Intrauterine Growth Restriction

Intrauterine Growth Restriction (IUGR)
Fetal Growth and Development

a. Determination of Gestational Age
Several terms are used to define the duration of pregnancy, and thus the the fetal age, but
these are somewhat confusing. They are shown schematically in figure 1. Gestational age
or menstrual age is the time elapsed since the first day of the menstrual period, a time that
actually precede conception. This starting time, which is usually about two weeks before
ovulation and fertilization and nearly 3 weeks before implantation of the blastocyst, has
traditionally been used because most women know their last period. Embryologists
describe embryo-fetal development in ovulation age. Or the time in days or weeks from
ovulation. Another term is preconceptional age, nearly identical to ovulation age.
Clinician customarily calculate gestational age as menstrual age as menstrual age.
About 280 days, or 40 weeks, elapse on average between the first day of last menstrual
period of the birth of the fetus. This corresponds to 9 and 1/3 calendar months a quick
estimate of the due date of a pregnancy based on menstrual data can be made ad follows:
add 7 days to the first day of the last period and substract 3 months. For example, if the
first day of the last menses was July 5, the due date is 07-05 minus 3 (months) plus 7
(days) = 04-12, or April of the following year. This calculaton has been termed
Naegeles rule. Many women undergo first- or early second trimester sonographic
examination to confirm gestational age. In these cases, the sonographic estimate is usually
a fw days later than that determined by the last period. To rectify this inconsistency and
to reduce the number of pregnancies diagnosed as postterm-some have suggested
assuming that average pregnancy is actually 283 days long and that 10 days be added to
the last menses instead of 7 (Olsen and Clausen, 1998).
The period of gestation can also be divided into three units of three calendar months
(13 weeks) each. These three trimesters have become important obstetrical milestones.

Normal Fetal Growth
Human fetal growth is characterized by sequential patterns of tissue and organ,
differentiation, and maturation. Development is determined by maternal provision of
substrate, placental transfer of these substrates, and fetal-growth potential governed by
genome. Steer (1998) has summarized the potential effects of evolutionary pressure on
human growth. In humans, there is an increasing conflict between the need to walk---
requiring a narrow pelvis---and the need to think---requiring a large brain. Humans may
resolving this dilemma by acquiring the ability to restrict growth late in pregnancy. Thus, the
ability growth restrict may be adaptive rather than pathological.
Lin and Santolaya-Forgas (1998) have divided cell growth into three consecutive
phases. The initial phase of hyperplasia occurs in the first 16 weeks and is characterized by
rapid increase in cell number. The second phase, which extends up to 32 weeks, includes both
cellular hyperplasia and hypertrophy, and it is during this phase that most fetal fat and
glycogen deposition take place. The corresponding fetal-growth rates during these three
phases are 5 g/day at 15 weeks, 15 to 20 g/day at 24 weeks, and 30 to 35 g/day at 34 weeks
(Williams and co0workers, 1982). As shown in figure, there is considerable biological
variation in the velocity of fetal growth.
Although many factors have been implicated, the precise cellular and molecular
mechanisms by which normal fetal growth occurs are not well understood. In early fetal life,
the major determinant is the fetal genome, but later in pregnancy, environmental, nutritional,
and hormonal influences become increasingly important (Holmes and colleagues, 1998). For
example, there is considerable evidence that insulin and insulin-like growth factor-I (IGF-I)
and II (IGF-II) have a role in the regulation of fetal growth and weight gain (Chiesa and
associates, 2008; Forbes and Westwood, 2008). These growth factors are produced by
virtually all fetal organs beginning early in development. They are potent stimulators of cell
division and differentiation.
Since the discovery of the obesity gene and its protein product, leptin, there has been
interest in maternal and fetal serum leptin levels. Fetal concentrations increase during the first
two trimesters, and they correlate with birthweight (Catov, 2007;Sivan, 1998; Tamura 1998;
and all their colleagues). This relationship however, is controversial in growth- restricted
foetuses (Kyriakakou, 2008; Mise, 2007; Mise, 2007; Savvidou, 2006, and all their
associates). Angiogenic factors have alse been studied. For example, higher levels of sFlt-1 at
10 to 14 weeks are associated with small-for gestational age infants (Smith and co-workers,
2007).

Figure () Increments in fetal weight gain in grams per day from 24 to weeks gestation. The
black line represents the mean and the outer blue lines depict 2 standard deviations. (Data
courtesy of Dr. Don McIntire).
Fetal growth is also dependent on an adequate supply of nutrients. Glucose transfer has
been extensively studied during pregnancy. Both excessive and diminished maternal glucose
availability affect fetal growth. Excessive glycemia produces macrosomia, whereas
diminished glucose levels have been associated with fetal-growth restriction. The
Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research
Group (2008) found that elevated cord c-peptide levels, which reflect fetal hyperinsulinemia,
have been associated with increased birthweight even in women with maternal glucose levels
below the threshold for diabetes.
There is less information concerning the physiology of maternal-fetal transfer of other
nutrients such as amino acids and lipids. Ronzoni and colleagues (1999) studied maternal-
fetal concentrations of amino acids in 26 normal pregnancies. These investigators reported
that an increase in maternal amino acid levels led to an increase in fetal levels. In growth-
restricted 3oetuses, amino acid disturbance similar to the biochemical changes seen in
postnatal protein-starvation states has also been detected (Economides and colleagues,
1989b). In a study of 38 growth-restricted infants, Jones and colleagues (1999) found
impaired used of circulating triglycerides consistent with peripheral adipose depletion.

Fetal-Growth Restriction
Low-birthweight infants who are small-for-gestational age are often designated as having
fetal-growth restriction. The term fetal-growth retardation has been discarded because
retardation implies abnormal mental function, which is not intent. It is estimated that 3 to
10 percent if infants are growth restricted.
Definition
In 1963, Lubchenco and co-workers published detailed comparisons of gestational ages with
birthweights in an effort to derive norms for expected fetal size at a given gestational week.
Battaglia and Lubchenco (1967) then classified small for-gestational-age (SGA) infants as
those whose weights were below the 10 percentile for their gestational age. Such infants were
shown to be at increased risk for neonatal death. For example, the neonatal mortality rate
SGA infants born at 38 weeks was 1 percents compared with 0.2 percent in those with
appropriate birthweights.
Many infants with birthweight less than 10
th
percentile, however, are not
pathologically growth restricted but are small simply because of normal biological factors.
Indeed, Manning and Hohler (1991) and Gardosi and colleagues (1992) concluded that 25 to
60 percent of SGA infants were in fact appropriately grown when maternal ethnic group,
parity, weight and height were considered.
Because of these disparities, other classifications have been developed. Seed (1984)
suggested a definition based on birth-weight below the 5
th
percentile. Usher and McLean
(1969) suggested that fetal-growth standards should be based on men weight-for-age with
normal limits defined by 2 standard deviations. This definition would limit SGA infants to
3 percent of birth instead of 10 percent. As demonstrated from their analysis of 122,754
pregnancies, McIntire and colleagues (1999) showed this definition to be clinically
meaningful. Also, as shown figure ( ), most adverse outcomes are in infants below the 3
rd

percentile. Lastly, individual fetal-growth potential has been proposed in place of a
population-based cutoff. In this model, a fetus who deviates from its individual optimal size
at given gestational age is considered either overgrown or growth restricted (Bukowski and
associates, 2008)

Figure () Relationship between birthweight percentile and perinatal mortality and morbidity
rates 1560 small-for-gestational age foetuses. A progressive increase in both mortality and
morbidity rates is observed as birthweight percentile falls. (Data from Manning, 1995)

Diagnosis and management of intrauterine
growth restriction
Ursula F. Harkness, MD, MPH*, Giancarlo Mari, MD
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,
University of Cincinnati, 231 Albert Sabin Way, PO Box 670526, Cincinnati, OH 45267-0526, USA

Normal growth on a cellular level is not homogeneous but rather follows a pattern that shifts over
time from rapid cellular duplication to rapid cellular enlargement [1]. Early growth is characterized by
an increase in cell number, and this period has proportional increases in weight, protein, and DNA
(phase of hyperplasia). This phase is followed by one in which cell division slows and existing cells
enlarge (phase of hyperplasia and hypertrophy). During this time, the increase in DNA is slower than
the increase in protein and weight. During the final phase, cell division decreases, and all further
growth is due to enlargement of cells (phase of hypertrophy). DNA does not continue to increase,
although net protein and weight do. The effects of stimuli that restrict growth may depend in part on
when in the sequence of cellular events they occur.
Fetal growth is determined by the mother, the fetus, and the placenta. Any factor that affects one of
these three environments can result in intrauterine growth restriction (IUGR).

Dating the pregnancy
Accurate dating is the most important step in the prenatal management ofthe IUGR fetus. Using the
last menstrual period (LMP) to determine gestationalage is often unreliable. In one study, menstrual
history could only be obtainedfrom 89.8% of the women enrolled, and 44.7% of these were unreliable
becauseof an unsure actual date of LMP, irregular menstrual cycles, recent oralcontraceptive use, or
first-trimester bleeding [2]. Ultrasound performed before18 weeks gestation was as good or better for
prediction of estimated date ofconfinement than even an optimal menstrual historydepending on the
gestational age at which the scan was performed [2].In the first trimester, the crown-rump length
(CRL) is used to estimategestational age. This measurement is highly accurate [3,4]. A longitudinal
viewof the fetus is found, and the calipers are placed at the outer edge of the cephalic pole and fetal
rump with care not to include the yolk sac or fetal limbs. Thepregnancy should be dated by
ultrasonography if there is a greater than 7-daydiscrepancy between LMP and CRL [5].
In the second trimester, fetal biometry can be used to date a pregnancyaccurately. Chervenak et al [6]
studied 152 singletons conceived through in vitrofertilization. These authors used stepwise multiple
linear regression to determinethe best equation for gestational age assessment using head
circumference (HC),biparietal diameter (BPD), femur length (FL), and abdominal circumference
(AC)alone or in combination. The most accurate single parameter was HC, which gavea random error
of 3.77 days. Adding AC and FL to HC slightly improved prediction (random error 3.35 days). Based
on this study, biometry should beused to date the pregnancy if the discrepancy between LMP and
ultrasound dating is greater than 7 days in the absence of congenital anomalies and severe growth
delay. The accuracy of a single ultrasonographic measurement for the detection of gestational age
decreases as gestational ages increases. The normal distribution of measurements becomes wider as
gestational age increases [7]. Serial ultrasound should be performed at 3-week intervals when dating
is to be determined using third-trimester sonography. Although precise sonographic assessment of
gestational age in the third trimester is not feasible in all cases based on fetal biometry alone, other
sonographic markers are currently used to estimate the gestational age. The ossification centers of
various long bones are most commonly used in practice. These centers become increasingly echo-
dense and larger with advancing gestational age. Although their presence does not give an exact
gestational age assessment, it can reassure the clinician that the pregnancy is relatively late into the
third trimester. The distal femoral epiphysis is noted at the distal end of the femur in the plane of
measurement of this bone. The distal femoral epiphysis is never seen before 28 weeks, and it is
observed in 72% of fetuses at 33 weeks, 94% of fetuses at 34 weeks, and 100% of fetuses at 36 weeks
[8]. The proximal tibial epiphysis is seen adjacent to the head of the tibia at its proximal end, in the
plane of measurement of this bone. The proximal tibial epiphysis is never seen before 34 weeks, and it
is found in 35% of fetuses at 35 weeks, 79% of fetuses at 37 weeks, and 100% of fetuses at 39 weeks
[8]. Finally, if the proximal humeral epiphysis is greater than or equal to 1 mm, there is at least a
probability of 0.69 that the pregnancy is at 40 to 42 weeks [9].

Estimating fetal weight
Many different formulae have been used to calculate gestational age. Two thatare commonly used are
the Shepard and Hadlock formulae. The Hadlock formula uses head circumference, abdominal
circumference, and femur length to estimate fetal weight [10]. The estimate of random error for this
method is plus or minus 15% (2 standard deviations). The Shepard formula is based on BPD and AC
[11]. The fetal weight estimate, once obtained, is compared with reference ranges. A value between
the 10th and 90th percentiles is usually considered normal. These cut-offs are used in an attempt to
identify fetuses at risk. Genetic and environmental factors may influence growth, however, and thus
different populationshave different growth curves.
Definitions
The terms small for gestational age (SGA) and IUGR are often used interchangeably,
although this is misleading. The growth-restricted fetus is a fetus that
fails to reach its growth potential and is at risk for adverse perinatal morbidity and
mortality. The American College of Obstetricians and Gynecologists (ACOG)
defines an IUGR fetus as a fetus with an estimated weight below the 10th
percentile [12]. Not all fetuses measuring less than the 10th percentile are at risk
for adverse perinatal outcome; many are just constitutionally small. IUGR refers
to the fetus who is SGA and displays other signs of chronic hypoxia or
malnutrition [5]. SGA is defined here as a fetus who measures less than the 10th
percentile for gestational age, whether it be because he is growth-restricted
(IUGR) or just constitutionally small. The authors will first discuss the fetus with
an estimated weight below the 10th percentile, then suggest ways to differentiate
the small fetus from the at-risk IUGR fetus and to manage the pregnancy
complicated by IUGR.
Traditionally, symmetric IUGR has been distinguished from asymmetric
IUGR [13]. The former is described as having an early onset. The insult affects
growth of skeletal, head, and abdominal measurements, because it occurs at a
time when fetal growth is affected primarily by cell division. Asymmetric IUGR,
by contrast, has its onset later in gestation, when fetal growth occurs secondary to
increases in cell size. Skeletal and head measurements are spared, but abdominal
circumference is small because of decreased liver size and subcutaneous fat.
More recently, the need to distinguish these entities has been questioned, because
it is unclear whether they can be associated with distinct causes or neonatal
outcomes [12]. One study demonstrated, however, that although the etiologies of
U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764 745
symmetrically and asymmetrically small fetuses overlap, the latter are at an
increased risk for neonatal and intrapartum complications [14].
Consequences of being small for gestational age
Short term
Estimated fetal weight below the 10th percentile is a leading risk factor forfetal death [15]. As birth
weight decreases from the 10th percentile to the firstpercentile, perinatal morbidity and mortality
increase markedly [16]. In term infants, the rates of low 5-minute Apgars, severe acidemia, need for
intubation in the delivery room, seizures in the first 24 hours of life, sepsis, and neonatal death
increase significantly among infants at or below the third percentile for gestational age [17]. In
preterm infants, by contrast, there is no specific birth-weight threshold below which neonatal
morbidity and mortality are increased; rather,respiratory distress (RDS) and neonatal death increase
along a continuum withdecreasing birth weight percentile. In a retrospective review of more than
1.4 million deliveries, the risk of RDS, intraventricular hemorrhage (IVH), and necrotizing
enterocolitis (NEC) was found to increase significantly in IUGR fetuses as compared with normally
grown fetuses beginning at 34 to 35 weeksgestation [18]. (Because the IUGR group was found using
an International Classification of Diseases, Ninth Revision [ICD-9] code search of a large
state database, it is difficult to assess whether only IUGR or both IUGR and SGA babies were
included.
The findings of the aforementioned study contrast with older studies that reported that small neonates
had a decreased incidence of RDS [19,20] and IVH [20,21] when compared with appropriate-for-
gestational-age preterm neonates, suggesting that in small fetuses there is an adaptive reaction to
intrauterine stress. Another study using the Vermont Oxford Network database described a significant
increase in neonatal death, RDS, and NEC among babies whose birth weight was less than the 10th
percentile and who weighed between 500 and 1500 g, as compared with appropriate-for-gestational-
age (AGA) babies [22]. These authors suggest that the inconsistency between their findings and those
of earlier studies may be due to the extent to which confounding variables are addressed and taken
into account.
Long term
The problems of the small fetus do not end at birth or soon after birth but continue well into childhood
and adulthood. Studies have shown that small children have an increased rate of impaired school
performance. One study described significantly higher numbers of children with late entry into
secondary school and failure to pass or take the baccalaureate examination in the small group as
compared with the AGA group, after controlling for maternal age, maternal educational level, parental
socioeconomic status, family size, and gender[23].
Another large follow-up study of 14,189 full-term infants from the United Kingdom showed
that at 5, 10, and 16 years of age, individuals born with a birth weight less than the fifth percentile had
small but significant deficits in academic achievement [24]. At 26 years of age, this same cohort of
once SGA babies showed lower levels of professional achievement, despite adjustment for potential
confounders. Other studies have described an association between fetuses with weight or height less
than the 10th percentile and the development of hypertension, hypercholesterolemia, impaired glucose
tolerance, and diabetes in later life [2527]. In the United Kingdom, a follow-up study on 5654 men
showed that those with the lowest weight at birth and at 1 year of age had the highest death rate from
ischemic heart disease [28]. The bfetal originsQ hypothesis asserts that changes in the intrauterine
nutritional or endocrine environment result in permanent alterations in structure, physiology, and
metabolism that predispose the affected individual to develop cardiovascular, metabolic, and
endocrine disease years later [26]. An endocrine-metabolic reprogramming occurs that enables the
small fetus to adapt to its adverse intrauterine environment; after birth, nutrient abundance may lead
to a metabolic syndrome and to the development of the above-noted cardiovascular risk factors [25].
This theory is the so-called Barkers hypothesis.
Screening for the small fetus
Fundal height assessment
Several studies have estimated that 41% to 86% of SGA babies could be
detected with routine use of symphysis-fundal height measurements [2932].
Some of these studies used standard value curves, with the small fundal height
defined as that below the 10th percentile of standard values for gestational age.
The most common method in practice, however, uses the concept that, between
20 and 34 weeks, the fundal height in centimeters equals the gestational age in
weeks [33]. A measurement in centimeters is taken from the upper edge of the
symphysis pubis to the top of the uterine fundus. A measurement of 3 to 4 cm
below the expected number suggests inappropriate growth.
Ultrasonographic measurements
According to one meta-analysis of ultrasonographic measurements, AC and
estimated fetal weight (EFW) were the best predictors of fetal weight below the
10th percentile [34]. In high-risk populations, the sensitivity using AC of less
than the 10th percentile was 73% to 95%, whereas using EFW the sensitivity was
43% to 89%; in low-risk populations, the corresponding sensitivities were 48% to
64% for AC and 31% to 73% for EFW. In another study, AC measurements were
shown to predict small fetuses better than BPD, HC, or a combination of
parameters [35]. The sensitivity of a single AC measurement after 25 weeks for
the detection of fetuses with birth weight below the 10th percentile was 48%. In
the same study, a normal AC was found to exclude fetal growth restriction with a
false-negative rate of about 10%. Another study showed that a single AC
measurement for the detection of babies with birth weight less than the 10th
percentile was only slightly better than serial fundal height measurements
(sensitivity 83% versus 76%); the difference was not statistically significant [36].
Thus there is no clear evidence that routine ultrasound is a better screening
method for SGA than fundal height measurement in the general population.

Diagnosis of intrauterine growth restriction

The data already reported refer to fetuses with an estimated weight below the 10th percentile. When a
fetus has an estimated weight below the 10th percentile in the absence of congenital anomalies and in
the presence of a normal amount of amniotic fluid, Doppler velocimetry gives the most important
information to differentiate the truly growth-restricted fetus (IUGR) from the fetus that is
constitutionally small but otherwise normal.

Umbilical artery

Normal pregnancy is characterized by a low-resistance feto-placental system with continuous forward
flow throughout the cardiac cycle. Although several indices to estimate vessel resistance as evaluated
by Doppler ultrasonography have been described, the most popular and the simplest of these is the
systolic/diastolic (S/D) ratio. This index is a ratio of the maximum systolic flow velocity divided by
the minimal end-diastolic flow velocity. Normal reference ranges throughout pregnancy are reported
in Fig. 1 [37]. In pregnancies complicated by IUGR, there is a chronological process characterized by
increased umbilical artery resistance (increased S/D ratio), absent end-diastolic flow, and finally
reverse end-diastolic flow (Fig. 2). Various hypotheses have been proposed to explain the
pathophysiology of IUGR and abnormal umbilical artery Doppler velocimetry [38]: (1) reduced
placental-stem artery number, (2) primary villus maldevelopment with small, hypovascular, and
fibrotic terminal villi, and (3) placental-stem vessel vasoconstriction.
Small fetuses with abnormal umbilical artery waveforms are admitted more frequently to the neonatal
intensive care unit and stay longer compared with those small fetuses who have normal Doppler
velocimetry in the umbilical artery [39,40]. Studies have shown that the perinatal mortality rate in
pregnancies complicated by growth restriction or hypertension is higher in fetuses with reversed end
diastolic flow (33% to 73%) or absent end-diastolic flow (9% to 41%) in the umbilical artery [4143].
Finally, fetuses with absent and reverse end-diastolic flow in the umbilical artery are at increased risk
for impaired mental development, severe motor deficits, and neurodevelopmental delay [44,45].
Eleven randomized studies involving close to 7000 women were included in a meta-analysis that
compared the use of Doppler ultrasound of the umbilical artery to no Doppler in high-risk
pregnancies, many of which were complicated by IUGR. A trend in reduction of perinatal deaths was
seen (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.50 to 1.01), as well as significantly fewer
inductions of labor and hospital admissions without untoward effects [46]. These data prompted
ACOG to endorse the use of Doppler in high-risk pregnancies. One area of debate and research is
whether Doppler can help in timing the delivery of an IUGR fetus. The question arises: In a fetus with
an abnormal umbilical artery waveform, is it better to deliver soon after making the diagnosis or to
prolong the pregnancy? Each of these managements carries a riskpossible intrauterine hypoxia with
continuation of the pregnancy; complications of pre-maturity with early delivery. The Growth
Restriction Intervention Trial was a randomized trial that addressed this question in 547 pregnancies
between 24 and 36 weeks with singleton or multiple gestations, in circumstances where the provider
was uncertain whether to deliver [47]. The median time to delivery was 0.9 days in the deliver-now
group (within 48 hours, to allow a steroid course to be given) and 4.9 days in the expectant-
management group. Total deaths before discharge were 29 (10%) in the deliver-now group and 27
(9%) in the expectantmanagement group (OR 1.1, 95% CI 0.61 to 1.8). Based on this study, no
difference exists between combined antenatal and neonatal mortality rates associated with immediate
delivery and rates associated with expectant management until the clinician is no longer uncertain that
intervention is necessary. Information on the developmental quotient of the survivors of this study at 2
years of age will be available in the near future. Many authors have suggested that small fetuses with
normal umbilical artery flow represent a group not at risk for adverse perinatal outcome. Most of
these babies are constitutionally small [4850]. Recently, Baschat and Weiner [51] reported on 308
women with ultrasonographic EFW less than the 10th percentile or AC less than the 2.5th percentile
for gestational age. Babies with abnormal umbilical artery Doppler had increased rates of fetal distress
associated with chronic hypoxemia, RDS, and admission to a neonatal intensive care unit. The authors
suggested that antenatal surveillance may not be necessary in SGA babies if the umbilical artery S/D
ratio and amniotic fluid are normal. One study of 167 women with small fetuses with normal
umbilical artery Dopplers randomly allocated participants to surveillance that occurred twice weekly
or every other week [52]. Although the two groups showed no differences in neonatal morbidity, the
more frequently tested group had a higher induction rate. Unfortunately, this study did not have the
power to detect clinically important differences in neonatal outcome. These babies could not be
assumed to be simply small and healthy, because 32% were admitted to the neonatal special care unit
(range of stay 0 to 66 days, mean 4 to 5 days), 20% had hypoglycemia, and 40% had a low ponderal
index at birth, despite the fact that the mean gestational age at delivery was 38 weeks. However, 10%
of the babies in this study had an abnormal cerebral artery/umbilical artery resistance ratio, a finding
that suggests that some of them were growth-restricted babies with blood flow redistribution.
Evidence shows that umbilical artery Doppler can be used to distinguish between the high-risk small
fetus that is truly growth-restricted and the lower-risk small fetus. A prospective randomized trial is
needed to examine the question of whether antenatal surveillance is necessary when fetal growth is
less than the 10th percentile, but the umbilical artery S/D and AFI are normal.

Middle cerebral artery
The fetal response to chronic hypoxia is redistribution of blood flow to the tissues that are most
needed, such as the brain, myocardium, and adrenal glands. This phenomenon has been called the
bbrain-sparing effect.Q In this scenario, oligohydramnios is thought to occur because of decreased
renal perfusion. Mari and Deter [53] described a parabolic pattern of middle cerebral artery (MCA)
pulsatility index ([peak systolic velocity ! lowest diastolic velocity]/mean velocity) in normal
singletons across gestational age, with higher values from 25 to 30 weeks (Table 1). These authors
showed that SGA babies with abnormal pulsatility indices were at a higher risk for perinatal death and
neonatal ICU stay of greater than 12 hours [53]. Fig. 3 demonstrates a normal MCA waveform and
one that suggests bbrain sparing. The IUGR fetus displays an increased placental resistance,
evidenced by an increased S/D ratio of the umbilical artery that is associated with a decreased cerebral
vascular resistance quantified by a decreased pulsatility index (PI) of the MCA. Therefore, the
cerebral-placental ratio may be a better index to assess the small fetus than the umbilical artery or
cerebral vessels [54,55]. The cerebral placental ratio generally refers to the ratio between the MCA PI
and the umbilical artery PI. This index, however, has alternatively been defined as the ratio of S/D
or resistance index in the MCA and umbilical artery. In small fetuses, cerebralplacental ratio is a good
predictor for longer neonatal ICU stays, low Apgar scores, cord gas pH, cesarean for fetal distress,
and other perinatal complications [5659]. The cerebral-placental ratio is a more sensitive predictor
than either MCA or umbilical artery velocimetry alone [5659]. Usually the cut-off cerebralplacental
ratio below which the fetus is considered to have brain sparing is 1.0 to 1.1 [56,58]. The cerebral-
placental ratio does not correlate significantly with perinatal morbidity after 34 weeks [59]. Although
an abnormal cerebral Doppler is frequently seen in fetuses with abnormal umbilical artery
velocimetry, MCA redistribution may be seen in fetuses with normal umbilical artery waveforms. One
study reported an increased rate of emergency cesarean section in small babies with normal umbilical
artery velocimetry when the MCA waveform was abnormal [60]. When the uterine artery waveform
was also abnormal, the rate of emergency cesarean was reported to be as high as 86%, versus 4%
when MCA and uterine artery velocimetry were both normal. The rate of severe morbidity (grades II
to IV intraventricular hemorrhage) was significantly increased in the pregnancies delivered by
emergency cesarean section. Although abnormal umbilical artery velocimetry is a better predictor of
adverse perinatal outcome in the small fetus, MCA PI has a better sensitivity (91.7%) and negative
predictive value (98.6%) for major adverse outcome, especially before 32 weeks (when the sensitivity
is 95.5% and the negative predictive value is 97.7%) [61]. The cerebral-placental ratio should be used
in small fetuses with normal umbilical artery waveforms. When there is absent or reversed flow of the
umbilical artery, this index is not needed.

Issues in management of intrauterine growth restriction

Ductus venosus
The ductus venosus (DV) originates from the umbilical vein before it turns
to the right to join the portal vein [62,63]. Blood from the DV then enters
the inferior vena cava. The DV waveform includes two peaks. The first peak
(S wave) reflects filling of the right atrium during ventricular systole. The second
peak (D wave) reflects the passive filling of the ventricles during early diastole.
The lowest point of the waveform (A wave) corresponds to atrial contraction
(atrial kick) in late diastole [5,62]. In the normal fetus, flow in the DV is forwardmoving
toward the heart during the entire cardiac cycle. When circulatory
compensation of the fetus fails, the DV waveform may become abnormal,
showing absent or reversed blood flow (Fig. 4) during atrial contraction. In these
cases, pulsations in the umbilical vein may be seen. These changes may be due to
increasing right ventricular afterload and right-sided heart failure due to
myocardial hypoxia [62].
The perinatal mortality in the presence of absent or reversed flow of the DV
ranges from 63% to 100% [6466]. It appears that the fetus should be delivered
before the development of absent or reversed flow of the DV. Therefore, the
inclusion of venous Doppler in antepartum surveillance for IUGR fetuses may be
beneficial, although a prospective randomized trial has not yet been done to
confirm this hypothesis [67]. In one study including 224 fetuses with IUGR who
underwent umbilical artery (UA), DV, and umbilical vein assessment, absent or
reversed UA waveform was shown to have the highest sensitivity and negative
Fig. 4. Ductus venosus velocimetry in a fetus with (A) a normal waveform and (B) reversed blood
flow during atrial contraction (arrow).
754 U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743764
predictive value for acidemia, asphyxia, stillbirth, and neonatal and perinatal
death [67]. Absent or reversed atrial systolic blood-flow velocity in the DV and
pulsatile flow in the umbilical vein, however, had the best specificity and positive
predictive values for prediction of the above outcomes. The authors suggested
that important intrauterine time can be gained for preterm fetuses who have
absent or reversed UA end-diastolic velocities but normal venous flows.
Results of a prospective multicenter longitudinal observational study also
suggested that Doppler velocimetry of the DV may be useful in timing the
delivery of the IUGR fetus [68]. Of 70 singleton IUGR fetuses delivered between
26 and 33 weeks gestation, DV PI was significantly higher, UA PI was significantly
higher, and short-term heart-rate variation (STV) was significantly
lower in the last 24 hours before delivery in babies with adverse outcomes. Poor
outcomes included perinatal death, cerebral hemorrhage of grade II or greater,
and bronchopulmonary dysplasia. Two to 7 days before delivery, only DV PI was
significantly higher. With logistic regression analysis, only DV waveform and
gestational agenot UA PI or STVwere predictive of adverse outcomes. Only
32% (6/19) of the infants with DV PI of 3 standard deviations or greater and 18%
(2/11) of the infants with absent or reversed DV A-wave flow in the 24 hours
before delivery had normal outcomes.
Although the results of these studies are promising for timing the delivery of
the IUGR fetus based on DV, data from randomized trials are not yet available to
support or refute its use. Currently, a multicenter prospective randomized trial is
being planned in Europe.
Other vessels
Many other vessels have been assessed by Doppler ultrasound in the AGA and
IUGR fetus [6977]. Those studies have improved our understanding of fetal
physiology and the pathophysiology of the IUGR fetus. However, they do not
add much beyond the information given from assessment of the UA, MCA,
and DV.
Temporal sequence of Doppler changes
Recent longitudinal studies have described a Doppler temporal sequence in
the IUGR fetus before fetal distress. Hecher et al [78] reported findings from a
prospective observational multicenter study on 93 singleton pregnancies after
24 weeks complicated by IUGR. Amniotic fluid index and UA PI were the first
to become abnormal. These were followed by abnormalities of MCAvelocimetry,
aorta Doppler studies, STV of the fetal heart rate, DV waveforms, and inferior
vena cava Doppler studies. This trend appeared both before and after 32 weeks.
In the group delivered after 32 weeks, however, the probability of having any
given abnormality in Doppler velocimetry was lower, and the changes in actual
Doppler values and STV were less pronounced.
Baschat et al [79] longitudinally studied 44 IUGR fetuses with elevated
umbilical artery PI who had a final biophysical profile of less than 6/10 before
delivery. In 42 fetuses (95.5%), one or more vascular parameters changed. UA
and DV indices markedly increased at a median of 4 days before the biophysical
score deteriorated. Fetal breathing movements declined beginning 2 to 3 days
before delivery; the following day, amniotic fluid volume dropped. Loss of fetal
movement and tone occurred on the day of delivery. In 70.5% of these fetuses,
Doppler deterioration was complete 24 hours before the biophysical profile
changed. Three patterns of Doppler deterioration were described in this study.
The majority of fetuses (72.7%) displayed a sequence of worsening of the UA
PI, development of brain sparing, then venous changes. Another group of fetuses
showed venous changes before brain sparing. Finally, some fetuses demonstrated
changes in the DV without ever showing Doppler changes consistent with
brain sparing.
Ferrazzi et al [80] evaluated 26 IUGR fetuses with abnormal uterine and UA
Doppler velocimetry. A temporal sequence of abnormal Doppler changes was
described. Early changes, assumed to reflect increased placental vascular resistance
and hypoxia, included absent end-diastolic flow in the UA and an abnormal
MCA PI. Half the fetuses showed these changes 15 to 16 days before delivery.
Late changes, thought to indicate circulatory collapse, were reverse flow in the
UA and abnormal DV, aortic, and pulmonary outflow tract velocimetry. Half the
fetuses were affected by these late changes 4 to 5 days before delivery. These late
Doppler changes correlated significantly with perinatal death.
Significantly, not all fetuses appear to follow the same pattern of circulatory
deterioration [79]. In addition, near-term fetuses may not show the same
progression of circulatory changes [79]. These differences need to be considered
when using Doppler velocimetry in the antenatal surveillance of the IUGR fetus.
Nonstress test
The heart rate of the fetus that is not affected by acidosis or neurologic depression
will accelerate in response to fetal movement. This reaction is the basis
of the nonstress test (NST). Although abnormal fetal heart-rate patterns are
related to impaired fetal oxygenation and subsequent neurologic outcome, these
are late changes. Ideally, the fetus should be delivered before evidence of
hypoxemia is noted on fetal heart-rate monitoring to avoid subsequent handicap
[81]. However, the NST remains the most common test used in evaluation of
pregnancies complicated by an IUGR fetus.
Biophysical profile
The biophysical profile (BPP) is based on the fact that the fetal central nervous
system initiates and regulates biophysical activity. Neuronal centers deprived of
oxygen have decreased or absent output, which results in alterations in fetal
movement, tone, and breathing. Systemic hypoxia is assumed to be absent as
long as brain activity is normal, because the brain is one of the most oxygendependent
tissues [82].
The BPP is a widely used antepartum testing modality. A significant decrease
in perinatal mortality is seen in high-risk pregnancies managed with BPP as
opposed to those managed with untested historical controls. The perinatal mortality
in one study was 1.86 per 1000 in those tested, compared with 7.69 per
1000 in those not tested, for a decrease of 76% [83]. In a large retrospective study
of 26,290 high-risk fetuses who received BPP testing and 58,659 fetuses who
did not receive BPP testing, there was a very significant inverse exponential
relationship between BPP before delivery and incidence of cerebral palsy [84].
The incidence of cerebral palsy when the last BPP score before delivery was
normal (10/10, 8/10, or 8/8) was 0.7 per 1000, whereas with a score of 0/10 the
incidence of cerebral palsy was 333 per 1000. In the same study, these same
high-risk fetuses were compared with mixed low-risk and high-risk patients not
followed by BPP; the rate of cerebral palsy was 4.74 per 1000 in the untested
population and 1.33 per 1000 in the tested group, a significant difference.
Although the mean birth weight is noted to be smaller in the tested population,
the actual number of SGA or IUGR fetuses in this study is unknown.
The authors of a review assessing the effects of BPP on perinatal outcome
conclude that there is currently inconclusive evidence from randomized
controlled trials to support or argue against the use of BPP as a test of fetal
well-being in high-risk pregnancies, including those with IUGR [85]. Surprisingly,
however, the number of patients enrolled in randomized trials using this
method of antepartum testing is small (2839).
Corticosteroids
One important consideration regarding the use of the BPP in the management
of high-risk pregnancies is the effect of corticosteroids on fetal behavior and thus
on the score itself. In a study of 35 women at risk for preterm delivery without
IUGR and between 28 and 34 weeks, BPPs and Doppler velocimetry of the UA
and MCA were performed daily before a first dose of betamethasone and for
120 hours afterward [86]. Though none of the BPPs were less than or equal to 6 at
baseline, at 24, 48, and 72 hours poststeroids, 13.3%, 76.7%, and 16.7% were
less than or equal to 6, respectively (P b 0.05). The change in BPP was due to
decreased fetal movement, decreased fetal breathing, and more frequent
nonreassuring heart-rate tracing. The alteration in BPP in these healthy fetuses
was transient. Doppler indices were not affected by corticosteroid administration.
Another prospective study showed findings of decreased fetal breathing and
decreased fetal limb and trunk movements 48 hours from a first dose of betamethasone,
with return to baseline at 96 hours; again, Doppler velocimetry of
the MCA and UA remained unchanged [87]. These effects should be considered
in managing women with IUGR after steroids have been administered.
The efficacy of antenatal corticosteroids for the preterm fetus with IUGR has
not been well studied. One study showed no significant difference in short-term
morbidity between infants with growth restriction delivered between 26 and
31 weeks who received corticosteroids and those who did not, but it did demonstrate
a significantly higher survival without disability or handicap in the steroid
group [88]. Another study reported no difference between growth-restricted
fetuses of less than 1750 g given steroids and AGA infants for several neonatal
outcomes, including RDS and intraventricular hemorrhage/periventricular leukomalacia
[89].
However, a very recent study demonstrated that of 19 fetuses with absent or
reversed end-diastolic flow (ARED) in the UA, 10 developed transient forward
end-diastolic flow after betamethasone injection, whereas nine fetuses showed
persistent ARED [90]. Although some babies respond to steroids with vasodilation
of the fetoplacental circulation and decreased vascular resistance, other
babies respond with an increase in vascular resistance that may lead to fetal
deterioration. The persistent ARED group had more frequent acute fetal deterioration.
The two patients with a fetal demise and the two patients with severe
acidosis were in the persistent ARED group. The authors suggest performing
Doppler studies the day after steroid administration in IUGR fetuses with ARED.
If no forward end-diastolic flow is seen, the fetal venous circulation should be
examined, and delivery should be considered if abnormalities exist. The response
of IUGR fetuses to corticosteroid administration should be studied further.
Prediction of intrauterine growth restriction
Uterine artery
IUGR and pre-eclampsia have been associated with abnormal velocimetry of
the uterine arteries. The uterine artery is typically measured using color Doppler
where it crosses over the external iliac artery. In the normal pregnancy, the normal
waveform shows high flow throughout diastole. An abnormal waveform is
characterized by high resistance and an early diastolic notch (Fig. 5). This finding
is thought to be related to a failure of trophoblastic invasion of spiral arteries and
the resultant low-resistance circulation.
One large study in 5121 unscreened women found that, at the 95th percentile
for mean PI at 23 weeks in the studied population (1.45), the likelihood ratio for
severe adverse outcomes was 5 for nonsmokers and 10 for smokers [91]. Severe
outcome was defined as pre-eclampsia associated with delivery before 34 weeks,
birth weight less than the 10th percentile associated with delivery before
34 weeks, fetal death, or placental abruption.
A multicenter study of 7851 women with singleton pregnancies in an
unselected population showed that the sensitivity of transvaginally obtained
uterine Doppler velocimetry with a PI of greater than 1.63 (95th percentile) at
23 weeks is 93.3% for predicting pre-eclampsia and fetal growth restriction
(FGR) and 56.3% for predicting FGR without pre-eclampsia when delivery
occurred before 32 weeks [92]. The negative predictive values were 100% and
99.9%, respectively. When all deliveries were included, the sensitivity decreased
to 69% for prediction of pre-eclampsia and FGR and 13.2% for FGR without preeclampsia.
When the screening test was PI greater than 1.63 or the presence
of bilateral notches, the sensitivity for pre-eclampsia and FGR increased to 100%
and for FGR without pre-eclampsia to 68.8% in patients delivered before
32 weeks, although the screen-positive rate increased from 5.1% to 11.9%.
At this time, we are unable to alter the pathophysiology of the progressive
disease process that is first evidenced by abnormal uterine artery Doppler
velocimetry at 23 weeks. These fetuses may, however, benefit from closer
antepartum surveillance.
Summary
The first step in the management of the IUGR fetus is diagnosis. Fundal height
is the best screening tool, and ultrasound biometry is the best method for
detecting the small fetus. Doppler velocimetry is the most important means
of diagnosing the IUGR fetus who is at risk for adverse perinatal morbidity
and mortality.
It is difficult to determine the best time to deliver the IUGR fetus: one must
balance the risks of prematurity with the risks of further intrauterine decompensation.
For the very preterm fetus, there may be some benefit to delaying
delivery until after venous evidence of circulatory decompensation is present,
but before the BPP becomes very abnormal. Two complicating factors in the
management of IUGR are its varied causes and the fact that not all IUGR fetuses
demonstrate the same patterns of decompensation. We need studies that compare
Fig. 5. Demonstration of (A) normal uterine artery waveform and (B) uterine artery notching (arrow).
NST, BPP, and Doppler surveillance to one another and to management strategies
that combine them. Perhaps an integration of the testing modalities that reflect
central nervous system phenomena (NST, BPP) and circulatory phenomena
(Doppler velocimetry) will emerge as the best antepartum method of testing fetal
well-being.
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Ultrasound Obstet Gynecol 2001;18:4419.

Early establishment of gestational age, attention to maternal weight gain, and careful
measurement of uterine fundal growth throughout pregnancy will identify many cases of
abnormal fetal growth in low-risk women. Risk factors, including a previous growth-
restricted fetus, increase the possibility of recurrence. Specifically, the rate of recurrence is
believed to be nearly 20 percent (Berghella, 2007). In women with risk factors, consideration
should be given to serial sonographic evaluation. Although frequency of examinations varies
depending on indications, an initial early dating examination followed by a second
examination at 32 to 34 weeks, or when otherwise clinically indicated, will identify many
cases of growth restriction. Even so, definitive diagnosis frequently cannot be made until
delivery. Identification of the inappropriately growing fetus remains a challenge. There are,
however, both simple clinical techniques and more complex technologies that may prove
useful.
Uterine Fundal Height
Carefully performed serial fundal height measurements are a simple, safe, inexpensive, and
reasonably accurate screening method to detect SGA fetuses (Gardosi and Francis, 1999). As
a screening tool, its principal drawback is imprecision (Jelks and colleagues, 2007). For
example, Jensen and Larsen (1991) and Walraven and co-workers (1995) found that this
method helped to correctly identify only 40 percent of such infants. Thus, SGA fetuses were
both overlooked and overdiagnosed. Despite this,these results do not diminish the importance
of carefully performed fundal measurements as a simple screening technique.
Technique. The method used by most for fundal height measurement was described by
Jimenez and colleagues (1983). Briefly, a tape calibrated in centimeters is applied over the
abdominal curvature from the upper edge of the symphysis to the upper edge of the uterine
fundus, which is identified by palpation or percussion. The tape is applied with the markings
apposed to the maternal abdomen and away from the examiners view to avoid bias. Between
18 and 30 weeks, the uterine fundal height in centimeters coincides within 2 weeks of
gestational age. Thus, if the measurement is more than 2 to 3 cm from the expected height,
inappropriate fetal growth may be suspected.
Sonographic Measurements
Central to the debate over whether all pregnancies should routinely undergo sonographic
evaluation is the potential for diagnosis
of growth restriction (Ewigman and colleagues, 1993). Typically, such routine screening
incorporates an initial sonographic examination at 16 to 20 weeks to establish gestational age
and identify anomalies. This is repeated at 32 to 34 weeks to evaluate fetal growth (see Chap.
16, p. 352). Ironically, Gardosi and Geirsson (1998) found that accurate gestational dating at
the initial examination resulted in a lower diagnosis rate of fetalgrowth restriction. In a study
of 8313 pregnancies, Verburg and co-workers (2008) found that sonography prior to 24
weeksoptimally at 10 to 12 weeksprovides a better prediction of gestational age than the
last menstrual period. With sonography, the most common method for establishing the
diagnosis of fetal-growth restriction is the estimation of fetal weight using multiple fetal
biometric measurements. Combining head, abdomen, and femur dimensions has been shown
to optimize accuracy with little incremental improvement by addition of other biometric
measurements (Platz and Newman, 2008). These are considered separately:
1. Femur length (FL) measurement is technically the easiest and the most reproducible
2. Biparietal diameter (BPD) and head circumference (HC) measurements are
dependent on the plane of section and may also be affected by deformative pressures
on the skull
3. Abdominal circumference (AC) measurement is more variable, but it is most
commonly abnormal in cases of fetal growth restriction because mostly soft tissue is
involved Figure ( ).
An abdominal circumference within the normal range for gestational age reliably excludes
growth restriction, whereas a measurement less than the 5th percentile is highly suggestive of
growth restriction (American College of Obstetricians and Gynecologists, 2000b). And as
shown in Figure 38-6, such small circumferences are linked to decreased fetal pO2 and pH.
Despite its accuracy, sonography used for detection of fetal growth restriction has false-
negative findings. Dashe and colleagues (2000) studied 8400 live births at Parkland Hospital
in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They
reported that 30 percent of growth restricted fetuses were not detected. In a study of 1000
high-risk fetuses, Larsen and associates (1992) performed serial sonographic examinations
beginning at 28 weeks and then every 3 weeks. Reporting results to clinicians significantly
increased the diagnosis of SGA fetuses. And although elective deliveries in this group were
increased, there was no overall improvement in neonatal outcome.

Amnionic Fluid Measurement. An association between pathological fetal-growth restriction
and oligohydramnios has long been recognized (see Chap. 21, p. 495). Chauhan and
coworkers (2007) found oligohydramnios in less than 10 percent of pregnancies suspected of
growth restriction, but this group of women was two times more likely to undergo cesarean
delivery for nonreassuring fetal heart rate patterns. As shown in Figure38-7, the smaller the
pocket of amnionic fluid, the greater the perinatal mortality rate. One likely explanation for
oligohydramniosis diminished fetal urine production caused by hypoxia and diminished renal
blood flow (Nicolaides and associates, 1990).
Doppler Velocimetry
Abnormal umbilical artery Doppler velocimetrycharacterized by absent or reversed end-
diastolic flowhas been uniquely associated with fetal-growth restriction The use of Doppler
velocimetry in the management of fetal growth restriction has been recommended as a
possible adjunct to techniques such as nonstress testing or biophysical profile (American
College of Obstetricians and Gynecologists, 2000b). Abnormalities in Doppler flow
characterize early versus severe fetal-growth restriction and represent the transition from fetal
adaptation to failure. Early changes in placenta-based growth restriction are detected in
peripheral vessels such as the umbilical and middle cerebral arteries. Late changes are
characterized by abnormal flow in the ductus venosus and aortic and pulmonary outflow
tracts, as well as by reversal of umbilical artery flow (Pardi and Cetin, 2006). An example of
this is shown in Figure ( )
In a series of 604 neonates < 33 weeks who had an abdominal circumference < 5th
percentile, Baschat and colleagues (2007) found that the ductus venosus Doppler parameters
were the primary cardiovascular factor in predicting neonatal outcome. These late changes
are felt to reflect myocardial deterioration and acidemia, which are major contributors to
adverse perinatal and neurological outcome. In their longitudinal evaluation of 46 growth-
restricted fetuses, Figueras and colleagues (2009) determined that Doppler flow abnormalities
at the aortic isthmus preceded those in the ductus venosus by one week. Similarly, Towers
and co-workers (2008) prospectively observed 104 fetuses with abdominal circumference
5th percentile. They broadly identified two patterns of progression of Doppler abnormalities:
(1) mild placental dysfunction, which remained Gross perinatal mortality per 1000 live births
confined to umbilical and middle cerebral arteries, and (2) progressive placental dysfunction,
which progressed from peripheral vessels to the ductus venosus at variable intervals
depending on gestational age. Both groups of investigators stressed that knowledge of these
patterns of progression is critical for planning subsequent fetal surveillance and timing of
delivery.

Prevention
Prevention of fetal-growth restriction ideally begins preconceptionally with optimization of
maternal medical conditions, medications, and nutrition. Smoking cessation is critical. Other
risk factors should be tailored to the maternal condition, such as antimalarial prophylaxis for
women living in endemic areas and correction of nutritional deficiencies. Studies have shown
that treatment of mild to moderate hypertension does not reduce the incidence of SGA
infants. During early pregnancy, accurate pregnancy dating is essential. In pregnancies at risk
for fetal-growth restriction, for example, those in women with hypertension or prior fetal-
growth restriction, prophylaxis with low-dose aspirin beginning early in gestation has been
shown to reduce growth restriction by only 10 percent (Berghella, 2007).
Management
Once fetal-growth restriction is suspected, efforts should be made to confirm the diagnosis,
assess fetal condition, and evaluate for anomalies. Growth restriction near term is easier to
manage but often missed. As aptly stated by Miller and associates (2008), although growth
restriction before 34 weeks is readily recognized, it presents a management challenge.
Cordocentesis allows rapid karyotyping for detection of a lethal aneuploidy, which may
simplify management. The American College of Obstetricians and Gynecologists (2000b) has
concluded that there are not enough data to warrant routine cord blood sampling in this
situation. The timing of delivery is crucial, and the risks of fetal death versus the hazards of
preterm delivery must be assessed as reported in the Growth Restriction Intervention Trial
(GRIT) by Thornton and colleagues (2004). Growth Restriction Near Term Prompt delivery
is likely best for the fetus at or near term who is considered growth restricted. In fact, most
clinicians recommend delivery at 34 weeks or beyond if there is clinically significant
oligohydramnios. With a reassuring fetal heart rate pattern, vaginal delivery may be
attempted. Some of these foetuses do not tolerate labor, and cesarean delivery is necessary.
Uncertainty about the diagnosis should preclude intervention until fetal lung maturity is
assured. Expectant management can be guided using antepartum fetal surveillance
techniques.
Growth Restriction Remote from Term
When growth restriction is identified in an anatomically normal fetus prior to 34 weeks, and
amnionic fluid volume and fetal surveillance are normal, observation is recommended.
Screening for toxoplasmosis, rubella, cytomegalovirus, herpes, and other infections is
recommended by some, however, we have not found this to be productive. As long as fetal
growth continues and fetal health remains normal, pregnancy is allowed to continue until
fetal maturity is reached. In some cases, amniocentesis may be helpful to assess pulmonary
maturity. Although the development of oligohydramnios is highly suggestive of fetal-growth
failure, it is important to recognize that normal amnionic fluid volume does not preclude
growth restriction. Owen and colleagues (2001) reported that 4- and 6-week evaluation
intervals were superior to 2-week intervals for predicting growth restriction. Depending on
the gestational age when fetal-growth restriction is first suspected, this interval may be
impractical clinically, and sonography is usually repeated more frequently. With growth
restriction remote from term, no specific treatment ameliorates the condition. For example,
there is no evidence that bed rest results in accelerated growth or improved outcome. Despite
this, many clinicians intuitively advise a program of modified rest. Nutrient supplementation,
attempts at plasma volume expansion, oxygen therapy, antihypertensive drugs, heparin, and
aspirin have all been shown to be ineffective (American College of Obstetricians and
Gynecologists, 2000b).
In most cases diagnosed prior to term, neither a precise etiology nor a specific therapy
is apparent. Management decisions hinge on an assessment of the relative risks of fetal death
with expectant management versus the risks from preterm delivery. Although reassuring fetal
testing may allow observation with continued maturation, there is concern regarding long-
term neurological outcome as discussed later (Blair and Stanley, 1992; Thornton and
colleagues, 2004). Some authorities believe that various tests of fetal well-being are
unnecessary to reduce risks for stillbirth. Weiner and associates (1996) performed nonstress
tests, biophysical profiles, and umbilical artery velocimetry within 3 days of delivery in 135
fetuses confirmed at birth to have growth restriction. Other than metabolic acidosis at
delivery, which was predicted by absent or reversed end-diastolic umbilical blood flow,
morbidity and mortality were determined primarily by gestational age and birthweight and
not by abnormal fetal testing. According to the American College of Obstetricians and
Gynecologists (2000a), there is no convincing evidence that such testing schemes reducethe
risk of long-term neurological deficits. And recently, Baschat and colleagues (2009) provided
data that substantiated this opinion. Specifically, they showed that neurodevelopmental
outcome at 2 years in growth-restricted fetuses was best predicted by birthweight and
gestational age.
A review of the status of Doppler velocimetry to aid in delivery timing was provided by
Baschat (2004). It is clear that serial changes in Doppler flow represent a new and promising
frontier in the management of pregnancies complicated by growth restriction. Nonetheless,
the optimal management of the preterm growth-restricted fetus remains problematic.
Labor and Delivery
Fetal-growth restriction is commonly the result of placental insufficiency due to faulty
maternal perfusion, ablation of functional placenta, or both. If present, these conditions are
likely aggravated by labor. Equally important, diminished amnionic fluid volume increases
the likelihood of cord compression during labor. For these reasons, a woman with a suspected
growth-restricted fetus should undergo high-risk intrapartum monitoring. For these and
other reasons, the incidence of cesarean delivery is increased. The risk of being born hypoxic
or with aspirated meconium is increased. Care for the newborn should be provided
immediately by an attendant who can skillfully clear the airway and ventilate the infant as
needed. The severely growth-restricted newborn is particularly susceptible to hypothermia
and may also develop other metabolic derangementsuch as hypoglycemia, polycythemia, and
hyperviscosity. In addition, low-birthweight infants are at increased risk for motor and other
neurological disabilities. Risk is highest at the lowest extremes of birthweight (Baschat and
colleagues, 2007, 2009; Nelson and Grether, 1997).
Long-Term Sequelae
In his book Fetal and Infant Origins of Adult Disease, Barker (1992) hypothesizes that adult
mortality and morbidity are related to fetal and infant health. In the context of fetal-growth
restriction, there are numerous reports of a relationship between suboptimal fetal nutrition
and an increased risk of subsequent adult hypertension and atherosclerosis (Skilton, 2008).
Low birthweight has also been implicated in subsequent development of type 2 diabetes,
however, some challenge this hypothesis (Hubinette and colleagues, 2001; Huxley and co-
workers, 2002). In their systematic review of 30 reports they considered relevant, Whincup
and associates (2008) found that in most populations, birthweight was inversely related to
type 2 diabetes risk. Smith and colleagues (2001) found that pregnancy complications
resulting in low-birthweight infants were associated with increased risk of subsequent
ischemic heart disease in the mother. This suggests that common genetic risk factors might
explain the link between low birthweight and risk of heart disease in both the developing
fetus and the mother. In addition to risk to long-term maternal health, epidemiological studies
have found that delivery of a small-for-gestational age infant increases the risk for a
subsequent pregnancy complicated by stillbirth (Salihu and associates, 2006; Surkan and co-
workers, 2004).

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