates was the deviated or a branching cervical canal. In this
actual performance of live ETs rather than prac- instance, time is not a limiting factor because the
ticing US-guided IUIs. Thus, how training in embryos are loaded into the inner catheter while
embryo transfer should be performed remains a the outer catheter is already in place. US will then
controversy [3]. allow ET time to be less than 30 s (Fig. 22.7).
Coaxial catheter US-guided ET approach US guidance is extremely instructive at training
involves initial placement of an outer catheter in facilities as it can provide feedback and reassur-
the internal uterine os (Fig. 22.6). The outer cath- ance to physicians in training. Coaxial live US
eter protects the inner catheter from mucus expo- guided ET allows teaching ET without a decline
sure and eliminates the need to renegotiate a in the center’s PR.
300 E. Confino et al.
performed to reassess the cervix and uterus 5. Sallam HN, Sadek SS. Ultrasound-guided embryo
transfer: a meta-analysis of randomized controlled tri-
(Fig. 22.3). Pre-ET US may measure the
als. Fertil Steril. 2003;80:1042–6.
endometrial lining, detect the presence of fluid 6. Matorras R, Urquijo E, Mendoza R, Corcostegui B,
in the endometrial cavity, and retrace on the Exposito A, Rodriguez-Escudero FJ. Ultrasound-
screen the measurement of the desired depth to guided embryo transfer improves pregnancy rates and
increases the frequency of easy transfers. Hum
achieve the ideal ET. However, a recent RCT
Reprod. 2002;17:1762–6.
involving single physician operator confirmed 7. Yoldemir T, Erenus M. Does the timing of mock
that US guidance significantly increased clinical embryo transfer trial improve implantation in intracy-
pregnancies and live birth rates compared to the toplasmic sperm injection cycles? Gynecol
Endocrinol. 2011;27:396–400.
clinical touch method [29].
8. Mansour R, Aboulghar M, Serour G. Dummy embryo
transfer: a technique that minimizes the problems of
Conclusion embryo transfer and improves the pregnancy rate in
Evidence-based guidelines encourage human in vitro fertilization. Fertil Steril. 1990;54:
678–81.
US-guided ET. This approach will result
9. Gera PS, Allemand MC, Tatpati LL, Galanits TM,
in easier ETs and better PRs. Difficult, Morbeck D, Coddington CC. Role of saline infusion
long, and bloody ET should be avoided. sonography in uterine evaluation before frozen
Recommendations based on expert opin- embryo transfer cycle. Fertil Steril. 2008;89:562–6.
10. Sankpal RS, Confino E, Matzel A, Cohen LS.
ions include the performance of a mock ET
Investigation of the uterine cavity and fallopian tubes
to identify a difficult ET, meticulous cervical using three-dimensional saline sonohysterosalpingog-
mucus removal, mid uterine cavity embryo raphy. Int J Gynaecol Obstet. 2001;73:125–9.
placement, a slow catheter withdrawal to 11. Abou-Setta AM, Mansour RT, Al-Inany HG,
Aboulghar MM, Aboulghar MA, Serour GI. Among
avoid embryo dragging to the cervix, and a
women undergoing embryo transfer, is the probability
short embryo load to unload time [30, 31]. of pregnancy and live birth improved with ultrasound
US has become an indispensable tool used guidance over clinical touch alone? A systemic review
to prepare the patient for the upcoming ET and meta-analysis of prospective randomized trials.
Fertil Steril. 2007;88:333–41.
and monitor, guide, and verify proper embryo
12. Brown JA, Buckingham K, Abou-Setta A, Buckett W.
deposition in the uterus. Importantly, patients Ultrasound versus ‘clinical touch’ for catheter guid-
take great comfort in having the ability to ance during embryo transfer in women. Cochrane
visualize the final step of a difficult process. Database Syst Rev. 2007;24(1):CD006107.
13. Brown J, Buckingham K, Abou-Setta AM, Buckett
The use of US guidance is an integral part of a
W. Ultrasound versus ‘clinical touch’ for catheter
perfect ET and is only expanding to improve guidance during embryo transfer in women. Cochrane
and may include 3D and 4D ultrasound. Database Syst Rev. 2010;(1):CD006107.
14. Flisser E, Grifo JA. Is what we clearly see really so
obvious? Ultrasonography and transcervical embryo
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Ultrasound and Ovarian
Hyperstimulation Syndrome 23
Laura Proud Smith
Ultrasound in the Prediction of the antral follicle pool is considered to reflect the
of Ovarian Hyperstimulation total number of remaining follicles [1]. Generally, a
Syndrome low antral follicle count suggests a poor response to
ovarian stimulation and a high antral follicle count
Because ovarian hyperstimulation syndrome suggests better ovarian response to gonadotropin
(OHSS) is one of the most severe iatrogenic com- stimulation and higher oocyte yield.
plications of in vitro fertilization (IVF), there have Several investigators have evaluated AFC to
been many attempts to predict which patients are predict the development of OHSS. Kwee et al.
most at risk. Unfortunately, there are no perfectly evaluated 110 patients with unexplained infertil-
reliable tests which universally predict the devel- ity, male factor, or cervical factor infertility,
opment of OHSS. Ultrasound determination of counted antral follicles in all patients, and corre-
antral follicle count, counting the number of fol- lated the number of antral follicles with level of
licles developing in response to controlled ovar- ovarian response to IVF [2]. They categorized
ian hyperstimulation, sonographic evidence of ovarian response as poor, normal, and high and
polycystic ovarian syndrome, assessment of ovar- then calculated the AFC cutoff which most accu-
ian volume, and Doppler flow studies of ovarian rately identified each group. The AFC value of
vasculature have all been evaluated as markers to >14 identified hyper-responders with a sensitiv-
identify a higher likelihood of developing OHSS. ity of 82 % and a specificity of 89 %. Oncal et al.
Among the sonographic tools used in the predic- also evaluated the predictive role of AFC in
tion of OHSS, quantitation of the antral follicle OHSS in 41 women identified to have moderate
count (AFC) is one of the most accurate tests. to severe OHSS and 41 age-matched controls
Antral follicles are 2–10 mm follicles which can be who did not develop OHSS [3]. They found that
identified by ultrasound in the early follicular phase. AFC had a moderate accuracy to predict the
Antral follicles appear as round, sonolucent struc- development of OHSS. Using an AFC cutoff of
tures scattered throughout the ovary when viewed eight, much lower than the AFC cutoff used by
by 2D transvaginal ultrasound (Fig. 23.1). The size Kwee et al., they calculated 78 % sensitivity and
65 % specificity. In a meta-analysis done by
Broer et al. investigating AFC as a predictor of
ovarian hyperstimulation, five studies were iden-
L.P. Smith, MD tified which met criteria for inclusion [4]. Two
Department of Reproductive Endocrinology and reported on AFC alone, three reported on both
Infertility, Reproductive Medicine and Surgery Center
of Virginia, P.L.C, 595 Martha Jefferson Drive,
anti-Mullerian hormone (AMH) and AFC, and
Suite 390, Charlottesville, VA 22902, USA all five were prospective cohort studies. Among
e-mail: laura.smith@rmscva.com the included studies, the definition of excessive
laboratory parameters (Fig. 23.4a). Some authors fertility treatments and presented to the emer-
have described OHSS as an abdominal compart- gency department complaining of a 12 h his-
ment syndrome because the rapid accumulation tory of severe lower abdominal pain [17].
of ascites can lead to increased intra-abdominal Transabdominal ultrasound showed enlarged
pressure [16]. Increased intra-abdominal pres- ovaries bilaterally (7 × 5 × 5 cm) with significant
sure can become acute and lead to organ dysfunc- anechoic peritoneal free fluid felt consistent with
tion. In severe forms, abdominal compartment ascites. She was diagnosed with OHSS. She
syndrome affects respiratory function, as in the then began to clinically decompensate with the
case of severe OHSS. development of pallor and peritoneal signs and
Given that abdominal ascites is a key char- underwent diagnostic paracentesis notable for
acteristic of the diagnosis of moderate OHSS, it non-clotting blood. Ultimately she was taken to
is critical that the ultrasound findings be inter- the operating room for emergent laparotomy and
preted correctly in the context of the clinical a bleeding ovarian cyst was identified and treated.
presentation. Gunabushanam et al. reported the This case demonstrates the dangers of assuming
case of a 22-year-old woman who had received the diagnosis of OHSS in all patients undergoing
308 L.P. Smith
fertility treatments, as other pelvic pathology can and arterial thromboembolism both in the typi-
clearly lead to the accumulation of pelvic fluid. cal locations such as lower extremities and lungs
Cyst rupture can certainly lead to significant and in sites which seem more specific to OHSS
intraperitoneal bleeding with risk of death, and such as the subclavian and internal jugular ves-
accurate communication between the sonogra- sels. It is unclear why thrombosis may be local-
pher, Radiologist, Emergency Department physi- ized to the neck rather than the lower extremities;
cian, and Reproductive Endocrinologist is critical some have hypothesized that increased perito-
to appropriate and timely diagnosis. neal fluid containing inflammatory mediators
Severe OHSS is one of the most serious drains into the thoracic duct and directly into the
complications of ovarian hyperstimulation subclavian veins, possibly locally increasing
(Fig. 23.4b). The incidence of severe OHSS is coagulation at those sites [22]. Rova et al. evalu-
estimated between 0.5 and 5 % per IVF cycle. ated the risk of venous thromboembolism in all
Severe OHSS has been reported to be fatal, so IVF cycles and particularly in the subset com-
the prompt diagnosis and treatment is paramount plicated by OHSS [21]. They found that the
[18]. Patients with severe OHSS describe rapid incidence of venous thromboembolism from the
weight gain, significant abdominal distention time of the IVF cycle into the first trimester of
with inability to fit into usual clothes, shortness pregnancy was 0.17 % (32 out of 19,194
of breath, pain which can be refractory to oral patients), which was a 10-fold increase over the
medications, oliguria, and severe and unrelent- background risk in spontaneous conceptions.
ing nausea or emesis with inability to tolerate Furthermore, in patients diagnosed with OHSS,
oral intake. Clinical findings include all of the the risk of venous thromboembolism was 1.4 %
features of moderate OHSS plus clinical ascites, (19/1,272), a 100-fold increase. Given this
sonographic ascites, ultrasound evidence of pleu- markedly increased risk, Doppler studies to
ral effusions, and serum laboratory abnormalities evaluate for thromboembolism are a critical part
such as hemoconcentration, coagulopathy, elec- of the evaluation of the patient with suspected
trolyte imbalance, and renal and hepatic dysfunc- moderate or severe OHSS. Even if thrombosis is
tion or failure [19]. not identified, it is generally recommended to
Current research indicates that the fluid shifts initiate prophylactic anticoagulation in hemo-
which occur in OHSS are directly caused by concentrated patients with heparin or low
increased VEGF. VEGF leads to increased vas- molecular weight heparin when the hematocrit
cular permeability, reduced colloid osmotic gra- is found to be 45–50 % in order to mediate this
dient, and spillage of fluid out of the vascular risk [23].
compartment and into the extravascular spaces
[20]. These fluid shifts can be identified sono-
graphically, and it is recommended that in the Ultrasound in the Management
evaluation of the patient suspected to have mod- and Treatment of Ovarian
erate or severe OHSS, ultrasound should be used Hyperstimulation Syndrome
to check for abdominal ascites or pleural effu-
sions. Generally, the volume of accumulated fluid Timely and accurate diagnosis of OHSS facili-
is not subtle and can easily be identified either tates proactive management and treatment. The
through abdominal or vaginal ultrasound or ultra- management strategy varies in the literature,
sound of the lung bases. The third spacing of fluid from some authors recommending immediate
into the peritoneal and pleural cavities leads to hospitalization upon the diagnosis of moderate or
respiratory compromise, hypotension, increased severe OHSS to others advocating active outpa-
intra-abdominal pressure, and renal compromise tient treatment. Regardless of the location, ultra-
related to decreased perfusion [21]. sound is critical in the management and treatment
The hemoconcentration and resultant hyper- of OHSS. Sonographic monitoring can determine
coagulability of severe OHSS can lead to venous decrease in volume of abdominal ascites which
23 Ultrasound and Ovarian Hyperstimulation Syndrome 309
povidone-iodine (Betadine) and then a #17 egg at pigtail catheter placement for continuous
retrieval needle is affixed to conventional oper- drainage of ascites. In 1992, Aboulghar et al.
ating room suction tubing and attached to wall reported three patients with OHSS who under-
suction. The suction can be set at any pressure; went transvaginal aspiration of ascites which was
generally 200 mmHg speeds the procedure. then autotransfused [32]. They described rapid
A vaginal ultrasound probe with a standard improvements in hematologic parameters and
needle guide is then inserted and the posterior improved clinical symptoms. Another group in
cul-de-sac with dependent ascites visualized. It Japan also described reinfusion of ascitic fluid
is often helpful to place the patient in reverse in two patients in 1994 [33]. In that report, asci-
Trendelenburg position in order to allow grav- tes was removed, underwent ultrafiltration, and
ity to assist with ascites pooling. Under direct was then reinfused, leading to resolution of the
ultrasound visualization, the egg retrieval needle severe OHSS. Subsequent reports moved away
is advanced into the deepest pocket of ascites, from autotransfusion and transitioned to the
taking care to avoid vital structures including the placement of pigtail catheters for continuous
cervix, uterus, bowel, and vessels. Wall suction is ascites drainage. In 2003, Abuzeid et al. reported
activated and ascites fluid drained. Paracentesis transabdominal-guided placement of an abdomi-
is continued until the fluid is identified to be nal pigtail catheter which was left in place until
maximally removed. There is no particular limit ascitic fluid ceased to drain [34]. In that report, 26
to the amount of ascites which may be aspirated. patients with severe OHSS were identified. Half
Generally, we limit the volume to <5 L of fluid (13) underwent placement of a pigtail catheter
given the hemodynamic changes which can and the other half were hospitalized without inter-
occur, but clinics vary in the specific parameters vention. They described the placement of a 6-0
of drainage. French, 2 mm pigtail catheter through the abdom-
In the largest series evaluating outpatient man- inal wall into the largest pocket of ascites fluid
agement of severe OHSS using transvaginal under continuous abdominal ultrasound guid-
paracentesis, we identified 183 patients with ance. The catheter was then attached to a drain-
OHSS presenting between 1999 and 2007 [23]. age bag and left in place until ascites resolved. In
During this time frame, 96 patients with OHSS those patients who underwent ultrasound-guided
underwent 146 outpatient transvaginal paracen- pigtail catheter placement, the catheter was left
teses. Of these patients, 36 % (35/96) required in place for an average of 12–13 days and mean
two paracenteses, 8 % (8/96) required three para- amount of ascites drained was 11 L. There were
centeses, 3 % (3/96) required a fourth procedure, no documented infections and no impact on the
and one patient underwent five transvaginal para- pregnancy rates between the two groups. The
centeses until OHSS symptoms resolved and authors concluded that pigtail catheter placement
ascitic fluid is no longer accumulated leading to was safe and effective and could be an alterna-
clinical symptoms. The mean volume of ascites tive to multiple paracenteses in patients with
aspirated was 2,155 mL (range 500–4,500 mL). severe OHSS. Another group tested the efficacy
There were no procedure-related complications of transvaginal pigtail catheter placement for
and no instances of pregnancy loss in this group. continuous ascites drainage [35]. They reported
The use of aggressive outpatient transvaginal on one patient with severe OHSS, obesity, and
paracentesis not only decreased the need for hos- generalized edema who had an extremely thick
pitalization but was also associated with a abdominal wall (15 cm) which limited ultrasound
decreased hospital stay in cases when hospital- visualization of both ascites and internal organs.
ization was required [23]. She therefore had an Oosterlinck drainage cath-
Other uses of ultrasound in the management eter placed vaginally and left in place for con-
of OHSS have included ultrasound-guided drain- tinuous drainage for a total of 4 days. A total of
age with autotransfusion of ascitic fluid as well 17.45 L of ascites were drained over this time
as transabdominal and transvaginal attempts frame and she was ultimately discharged to home
23 Ultrasound and Ovarian Hyperstimulation Syndrome 311
in good condition without complications. The The two patients reported both underwent thera-
investigators concluded that ultrasound-guided peutic thoracentesis with resolution of dyspnea.
transvaginal pigtail catheter placement was an Therefore, in patients with OHSS and clinical
alternative to the transabdominal approach when evidence of pulmonary compromise, pleural
body habitus limits abdominal visualization. effusions should be actively sought and treated.
The final way in which ultrasound may be It should not be simply assumed that dyspnea is
used in the management and treatment of OHSS attributable to abdominal distension from ascites
is to assist with thoracentesis in the case of severe and compression of the lung bases since pleural
OHSS with pulmonary compromise and pleural effusions are found in approximately 10–30 % of
effusions. Similar to the case of abdominal ascites, patients with severe OHSS and may require treat-
protein-poor fluid can accumulate in the pleural ment with thoracentesis.
cavity and lead to problems due to restriction of In conclusion, ultrasound plays important roles
diaphragm movement, restriction of lung expan- in the prevention, diagnosis, and treatment of
sion with collapse of pulmonary parenchyma, poor OHSS. By fully and accurately using ultrasound,
ventilation, and shunting [36]. It is estimated that clinicians can be proactive in the evaluation and
pleural effusions occur in about 10 % of patients management of this severe iatrogenic complica-
with severe OHSS. Chest X-ray (CXR) is the tion of ovulation induction. By using ultrasound
typical imaging modality used to diagnose pleural to determine AFC, diagnose PCOS, and monitor
effusions, with ultrasound used to guide needle follicle development during gonadotropin stimu-
placement for thoracentesis as in the case of para- lation, clinicians may anticipate the risk of OHSS
centesis. Abramov et al. in 1999 evaluated 2,902 and modulate the IVF treatment plan. If clinically
patients with OHSS between 1987 and 1996, 209 suspected, ultrasound is key to speedy diagnosis
of whom were diagnosed with severe OHSS [36]. of OHSS into mild, moderate, or severe disease.
They characterized the pulmonary findings in Once OHSS is found to occur, ultrasound guid-
these patients and the required interventions. Not ance for transabdominal or transvaginal paracen-
surprisingly, 92.3 % (193) presented with dyspnea tesis, sonographic monitoring for improvement in
and 71 % had bilaterally elevated diaphragms on ascites, and ultrasound assistance for thoracente-
CXR. Almost a third (29 %) were diagnosed with sis will improve patient symptoms, lessen hemo-
pleural effusions on CXR, right lung > left lung, dynamic, pulmonary, and renal compromise, and
and 13 % underwent thoracentesis. The hypoth- may avoid the need for hospitalization.
esis for the laterality of pleural effusions which
seem to favor the right lung is that in the face of
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Pregnancy of Unknown Viability
24
Emily N.B. Myer, Jane Arrington,
and Steven L. Warsof
proved to be problematic since as many as 39 % pregnancy. Subsequent studies have shown the
of laparoscopies were unnecessarily performed normal rate of rise of β-hCG has a wider vari-
in women later confirmed to have a normal intra- ance. In 2004, Barnhart followed β-hCG levels at
uterine pregnancy (IUP) [6]. Today we have a 0 and 48 h in 300 women and defined the mini-
better understanding of the utility of β-hCG mal rise as 53 % with 99 % accuracy [12]. In
beyond diagnosis of pregnancy [7, 8]. 2012, Morse reported the lowest rate of rise asso-
In a normal intrauterine pregnancy (IUP), ciated with a normal IUP in a series of 1,000
fetal growth and placental hormone secretion women is 35 % in 48 h [13]. Below this rate of
occur together. β-hCG rises in a predictable loga- rise, the pregnancy can be considered abnormal
rithmic fashion from the fourth to the tenth week with no chance of viability [14, 15].
of gestation, after which there is a wide biologi- It is still true that pregnancies with a lower
cal variation (Table 24.1, Fig. 24.1) [3, 7, 9]. In rate of rise of β-hCG are more likely to fail. On
1984, Kadar defined a normal pregnancy by the the other hand, a normal rise does not necessarily
rise of β-hCG. He measured β-hCG levels at 0 guarantee the pregnancy will be normal. Up to
and 48 h in 20 women. A rise of 66 % predicted a 30 % of ectopic pregnancies mimic the β-hCG
normal intrauterine pregnancy (IUP) with 85 % trend of an IUP. Therefore, rising β-hCG
accuracy [10, 11]. This became known as the alone has a poor sensitivity and specificity for
“doubling time” which is now frequently used to diagnosing ectopic pregnancy, and visual confir-
determine the viability of a pregnancy. A com- mation of pregnancy location is necessary [16,
mon misconception is that failure of β-hCG to 17]. Condous and Kirk have advocated the use of
double in 48 h is diagnostic of an abnormal a β-hCG ratio as a more reliable indicator of
pregnancy viability for non-visible pregnancies
Table 24.1 Range of β-hCG as measured in viable (see Table 24.2) [18, 19]. It is important to note
pregnancies delivering at term that this anticipated rise only applies if β-hCG is
Embryonic week Lower limit of Upper limit of <2,000 mIU/ml, as above this level the rise is less
of gestation β-hCG (mIU/ml) β-hCG (mIU/ml) predictable.
4 12 2,548 To assist in the diagnosis of abnormal
5 330 37,290 pregnancy, Kadar proposed the use of a “discrim-
6 440 142,230 inatory zone,” the β-hCG concentration above
8–12 (peak) 53,715 which the gestational sac of an intrauterine
18–40 (plateau) 11,806 pregnancy should be identified on ultrasound.
Adapted from Refs. [3, 7] His study of 53 women found that at β-hCG
55
50
45
40
35
hCG (lU/ml)
30
25
20
Fig. 24.1 Mean serum
15
β-hCG levels throughout
normal pregnancy: arithmetic 10
scale used on ordinate. Bars 5
represent SEM (Reprinted
from Braunstein et al. [9].
With permission from 0 4 8 12 16 20 24 28 32 36 40
Elsevier) Weeks after last menstrual period
318 E.N.B. Myer et al.
Table 24.2 β-hCG ratio as predictors of pregnancy experience, maternal body habits, uterine
viability (β-hCG ratio = β-hCG at 48 h divided by β-hCG
orientation, and fibroids. [23] Additionally,
at 0 h)
pregnancies with structural or chromosomal
β-hCG ratio >1.66 Likely normal IUP anomalies, multifetal gestation, or those com-
β-hCG ratio <0.79 Concerning for ectopic
plicated by ovarian hyperstimulation syndrome
pregnancy
β-hCG ratio 0.79–1.66 Likely failed pregnancy
may have a β-hCG above the discriminatory
zone while being too early to visualize on ultra-
Adapted from Refs. [18, 19]
sound [23, 24]. Pregnancies complicated by
ovarian hyperstimulation syndrome will ini-
≥6,000–6,500 mIU/ml, a transabdominal ultra- tially have a high β-hCG due to hemoconcentra-
sound (TAU/S) was consistently able to detect tion; levels then appear to plateau as
the gestational sac, though not necessarily the post-hydration hemodilution sets in [25].
fetal pole or cardiac activity, of an IUP. Below Therefore, it is important to correlate clinical
β-hCG of 6,000 mIU/ml, seeing an intrauterine age based on LMP or known date of conception
gestational sac would not be anticipated [14]. with the β-hCG level and patient symptoms to
With the advent of TVU/S with improved resolu- avoid iatrogenic compromise of a potentially
tion due to a higher-frequency probe and less normal pregnancy.
dependence of maternal body mass index for If the β-hCG is below the discriminatory zone
adequate visualization, the discriminatory in an asymptomatic patient, TVU/S will rarely be
zone has been lowered to 1,500–2,000 mIU/ml. diagnostic and therefore should not be ordered
[20–22] A more recent retrospective cohort study as its clinical utility and cost-effectiveness is
by Connolly reevaluated the discriminatory zone low. TVU/S is clinically useful in a symptomatic
in 1,015 women presenting with vaginal bleed- patient with bleeding or pelvic pain even if the
ing, pain, or both in the first trimester of preg- β-hCG is below the discriminatory zone as a life-
nancy. Using the higher-frequency 8–9-MHz threatening ectopic pregnancy or abortion may
TVU/S probe, the discriminatory zone for detec- be diagnosed. An ectopic pregnancy can often
tion of the gestational sac, yolk sac, and fetal pole be visualized below the discriminatory zone as
was 2,317, 9,975, and 35,486 mIU/ml, respec- ectopic pregnancies usually do not follow the
tively [23]. The value for the gestational sac is normal β-hCG curve. Therefore, the ectopic
higher than previously reported values. pregnancy may be further along than suggested
Additionally, this is the first report of a discrimi- by the β-hCG. If the ultrasound is nondiagnos-
natory zone for the yolk sac and fetal pole. This tic and the patient is stable with no other symp-
study also found a lower than previously reported toms, serial β-hCG levels can be obtained every
threshold β-hCG for visualization of the gesta- 2 days until the discriminatory zone is reached
tional sac, 390 mIU/ml. The threshold values for or the location of the pregnancy becomes clini-
yolk sac and fetal pole visualization were 1,094 cally apparent. This more conservative approach
and 1,394 mIU/ml, respectively, in viable preg- of waiting for a ultrasonographic diagnosis
nancies [23]. And as sonographic technology of ectopic in a stable patient rather than mak-
changes, the discriminatory zone and minimal ing ectopic a diagnosis of exclusion by empty
threshold values will continue to evolve. uterus with positive β-hCG can save numerous
The American College of Radiology empha- normal pregnancies from iatrogenic termination
sizes that the discriminatory zone should not be [24]. If clinical suspicion for ectopic pregnancy
taken as an absolute. Failure to visualize a preg- is high, one can admit the patient to the hospital
nancy with a β-hCG above the discriminatory for serial abdominal exams and hemodynamic
zone does not necessarily mean the pregnancy is monitoring. Alternatively, if concerned for tubal
abnormal. The ability to visualize a pregnancy rupture and hemoperitoneum, it is advisable to
at a very early gestation is influenced by fac- proceed directly to surgery even prior to obtain-
tors such as ultrasound resolution, sonographer ing a TVU/S as a ruptured ectopic can lead to
24 Pregnancy of Unknown Viability 319
Ultrasound Characteristics
of Abnormal Pregnancy
Table 24.4 Anticipated sonographic findings in a normal intrauterine pregnancy by estimated gestational age
Gestational sac (mean Embryo (crown rump
Weeks sac diameter, MSD) Yolk sac length CRL) Fetal cardiac activity
4+ 0/7 – 4+ 6/7 2–3 mm
5+ 0/7 – 5+ 6/7 5–13 mm Visible
6+ 0/7 – 6+ 6/7 8–16 mm Visible Visible
7+ 0/7 – 7+ 6/7 16–20 mm Visible Visible, CRL 16 mm Visible
Expected growth 0.2–1 mm/day 0.2–0.6 mm/day
Estimated gestational age in days MSD(mm) + 30
Adapted from Abdallah et al. [31]. With permission from John Wiley & Sons, Inc.
may be a failing or ectopic pregnancy. If the an early unruptured ectopic pregnancy is diag-
β-hCG continues to rise without visualizing an nosed and the patient is stable and has no other
IUP, then the diagnosis is ectopic pregnancy. If contraindications, medical management with
322 E.N.B. Myer et al.
TVU/S in 1 week
Serum β-hCG in 48 h
IUP IPUV PUL EP§
Serum β−hCG
Appropriate rise >66 % Suboptimal rise 15–66 % Inappropriate rise <15 % or falling β−hCG plateaus
Table 24.5 Characteristics of definitive intrauterine gestation and/or definitive viability above which absence of these
features defines pregnancy failure when assessed with a transvaginal ultrasound
Estimated Gestational sac Β-hCG
Organization gestational age (mean sac diameter) Yolk sac Fetus (mIU/ml) Probe (MHz)
ACR 4.5–5 2–3 mm
ACR 8 mm Visible 9–5
SCOG
ACR 8–16 mm Visible ≥10,000
SCOG 20 mm (transabdominal)
ACOG 20 mm Visible
ACR 6.2–7 ≥5 mm CRL M-mode
ACOG Cardiac activity
SCOG
Adapted from Refs. [24, 25, 33, 46]
ACR American College of Radiology, ACOG American Congress of Obstetricians and Gynecologist, SCOG Society
of Obstetricians and Gynaecologists of Canada, RCOG Royal College of Obstetricians and Gynecologists
location. In this difficult scenario, some recom- clinical diagnosis based on ultrasound is uncer-
mend definitive diagnosis and treatment by dila- tain, follow up ultrasound in 7–14 days to confirm
tion and curettage, laparoscopy, or methotrexate pregnancy viability is recommended. [30]. This
due to the risk of ectopic pregnancy. In some time frame is appropriate as approximately 90 %
cases with a low β-hCG, a more conservative of incomplete abortions and 50 % of missed abor-
approach with expectant management has been tions can be expected to spontaneously abort
shown to be safe and not associated with adverse within 2 weeks of initial presentation and ultra-
outcomes [42, 43]. sound [39]. If there is any uncertainty in the diag-
nosis, failure to visualize a yolk sac or embryo on
a repeat scan after at least 7 days is always associ-
Ultrasound Characteristics of Early ated with spontaneous abortion [46].
Pregnancy Failure and Intrauterine
Pregnancy of Unknown Viability
Case Scenario
When the ultrasound reveals an IUP but neither The patient’s serum β-hCG is 652 mIU/ml.
an embryonic pole nor fetal heart activity is Though the β-hCG is below the discrim-
identified, the pregnancy is classified as an intra- inatory zone, the patient presented with
uterine pregnancy of unknown viability (IPUV). pelvic pain concerning for an ectopic preg-
Jeve et al. performed a metanalysis of sono- nancy or abortion. A TVU/S was ordered.
graphic features associated with early embry- The ultrasound report reads “Normal sized
onic demise and found a false-negative rate of uterus and ovaries. No intrauterine preg-
zero with: nancy visualized. No ectopic pregnancy
1. MSD ≥16–17 mm with neither a yolk sac nor noted in right or left adnexal region but the
fetal pole possibility of ectopic pregnancy is not
2. CRL ≥5–6 mm with absence of fetal cardiac excluded, please correlate clinically.”
activity [44, 45] The patient’s pain improved with
The reported measurements for diagnosing acetaminophen and hydration. She
pregnancy failure are listed by national organiza- feels comfortable going home know-
tion in Table 24.5. These measurements are highly ing her symptoms are attributable to
reproducible, making them an accurate way to her pregnancy. The patient understands
determine viability [9]. In situations where the
24 Pregnancy of Unknown Viability 325
Conclusion
the limitation of ultrasound to see the Patients presenting in early pregnancy with
conception at such an early stage. She is either bleeding or pain continue to present
sent home with strict ectopic precautions diagnostic and management dilemmas. With
to return for worsening bleeding or pain. the availability of medical treatment options
She is scheduled to have a repeat β-hCG in with methotrexate as well as surgery, recogni-
48 h, and if the level is above the discrimi- tion of an ectopic pregnancy at the earliest
natory zone at that time, an ultrasound will time, especially prior to rupture, will enhance
be scheduled. the patient’s future fertility potential. The
The repeat β-hCG level at 48 h was combination of quantitative β-hCG and trans-
1,652 mIU/ml. The β-hCG level is now vaginal ultrasound of the pelvis will lead to
above the discriminatory zone. An ultra- accurate diagnosis in the majority of cases.
sound is scheduled for 2 days later. The fol- When initial evaluation is uncertain, patience,
lowing day, however, the patient returns to close observation, and follow-up TVU/S and
the emergency department due to worsen- β-hCG will clarify the situation. Surgical or
ing abdominal cramping and the fact that medical management must be delayed until a
she started having her “period.” definitive diagnosis is made. Maternal aware-
Her vital signs are stable. Physical exam ness and participation in all aspects of her
reveals mild right adnexal tenderness and a evaluation and treatment will be helpful to
closed cervix with scant blood avoid untoward clinical or medical legal
A transvaginal ultrasound reveals a ges- consequences.
tational sac noted in the uterus measuring
7 mm. There is no visible yolk sac or
embryo. The left and right ovary measure
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Ultrasound Evaluation of Ectopic
Pregnancy 25
Donald L. Fylstra
Ectopic pregnancy, the implantation of a The imaging modality of choice for the
fertilized ovum outside the uterine cavity, has diagnosis of early pregnancy, regardless of
been increasing in number at a staggering pace implantation site, is transvaginal ultrasound.
and now accounts for 2 % of all pregnancies in The discriminatory zone of human chorionic
the United States [1]. Since many ectopic preg- gonadotropin (hCG) is that level of hCG, which,
nancies are now treated in an outpatient setting, when reached, an intrauterine pregnancy should
true current numbers are hard to obtain. Nearly be identified within the endometrial cavity with
all ectopic pregnancies (97 %) are implanted transvaginal ultrasound, when the pregnancy is
within the fallopian tube, and a common factor normal and singleton. The discriminatory zone
for the development of such ectopics is the pres- of hCG is usually 1,500 mIU/ml. Normal and
ence of a pathological fallopian tube. Causes of singleton is important because of the frequent
such pathology include genital tract infection misinterpretation of the hCG discriminatory
caused by gonorrhea and chlamydia, tubal sur- zone. Waiting until the discriminatory zone of
gery including tubal sterilization, previous ecto- hCG is reached before performing a transvaginal
pic pregnancy, and in utero exposure to ultrasound could miss early gestational pathol-
diethylstilbestrol [2, 3]. Other risk factors for ogy such as an extrauterine implantation (abnor-
tubal ectopic pregnancy include conception with mal pregnancies may have hormone levels that
an intrauterine contraceptive device in place and are lower at any given gestation age). Likewise,
conception while using a progesterone-only con- failure to identify an intrauterine gestation with
traceptive method [4, 5]. transvaginal ultrasound when the hCG level is
Ectopic implantation can also occur outside greater than the discriminatory zone may miss an
of the fallopian tube, within the cervix, ovary, early multiple gestation, particularly those preg-
abdomen, uterine cornua, and cesarean scars. nancies that are the result of assisted reproduc-
These extratubal implantations may not be tive technologies.
associated with tubal pathology or the expected The confirmation of an intrauterine pregnancy
preexisting risk factors for tubal ectopic with transvaginal ultrasound relies upon recogni-
implantation. tion, initially of a true gestational sac, followed
soon thereafter, by recognition of structures within
the sac consistent with a developing embryo. The
term “gestational sac” is a sonographic term and
D.L. Fylstra, MD not an anatomical structure. A true gestational sac
Department of OBGYN, Medical University
has a thick echogenic rim, a trophoblastic decidual
of South Carolina, 96 Jonathan Lucas St., LSB 634 F,
Charleston 29425, SC, USA reaction, surrounding a sonolucent center, the cho-
e-mail: fylstrad@musc.edu rionic sac. The intradecidual sign is the presence
of such a sac buried beneath the surface of the sonolucent center (Fig. 25.3) and is recognized 3
endometrium, appearing eccentrically positioned weeks post-conception (5 weeks after the last
within the endometrium (Fig. 25.1). A “pseudo- menstrual period). The embryo is first recognized
sac” is a collection of fluid within the endometrial as a thickening along an edge of the yoke sac
cavity itself, created by bleeding from the decidu- (Fig. 25.4), and embryonic cardiac motion can be
alized endometrium associated with an extrauter- first observed 3 1/2 to 4 weeks post-conception
ine pregnancy implantation (Fig. 25.2). The (5 1/2–6 weeks after last menstrual period).
precise location of such an early sonolucent uter- When exact pregnancy dating is available, an
ine fluid collection should distinguish between a intrauterine pregnancy, regardless of embryonic
true gestational sac and a pseudosac. number, should be identified within the
The yoke sac is the first visible structure endometrial cavity with transvaginal ultrasonog-
within the gestational sac and is a distinct circu- raphy by 24 embryonic days or 38 menstrual
lar structure with a bright echogenic rim and days (exact 28 day menstrual cycle). This exact
25 Ultrasound Evaluation of Ectopic Pregnancy 331
pregnancy dating does not rely on human Additional information can be gained from
chorionic gonadotropin, hCG, levels. Without transvaginal ultrasound measurement of the
such exact pregnancy dating and with no intra- endometrial echo in early gestation, before the
uterine pregnancy identified with transvaginal recognition of a gestational sac. Spandorfer
sonography, the “nondiagnostic ultrasound,” and Barnhart reported statistically different
a serum level of hCG is needed for ultrasound endometrial echo thicknesses between patients
interpretation [6]. A word of caution, because of with normal intrauterine, failed intrauterine,
the variation in vaginal ultrasound technical and and ectopic gestations [7]. Patients with nor-
interpretive abilities and lab hCG levels, before mal pregnancies had endometrial echo thick-
embarking on treatment for a presumed ectopic nesses of 13.42 ± 0.68 mm. In contrast, those
pregnancy, especially with methotrexate, give with failed intrauterine and ectopic gestations
every pregnancy the “benefit of the doubt.” measured 9.28 ± 0.88 and 5.95 ± 0.35 mm,
Be certain of the diagnosis or use diagnostic lapa- respectively (P < .01). In this report, 97 % of
roscopy for confirmation. patients with an echo no greater than 8 mm
332 D.L. Fylstra
had abnormal pregnancies, and 71 % of these The etiology of such implantations is unknown,
abnormal pregnancies were ectopic in loca- but predisposing factors include prior uterine
tion. Only 41 % of those patients with an echo curettage, induced abortion, Asherman’s syn-
thickness greater than 8 mm were abnormal, drome, leiomyomata, presence of an intrauterine
and only 14.7 % were ectopic in location. No device, in vitro fertilization, and prior in utero
patient with an endometrial echo thickness exposure to diethylstilbestrol [13–16].
greater than 13 mm had an ectopic pregnancy, Before the now common use of early preg-
and no patients with an echo thickness less than nancy transvaginal ultrasound, cervical pregnan-
6 mm had a normal pregnancy. These are well- cies were frequently diagnosed at the time of
stratified differences, but other authors have spontaneous abortion or reached the second tri-
seen much more overlap with endometrial echo mester, both associated with life-threatening
measurements. hemorrhage frequently requiring hysterectomy
Usually, the transvaginal ultrasound identifi- as treatment. Usually, the first complaint is pain-
cation of an intrauterine pregnancy reliably less vaginal bleeding and speculum examination
excludes an extrauterine implantation, except in may reveal an open external cervical os with a
the case of heterotopic pregnancy: the coexis- fleshy-type endocervical mass presenting. With
tence of an extrauterine implantation with an early transvaginal ultrasound, these implanta-
intrauterine pregnancy. The natural occurrence of tions are easily identified (Fig. 25.5) and can,
heterotopic pregnancy is 1 in 4,000 pregnancies, thus, be treated with conservative fertility-sparing
but the frequency is much greater with pregnan- options.
cies conceived with assisted reproductive tech- Rankin suggested that the diagnosis by
nologies. Should a clinical presentation or ultrasound examination of cervical pregnancy
abnormal pelvic ultrasound appearance suggest required 4 criteria: enlargement of the cervix,
an ectopic pregnancy, despite visualization of an uterine enlargement, diffuse amorphous intra-
intrauterine gestation, the diagnosis of hetero- uterine echoes, and absence of an intrauterine
topic pregnancy should be considered, with the pregnancy [17]. Timor-Tritsch et al. refined the
probable need for diagnostic laparoscopy confir- criteria to include the placenta and entire chori-
mation and treatment. onic sac containing the pregnancy must be below
The possibility of ectopic pregnancy is fre- the internal cervical os and the cervical canal
quently considered before hCG has reached the must be dilated and barrel shape [18].
discriminatory zone and before ultrasound rec- If necessary to exclude the diagnosis of a
ognition [8]. Human chorionic gonadotropin spontaneous abortion in progress, the presence of
rises exponentially in early normal pregnancy embryonic cardiac activity and/or Doppler ultra-
and should rise at least by 53 % in 48 h [9]. sound indicating vascular attachment confirms a
This exponential rise is less reliable after living pregnancy.
10,000 mIU/ml, and at this level, pregnancy is
better evaluated with ultrasound. Fifteen per-
cent of normal intrauterine pregnancies can Ovarian Pregnancy
demonstrate an abnormal early rise of hCG, but
for the majority of gestations, when the hCG One half of one percent to almost 3 % of ectopics
rise is abnormal, at a plateau, or falling, an are implanted within the ovary [11, 19]. Ovarian
abnormal pregnancy is confirmed but not its pregnancy like other non-tubal ectopic pregnan-
location [10]. cies may occur without the usual expected ante-
cedent risk factors for ectopic pregnancy but
does seem to have a strong association with con-
Cervical Pregnancy ceptions with an intrauterine contraceptive device
in place [20, 21]. The presenting signs and symp-
Less than 1 %, and the rarest, of ectopics are toms are similar to other ectopic pregnancies:
implanted within the cervical canal below positive pregnancy test, abdominal pain, and
the level of the internal cervical os [11, 12]. vaginal bleeding.
25 Ultrasound Evaluation of Ectopic Pregnancy 333
Fig. 25.5 (a) Transvaginal ultrasound, midline sagittal canal. (b) Transvaginal ultrasound: 3D rendering of a cer-
image: cervical pregnancy, (closed arrow) points to the cer- vical pregnancy, (closed arrow) points to the internal cervi-
vical pregnancy within the (open arrow) points to cervical cal os
distinguish between a corpus luteum and an inspection, and cystectomy and pathology only
ovarian pregnancy implantation (Fig. 25.6). This will reveal the true diagnosis. However, when an
diagnosis is usually a pathological diagnosis: adnexal ectopic is diagnosed with a nonsurgical
made by microscopic examination of a surgi- algorithm, conservative medical therapy can be
cally removed adnexal mass, via laparotomy or successful without a true diagnosis of location.
laparoscopy, based on Speigelberg’s criteria: the
tube must be intact and distinctly separate from
the ovary, the gestational sac must occupy the Abdominal Pregnancy
normal anatomical location of the ovary, the ges-
tational sac must be connected to the uterus by Less than 1 % of ectopic pregnancies are
the utero-ovarian ligament, and unquestioned implanted within the abdominal cavity [11, 23].
ovarian tissue must be demonstrated in the wall The pathogenesis of abdominal implantation is
of the gestational sac [22]. controversial. Many are the result of secondary
It is important for the laparoscopic surgeon to nidation within the peritoneal cavity after tubal
understand that an ovarian pregnancy can look abortion, tubal rupture or uterine rupture [24].
like a corpus luteum ovarian cyst upon direct True primary abdominal implantation must
25 Ultrasound Evaluation of Ectopic Pregnancy 335
satisfy the criteria of Studdiford. Studdiford, of suspicion: early ultrasound in a woman with a
reporting a primary peritoneal implantation in prior cesarean delivery (Fig. 25.7).
1942, established three criteria for such a Endometrial and myometrial disruption or
primary abdominal pregnancy: normal fallopian scarring can predispose to abnormal pregnancy
tubes with no evidence of recent or remote implantation. Trophoblast adherence or invasion
trauma, the absence of any uteroperitoneal is enhanced when the scant decidualization of the
fistula, and the presence of a pregnancy related lower uterine segment is impaired further by pre-
exclusively to the peritoneal surface and early vious myometrial disruption. Implantation of a
enough to eliminate the possibility of secondary pregnancy within the uterine scar of a prior cesar-
implantation following a primary nidation within ean delivery is different from an intrauterine
the tube [25]. pregnancy with placenta accreta. Cesarean scar
The most common abdominal implantation implantation is a gestation completely surrounded
site is the posterior cul-de-sac, followed by the by myometrium and the fibrous tissue of the scar
mesosalpinx, the omentum, the bowel and its and separated from the endometrial cavity or fal-
mesentery, and the peritoneum of the pelvic and lopian tube (Fig. 25.7). The mechanism that most
abdominal walls, including the anterior cul-de- probably explains scar implantation, like intramu-
sac [23]. Other reported locations include the ret- ral implantation, is invasion of the myometrium
roperitoneal space, the appendix, the liver, and through a microscopic tract. Like intramural preg-
the spleen [26–31]. nancy, such a tract is believed to develop from the
With the universal use of early pregnancy trauma of previous uterine surgery, such as curet-
imaging, the diagnosis can be confirmed at an tage, cesarean delivery, myomectomy, metro-
early gestational age, but this requires imaging plasty, hysteroscopy, and even manual removal of
demonstrating a continuity of the cervix and the placenta [33–35]. The time interval between
uterus without pregnancy contents, like other such trauma and a subsequent pregnancy may
ectopic implantations. The presence of an adnexal impact upon implantation events. Some of the
mass suggestive of ectopic pregnancy, when no reported cases were diagnosed and treated within
intrauterine gestation is identified, could be an a few months of a prior cesarean delivery suggest-
ectopic pregnancy of any location, including an ing that incomplete healing of the uterine scar
abdominal implantation. Failure to follow basic may contribute to scar implantation [36, 37].
ultrasound principles can miss the diagnosis. Early diagnosis with ultrasound can offer treat-
Such early diagnosis can spare maternal mortal- ment options capable of avoiding uterine rupture
ity at the expense of fetal mortality, with a perina- and hemorrhage and, thereby, preserve the uterus.
tal mortality rate of 40–95 % [32]. The differential diagnosis between spontaneous
abortion in progress, cervico-isthmic pregnancy,
and implantation within a cesarean scar can be
Cesarean Scar Ectopic Pregnancy difficult. Strict ultrasound imaging criteria must
be used to assess the diagnosis of cesarean scar
Although previously rare, the incidence of preg- pregnancy. Ultrasound should reveal an empty
nancy implantation within the scar of a prior uterine cavity, an empty cervical canal, develop-
cesarean is increasing due to the increasing num- ment of the gestational sac in the anterior part of
ber of cesarean deliveries. The natural history of the uterine isthmus, and an absence of healthy
such a condition is unknown, but uterine scar myometrium between the bladder and the gesta-
rupture and hemorrhage, even in the first trimes- tional sac, this last criterion allowing differentia-
ter, seems likely if the pregnancy is allowed to tion from cervico-isthmic implantation [38].
continue, with possible serious maternal morbid- Although cesarean scar pregnancy is an
ity and the possible need for hysterectomy and uncommon occurrence, only with a high index of
loss of subsequent fertility. Early diagnosis of suspicion and the use of early endovaginal
such implantation is made only with a high level sonography can the diagnosis be made early
336 D.L. Fylstra
Fig. 25.7 (a) Transvaginal ultrasound: midline sagittal image with gestation in the anatomical location of a prior
cesarean scar. (b) Transvaginal ultrasound: 3D rendering of cesarean scar ectopic
Interstitial Ectopic Pregnancy before rupture than more distal portions of the
fallopian tube [40]. Since implantation within
Two to three percent of ectopics are implanted this portion of the fallopian is still “within the
within the interstitial portion of the fallopian tube,” it is associated with the same commonly
tube, that portion of the tube that transitions from recognized risk factors for tubal ectopic preg-
the endometrial cavity to the tubal isthmus nancy. No single factor clearly differentiates
through a wall of myometrium [11]. The intersti- women with an interstitial pregnancy from those
tial, or cornual, portion of the fallopian tube is with isthmic or ampullary ectopic pregnancies.
tortuous, 0.7 mm in diameter, and 1–2 cm in Transvaginal ultrasound is the primary
length [39]. This is a relatively thick segment of method for diagnosing interstitial implantation
fallopian tube with a greater capability to expand (Fig. 25.8). However, many early ultrasounds
show that these pregnancies are surrounded by distinguished from interstitial implantations.
myometrium and can be mistaken for normally Angular pregnancies lead to an asymmetric
implanted pregnancies. Ultrasound findings that enlargement of the uterus (Fig. 25.9). What dis-
are highly suggestive of interstitial implantation tinguishes an interstitial ectopic pregnancy from
are the identification of an echogenic line between an angular pregnancy is that the laparoscopic
the gestational sac and the endometrial cavity, appearance of the bulge of an interstitial preg-
“the interstitial line sign,” an empty uterine cavity nancy is lateral to the round ligament, whereas
with a gestational sac eccentrically located out- the bulge of an angular pregnancy is medial to
side the endometrial cavity with a thin mantle of the round ligament, displacing the round liga-
surrounding myometrium less than 5 mm in ment laterally. Over one third of angular preg-
thickness [41]. Collectively, these ultrasound nancies end in early abortion, but for those that
findings are 88–93 % specific but with a sensitiv- continue pelvic pain, persistent vaginal bleed-
ity of only 40 % [42, 43]. Coronal images gener- ing, placental retention during the third stage of
ated by 3D sonography are helpful in identifying labor, and rarely uterine rupture can be expected
these features [44] (Fig. 25.8). complications.
Interstitial ectopic pregnancies are frequently
mislabeled as “cornual ectopics.” Cornual preg-
nancy refers to a pregnancy within the horn of a Ectopic After Hysterectomy
bicornuate uterus, communicating or non-
communicating, and the clinical outcome of this Only 56 cases of ectopic pregnancy after hyster-
implantation varies greatly and depends upon ectomy have been reported in the world’s litera-
the size and expansile capacity of the affected ture and are rarely suspected before surgical
horn [40]. intervention [45]. Over half of such pregnancies
Angular pregnancies are implanted in one have been “early presentations,” this occurring
of the lateral angles of the uterine cavity, because an unrecognized, preclinical preg-
medial to the uterotubal junction, and must be nancy existed at the time of hysterectomy:
25 Ultrasound Evaluation of Ectopic Pregnancy 339
a preimplanted fertilized ovum was in transit and intervention [46]. Therefore, it is extremely
confined to the fallopian tube, or sperm was prudent to diagnose gestational pathology early
present within the fallopian when the hysterec- with transvaginal sonography.
tomy was performed during a peri-ovulatory
period, allowing postoperative fertilization and
tubal implantation. An immediate pre-hysterec- References
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Focused Ultrasound
for Treatment of Fibroids 26
Gloria Richard-Davis and Elosha Eiland
improvement in symptoms. Retreatment rates are to destroy fibroid masses by producing precise
low with all options but lowest for myomectomy amounts of heat and vibration within the body
(7.4 %) versus UAE (10 %) followed by MRgFUS with pinpoint accuracy. It uses heat rather than
(14 %). Complication rates across the board are radiation to destroy tissue and can be used again
relatively low. The greatest differences are in the and again without harmful side effects. MRgFUS
recovery time, where myomectomy is an inpa- has only a few serious FDA reportable adverse
tient procedure with 2–4 weeks of recovery time. events including skin burns, which result from
UAE is an outpatient procedure but does require poor coupling from hair and scars on the skin,
an average 13 days’ recovery, while MRgFUS is and nerve damage, which resolved within a year
also an outpatient procedure but has a 1–4 days’ [8]. There is also a slight risk of damage to adja-
recovery time. This is the primary distinguishing cent organs, such as bowel perforation.
factor. Pregnancy outcome data is more challeng- Currently, MRgFUS treatment for uterine
ing to compare, as UAE and MRgFUS have been fibroids is offered at medical centers in 15
limited to women not planning future pregnan- states in the United States and in 14 countries
cies. Therefore, data on pregnancies post proce- around the world. Over 3,000 patients have
dure is limited. Recent clinical trials are focusing been treated worldwide, including 370 who are
on MRgFUS and pregnancy outcomes. Therefore, being followed for the FDA post market. Four
data should be forthcoming in the near future. more companies are developing and testing
Magnetic resonance-guided focused ultra- similar technology for fibroid treatment [9].
sound—approved by the FDA in October 2004— The technology is evolving, as are guidelines
has the potential to completely revolutionize the for treatment. Several studies have shown that
treatment of uterine fibroids [7]. MRgFUS pro- MRgFUS significantly improves clinical
vides a nonsurgical outpatient method of ablating symptoms in 70–80 % of women with uterine
fibroids that preserves the uterus and enables fibroids [6–8, 10, 11]. Studies have demon-
patients to return to normal activity within 1 or 2 strated a correlation between the treated vol-
days. Based on two groundbreaking core tech- ume of the fibroids, improvement in symptoms,
nologies, MRgFUS gives physicians the ability and lesion shrinkage [12].
26 Focused Ultrasound for Treatment of Fibroids 343
Th e r m
Exposure time in seconds
100
al dos
Tissue
Thermal
e thre
boiling
necrosis
shold
10
No damage
to healthy
tissue
1
C 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110
F 95 104 113 122 131 140 149 158 167 176 185 194 203 212 221 230
Temperature
25 %, a positive pregnancy test, major medical or pelvic nerves; exclude adenomyosis or lesions
disease, or contraindication to magnetic reso- suspicious for uterine sarcomas; and demonstrate
nance imaging such as a pacemaker or weight pretreatment vascularization of the leiomyoma
over 250 lb. by using the intravenous contrast agent gadolin-
The FDA relaxed treatment protocols on April ium. African-American women have an increased
30, 2004, so that patients treated after that date in incidence of fibroids, earlier onset of disease, and
phase 3 continued-access protocol and the post- more severe symptoms [14–16]. Despite their
market study, both in the United States and abroad increased risk of disease, African-American
(n = 64 and 61, respectively, overall 34 %), were women historically comprise only approximately
allowed to have more extensive treatment. 15 % of subjects in fibroid studies [17]. Recent
Treatment volume allowances were increased ongoing Fibroid Interventions: Reducing
from 33 to 50 % for all leiomyomata except sub- Symptoms Today and Tomorrow (FIRSTT) trial
mucosal ones, and maximal treatment volume was is focused on recruitment of African-American
increased to 150 mL per leiomyoma. Extension of women to analyze differences. This trial will pro-
treatment time from 120 to 180 min and treatment vide for sub-analysis of the data specific to
border restrictions increased to 1.5 cm from the African-American women and explore further
endometrium and 0.5 cm from the leiomyoma the genetic linkage [18].
capsule to the serosal surface were eliminated. Current inclusion criteria to receive MRgFUS
This allowed more patients to be treated with as a viable treatment option include the follow-
MRgFUS safely based on clinical trial data. ing: (1) a patient must first have a uterine
A post-marketing study of African-American fibroid(s), (2) the fibroid(s) must be relevant to
women was mandated by the FDA and required the patient’s symptoms, and (3) the location and
treatment candidates to be “consistent with product size of the fibroids must correlate with the
labeling,” thus making the same enrollment criteria patient’s symptoms. For example, subserosal
as noted previously implicit rather than explicit. fibroids located just underneath the serosa of the
A pretreatment magnetic resonance imaging uterus grow outward resulting in compression
scan was required for treatment planning to symptoms to adjacent organs, i.e., bladder
assess the accessibility of leiomyomata to (urinary frequency) and intestines (constipation)
treatment without injury to the bowel, bladder, (see Table 26.2). Subserosal fibroids associated
26 Focused Ultrasound for Treatment of Fibroids 345
Table 26.2 Patient inclusion criteria for MRgFUS Table 26.3 Patient exclusion criteria for MRgFUS
1. Patient should have a definitive diagnosis of a uterine 1. Hemoglobin <10 mg/dL
fibroid(s) as the cause for her symptoms 2. Hemolytic anemia
2. Patient’s uterus should be <24 cm without the 3. Unstable cardiac status including:
cervix (alternatively, maximal fibroid volume (a) Unstable angina pectoris on medication
should be <900 cc)
(b) Documented myocardial infarction within 6
3. Patient may have up to six clinically significant months of protocol entry
fibroids less than 4 cm in size
(c) Congestive heart failure requiring medication
4. Patient should be pre- or perimenopausal (other than diuretic)
5. Patient should be able to have a catheter during (d) Currently taking antiarrhythmic drugs
treatment
(e) Severe hypertension (diastolic BP >100 on
medication)
(f) Presence of cardiac pacemaker
with uterine bleeding instead of compression 4. Severe cerebrovascular disease (multiple CVA
symptoms may not be a candidate for removal by or CVA with 6 months)
MRgFUS [8]. Exclusion criteria are extensive 5. Currently on anticoagulation therapy
6. Presence of underlying bleeding disorder
and include pregnancy, other uterine pathology,
7. Current pregnancy
severe anemia, and other medical conditions
8. Presence acute pelvic infection
(see Table 26.3).
9. Evidence of uterine pathology other than leiomyoma
Patients with scars or moles in the mid-
10. Presence of undiagnosed pelvic mass outside of the
abdominal region could possibly be excluded uterus
from having this procedure performed because 11. Presence of symptomatic pedunculated submucosal
scars have high ultrasound absorption and may or pedunculated subserosal myoma
lead to pain or damage to the skin [7]. Individuals 12. Presence of severe adenomyosis (only for United
that have been diagnosed with other pelvic dis- States)
13. Evidence of high-grade SIL by pap smears or HPV
eases should also be excluded from this proce-
testing
dure. Women who weigh more than 250 lb. are
14. Weight >110 kg (250 lb)
not candidates for MRgFUS [7]. Communication 15. Presence of extensive longitudinal abdominal
is important throughout the procedure and it is scarring in an area of the abdomen directly
vital that the patient is able to do so. Pre- or peri- anterior to the treatment area that may block
menopausal women, pregnant women, or women the energy path (only for United States)
with an active pelvic infection will not be able to 16. Presence of standard contraindications for MR
imaging, such as non-MRI compatible implanted
undergo therapy. The MRgFUS treatment also metallic devices, does not have severe
requires a urinary catheterization. Patients should claustrophobia. Size and weight should allow fitting
be aware that a catheter will be in place. Severe in MRI device, etc.
adenomyosis is also a contraindication to receiv- 17. Individuals who are not able or willing to tolerate
the required prolonged stationary prone position
ing treatment. However, recent studies have
during treatment (approximately 3 h)
shown that MRgFUS can be used to ablate ade-
nomyosis and improve symptoms during a period
of 3–6 months. However, no long-term evidence damage which can occur as a result of nerves
exists that demonstrates that there is a clinical lying next to heated bone surfaces [8]. Bone
benefit in the treatment of adenomyosis [8]. absorbs ultrasound waves more readily than soft
The location of fibroids is one of the primary tissue. As a result, low energies can cause high
concerns with this MRgFUS technique. MRI is temperatures in bone surfaces and result in nerve
used to precisely measure fibroids and location to damage to adjacent nerves.
determine eligibility of treatment. Fibroids must Patients should not have more than 6 fibroids
be reachable by the MRgFUS device and not be that are more than 4 cm in size each, as this is
too far away from the skin line but at least 4 cm usually associated with the fibroids being in close
from the sacrum. This distance decreases the proximity to the sacrum or being inaccessible,
amount of heating of the bone and reduces nerve i.e., hidden behind bowel [8]. Patients should not
346 G. Richard-Davis and E. Eiland
Table 26.4 Technical suitability for MRgFUS (cesarean section). However, 19 of those 88
1. Fibroid(s) should be clearly visible on non-contrast (22 %) women experienced spontaneous abor-
MRI tions. Rabinovici noted that uterine rupture, pre-
2. Fibroid(s) should be device accessible (i.e., term labor, placental abruption, and abnormal
positioned in the uterus such that they can be
placentation leading to fetal growth restriction
accessed without being shielded by bowel or bone)
3. Fibroid(s) center should be at least 4 cm from the
were not observed in any of the cases [11].
sacrum surface Several case reports of women conceiving
4. Fibroid(s) should be hypo- or iso-intense on MR T2 after MRgFUS ablation have been published
images (relative to the uterus muscle) [19].The largest series was published by
5. Fibroid(s) should enhance on MR contrast imaging Rabinovici. In 2003, he reported on 54 pregnan-
6. Fibroid(s) envelope should not be significantly cies in 51 women who were treated with
calcified
MRgFUS for symptomatic uterine fibroids and/
7. Patients should not have imaging suggestive of
malignant disease of uterus, ovary, or cervix or focal adenomyosis. Of the delivered pregnan-
8. Patients should not have severe adenomyosis (only cies in which gestational age was reported, there
for US patients) was a 93 % (14 of 15) term delivery rate and one
preterm birth which occurred at 36 weeks. The
current series of pregnancies reassures that term
have fibroids that have more than a significant (and ongoing) pregnancies can be achieved in a
proportion of the fibroid 12 cm in depth away substantial percentage of women conceiving
from the skin line, as the maximum depth of pen- after MRgFUS treatment of uterine fibroids [4].
etration of the sound is 12 cm. Mitigation tech- Clinical studies are ongoing to evaluate fertility
niques can sometimes be used to decrease the outcomes after MRgFUS.
depth. However, if the mitigation techniques are
unsuccessful, the fibroid must be excluded.
Examples of mitigation techniques include filling Other Conditions That Can Be
the rectum with ultrasound gel to elevate the Treated
uterus and fibroids anteriorly and using a thinner
acoustic coupling gel pad, which reduces the dis- Adenomyosis
tance between the patient and the transducer [8]
(see Table 26.4). The MRgFUS procedure can ablate adenomyosis
Patients who have a calcified fibroid envelope tissue sufficiently and can improve symptoms
(capsule) are excluded from this procedure due to significantly during a period of 3–6 months post-
the ultrasound’s inability to penetrate the calci- treatment especially those with low-signal inten-
fied capsule and enter the body of the fibroid sity adenomyosis on T2-weighted MR images
mass [8]. Pedunculated fibroids attached to the [8]. It is not yet an approved FDA indication.
uterus by a stalk are excluded because during the Additional clinical data is still needed. A case
procedure, they may become detached and enter report submitted by Rabinovici et al. details a
the abdominal cavity, requiring further surgical, patient who underwent MRgFUS to ablate focal
perhaps invasive, interventions [8]. uterine adenomyosis [20]. The patient experi-
enced significant reduction in menometrorrhagia
in the weeks following therapy, and at her 6-week
Impact on Future Fertility follow-up visit, her adenomyotic tumor was
noted to decrease in size from 6.5 × 4.9 × 4.8 cm
Review of the literature on pregnancy outcome pretreatment to 3.5 × 4.3 cm posttreatment. The
after MRgFUS revealed 88 women became preg- patient went on to conceive spontaneously three
nant. The mean time to conception was 8 months menstrual cycles after therapy. She had an
after treatment [4]. Of those 88 pregnancies, uneventful pregnancy, labor, and vaginal delivery
there were 45 (51 %) total deliveries, 67 % SVD that resulted in the delivery of a full term, normal
(spontaneous vaginal deliveries), and 33 % C/S weight neonate.
26 Focused Ultrasound for Treatment of Fibroids 347
MRgFUS offers a safer treatment with a (± 24 cm3) for multiple fibroids. The actual vol-
much faster recovery time than other surgeries. ume that received a thermal dose as measured
Patients are generally able to return to the nor- using MR thermometry was 36 cm3 (± 18 cm3),
mal activities the day after the procedure with around 10 % of the fibroid volume for single
little to no medication. Patients follow up 2 fibroids, and 32 cm3 (± 23 cm3) about 11 % for
weeks after the procedure both with their gyne- multiple fibroids. At 6-month follow-up, the
cologist and at the interventional radiologist. mean fibroid volume was reduced by 13.5 %, ±
Those patients with larger or multiple fibroids in 32. Although the change in fibroid volume is
which the treatment could not be completed can modest, the average non-perfused volume at the
have a repeat treatment planned from 1 week end of the treatment was approximately 25 %.
onward [8]. After 6 months, a follow contrast- The expected impact was modest shrinkage of
enhanced MRI is performed to assess fibroid the fibroid. In addition, the mean non-perfused
size [8]. volume was 51.2 cm3 (± 62.2 cm3). Overall,
79.3 % of patients achieved a greater than
10-point reduction in the UFS-QLQ score (n =
Outcomes 82, p < 0.0001). The mean reduction in the symp-
tom severity score on UFS-QLQ was 27.3 points
In 2004, early reports by Hindley demonstrated (p < 0.0.0001; range, 18.75 to –81.25 points), and
greater improvement in the Uterine Fibroid although most of this improvement occurs in the
Symptoms and Quality of Life Questionnaire first 3 months after treatment (24.1 points),
(UFS-QLQ) by patients who had a greater pro- improvement continued up to 6 months.
portion of the fibroid treated [7]. The UFS-QLQ Hindley reported that the greater percentage
is a validated uterine fibroid-specific question- of the non-perfused volume (NPV) of fibroids
naire developed to evaluate the symptoms of posttreatment correlated to improvement in
uterine fibroids and their impact on health-related symptoms. The average improvement in the
quality of life [21]. It consists of an eight-item scores was 25.8 at 6 months in those patients with
symptom scale and 29 health-related quality of NPV after treatment of less than 30 %, compared
life (HRQL) items comprising 6 domains: con- to 31.7 in patients who had more than 30 % NPV.
cern, activities, energy/mood, control, self- The volume of the fibroid treated in early studies
consciousness, and sexual functioning. All items was limited by safety margins imposed by the
are scored on a five-point Likert scale, summed regulatory authorities.
and transformed into a 0–100 point scale. Patients Stewart et al. report longer follow-up con-
had to have a minimum of 21 points, out of a total firmed a positive correlation in the volume reduc-
of 40 points, on the symptom severity scale to be tion of the fibroid to symptom improvement after
included in the study. One hundred nine patients 2 years [15]. Stewart et al. in 2007 [12] reported
qualified and were treated at seven sites. Fifty- women undergoing MRgFUS for symptomatic
two patients were treated in the United States, uterine leiomyomata had durable symptom relief,
and 57 patients were treated in Europe and Israel. as measured by the symptom severity score at 24
The mean age was 44.8 ± 4.9 [SD] years (the months with significantly greater improvement
range was 30–58). 11 % of patients were AA with with more complete ablation (p < .001). Patients
mean body mass index of 25.8 ± 5.2. Of the also reported an “improved quality of life”
fibroids treated, 22 % were submucosal, 57 % months after the treatment had taken place [7].
were intramural, and 21 % were subserosal. The Treated fibroid decreased by 12 % volume at 1
mean fibroid volume in patients with only a sin- month and 15 % by 3 months. Higher mean NPV
gle fibroid treated (n =60) was 346, ± 245 cm3. In ration immediately posttreatment correlated with
patients with multiple fibroids treated (n = 32), higher probability of intervention-free survival
the mean fibroid volume was less at 294, (Fig. 26.4).
± 188 cm3. The region of treatment was 39 cm3 As restrictions were lifted, an increase pro-
(± 27 cm3) for single fibroids and 38 cm3 portion of the fibroid could be treated [22].
26 Focused Ultrasound for Treatment of Fibroids 349
70 Cost
Symptoms severity score
60
Other than the limitations listed previously, the
50 cost of the therapy seems to remain the most
challenging barrier to treatment with MRgFUS.
40
The cost of the procedure ranges between $5,000
30 and $15,000 at 90 % of the treatment centers.
Despite several studies that have shown that
20
0 5 10 15 20 25 MRgFUS is cost-effective compared to other
Months treatment modalities, such as UAE, myomec-
tomy, and hysterectomy, reimbursement for the
Fig. 26.4 Symptoms severity score (Courtesy of
Insightec, Inc.) procedure by major insurance companies is not
universal and patients are responsible for the
entire cost of the procedure [24–26]. Many insur-
Therefore, later investigators reported on safely ance companies still consider MRgFUS treat-
treating larger percentage of fibroid. Recently, ment of fibroids experimental and will not cover
Zhang et al. treated 21 out of 23 patients with a the cost. A physician survey conducted by Taran
mean fibroid volume of 97.0 ± 78.3 cm3. An aver- et al. during an international symposium in
age of 75 ± 11.4 % of fibroid volume was treated. October 2008 reported that 81 % ± 19 of patients
The average NPV was 83.3 ± 71.7. Zhang do not receive MRgFUS treatment secondary to
reported no statistical difference between the declined reimbursement [9]. It was noted that
treatment volume and the NPV. An MRI at 3 reimbursement of services by insurance compa-
months in 12 patients revealed a decrease in nies occurred more frequently when services
fibroid volume of 31.4 ± 29.3 %, which was sta- were provided at academic institutions compared
tistically significant by paired t-test (p = 0.002). with private practices. A retrospective study con-
The average treatment time was 2.5 ± 1.4 h which ducted by Behera et al. of patients who were
was well tolerated by patients with few side referred for minimally invasive treatment of
effects [23]. fibroids during the time period of November
Overall, MRgFUS treatment has had few side 2007 and February 2009 showed that 12 % of
effects. Taran noted in a survey of 12 experts patients declined MRgFUS for financial reasons
underreporting of adverse events. The author but that another 48 % declined MRgFUS for
searched the FDA’s Manufacturer and User unstated reasons, often after obtaining financial
Facility Device Experience Database (MAUDE) and insurance coverage information [26].
from January 1, 2004, to October 31, 2008, with
the search terms “Product Class: Ablation Conclusion
System, High-Intensity Focused Ultrasound In October 2004, the FDA approved the
(Hifu), MR-Guided,” “Manufacturer: InSightec,” ExAblate 2000 for treatment of uterine fibroids
and “Brand Name: ExAblate and ExAblate [7]. ExAblate is the only commercially
2000” and found 11 reported adverse events. approved noninvasive therapeutic system.
Twelve participants reported 17 adverse events Several studies have shown that MRgFUS sig-
not previously reported and found in searching nificantly improves clinical symptoms in
MAUDE. These included five neuropathies, four 70–80 % of women with uterine fibroids.
grade 1–2 skin burns, performance of two emer- MRgFUS is noninvasive and can be performed
gent hysterectomies, two abdominal wall ede- as an outpatient procedure and allows the
mas, one bowel injury, one bladder injury, one majority of patient to return to work and their
deep vein thrombosis (DVT), and one fat necro- normal activities in 1–2 days. MRgFUS is a
sis. There were no patient deaths. The authors technique that has minimum complications,
concluded there is an underreporting of adverse requires no general anesthesia, and has no
events in MAUDE [9]. overnight stay. Clinical trials are ongoing to
350 G. Richard-Davis and E. Eiland
evaluate future fertility in patients that have 12. Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief
undergone MRgFUS and look promising. Other of leiomyoma symptoms by using focused ultrasound
surgery. Obstet Gynecol. 2007;110(2 Pt 1):279–87.
uses for MRgFUS are also under investigation, 13. Al Hilli MM, Stewart EA. Magnetic resonance-
such as treatment of adenomyosis. Several guided focused ultrasound surgery. Semin Reprod
other companies are developing similar tech- Med. 2010;28(3):242–9. Epub 2010 Apr 22.
nology that may be launched soon, adding to 14. Baird DD, Dunson DB, Hill MC, Cousins D,
Schectman JM. High cumulative incidence of uterine
nonsurgical therapeutic options, body of work, leiomyoma in black and white women: ultrasound
and standardization of insurance coverage. evidence. Am J Obstet Gynecol. 2003;188:100–7.
PubMed: 12548202.
15. Stewart EA. Uterine fibroids. Lancet. 2001;357:
293–8. PubMed: 11214143.
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Index
Ectopic pregnancy F
abdominal pregnancy, 334–335 Faivre, E., 109
after hysterectomy, 338–339 Fallopian tube
cervical pregnancy, 332 anatomy of, 189–190
cesarean scar, 335–336 fimbrial phimosis, 190
hCG level, 329 function, 190
interstitial, 337–338 hydrosalpinx (see Hydrosalpinx)
ovarian pregnancy, 332–334 Fedele, L., 153
transvaginal ultrasound Fetal imaging, 4
endometrial echo, 331 Fimbrial phimosis, 190
intradecidual sign, 329, 330
intrauterine pseudosac, 329, 330
yoke sac, 330, 331 G
Ectors, F.J., 272 Gambadauro, P., 162
Ejaculatory duct obstruction, 220–222 Gargett, C.E., 162
El-Mazny, A., 153 Genital tuberculosis, 152
Embryo transfers Glass-body rendering (GBR), 20
anteverted uterus, 295, 296 Gleicher, N., 288
disadvantages of, ultrasound guided, 300–301 Goldstein, S., 168
pre-ET vaginal US measurement, 295, 296 Goswamy, R.K., 153
tactile ET vs. ultrasound-guided ET, 296–298 Goudas, V.T., 286
training in Grimbizis, G.F., 140, 142
abdominal US, 299, 300 Gunabushanam, G., 307
coaxial catheter US-guided ET
approach, 299
marker bubbles, 298 H
transvaginal vs. transabdominal ultrasound, 298 Hackeloer, B.J., 251
T-shaped uterus, 295 Healthcare fraud, 44
Endometrial polyps Healy, D.L., 162
abnormal uterine bleeding, 133, 136, 145 Hemorrhagic cysts, 68, 69
cervical polyps, 136 Hendricks, 65
cornual polyps, 133, 135 Herwig, R., 222
diagnosis of Hurley, V.A., 290
ART cycles, 143–145 Hurst, B.S., 117–129, 159
artifacts, 142 Hydrocele, 209, 211
computed tomography scanning, 140 Hydrosalpinx
3D SIS, 139 assisted reproduction, 195–196
3D TV sonography, 139–140 color Doppler sonography, 193–194
hysterosalpingography, 140 definition, 190–191
hysteroscopy, 140, 146 effects on pregnancy, 191–192
infertility, 142–143 hysterosalpingogram (HSG), 192–193
recurrent implantation failure, 145 prevalence and etiology, 190–191
sonohysterography, 138 signs and symptoms, 191
transient endometrial changes, 140–142 surgery utility, 195
TVUS, 136–138 ultrasound appearance, 193
T2-weighted MRI, 140 Hysterosalpingo-contrast-sonography (HyCoSy), 22,
endometrial ablation, 135 174, 175
incidence of, 133 advantages, 183
malignancy, 135–136 balloon catheter, 182
molecular mechanisms, 133 blood-flow and Doppler imaging, 184–186
multiple polyps and submucosal cervix cleaning, aseptic solution, 182
fibroids, 133, 134 contrast agent, 181–182
natural course of, 133 contrast medium injection, 183
prevalence of, 133 conventional B-mode transvaginal scan, 183
progestin treatment, 133, 135 Cusco’s (bivalve) speculum insertion, 182
sessile/pedunculated polyps, 133, 134 documentation, 183
single polyp, 133, 134 vs. laparoscopy, 183
uterine fundus, 133, 135 with SonoVue® dye, 181
Engmann, L., 36 three-dimensional coded contrast imaging, 184, 185
Epididymal cysts, 209 verbal consent, 182
Epididymis, 211–212 with water and air, 181
354 Index