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Female subfertility
Cynthia M. Farquhar1*, Siladitya Bhattacharya2, Sjoerd Repping3,
Sebastiaan Mastenbroek3, Mohan S. Kamath4, Jane Marjoribanks1 and Jacky Boivin5
Abstract | Subfertility is common and affects one in six couples, half of whom lack an explanation
for their delay in conceiving. Developments in the diagnosis and treatment of subfertility over
the past 50 years have been truly remarkable. Indeed, current generations of couples with
subfertility are more fortunate than previous generations, as they have many more opportunities
to become parents. The timely access to effective treatment for subfertility is important as many
couples have a narrow window of opportunity before the age-​related effects of subfertility limit
the likelihood of success. Assisted reproduction can overcome the barriers to fertility caused by
tubal disease and low sperm count, but little progress has been made in reducing the effect of
increasing age on ovarian function. The next 5–10 years will likely see further increases in birth
rates in women with subfertility , a greater awareness of lifestyle factors and a possible refinement
of current assisted reproduction techniques and the development of new ones. Such progress will
bring challenging questions regarding the potential benefits and harms of treatments involving
germ cell manipulation, artificial gametes, genetic screening of embryos and gene editing of
embryos. We hope to see a major increase in fertility awareness, access to safe and cost-​effective
fertility care in low-​income countries and a reduction in the current disparity of access
to fertility care.

Subfertility (also commonly referred to as infertility) leading to oocyte release from the ovary requires a
is defined as “a disease characterized by the failure to normal menstrual cycle, which is coordinated by a com-
establish a clinical pregnancy after 12 months of regular, plex interplay of pituitary-​derived and follicle-​derived
unprotected sexual intercourse or due to an impairment hormones. After an oocyte is released, it enters the
Department of Obstetrics of a person’s capacity to reproduce either as an individual fallopian tube where it can be fertilized by spermatozoa
and Gynaecology, University or with his/her partner”. A clinical pregnancy is defined (sperm) that have travelled through the female genital
of Auckland, Auckland, as “ultrasonographic visualization of one or more ges- tract (Fig. 1). The fertilized oocyte develops as it moves
New Zealand.
tational sacs or definitive clinical signs of pregnancy”. through the fallopian tube into the uterine cavity, where
College of Biomedical
Both of these comprehensive definitions were reached it implants in the endometrium. In women, subfertility
and Life Sciences, Cardiff
University School of Medicine,
through a consensus process at the WHO and were sub- can involve any of these processes, whereas in men,
Cardiff, UK. sequently supported by regional fertility societies and subfertility centres around absent or inadequate sperm
Amsterdam UMC, University international professional societies that address fertility production (Box 1).
of Amsterdam, Center for care and infertility1,2. Primary female subfertility refers Common causes of female subfertility include ovula-
Reproductive Medicine, to women who have never achieved a clinical pregnancy, tory dysfunction (such as ovarian insufficiency or poly­
Amsterdam Reproduction
whereas secondary female subfertility refers to women cystic ovary syndrome (PCOS)), damaged or blocked
& Development research
institute, Amsterdam,
who have previously achieved a clinical pregnancy who fallopian tubes, endometriosis and uterine fibroids.
Netherlands. cannot establish a subsequent clinical pregnancy1,2. Ovarian insufficiency is a loss of function of the ova-
Department of Reproductive These definitions are clinical definitions that are ries that reduces the chance of pregnancy in all women
Medicine, Christian Medical designed for the early detection and treatment of sub- from ~35 years of age but occurs prematurely in some
College, Vellore, India. fertility. Other definitions are used for demographic women. Blocked or damaged fallopian tubes can cause
School of Psychology, or epidemiological purposes. For example, an alterna- subfertility or an increased risk of tubal pregnancy5,6.
College of Biomedical and tive definition of primary subfertility is the inability to Endometriosis can create an unfavourable pelvic envi-
Life Sciences, Cardiff
University, Cardiff, UK.
ever bear a live child, and an alternative definition of ronment, whereas uterine fibroids can impede tubal
secondary subfertility is the inability to bear a live child transport, cause tubal obstruction or affect embryo
*e-​mail: c.farquhar@ following a previous pregnancy or live birth3,4. implantation, any of which can lead to subfertility in Several critical steps are involved in achieving unas- women (Fig. 1). In up to 30% of couples, no identifiable
s41572-018-0058-8 sisted pregnancy in women. Follicular development cause of subfertility can be found after completion of a

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 1


Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Oocyte and sperm Fertilization Morula

(insemination) (syngamy) Cleavage stage stage
Blastocyst stage
Arrested embryonic development

Blocked or
dysfunctional Uterine Fundus
Uterine cavity
fallopian abnormalities Fallopian

Day 7–8 Ovary

Corpus Implantation Myometrium
albicans of the
Failure to Cervix
Oocyte Corpus luteum implant blastocyst
Cervical Vagina
Fertilization malformations
failure Developing
corpus luteum
dysfunction Male
Ovulation subfertility

Fig. 1 | The female genital tract and factors that affect fertility. Several steps are required for conception, including the
appropriate development and release of a mature oocyte from the ovaries, fertilization by spermatozoa, passage through
the fallopian tubes and implantation into the uterus. Aberrant development of sperm (including low sperm count, low
motility or low number of sperm with normal morphology) or oocytes (such as that caused by anovulation) or the failure of
the sperm to reach and fertilize the oocyte (such as owing to a blockage, malformation or infection of the female or male
genital tracts) prevents the generation of an embryo. The embryo can fail to develop during the preimplantation stages,
implant outside of the uterus (ectopic pregnancy) or fail to implant in the uterus. A receptive uterine environment is
required for proper embryo implantation and development, including appropriate biophysical conditions (such as
temperature and pH) and developmental synchrony between a healthy embryo and a functionally competent
endometrium, and a successful molecular dialogue between the two243–246. Consequently , uterine abnormalities, such as
congenital abnormalities, fibroids or other adhesions, may prevent the implanted embryo from developing further.
In addition, the cervix needs to be accessible, open and have the right environment to allow for passage, activation and
capacitation of sperm. The position of the embryo in the genital tract during each stage of development is unknown,
and the timings in this figure are an estimation only.

standard investigation protocol, and tests of ovulation, financial burden of treatment can be substantial. Timely
tubal patency and semen analysis, among others, are access to effective treatment is important, as many cou-
normal7. These cases are commonly referred to as unex- ples have a narrow window of opportunity before age
plained subfertility; in this Primer, we retain this term limits the likelihood of success.
for consistency with the literature but with the proviso This Primer reviews the epidemiology, pathophysiol-
that unexplained does not mean that subfertility has no ogy, assessment, and clinical and psychosocial manage-
underlying cause, rather, it means that the cause has not ment of subfertility in women and considers priorities
been identified. for future research.
Over the past 20 years, there has been a move towards
evidence-​based, cost-​effective and safer fertility treat- Epidemiology
ment. In addition, there is a general recognition by clini- Up to one in six couples in Western countries have sub-
cians that subfertility differs from health conditions that fertility8, which is a recognized cause of psychological
are diagnosed on the basis of demonstrable pathology. distress in both men and women9. Between 48.5 and
As a consequence, management strategies are appro- 72.4 million couples worldwide are estimated to have
priately moving away from a traditional aetiological subfertility3,10, with 10 million couples in sub-​Saharan
approach towards a prognostic approach, in which the Africa and 14 million couples in south Asia3. The preva-
decision to treat is based on the balance between lence of subfertility varies widely between studies owing
the unassisted and the treatment-​related chances of to variability in the populations sampled and incon-
pregnancy. However, the physical, psychological and sistency in the definition of subfertility and sampling

2 | Article citation ID: (2019) 5:7


methods used11. Clinical definitions of subfertility that Risk factors

are based on lack of pregnancy after 12 months of unpro- Lifestyle factors. In observational studies, lifestyle fac-
tected sexual intercourse estimate a median prevalence tors such as smoking, excessive alcohol consumption
of 9% globally10, although demographic definitions and caffeine use have been associated with reduced fer-
that are based on a 5-year period of childlessness esti- tility19,20. A case–control study in the United Kingdom
mate rates of primary infertility as ~2% and secondary identified negative lifestyle factors significantly asso-
infertility of ~10%3 (Fig. 2). ciated with current subfertility, including overweight
Couples are typically referred for fertility investi- (by >13 kg), unprotected sexual intercourse with multi-
gations if they have not been able to conceive within ple partners and stress one cannot cope with19. Cigarette
12 months of sexual intercourse without using con- smoking and marijuana use were significantly associated
traception. Although some couples might equate their with increased time to conceive20. However, prospective
condition of subfertility with sterility, this is an over- research is needed to confirm these cross-​sectional asso-
simplification, as many will subsequently conceive12. ciations. Occupations involving exposure to reproduc-
The definition of subfertility is prognosis-​driven and tive toxins that can affect fertility such as nitrosamines
is based on data demonstrating that 84% of couples and formaldehyde should be documented21.
not using contraception would be expected to conceive
within 1 year and that 92% would be expected to con- Age. One of the best-​known and best-​established factors
ceive within 2 years13. However, to be meaningful, a that affect fertility is the age of the woman22 (Fig. 3). This
prognosis-​based approach should accommodate factors risk factor is increasingly relevant as women worldwide
other than duration of subfertility, such as female age, delay childbearing and as the age at which a woman
frequency of intercourse, semen quality and the presence has her first child rises in many societies23. In addition,
of pelvic pathology that could influence the chance of the fertility rate (that is, the total number of children
conception14. Ideally a model would also include psycho­ that would be born to each woman if she were to live to
logical and lifestyle factors that affect fertility either the end of her childbearing years) has also fallen sub-
directly or indirectly15. stantially24. For women, the likelihood of pregnancy is
Few studies have examined long-​term trends in sub- stable from puberty to ~30 years of age, after which it
fertility. Although the demand for assisted reproduc- declines in an accelerating rate until menopause, when
tive technology (ART) has risen steadily over the past the chance of pregnancy approaches zero25–27.
20–30 years16, this trend does not seem to be accompa-
nied by a corresponding increase in the observed prev- Mechanisms/pathophysiology
alence of subfertility17,18. Some reasons for the increased Unlike many other conditions, subfertility involves two
demand for ART are expanding indications for in vitro individuals (or three, in the case of donor gametes or
fertilization (IVF) treatment, such as unexplained surrogacy). An individual might experience subfer-
subfertility and diminished ovarian reserve, increased tility with one partner but not with another, and with
access to more patient-​friendly IVF programmes and the increasing age, all women have subfertility secondary to
appeal of newer technologies. the complete loss of oocytes. By contrast, men continue
to produce viable sperm throughout their life.
A key concept of fertility is the chance of achieving
Box 1 | Male subfertility pregnancy in a specific ovulatory cycle at any given
point in time; in contrast to other species in which
The male’s contribution to fertility is limited to the production of functional spermatozoa chances of conceiving are close to 100% during every
that can fertilize the oocyte. A decrease in motility (asthenozoospermia) or abnormal
menstrual cycle, in humans, even at their most fertile
morphology (teratozoospermia) of spermatozoa, in addition to the presence of a low
number of spermatozoa (oligozoospermia) or the complete absence of spermatozoa in
stages of life, chances of conceiving are, at most, 30% in
the ejaculate (azoospermia), can lower the chance of pregnancy233. a menstrual cycle28, presumably secondary to the short
Azoospermia can be caused by an obstruction or absence of the vas deferens window of oocyte maturation in humans. Accordingly,
(obstructive azoospermia) or reduced or absent sperm production in the testis (non-​ distinguishing whether the absence of pregnancy in a
obstructive azoospermia). Most men with obstructive azoospermia and approximately single cycle is due to natural reproductive inefficiency or
half of men with non-​obstructive azoospermia still have residual spermatogenesis in the result of a specific pathophysiological situation that
their testes, which allows for surgical retrieval of spermatozoa for intracytoplasmic requires treatment is often difficult. Likewise, decisions
sperm injection and subsequent genetic parenthood234. If no sperm are available in the about treatment of subfertility should be made after con-
testis, donor sperm can be used to establish a pregnancy. Men who have non-​obstructive sidering the chance of establishing a pregnancy without
azoospermia and who also do not produce functional spermatozoa in their testis have a
treatment (see Management)12
block in meiosis (maturation arrest), a complete absence of germ cells (Sertoli cell-​only
syndrome) or a combination of both. Several molecular mechanisms underlie maturation
arrest, of which deletions of small or large parts of the Y chromosome are the most Age and oocyte quality
common detected cause235. Such deletions cause the loss of genes that are essential for Ovarian age is a strong predictor of the chance of
sperm production. Azoospermia can also be an adverse effect of chemotherapy or local pregnancy and reflects the number of follicles present
radiotherapy. In such cases, cryopreservation of ejaculated or surgically retrieved in the ovaries. At birth, girls have ~2 million oocytes in
spermatozoa before chemotherapy is commonly used to preserve fertility in adult men. their ovaries, of which more than half are lost before
In prepubertal boys with cancer in whom spermatozoa cannot be cryopreserved before puberty29. Following the onset of ovulation, a cohort of
treatment, the surgical retrieval of testicular tissue to allow for future fertility restoration 40–500 follicles develops each month, of which usually
using testicular transplants or spermatogonial stem cell transplantation is currently only one (the so-​called dominant follicle) releases an
under development236.
oocyte30. The other follicles degenerate and are ultimately

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 3


lost through the process of follicular atresia. The number maternal age36,37. The reduction in chiasmata frequency
and quality of remaining oocytes reduce with increasing could also explain the increased number of aneuploidies
age25 (Fig. 3), leading to the age-​related decline in female in oocytes, embryos and other products of conception in
fertility. Estimating the number of follicles inside the miscarriages in older women38–40.
ovaries (that is, ovarian reserve) is possible using ultra- In addition, data from mouse models suggest that
sonography to measure the antral follicle count (AFC) shortening of telomeres in oocytes is also associated with
or by measuring the serum anti-Müllerian hormone increasing age and could also cause decreased oocyte and
(AMH) level27,31,32. embryo competence41,42. The female germ line could also
Recruitment and maturation of follicles in the ovary be affected by general mechanisms underlying cellular
requires a balanced interaction between hormones ageing, such as epigenetic alterations, loss of proteostasis,
released by the hypothalamus and pituitary gland (such dysregulated nutrient sensing, altered intercellular func-
as follicle-​stimulating hormone (FSH) and luteinizing tion and mitochondrial dysfunction, all of which could
hormone (LH)) and those released in the ovary (such as, contribute to subfertility43,44. As previously mentioned,
AMH, inhibin A, inhibin B and oestradiol)27. As these the age-​dependent decline in oocyte quality accelerates
ovarian factors are produced by the granulosa cells between 35 and 40 years of age, suggesting that oocyte
of the antral follicles, reduced ovarian reserve results ageing is time limited rather than a gradual process. This
in lower levels of these hormones, which in turn, results in finding suggests that an underlying biological threshold
higher FSH levels. These aberrant hormonal levels cause value or trigger is involved in oocyte ageing, for example,
menstrual cycle irregularities and affect the quantity and the number of primordial follicles dropping below a criti­
quality of available oocytes. cal threshold could trigger subtle physiological events,
The effect of increased age on oocyte quality and such as changes in levels of hormones such as growth
chance of pregnancy is illustrated by pregnancy out- hormone and androgens. These hormonal changes could
comes in women who receive oocytes from young affect the oocytes themselves, the surrounding granulosa
donors33; oocytes from young donors have a higher cells, the process of selection from the cohort of oocytes
rate of subsequent pregnancy than oocytes from older each menstrual cycle and oocyte maturation.
donors, even if the recipient is undergoing menopause. Oocyte quality can also affect development of the
Except for the use of donor oocytes, no other estab- preimplantation embryo45. This theory is supported
lished interventions to prevent the age-​related decline by the increased presence of aneuploidies in oocytes of
in fertility are available. older women (Fig. 3). However, this age-​related increase
The precise mechanism by which age affects oocyte in aneuploidies is likely to be a consequence of poor
quality is unknown. One hypothesis is an accumulation oocyte quality rather than the cause. Oocyte quality also
of DNA damage in oocytes over time through environ- influences embryonic and fetal development, as demon-
mental stressors, for example, by certain food or drug strated by the increased risk of miscarriage in older
residues or by reactive oxygen species34,35. Alternatively, women, which can be reversed by the use of oocytes
a first-​in-first-​out principle (also known as a produc- from young donors46,47.
tion line principle) has been proposed, whereby high-​
quality oocytes are primarily ovulated early in life, Specific causes of subfertility
causing lower quality oocytes to be ovulated at later ages. Ovulatory dysfunction. Anovulation (a failure to ovu-
This hypothesis is based on the decrease in the frequency late) is indicated by a disturbed frequency and duration
of chiasmata (the physical crossover of homologous of the menstrual cycle (Fig. 4). Typically, the menstrual
chromo­s omes) in mouse oocytes with increasing cycle is 25–35 days in duration, but some woman never
menstruate (primary amenorrhoea), whereas some
menstruate but have prolonged episodes of >6 months
Latin America and Caribbean without a period (secondary amenorrhoea) or have an
Sub-Saharan Africa irregular menstrual cycle (oligomenorrhoea).
Primary amenorrhoea can be unexplained, or can
North Africa and Middle East result from the failure of normal gonadal development.
Central Europe, eastern Europe and The failure of gonadal development can be idiopathic,
central Asia or can be associated with a wide range of conditions,
East Asia and Pacific
including Turner syndrome (in individuals with a 45,
South Asia XO karyotype), and hypothalamic problems secondary
to a spectrum of disorders (such as extremes of body
High income
weight, high stress levels or chronic disease such as coe-
World liac disease). Structural anatomical conditions, includ-
ing imperforate hymen and the complete absence of the
0.0 0.5 1.0 1.5 2.0 2.5 3.0 genital organs owing to the failure of normal gonadal
Age-standardized prevalence of primary infertility (%) development, can also present as primary amenorrhoea.
Fig. 2 | The prevalence of primary infertility in 2010. These data are from women Secondary amenorrhoea and oligomenorrhoea can
between 20 and 44 years of age with no previous live births. A demographic definition be caused by endocrine disorders involving the hypo­
of infertility was used in this study , which was based on childlessness after 5 years of thalamus, pituitary gland, thyroid gland, the adrenal
unprotected sexual intercourse. Adapted from ref.3, gland and the ovaries48. The correction of thyroid func-
licenses/by/3.0/. tion is required before any fertility treatment commences,

4 | Article citation ID: (2019) 5:7


Decline of ovarian follicle pool End of fertility Menopause

Qualitative Irregular
Quantitative Optimal fertility Declining fertility cycles

107 100

Embryos with aneuploidy (%)

106 80
Number of follicles 70
105 60
104 40
103 20
102 0
0 10 20 30 40 50 60
Age (years)

Fig. 3 | Reduction in natural fertility with increasing age. The reduction of the ovarian follicle or oocyte pool with
increasing age likely dictates the onset of declining fertility , the transition from regular to irregular menstrual cycles
and the onset of menopause. Ageing is associated with a logarithmic decline in the number of ovarian follicles and a
simultaneous decrease in oocyte quality , the latter of which is reflected here by an increased percentage of embryos with
aneuploidies. Adapted with permission from de Bruin, J. P. & te Velde, E. R . in Preservation of Fertility (eds Tulandi, T. &
Gosden, R . G.) 3 (Taylor and Francis, 2004)247, and from ref.248, Elsevier.

as disorders of thyroid function are associated with that affect follicular growth and maturation. In Turner
problems in fetal development 48. Pituitary adeno- syndrome, POF or POI is due to the accelerated loss of
mas produce high levels of prolactin, which inhibits oocytes from the ovaries after the 18th week of fetal life
gonadotropin-​releasing hormone (GnRH) secretion and or during the postnatal period52. Fragile X syndrome is
the production of gonadotropins, leading to suppression caused by an increase in the number of CGG trinucleo-
of ovulation. Rarely, anterior pituitary failure occurs tide repeats in FMR1 (encoding fragile X mental retarda-
following severe postpartum haemorrhage (known as tion 1 protein)53. Women with too many or too few CGG
Sheehan syndrome) and may result in hypopituitarism repeats in FMR1 have an increased risk of menstrual
with low levels of gonadotropins, growth hormone, cycle disturbances, POF, non-​identical twinning and
adrenocorticotropic hormone, thyroid-​stimulating possibly increased rates of aneuploidy and miscarriage53.
hormone (TSH) and prolactin. Replacement therapy
will be necessary, and when fertility is desired, ovarian Ovarian cysts. Ovarian cysts are frequently detected
stimulation with gonadotropins can be given. because of the increased use of imaging such as ultra­
The most common cause of anovulation associated sonography and MRI. They range from simple cysts
with oligomenorrhoea and amenorrhoea is PCOS49. The associated with the menstrual cycle (such as persistent
exact causes of PCOS are not known, but women with follicular cysts) to cysts of endometriosis (endometrio­
PCOS have an increased frequency of pulses of GnRH mata) or teratomas such as dermoid cysts. In women
release from the hypothalamus, which increases the who wish to conceive, these cysts generally do not neg-
LH:FSH ratio, leading to higher androgen levels, ham- atively affect fertility unless they are large enough to
pered follicle maturation and possible anovulation49. distort tubal anatomy. Indications for removal of these
Although women with PCOS have high rates of subfer- cysts depends on the symptoms and the benefits and
tility compared with women without PCOS, the majority harms of the surgery54.
do usually conceive with or without treatment50.
Tubal, pelvic and uterine abnormalities. Tubal abnor-
POF and POI. In some women, decreased ovarian malities range in severity from scarring and mild
reserve occurs prematurely and menopause is reached adhesions (fibrous bands between organs) to complete
earlier, in some cases when women are teenagers, which blockage or absence of the fallopian tubes. In some
is referred to as premature ovarian failure (POF) or cases, the fallopian tube is blocked at least at the dis-
primary ovarian insufficiency (POI). Causes of POF tal end and is filled with fluid (hydrosalpinx). Tubal
and POI include a low initial number of ovarian fol- abnormalities can be caused by infections (such as
licles, which can be idiopathic, an abnormally high chlamydia, gonorrhoea and tuberculosis) often trans-
rate of follicular atresia (for example, in women with mitted sexually, which cause scarring and damage
Turner syndrome or fragile X syndrome) and cytotoxic of the tubal tissue, or can be due to peritoneal infec-
therapies51. Some women with POI have a sufficient tion, previous surgeries, endometriosis55,56 or (rarely)
number of follicles but have specific genetic defects, genetic defects57. Subfertility is common in women
enzyme deficiencies or specific autoimmune responses with HIV and is usually associated with tubal blockage

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 5


(most commonly, hydrosalpinges), particularly in Endometriosis is a condition in which tissue from the
women with a history of induced abortions and tubal lining of the uterine cavity grows outside the uterus into
pathologies58. Uterine abnormalities can be caused by the peritoneal cavity59. Endometriosis not only involves the
uterine fibroids, polyps or adenomyosis or congenital fallopian tubes but may also be present in the ovaries
malformations. and the tissue lining the pelvis, often leading to dis-
torted and abnormal anatomy. This aberrantly located
Pituitary hormones endometrial tissue is affected by the hormonal changes
50 50 of the menstrual cycle, which make it grow, thicken and
40 40 subsequently break down each cycle, potentially leading
FSH (IU/l)

to painful periods, heavy menstrual bleeding or bleeding

LH (IU/l)
30 30
between periods. In addition, endometriosis can cause
20 20
subfertility, as the aberrant endometrial tissue can result
10 10
in scar formation and adhesions. The severity of endo-
0 0 metriosis depends on the number, size, location and
Ovarian hormones depth of the endometrial implants outside the uterus60–62.
1,000 50
Defects in the development of the Müllerian duct
(which forms the cervix, uterus, fallopian tubes and part

Progesterone (mmol/l)
Oestradiol (pmol/l)

800 40 of the vagina) can lead to abnormal development of these

600 30 structures and can cause subfertility. Approximately
1 in 4,500 women have Mayer–Rokitansky–Küster–
400 20
Hauser syndrome, in which abnormal development of
200 10 the Müllerian duct system results in the absence of the
0 0 upper vagina, uterus and, in some women, the fallopian
Cervical mucus tubes, but is associated with intact ovaries and normal
+4 external genitalia63. Genes that are involved in prenatal
Volume or viscosity

+3 Viscosity development are causative but differ between individ­

+2 Volume uals. More subtle defects in Müllerian duct development
can lead to a unicornuate uterus (only half of the uterus
with a single fallopian tube is present), a bicornuate
0 uterus (an indentation in the fundus of the uterus, lead-
Basal body temperature
ing to an approximately heart-​shaped uterus) or a septate
uterus (the uterine cavity is partly partitioned by a longi­
temperature (ºC)

tudinal septum). These congenital uterine malforma-

Basal body

tions are of unknown cause. Women with these uterine

malformations can be asymptomatic, can be unaware of
having these conditions and can have normal pregnan-
cies. Some uterine malformations are associated with an
1 7 12 14 15 21 28
increased risk of recurrent pregnancy loss and preterm
Ovarian cycle birth, but an association with subfertility is less clear64–67.
Other uterine abnormalities can be caused by
fibroids, polyps or adenomyosis (in which endo­metrial
tissue grows within the muscle walls of the uterus).
1 7 12 14 15 21 28 Although these conditions are often thought to be asso-
Endometrial changes ciated with a reduced chance of ongoing pregnancy
owing to miscarriage, there is no conclusive evidence
that they adversely affect conception68,69. Rare uterine
abnormalities can include other congenital anomalies
(for example, such as those acquired by prenatal expo-
1 7 12 14 15 21 28
sure to diethylstilbestrol) or may result from surgery (for
Time (days)
example, surgery for intrauterine adhesions in women
Fig. 4 | The ovarian and menstrual cycle. Follicle-​stimulating hormone (FSH) levels with a thin endometrium (Asherman syndrome)). Such
are slightly raised at the start of the menstrual cycle and promote the growth of the conditions reduce the likelihood of implantation and
follicles.  Luteinizing hormone (LH) levels rise 1–2 days after FSH and in a natural cycle ongoing pregnancy70.
ensure ovulation. Progesterone is released following ovulation and levels increase until
the corpus luteum starts to degenerate and has a role in preparing the endometrium for Diagnosis, screening and prevention
implantation. Oestradiol is secreted by maturing follicles stimulated by gonadotropins
Few standard tests for the diagnosis of subfertility are
(FSH and LH). The very high levels at the end of the late follicular phase of menstruation
are responsible for the LH surge required for ovulation to occur. Basal body temperature
available. Geographical variation in the uptake and avail-
rises by 0.2 °C ~24 hours after ovulation. The endometrium changes from proliferative ability of investigations is likely owing to the affordability
under the influence of rising oestradiol levels to secretory in the post-​ovulation luteal of these tests. Moreover, practice guidelines vary, as
phase under the influence of progesterone and enables implantation. If no pregnancy shown by recommendations for PCOS and systematic
occurs, progesterone levels fall and menstruation commences. IU, international units. reviews of the diagnostic evaluation of male infertility
Adapted with permission from ref.249, University of Auckland. and endometriosis71–73.

6 | Article citation ID: (2019) 5:7


Recommended tests Subfertile couple


Woman Man
If unable to do semen analysis, consider PCT

History taking and clinical examination Semen analysis If abnormal, follow pathway for male factor
subfertility including antisperm antibodies

No clinical flags Painful periods Past history of Past history of Abnormal uterine Does not have In areas with
with or without chlamydia and abdominal or bleeding (heavy, regular periods high TB
abnormal exam gonorrhoeal pelvic surgery prolonged or or HIV
Baseline testing including genital infection intermenstrual, prevalence
pelvic mass with or without
abnormal exam)
Mid-luteal- • Chlamydia
phase antibodies • Laparoscopy • CAT • HSG or • TVS • Hormone • Endometrial
progesterone • HSG or • TVS • HSG HyCoSy • Hysteroscopy test for PCOS biopsy
HyCoSy • Laparoscopy • Laparoscopy or laparoscopy • Ovarian • TVS
if TVS is reserve
abnormal testing (AMH)
Confirmed ovulation
and patent tubes
secondary to
Tubal subfertility Tubal subfertility uterine PCOS, Subfertility
Unexplained subfertility secondary to secondary to endometrial diminished secondary
(provided normal semen analysis) Endometriosis genital infection pelvic adhesions pathology ovarian reserve to TB

Fig. 5 | Investigations for subfertility. The baseline investigations for subfertility consist of tests for confirming ovulation
and transvaginal ultrasonography (TVS) for the female and semen analysis for the male partner. Tubal patency tests are
advised for suspected tubal diseases, whereas hormonal tests (for example, serum prolactin, follicle-​stimulating hormone
(FSH) and luteinizing hormone (LH) levels) are advised for suspected ovulatory dysfunction. For suspected uterine
abnormalities, 2D ultrasonography is the first-​line investigation, whereas women at risk of diminished ovarian reserve are
offered ovarian reserve tests (for example, anti-​Müllerian hormone (AMH) levels). CAT, chlamydia antibody test; HSG,
hysterosalpingography ; HyCoSy , hysterosalpingo contrast sonography ; PCOS, polycystic ovary syndrome; PCT, postcoital
test; TB, tuberculosis.

Diagnosis lead to a temporary disturbance in menstrual cycli­city75.

In countries with fertility care provision, couples are A discussion of lifestyle is important, as some factors can
gene­rally investigated after 12 months of unsuccessful affect fertility.
attempts to conceive or earlier if there is a clear clini­cal Examining the medical and/or surgical treatment
indication1. A comprehensive fertility assessment involves history and any associated infection of women with
both partners and includes detailed history taking, clini­ a history of miscarriage or abortion might be useful to
cal examination and appropriate investigations (Fig. 5). identify potential causes of secondary subfertility. A his-
The aim of this assessment is to identify underlying causes tory of ectopic pregnancy and salpingectomy (the sur-
of subfertility and establish a prognosis for the couple15,74. gical removal of a fallopian tube) is suggestive of tubal
damage, whereas amenorrhoea associated with peripar-
Comprehensive history. A detailed history-​taking should tum or postpartum haemorrhage might be associated
document the length of time a couple has been trying with either pituitary infarction or intrauterine adhesions
to conceive, menstrual patterns, previous pregnancies, (Asherman syndrome) owing to vigorous dilatation
medical and surgical factors, lifestyle and family history. and curettage.
The age of menarche should be recorded, as an In addition, the presence of coexisting or previous
absence or delay in the onset of menarche could be medical conditions should be carefully evaluated. Any
associated with ovulatory dysfunction. Regular men- symptoms and signs of breast disease should be inves-
strual cycles are suggestive of ovulation, whereas irregular tigated, and a cervical smear history should be sought.
cycles and abnormal flow can be suggestive of hormo- A history of gonadotoxic therapy for a malignant dis-
nal, endometrial or uterine pathology. Dysmenorrhoea order or an autoimmune condition can affect ovarian
(menstrual cramps), chronic or cyclical pelvic pain and reserve76, whereas infectious diseases such as tubercu-
dyspareunia (painful sexual intercourse) can indicate losis or HIV can be associated with pelvic inflamma-
the presence of pelvic endometriosis, while pressure tory disease and subfertility77,78. Pelvic operations can
symptoms (for example, on the bladder or other organs) result in adhesions leading to distorted pelvic anatomy
can be indicative of uterine fibroids and ovarian cysts. and can affect tubal function, whereas ovarian surgery,
Contraceptive history is important, as some hormonal such as for endometriomas (endometriotic cysts), can
methods (such as combined oral contraceptives) can compromise ovarian reserve.

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 7


Table 1 | WHO classification of anovulation254 chlamydial swab can be obtained during a speculum
examination to assess for infectious diseases.
WHO Cause Examples Hormonal alteration Transvaginal ultrasonography of the pelvis is an
accurate way to visualize the uterus and ovaries and
Type I Hypothalamic– Low body weight Low levels of circulating can identify ovarian cysts, endometriomas and hydro-
pituitary failure and excessive gonadotropins and serum
exercise oestradiol
salpinges, among other disorders. However, transvaginal
ultrasonography should be used as an adjunct to, rather
Type II Hypothalamic– Polycystic ovary Normal levels of circulating than a replacement for, bimanual pelvic examination.
pituitary–ovarian syndrome gonadotropins and serum
axis dysfunction oestradiol The latter remains the best way of assessing the position,
consistency and mobility of large pelvic masses such as
Type III Ovarian failure Premature ovarian High levels of circulating
failure gonadotropin and low fibroids and ovarian cysts, whereas palpation of a retro-
levels of serum oestradiol verted fixed uterus and nodules in the pouch of Douglas
(also known as the recto-​uterine pouch) may be the only
signs of deep infiltrating endometriosis83.
As previously mentioned, fertility can be affected
by disorders such as PCOS, ovarian insufficiency and Ovulation tests. A history of regular menstrual cycles
endometriosis, which can be familial; the identifica- is suggestive of satisfactory ovulation in most women,
tion of these disorders might require clinical assess- although a test to confirm ovulation such as a mid-​
ment and appropriate genetic counselling. In some luteal-phase progesterone is usually recommended84.
contexts, cultural practices such as female genital muti- Many women may choose to use menstrual diaries,
lation and consanguinity can be associated with fertility fertility tracking software or applications to track
problems79,80. The occupation of both female and male ovulation85. In terms of clinical tests of ovulation, serum
partners should be documented, and where relevant, risk mid-​luteal-phase progesterone levels are considered the
of exposure to reproductive toxins should be assessed. gold standard and are the most commonly used; the tim-
ing of this test is important, and samples should ideally
Physical examination. A general physical examination be taken 7 days before the expected onset of the next
is useful for the diagnosis of hyperandrogenism, endo- menstrual period. Progesterone tracking (taking two
crinopathies and uterine, pelvic and ovarian abnor- or three samples over several days) can be helpful in
malities and includes evaluation of body mass index women whose cycle length, although regular, can vary
(BMI), blood pressure, the thyroid (for thyroid enlarge- by a few days86. Other diagnostic tests to assess ovulation
ment) and general assessment of secondary sexual include ultrasonography-​based monitoring of a develo­p­
characteristics and hair distribution. ing follicle and detection of an LH surge by serial meas-
Clinical signs of hyperandrogenism such as acne and urements of serum or urinary LH levels. Although the
hirsutism can suggest PCOS. The modified Ferriman– detection of secretory endometrium via endometrial
Gallwey score is used to assess hirsutism objectively, and biopsy is suggestive of ovulation, this procedure is inva-
the score is interpreted in the context of the woman’s sive and requires correct timing and is, therefore, no
ethnicity. For example, for women from southeast Asia, longer recommended in contemporary practice86.
using a cut-​off point lower than the conventionally agreed The choice of ovulation test depends on patient pref­
threshold has been suggested, as these women have a e­rences and the cost and availability of resources to do
lower density of facial terminal hair81. Acanthosis nigri- the tests. Ultrasonography for the detection of ovulation
cans, observed in women with PCOS, is characterized by relies on findings such as the detection of the collapse
hyperpigmented velvety skin patches on the back of the of a dominant follicle and has a sensitivity of 84% and
neck, axilla and inguinal creases82. Androgen-​secreting a specificity of 89% for the confirmation of ovulation87.
tumours such as tumours of the adrenal gland or ovaries One of the advantages of urinary LH estimation is that
lead to more pronounced signs of androgen excess than this allows self-​testing and has a concordance rate of
those seen with PCOS, which are characterized by features ~90–97% with ultrasonography-​detected ovulation88,89.
of virilization (masculine traits, such as severe acne, deep- In women with very irregular cycles, amenorrhoea
ening of voice, male pattern baldness and clitoromegaly). or confirmed anovulation, measurement of serum lev-
Demonstrable galactorrhoea (milky discharge from breast els of oestradiol, FSH, LH, TSH, testosterone and pro­
unrelated to pregnancy or breastfeeding) should trigger lactin are warranted to identify the cause of anovulation.
investigations to rule out a prolactinoma. Anovulation can be classified as WHO type I (or hypo­
Surgical scars suggest the type of any previous sur- gonadotropic hypogonadism), type II (or normogonado­
gery and can guide decisions about future diagnostic tropic) or type III (hypergonadotropic) on the basis of
or therapeutic procedures. Clear swelling in the lower serum gonadotropin and oestradiol levels (Table 1). PCOS
abdomen can indicate a large fibroid or ovarian cyst, is the most frequent cause of anovulation in general, and
which can be confirmed using radiographic imaging. of type II anovulation in particular, and is often associated
External inspection of the genitalia followed by a specu­ with hyperandrogenism. PCOS is defined by the presence
lum examination should be carried out to assess the of two out of the three following features: oligo-​ovulation
cervix and rule out the presence of infection, cervical or anovulation, clinical and/or biochemical signs of
polyps, vaginal septum or double cervix (associated hyperandrogenism or polycystic ovaries detected using
with congenital uterine abnormalities such as uterine ultrasonography, after excluding other related disorders90.
didelphys and bicornuate uterus). A high vaginal and Rarely, adrenal disorders or an androgen-​producing

8 | Article citation ID: (2019) 5:7


tumour could cause ovulatory dysfunction associated include anaesthetic complications as well as blood vessel
with hyperandrogenism. In these cases, measurement of and bowel injury94.
17-hydroxyprogesterone, serum testosterone, androsten- The choice of tubal tests depends on the presence
edione and dehydroepiandrosterone levels is advised to of risk factors, such as history of pelvic inflammatory
discriminate between ovarian and adrenal causes. disease, and clinical considerations such as BMI and
previous abdominal surgery. Tubal patency tests should
Assessment of tubal patency. Tubal patency tests are be scheduled immediately after menses (up to day 12)
used when initial tests confirm ovulation and, in male to avoid disruption of an early undetected pregnancy.
sexual partners, normal semen parameters. In women These tests are invasive and are associated with risk
with anovulation, patency tests can be used before of infection, and therefore, chlamydia screening and
ovulation induction or can be delayed until after three prophylactic antibiotic administration may be required.
drug-​induced ovulatory cycles. Tubal patency testing
is generally considered unnecessary in couples who Assessment of uterine and peritoneal factors. All women
require ART to conceive either because of severe male with subfertility are offered transvaginal ultrasono­
factor infertility (for example, sperm count <5 million graphy if they have symptoms suggesting underlying
per ml) or in women of advanced age because in ART pathology83. Transvaginal ultrasonography can detect
the embryo is directly placed into the uterine cavity, uterine cavity abnormalities, fibroids and adenomyosis,
bypassing the fallopian tubes. Women with a recent allows visualization of the ovaries (to detect and assess
intrauterine pregnancy loss do not require tubal patency ovarian cysts or endometriomas) and can be used to
testing unless post-​miscarriage infection is indicated. assess the AFC. The accuracy of transvaginal ultrasono­
Commonly performed tubal patency tests include graphy for detecting intrauterine lesions varies from 52.6%
hysterosalpingography (HSG), hysterosalpingo con- to 77.2% but is ~90.6% for uterine malformations95,96.
trast sonography (HyCoSy) and diagnostic laparos- Saline infusion sonography (whereby saline is injected
copy with chromotubation. HSG involves the injection into the uterine cavity to allow visualization of intra­
of a water-​based or oil-​based radio opaque iodine dye cavitary pathologies) has a sensitivity of 88% and a speci­
through the cervix, under fluoroscopic guidance, and ficity of 94% detecting all intrauterine abnormalities97.
has a sensitivity of 53% and a specificity of 87% for tubal MRI is superior to ultrasonography for the detection of
pathologies (46% and 95% for bilateral tubal patholo- congenital malformations of the uterus and lower geni­
gies, respectively)91. HSG is useful in ruling out tubal tal tract and might be useful to guide management of
blockage but has limited diagnostic value for other tubal fibroids and recto-​vaginal endometriosis72,98.
pathologies, such as peritubal adhesions92. HyCoSy is Diagnostic hysteroscopy is the gold standard proce-
less invasive than HSG and carries no risk of exposure dure for assessing the uterine cavity, and concurrent treat-
to radiation; it involves the injection of a contrast fluid ment can be provided for conditions such as endometrial
during transvaginal ultrasonography to outline the polyps, uterine septum and intrauterine adhesions. The
uterine cavity and fallopian tubes. HyCoSy has a sen- overall complication rate and risk of uterine perforation
sitivity of 80% and a specificity of 84% for tubal patho­ with diagnostic hysteroscopy are ~0.28% and 0.13%,
logy compared with laparoscopy93. Although diagnostic respectively99. However, there is no evidence that rou-
laparoscopy with chro­motubation is considered the gold tine hysteroscopy in women before assisted reproduction
standard for tubal patency assessment, this procedure improves chances of conception69,100.
is invasive and expensive. Laparoscopy with chromo­
tubation is performed under general anaesthesia, allows Tests for ovarian reserve. Ovarian reserve tests can
direct visualization of the entire pelvis and facilitates be used to identify women with POF and are used to
the detection of, for example, endometriosis and pelvic identify women at high risk of compromised ovarian
adhesions (Fig. 6). In addition, this procedure allows for function owing to increased age (>35 years of age), a
surgical interventions such as treatment of endometrio- family history of early menopause or previous gonado-
sis, adhesiolysis for pelvic adhesions or cannulation for toxic therapy or ovarian surgery. Tests of ovarian reserve
tubal blockage (see Management). Complications occur are essentially tests of ovarian responsiveness to exo­
at a rate of 0.6 per 1,000 laparoscopies, and major risks genous stimulation and can be useful for planning the

a b c
Uterus Uterus Uterus

Fallopian tube
Ovary Ovarian

Fig. 6 | Assessment of tubal patency. Pelvic images during laparoscopy are shown: normal pelvic anatomy (part a), pelvic
inflammatory disease with bilateral hydrosalpinges (complete tubal blockage; part b) and pelvic endometriosis with right
ovarian endometrioma and adhesions (part c). Parts a–c adapted from ref.250 © L. Mencaglia, L. Minelli, A. Wattiez / KARL
STORZ Endoskope, Germany.

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 9


dose of ovarian stimulation in women who intend to and antibiotic prophylaxis should be considered when-
use ART101. Common tests of ovarian reserve include ever indicated to reduce the risk of infections. Genital
levels of FSH and AMH, and the AFC. Increased lev- tuberculosis continues to be a major cause of tubal and
els of serum FSH during the early follicular phase of uterine factor subfertility in regions with a high burden
the menstrual cycle are associated with reduced ovar- of the disease such as south and southeast Asia and sub-​
ian reserve. AMH is secreted by the granulosa cells of Saharan Africa77,114, and the early detection and treat-
pre-​antral and small antral follicles (<8 mm), and AMH ment of this condition help reduce the risk of damage to
levels are a more accurate test of ovarian reserve, as they reproductive organs115.
show minimal intracycle and intercycle variation102. Environmental or lifestyle risk factors for subfertil-
However, concerns have been raised about the lack of ity should be addressed. Several environmental toxins,
universal standards for AMH resulting in differences in such as dioxin, certain phthalates, pesticides and heavy
results based on alternative assays. metals, have been linked to subfertility116,117, and when-
The number of ovarian antral follicles (measuring ever possible, exposure to these toxins should be avoided.
2–10 mm in diameter) in the early follicular phase can In terms of lifestyle factors, smoking and obesity are
be measured using transvaginal ultrasonography. An associated with subfertility15. The cessation of smoking
AFC of ≥12 or ≥20 per ovary when measured using a and the optimization of body weight through health
transvaginal transducer with a frequency of 7.5 MHz or promotion initiatives are integral preventive measures,
8.0 MHz, respectively, is used to define polycystic ovar- though they are not always effective. Fertility preserva-
ian morphology73,90, whereas an AFC of ≤10 is suggestive tion is a key preventive measure in women who require
of diminished ovarian reserve103. A low AFC (3–6 total chemotherapy and pelvic radiotherapy. In these women,
antral follicles) is a predictor of poor response during interventions for fertility preservation include cryopreser­
IVF104. AMH levels and AFC are good predictors of vation of oocyte or embryos, GnRH suppression and
ovarian response to gonadotropin stimulation during laparoscopic ovarian transposition (surgically moving
IVF but are poor at predicting pregnancy105. ovaries out of the radiotherapy field) for those women
who require pelvic irradiation. A multidisciplinary
Screening and prevention approach involving the treating physician and fertility
Prior knowledge regarding fertility, levels of anxiety, specialist is key to an effective preventive strategy.
previous medical history and cultural pressures are
drivers for health-​seeking behaviour. In many coun- Management
tries, socio-​cultural issues, misconceptions and lack of The initial management of women with subfertility
education and/or funds act as barriers and can lead to requires explanation of any identified cause of subfer-
underestimation of the burden of subfertility106. tility, the provision of a realistic prognosis (with and
Educational interventions should be directed at without treatment), advice on management options
improving knowledge of fertility health, which is cur- (including non-​intervention) and provision of informa-
rently modest. Indeed, one large international study tion and support118 (Table 2). The clinician should check
surveyed fertility knowledge in 10,045 people from that all couples are aware of the basic concepts of fertility
79 countries who had been trying to conceive for an such as timed intercourse and should provide advice as
average of 2.8 years and demonstrated an average cor- required on lifestyle factors such as smoking, alcohol
rect score of 57% on a 13-item correct–incorrect scale consumption and weight (Box 2).
of risk factors, misconceptions and basic fertility facts107.
Women should be educated to understand the effects Unexplained subfertility
of increasing age on decreasing fertility and should be Expectant management. The likelihood of unassisted
encouraged to check their personal reproductive risk pregnancy for women with unexplained subfertility can be
profile108 and to use fertility awareness tools to facilitate estimated using a prognostic model, such as the Hunault
informed choices about their own fertility health20,109. model, which takes several factors into account, includ-
Tools such as FertiSTAT 20 are available to provide ing female age, duration of trying to conceive, source of
women with personalized fertility guidance. However, referral (from secondary or tertiary care), sperm motility
as increased knowledge of fertility problems can be and the occurrence of previous pregnancy regardless of
associated with increased anxiety, particularly in young outcome119. For couples with a good prognosis (defined
men and women, psychological approaches are also by the Hunault model as ≥30% chance of spontaneous
needed to alleviate possible anxiety caused by fertility conception within 1 year), expectant management is
information110,111. In addition, the use of tools tailored appropriate as many couples will conceive without fer-
to cultural contexts is important to provide education tility interventions. Indeed, in a prospective cohort study,
globally112. 60% of women with unexplained subfertility achieved
Tubal diseases associated with pelvic infections pregnancy without treatment within 5 years120. However,
account for up to 35% of female subfertility in many prognostic models do not indicate when couples should
parts of the world113. Screening, early detection and treat- stop expectant management in favour of active treatment.
ment of sexually transmitted diseases, particularly chla- In addition, the currently available models are limited to
mydia and gonococcal infections, are important steps prediction at the time of diagnosis and cannot compare
in reducing the long-​term complications of these disor- the effectiveness of different treatments at multiple points
ders, such as tubal subfertility. In addition, postpartum in time121. Moreover, these models do not take account of
and post-​miscarriage infections can cause tubal damage, other considerations, such as family size.

10 | Article citation ID: (2019) 5:7


Table 2 | Options for fertility treatments

Category Unexplained infertility Anovulation or PCOS Tubal factors, Advanced age,
endometriosis or fibroids diminished ovarian
reserve and POI
Early • Identify and address lifestyle Ovulation induction with oral Fibroids 81.161 pt
management behaviours that compromise fertility20 agents (up to 12 cycles)157 • Merits of surgery are
options • Use a locally applicable prediction uncertain. Consider
model for natural conception (for hysteroscopic
example, the Hunault model119): if myomectomy68,98
prediction score ≥30%, then continue Endometriosis
trying for unassisted pregnancy for up • Minimal disease: surgical
to 3 years excision of lesions166
• If prediction score <30%, then • If using ART, pretreat with
consider three cycles of intrauterine 3 months of a GnRH
insemination with oral ovarian agonist166
Second-​ NA • Ovulation induction with NA NA
line early gonadotropin157
management • Laparoscopic ovarian drilling
options for women who do not ovulate
at maximum daily dose of
clomiphene citrate161
Assisted IVF IVF (third line)151 IVF • Advanced age or
reproduction diminished ovarian
reserve: IVF
• POI: oocyte or
embryo donation167
ART, assisted reproductive technology ; GnRH, gonadotropin-​releasing hormone; IVF, in vitro fertilization; NA , not available; PCOS, polycystic ovary syndrome.
POI, primary ovarian insufficiency. Prediction model

Dutch fertility guidelines recommend 6–12 months medium) is associated with subclinical hypothyroidism
of expectant management for couples with a good in a proportion of women, and thyroid function test-
prognosis of spontaneous pregnancy, as defined by the ing is recommended before and after this procedure128.
Hunault model122. This approach was as effective as start- Whether any type of HSG is superior to expectant man-
ing medically assisted reproduction immediately and agement in terms of the chances of conceiving naturally
did not compromise ongoing birth rates in an audit of is unclear owing to lack of evidence.
guideline adherence in 25 clinics123. By comparison, the
2013 National Institute for Health Care and Excellence Intrauterine insemination. Intrauterine insemination
(NICE) guidance in the United Kingdom recommends (IUI) is a widely used and minimally invasive interven-
that IVF is offered to women with unexplained infertility tion for unexplained subfertility. Spermatozoa isolated
who have not conceived after 2 years of regular unpro- from the ejaculate are directly inserted into the uterus at
tected sexual intercourse, which can include up to 1 year the estimated time of ovulation, either during a natural
before their fertility investigations and can be shorter in menstrual cycle or after ovarian stimulation using oral
women >36 years or older86. medications such as clomiphene citrate and letrozole or
If expectant management is not effective, or in injectable gonadotropins. However, until recently, this
women with a poor prognosis, options for active inter- intervention had little supporting evidence129. Three
vention include HSG, intrauterine insemination or randomized controlled trials (RCTs) have compared IUI
IVF, any of which might be the next step depending with expectant management; two trials demonstrated no
on prognostic factors, patient preference and treat- benefit of IUI130,131, but one trial demonstrated a bene-
ment availability. All treatment options require a shared ficial result. The positive RCT differed from the other
decision-​making approach124. trials in that it used ovarian stimulation and included
women with an unfavourable prognosis and an average
Hysterosalpingography. HSG is a routine test carried of 4 years of subfertility (Hunault score <30%). This trial
out as part of a fertility work-​up but might also have a demonstrated that three cycles of IUI are more effective
role in the treatment of subfertility. Tubal flushing with than expectant management, with live birth rates of 31%
an oil-​based dye increases pregnancy rates in women and 9%, respectively132.
with normal fallopian tubes (39.7%) compared with Pelvic inflammatory disease is a potential complica-
tubal flushing with a water-​based dye (29.1%), both of tion of IUI, but the average incidence of post-​IUI pelvic
which are well-​tolerated125,126. The mechanism of action inflammatory disease is only 0.16 per 1,000 cycles133.
of HSG on subfertility is not well understood but might Use of oral ovarian stimulation with IUI might be
involve altering the immunological environment in the associated with a small increased risk of multiple preg-
peritoneal cavity to make it more favourable for fertility nancy (6%) and, rarely, of ovarian hyperstimulation
and/or might facilitate the passage of oocytes through syndrome (OHSS)129. The 2013 NICE guidance recom-
the fallopian tubes127. HSG with lipiodol (an oil-​based mends against use of IUI86; however, few clinics use this

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 11


advice134, and (as noted above) some evidence suggests in extensively pretreated women, but the birth rate in
that IUI with ovarian stimulation is a safe and effective the expectant management arm was very low137. IVF was
treatment for women with unexplained infertility who more effective than unstimulated IUI138,139.
have an unfavourable prognosis for natural conception. The success rates of IVF appear to be similar regard-
less of the cause of subfertility. However, reporting and
In  vitro fertilization. IVF is a fertility treatment comparing data on the outcomes of IVF are difficult
whereby mature oocytes are collected from the ovaries owing to a lack of a universally agreed way of reporting
and fertilized by sperm outside the body and the result- and difficulties in accounting for differences between
ing embryo(s) judged to have the best chance of preg- women (for example, age and length of subfertility)
nancy are introduced directly into the uterus (Fig. 7). and in the number of embryos transferred. Data
A related treatment is in vitro maturation, whereby from >144,000 embryo transfer cycles in European
immature oocytes are collected and are matured outside centres in 2013 (including women with all causes of
the body. subfertility) showed a clinical pregnancy rate of 34.5%
IVF is the mainstay of treatment for women with per embryo transfer140. Single embryos were transferred in
tubal disease and men with poor sperm quality but 31% of women, whereas two embryos were transferred
is also frequently used for unexplained subfertility in 56% of women140. In Australia and New Zealand in
although the evidence supporting the effectiveness 2016, 87.7% of cycles transferred one embryo, and the
of IVF in this population is scant. A Cochrane review overall clinical pregnancy rate was 33% for cycles that
found no conclusive evidence that IVF is more effective reached embryo transfer141.
than expectant management or IUI with ovarian stimu­ The treatment pathway for IVF is complex, com-
lation in treatment-​naive women with unexplained prising many steps and decision points; each step has
subfertility135. Five RCTs compared IVF and IUI with alternative clinical approaches, some of which are sup-
ovarian stimulation. Four of these RCTs included ported by robust evidence, whereas others require more
treatment-​naive women and found no evidence of a research142 (Fig. 7 and Supplementary Table 1). Several
difference between the two treatments. However, one factors can hinder the success of IVF or can increase
RCT in which all women were pretreated with IUI and the risk of adverse effects, such as smoking, obesity,
clomiphene demonstrated a higher live birth rate in hydrosalpinx, septate uterus, endometrial polyps and
women who proceeded straight to IVF than in women submucosal fibroids, and these should be addressed
who received further pretreatment with gonadotropins before IVF starts. Some women do not respond well to
and IUI before IVF136. One small RCT demonstrated a the ovarian stimulation drugs and might be described
benefit of IVF compared with expectant management as poor ovarian responders; however, there is little
agreement about the definition of poor response or the
best management strategy for these women143,144. Single
Box 2 | Lifestyle factors and the management of female subfertility embryo transfer (SET) during IVF reduces the risk of
The likely benefit of a weight loss programme for improving fertility in women is unclear. multiple pregnancies, and a strategy of successive SETs
One systematic review of weight loss interventions for treating subfertility237 included achieves similar outcomes to double embryo transfer but
six randomized controlled trials (RCTs) reporting pregnancy in subfertile women and with reduced multiple pregnancy rates145. Several factors
demonstrated a higher rate of pregnancy in women who underwent a combination of are important for embryo transfer, including the use of
reducing diet and exercise (54.8%) than in those who underwent standard care (49.9%). drug regimens to increase the receptivity of the endo­
However, live birth rates did not differ significantly between the groups (48.9% versus metrium, timing of embryo transfer, type of transfer catheter
46.8%). The largest RCT in this systematic review (which the review authors assessed as and use of ultrasonography for guidance142. The retrieval
having the lowest risk of bias), included 577 women with obesity and subfertility and
of multiple oocytes after ovarian stimulation, cryopreser-
demonstrated that a 6-month weight loss intervention before fertility treatment did not
increase rates of a vaginal birth of a healthy singleton at term within 24 months
vation of spare embryos and their use for further embryo
compared with immediate in vitro fertilization (IVF)153,238. In this trial, only 38% of transfers could avert the need for repeated ovarian stimu­
participants achieved their target weight loss, and 22% discontinued the intervention, lation and oocyte retrieval. Pregnancy outcomes for
and the unassisted pregnancy rate in the intervention group was 26% (versus 16% in frozen embryo transfer and fresh transfer are similar146.
controls), suggesting some benefit with weight reduction. In both unassisted pregnancy and IVF cycles, implan-
Obese and overweight women with subfertility should be encouraged to lose weight, tation is a key step in achieving pregnancy and, accord-
but as no compelling evidence supports the use of weight loss to improve live birth rates ingly, is often referred to as the rate-​limiting step147.
in women undergoing IVF, it may be advisable to start fertility treatment earlier than If three IVF attempts are unsuccessful, a diagnosis of
previously recommended in women who fail to meet weight targets despite their best repeated (or recurrent) implantation failure (RIF) is
efforts239. A healthy weight before starting fertility treatment not only improves
often made148,149. However, some data suggest that a reli-
pregnancy outcomes with or without assisted reproductive technology but also reduces
maternal and perinatal complications during pregnancy239. The long-​term health of
able diagnosis of RIF cannot be made after three IVF
offspring is also a factor, as maternal obesity (that is, a body mass index (BMI) >30 kg/m2) cycles and that diagnosis is likely to be more reliable and
is associated with an increased risk of premature death in adult offspring240. cost-​effective after six IVF cycles, especially in women
No RCTs have been carried out on the effect on fertility outcomes of smoking cessation with a poor prognosis and in centres with lower IVF
or abstinence from alcohol. A systematic review of preconception lifestyle advice found success rates150. Cohort data support a change to the
a single RCT, which examined the effect of advising women with subfertility to stop definition of RIF, as the live birth rate associated with
smoking and found no evidence that this influenced readiness to stop smoking. This RCT the fourth embryo transfer cycle was not significantly
did not report fertility outcomes241. However, animal and observational studies indicate different from the rate associated with the third cycle141.
that cigarette smoking impairs all aspects of fertility in women, including ovarian Women with RIF can be offered further investigations
function, fallopian tube function, fertilization and implantation242.
to establish causation, including endometrial receptivity

12 | Article citation ID: (2019) 5:7


1 2 3 4 5
Ovarian stimulation Oocyte retrieval via Embryo Embryo transfer
IVF or
and assessment transvaginal probe culture
(2–6 days)

of spare embryos

Embryo thawing

Fig. 7 | IVF procedure. Gonadotropins are given to stimulate the growth of ovarian follicles, and gonadotropin-​releasing
hormone (GnRH) agonists are given to suppress the natural menstrual cycle and downregulate the pituitary gland (step 1).
GnRH antagonists are an alternative to GnRH agonists, as they are not associated with hypo-​oestrogenic adverse effects,
flare-​up or a long downregulation period and can be used at any time during the follicular phase; both regimens have
similar live birth rates251. During the ovulation stimulation phase, regular monitoring using ultrasonography (with or
without blood tests) is undertaken to assess the growth of the ovarian follicles and to avoid ovarian hyperstimulation252.
When the follicles have reached an appropriate size, final maturation of the oocytes is induced (ovulation triggering).
Human chorionic gonadotropin (hCG) is commonly used as a trigger but can negatively affect endometrial receptivity and
embryo quality and increase rates of ovarian hyperstimulation syndrome (OHSS). An alternative is the agonist trigger,
which is given if there is an increased risk of OHSS. Oocytes are collected, usually with a transvaginal ultrasonography
probe for guidance, under general or local anaesthesia with sedation (step 2). Oocytes and sperm are combined in a Petri
dish for in vitro fertilization (IVF), or alternatively , intracytoplasmic sperm injection (ICSI) can be used when sperm
concentration and motility are low (step 3). The fertilized oocyte, now called a preimplantation embryo, is cultured for
2–6 days in vitro (step 4). From the pool of available embryos, one (on occasion, two) embryo is selected for transfer
(step 5). Supernumerary embryos of good quality are cryopreserved and can be thawed and transferred one-​by-one if
pregnancy was not established after fresh embryo transfer or if the couple desires an additional child. Drugs such as
progesterone or hCG are administered for luteal support to improve the likelihood of implantation and pregnancy and are
usually stopped at 12 weeks of gestation253.

tests, preimplantation genetic screening, time-​lapse apparent, such as cost or unavailability, other drugs can
imaging and immunological tests, but these tests can be be used, such as clomiphene citrate, with or without
invasive and costly. metformin154,156. Metformin reduces insulin resistance
and improves ovulation and pregnancy rates when used
Ovulation disorders in combination with clomiphene citrate in women with
The first-​line treatment for subfertility in women with PCOS who do not respond to clomiphene alone73. All
PCOS is lifestyle management. Advice can be aligned women should be advised of potential complications
with recommendations that are applicable to the general associated with ovulation induction agents, such as
population, such as obtaining a healthy weight, ceasing multiple pregnancies. Women should also be advised
smoking, omitting alcohol, performing exercise and if the use of such agents is off-​label (although permit-
managing mental health issues151. Women with ovu- ted) in countries where this is the case151. Women who
latory disorders who are overweight or obese can be have achieved regular ovulation with oral induction
advised to lose weight to improve menstrual regular- agents can continue this treatment for up to 12 months,
ity152. Indeed, in one RCT, a 6-month weight loss inter- as pregnancy and complication rates are acceptable for
vention increased the rate of live births conceived within this time period157. However, prolonged use of ovula-
24 months in obese women who were anovulatory but tion induction agents should be avoided owing to low
not in those who were ovulatory153. A post hoc analysis success rates151.
demonstrated that among anovulatory women, the like- A second-​line treatment for women who fail to
lihood of having a live birth conceived within 24 months respond to oral induction agents is gonadotropins, which
of the intervention was 40%153. are injectable drugs158. Administration of FSH (a type of
If lifestyle management is not effective, women with gonadotropin) is associated with higher live birth rates
anovulatory PCOS and no other subfertility factors than clomiphene citrate (52% versus 41%) but is expen-
should be offered ovulation stimulation and should be sive and requires strict cycle monitoring owing to the
educated about timed intercourse. The first-​line ovu- increased risk of multiple pregnancy. FSH is admin-
lation induction drug is letrozole, an oral aromatase istered by daily subcutaneous injection in a chronic
inhibitor, which is associated with higher rates of ovu- low-dose regimen159. The addition of IUI to gonadotro-
lation and live birth than clomiphene citrate (an oral pins does not significantly improve the chance of concep-
antioestrogen drug) and possibly with fewer multi- tion in women with anovulatory PCOS158. Preliminary
ple pregnancies151,154,155. If barriers to letrozole use are evidence suggests that metformin might increase the

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 13


live birth rate in women undergoing ovulation induction Endometriosis. For women with minimal or mild endo-
with FSH compared with use of FSH alone160. metriosis, excision of the lesions improves pregnancy
A surgical option for ovulation induction is laparo- rates in the 9–12 months following surgery (compared
scopic ovarian surgery, which can be offered to women with ablation alone), and laparoscopic surgery is more
with PCOS. No difference in pregnancy rates has been effective than diagnostic laparoscopy166. In women
demonstrated between laparoscopic ovarian surgery and with endometriosis using ART, a 3-month course of a
FSH therapy as second-​line treatment for women resist- GnRH agonist improves pregnancy rates166. As ovarian
ant to clomiphene citrate154. Multiple pregnancy rates surgery may diminish ovarian reserve, the need for sur-
are markedly decreased following ovarian surgery com- gery should be very carefully considered, especially in
pared with treatment with gonadotropins161. When other the case of recurrent endometriosis. There is no good
ovulation induction therapies have failed, women with evidence that medical treatment is effective166.
PCOS and anovulatory subfertility can be offered IVF
as a third-​line treatment in the absence of a clear indica- POI
tion for IVF. However, IVF is usually necessary only in Approximately 5–10% of women with POI have a
women with PCOS who have other factors contributing chance of spontaneous pregnancy, but most will require
to subfertility151. oocyte donation and IVF167. Oocyte donation involves
a woman with good ovarian reserve allowing several of
Fallopian tube disease her oocytes to be aspirated following ovarian stimula-
Subfertility associated with tubal adhesions can be tion during IVF treatment167. The oocytes are then fer-
treated surgically, ideally using laparoscopic techniques tilized, and the resulting embryos are transferred to the
to remove adhesions and restore normal anatomy as uterus of the prospective mother. Oocyte donation can
much as possible. The surgery may be a stand-​alone also be used for women with ovarian failure following
procedure or may precede IVF. The safety and effective- chemotherapy or pelvic radiation.
ness of surgery for tubal subfertility are unknown, as no
randomized studies have been conducted. Tubal surgery Quality of life
is associated with higher pregnancy rates in women Quality of life (QOL) and emotional well-​being are
with mild tubal disease than in those with severe tubal important considerations for the management of subfer-
pathology162. Fertility may be restored in women with tility, and supporting women and their partners should
restored tubal patency, which might allow for more than be an integral part of fertility care. Although fertility
one live birth to occur; however, these women have an clinic staff share this aim, they often lack the resources,
increased risk of ectopic pregnancy163. such as time and know-​how, to do so168. Guidelines
Bilateral tubal blockage was the original indication from the European Society for Human Reproduction
for the use of IVF, and IVF is considered a first-​line and Embryology provide helpful tools for clinic staff
intervention for this indication. RCTs are generally con- to optimize patient support (for example, pocket
sidered unnecessary for women with tubal subfertility, as guides, screening tools, patient information leaflets and
the majority of women will have complete tubal block- patient-administered interventions)169.
age and no potential alternative treatment. Tubal surgery The effect of subfertility and associated treatment
(such as salpingectomy or tubal occlusion) improves on well-​being has been extensively studied using self-​
IVF success rates in women with hydrosalpinges164; report questionnaires about general health and fertility-​
although the mechanism of action is unknown, it prob- specific QOL (for example, Fertility Quality of Life
ably involves improvement of implantation by reducing (FertiQoL)170) and emotional distress (such as anxiety
inflammation in the genital tract. and depression). Subfertility is consistently associated
with poorer QOL and higher levels of emotional distress
Fibroids. The best way to treat fibroids in order to than population norms and healthy or gynaecological
enhance fertility is controversial. Most clinical guide- controls (typically, women attending gynaecology ser-
lines recommend hysteroscopic myomectomy in vices for non-​fertility reasons)171–173. In addition, the
women seeking to conceive who have symptomatic effects of subfertility on emotional distress can persist
fibroids classified as type 0 or 1 by the International into pregnancy; women using ARTs report more anxiety
Federation of Gynecology and Obstetrics (FIGO), and about fetal viability and health than women with good
some guidelines also recommend this procedure for fertility174,175 but have a similar rate of postpartum
asymptomatic fibroids98. However, a 2015 Cochrane depression176. Longer-​term adjustment to subfertil-
review with only three studies concluded that more ity in longitudinal research (>10 years) shows positive
randomized studies are needed to substantiate the adjustment for most women177.
effectiveness of this intervention68. A recent review The negative effect of subfertility on well-​being is
suggests that the decision regarding such surgery can principally due to the unfulfilled child wish177 but also
be guided by the location, size and number of fibroids to the presence of reproductive disease and treatment.
and by the availability of clinical expertise and equip- The physical aspects of underlying disorders can be
ment165. Research is in progress on medical therapies stigmatizing, painful and emotionally demanding (such
(such as selective progesterone receptor modulators) as as hirsutism and acne in PCOS178,179 and severe pelvic
alternatives or adjuncts to surgery for treating fibroids pain and dyspareunia in endometriosis180), as can com-
in women seeking fertility, but there is no conclusive ponents of treatment such as ovarian stimulation181,
evidence in this area165. waiting for pregnancy test results 182 and treatment

14 | Article citation ID: (2019) 5:7


failure183. Pre-​existing psychological disorders184 and sepsis and unsafe abortion, and in these cases, IVF is
coping through avoidance (such as by avoiding pregnant often the only treatment option. Despite the global
women) can amplify these effects, whereas perceived expansion of fertility services over the past decade, IVF
partner and social support can be attenuating185. remains inaccessible in many parts of the world, par-
Psychosocial interventions have been recommended ticularly in sub-​Saharan Africa196. New low-​cost initia-
to support women with subfertility, but consensus about tives are needed to improve the worldwide accessibility,
their effect and evaluation has not been reached. The affordability and acceptability of IVF and other subfer-
benefits of psychosocial interventions on pregnancy tility treatments192. Indeed, simplified techniques are
(if any) are likely indirect, occurring via treatment being developed to increase the global accessibility of
uptake. This benefit has been suggested by evidence IVF197–199 and to provide high-​quality affordable centres
that distressed individuals undergo fewer treatments186, in low-​income countries that integrate subfertility care
and meta-​analyses have demonstrated that emotional (including IVF) within family planning196.
distress is not associated with the failure of a single ART
cycle187 but is associated with failure in studies with a Improving diagnosis
longer follow-​up period188. Also supportive is the finding Prompt diagnosis of fertility problems is another chal-
that 22% of women discontinue treatment before achiev- lenge. One-​third of women with PCOS had to wait
ing pregnancy189; the most commonly cited reason for >2 years to reach a diagnosis, and nearly half had been
discontinuation is the psychological and relationship seen by three or more health professionals in the process,
burden of treatment190. in one international study. Timely diagnosis of PCOS is
Systematic reviews of QOL studies in individuals important, as this facilitates early lifestyle interventions
with infertility are limited by the fact that most of the that might prevent subsequent fertility problems200.
primary studies include women undergoing treatment There has also been a call for early diagnosis of common
who are from Western countries (in which women may reproductive disorders such as endometriosis201 and uter-
be more resilient and have greater support). A review ine fibroids165, though few data are available regarding
of population studies shows that clinical populations the benefit on fertility outcomes of earlier diagnosis fol-
represent only ~55% of the infertile population in well-​ lowed by treatment of these conditions. Such conditions
developed (such as Europe and the United States) and often have few or no symptoms to differentiate them, and
less well-​developed (such as Chile, Gambia, Malawi diagnostic tests are expensive or invasive. No longitudi-
and India) countries10. Danish register-​based cohort nal studies of increased surveillance for endometriosis
studies show that women using ART have lower rates or uterine fibroids have been undertaken, making any
of depressive disorder186 and relationship dissolution recommendations about screening or earlier diagnosis
than age-​matched population reference groups within difficult to support72,98. Accordingly, greater investment
5 years of starting treatment173,186. Severe social effects, in research on the prevalence of these conditions and the
such as social stigma, marital instability and harassment value of earlier detection is required. In addition, inves-
by in-​laws, are more common and consistently reported tigation and treatment of non-​tubal causes of infertility,
in reviews of non-​Western191 than Western samples171,172. such as male infertility, should not be overlooked.

Outlook Improving prevention

Alongside efforts to improve established ART tech- Education is key to preventing subfertility in both high-​
niques, we also support three priorities for future income and low-​income nations, and many young
research, such as addressing the preventable causes of adults lack understanding of the potential limitations of
subfertility, providing support and alternatives for indi- their fertility (and its treatment) and how to optimize their
viduals with subfertility and encouraging new initiatives chance of conceiving107,110,202,203. Indeed, one RCT in
to increase the global accessibility, affordability and Japan showed accelerated birth timing in the 12 months
acceptability of ART192. following provision of fertility education compared
with healthy pregnancy information in partnered
Subfertility in low-​income settings individuals204. Given the steady increase in the median
A lack of political interest coupled with the high cost of maternal age at first birth, future research should address
ART has led to a major gulf between high-​income and the potential link between fertility knowledge, treatment
low-​income countries in the provision of fertility treat- beliefs and planning of parenthood. Public health pro-
ment. In these countries, education, prevention, develop­ grammes need to raise awareness of the effects on fer-
ment of low-​cost interventions and provision of more tility of lifestyle choices and of practices such as female
equitable access to new technologies could be achieved193. genital mutilation and consanguineous marriage112.
Given the competing priorities for public funding, Increased research is required on effective ways to
coupled with the severe effect of childlessness in develop­ address lifestyle factors that affect fertility. In  addition,
ing countries, substantial efforts should focus on some cases of subfertility could be averted by improved
prevention of subfertility191,194. To this end, subfertility education on sexually transmitted infection (STI) pre-
might be resolved in low-​income countries by improved vention and more comprehensive screening for STIs,
education and utilization of existing resources. However, including HIV and hepatitis193. Depending upon local
tubal blockage is very common in some areas113,195, most prevalence rates, screening should include STIs, in addi-
likely secondary to the high prevalence of infectious dis- tion to pregnancy-​related or abortion-​related infections
eases (such as genital tuberculosis and HIV), maternal and genital tuberculosis. There has been a call for more

NATuRe RevIewS | DISEASE PRIMERS | Article citation ID: (2019) 5:7 15


research into the pathogens responsible for subfertil- and the Netherlands) have state funding for multiple
ity205. When subfertility cannot be prevented, more cycles and have some of the lowest multiple pregnancy
global effort is needed to de-​stigmatize childlessness and rates (≤5%)33,140,213,214. To reduce the morbidity and
to support those — mainly women — who find them- mortality associated with multiple pregnancy, govern-
selves ostracized within societies where parenthood is ments funding fertility clinics need to consider linking
socially mandatory192,206. the provision of ART with mandatory SET for the first
few cycles. The savings in neonatal, child and mater-
Assisted reproductive technology nal health care would more than offset the provision
Current ART procedures will continue to improve. of IVF215.
Research continues to seek improvements in ART OHSS — a life-​threatening complication of ART —
outcomes, including better ways to assess embryo and has reduced in prevalence over the past decade owing
oocyte quality, refinement and individualization of to a greater recognition of risk factors and improved
stimulation and triggering protocols, optimizing cul- management options. Hospital admission for OHSS is
ture media, improvements in ovary, testicular tissue, rare (with 0.4% of stimulated cycles in European coun-
gamete and embryo preservation and techniques for tries reporting OHSS in 2013), although there were three
identifying and optimizing endometrial receptivity207,208. deaths in 2012 and two deaths in 2013 in the European
Treatments are currently lacking that directly target the Society of Human Reproduction and Embryology
age-​related decline in oocyte quality. report140. Recommendations for further research include
Many ART clinics around the world are currently appropriately powered, well-​conducted RCTs to support
offering add-​on interventions including time-​lapse the current evidence base for interventions to prevent
imaging, preimplantation genetic screening, mitochon- OHSS, including dose-​finding studies and research to
drial DNA load measurement and assisted hatching209–211 determine the optimal timing of interventions216.
that may be still in the early stages of development, may Increased imprinting disorders have been reported
lack clinical evidence of safety and effectiveness and are in children conceived through IVF and intracytoplas-
often costly211,212. It could be argued that encouraging mic sperm injection, although there was insufficient evi-
women and couples to pay for untested and unproven dence of an association between ART and methylation
technologies deprives them of the genuine added chance in other imprinted genes217.
of pregnancy associated with having more cycles of con-
ventional treatment189. In addition, some procedures Better fertility studies. Long-​term follow-​up studies to
(such as assisted hatching and preimplantation genetic measure important clinical outcomes in mothers who
screening) have been offered in routine clinical practice used ART and in their offspring, in both childhood and
for more than a decade despite having been demon- beyond, are needed218. With the exception of national or
strated to be ineffective or even likely to reduce the large longitudinal studies, most IVF monitoring stops
chance of pregnancy in RCTs211,212. Thus, it is our view shortly after birth219, and in clinical trials, simple out-
that high-​quality evidence of the safety and effectivenesscomes such as birthweight are rarely reported220, and
of ART interventions should precede, not follow, their later child outcomes are mostly absent221. Accordingly,
introduction in routine clinical practice. Reproductive the development of a core outcome set for subfertility
medicine will benefit from investment in proper evalu­ trials will improve reporting222.
ation of current and new procedures and finding out Owing to the increasing use of gamete donation and
what is of true benefit to the patient. surrogacy, following up the health of donors and the
resulting children for physical and psychological health
Safety and assisted reproductive technology. ART has is important223. In some parts of the world, notably the
several ongoing safety concerns, including the need to United Kingdom, New Zealand, the Netherlands, Sweden
reduce multiple pregnancies and OHSS and to ascer- and Finland, and some states in Australia, donors can
tain the outcomes of gamete donation and the long-​ no longer remain anonymous and must consent to
term health of the mother and offspring. Despite good the release of their identity if offspring request it when
evidence favouring repeated SET over double embryo they reach 18 years of age. In other regions, no disclo-
transfer, and despite improvement in cryopreservation sure is required or disclosure is prohibited, for exam-
techniques and evidence that frozen transfers are at least ple, in Spain. In the United Kingdom, no children have
as good as fresh transfers145, there has been slow uptake yet reached the age where they can access information
of SET in many parts of the world including China, the themselves: this will be possible in 2023. However, donors
United States, the United Kingdom and other parts and offspring can find each other in other ways (such as
of Europe, and >15% of births following ART are still registers). Positive outcomes have been reported result-
multiple213. The United Kingdom attempted to improve ing from donor–offspring meetings224. A greater under-
the uptake of SET by providing a target of <10% for standing of these sometimes complex social issues would
multiple pregnancies, but this was abandoned in 2013 be welcome.
following a legal challenge. Successful strategies to
encourage SET uptake have included providing suffi- New ART approaches. Radical new approaches in
cient funding of ART. If only one IVF cycle is funded ART include the use of stem cells to create oocytes or
or if IVF is self-​funded, couples might be less likely to sperm, the creation of synthetic embryos, gene editing,
accept SET. Countries with good uptake of SET (for prolonged embryo culture, artificial gametes and the
example, Belgium, Sweden, Australia, New Zealand development of an artificial uterus. Although these are

16 | Article citation ID: (2019) 5:7


exciting approaches, careful development and evalua- with informed consent is that a patient could agree to
tion are crucial, as there is a risk that these techniques treatment with a technique of unknown effectiveness,
might progress to clinical use without sufficient atten- but the clinician still remains responsible for what he or
tion to safety, effectiveness and their societal and ethical she does228. Unproven procedures should be offered only
implications225. A large Dutch cross-​sectional survey within properly designed trials.
of clinicians, couples with subfertility and the general
public found that such treatments were considered Barriers to treatment
acceptable for six out of eight proposed indications but Barriers to fertility care are evident worldwide. Women
that they required regulation, preferably by a national with subfertility in the United States were more likely
bioethics committee226. to receive a medical subfertility evaluation if they
Responsible implementation of novel techniques were younger and had healthy lifestyle behaviours, a
is particularly important for reproductive medicine, male partner with high educational attainment and
as their effects can potentially affect future genera- state-​mandated insurance coverage for subfertility
tions226,227. The example of the widespread enthusiasm treatment229. Similarly, in the United Kingdom, only
to introduce add-​ons before there was evidence of their 57% of women with subfertility reported seeking any
effectiveness suggests the need for greater investment in medical or professional help, and those with lower
evaluative research. The lack of evidence-​based medi- incomes were less likely to have sought help230, mirror-
cine for subfertility may be in part due to strong beliefs, ing the global pattern of infertility medical-​help-seeking
which are often guided by the commercial interests of among women with subfertility10. Other studies have
pharmaceutical companies, device manufacturers and reported that greater affordability of ART is associated
clinics. Individuals undertaking fertility treatment are with greater ART use231.
often not sufficiently knowledgeable in this regard, In addition, affordability is also a driver of the use
and leaders in the field have a responsibility to provide of safer ART practices232. In women who receive inter-
them with effective treatments underpinned by quality ventions for subfertility, many choose to discontinue
research. Some individuals have recommended that fer- owing to the emotional, relational and physical bur-
tility clinics and national and international bodies have den of treatment190. Thus, better care, organization and
a ‘duty of care’ to collect “long-​term data pertaining to support for patients should be a priority. The recent
the health of any children born as a result of their use”211. report of an international commission suggests that the
Furthermore, doctors and scientists who recommend affordability of ART could be dramatically improved by
an unproven procedure to their patients should provide the use of less expensive drugs for ovarian stimulation
comprehensive information about the lack of evidence and simpler laboratory and culture systems for IVF and
on the safety of the intervention on the offspring and embryo transfer193.
regulatory bodies should require clinical trials to ensure
long-​term maternal and neonatal follow-​up211. One issue Published online xx xx xxxx

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241. Anderson, K., Norman, R. J. & Middleton, P. 15,169 consecutive trophectoderm biopsies Competing interests
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dynamics in the female reproductive tract and their for assisted reproduction cycles. Cochrane Database Springer Nature remains neutral with regard to jurisdictional
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