DOI: 10.1111/tog.

12253 2016;18:107–15
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Unexplained subfertility: diagnosis and management

a, b
Anupa Nandi MRCOG, * Roy Homburg FRCOG
a
Clinical Research Fellow, Homerton Fertility Centre, Homerton University Hospitals NHS Trust, Homerton Row, London E9 6SR, UK
b
Head of Research, Professor in Reproductive Medicine, Homerton Fertility Centre, Homerton University Hospitals NHS Trust, Homerton Row,
London E9 6SR, UK
*
Correspondence: Anupa Nandi. Email: [email protected]

Accepted on 14 August 2015

Key content Learning objectives

 Unexplained subfertility is diagnosed when standard investigations  To summarise the available recent evidence and help the reader
(tests for ovulation, tubal patency and semen analysis) are all obtain a clear understanding of the continuing debates in this field.
normal. Between 30% and 40% of subfertile couples fall  To help clinicians in counselling couples with
into this category. unexplained subfertility.
 In some couples, unexplained subfertility may result from subtle
Ethical issues
undetectable factors; in other couples, it may be associated with a  Should couples be advised to try to conceive naturally for 2 years
genuine absence of any abnormality.
 There is currently much controversy about the selection of
(regardless of their age) before they are offered treatment, even
though fecundity declines with age?
appropriate management options for such couples, especially  What does the evidence suggest should be the first line of
following the National Institute for Health and Care Excellence
management for couples with unexplained subfertility: intrauterine
(NICE) guideline published in 2013. Therefore, a clear
insemination or in vitro fertilisation?
understanding of the available evidence is essential for the
management of couples with unexplained subfertility. Keywords: IUI / IVF / unexplained infertility / unexplained
 The potential contributing factors, diagnosis and management of subfertility
unexplained subfertility are discussed.

Please cite this paper as: Nandi A, Homburg R. Unexplained subfertility: diagnosis and management. The Obstetrician & Gynaecologist 2016;18:107–15. DOI:
10.1111/tog.12253

contributing factors that can be responsible for

Introduction
subfertility (Box 1).
Unexplained subfertility is usually diagnosed if a couple fails
to conceive after 1 year of regular unprotected sexual Increased age of the female partner
intercourse even though investigations for ovulation, tubal As the female partner’s age increases, there is a decline in
patency and semen analysis are normal.1,2 For as many as the total number of remaining oocytes and their quality.9
30–40% of couples experiencing subfertility, their subfertility Because of the decline in oocyte quality, there is an
remains unexplained.3,4 While the average cycle fecundity increase in the embryonic aneuploidy rate in older women,
without treatment in women with unexplained subfertility is
1.3–4.1%,5 prognosis depends on the age of the female partner,
duration of subfertility and previous obstetric history.6,7
Box 1. Potential contributing factors for subfertility
Differences of opinion exist among fertility specialists
regarding the optimal treatment for couples experiencing
1. Low ovarian reserve
unexplained subfertility.8 This review aims to discuss the 2. Increased age (over 35 years) and low oocyte quality
diagnosis and management of unexplained subfertility and 3. Lifestyle factors
highlight the continuing controversies in this field. 4. Tubal function defects
5. Fertilisation defects
6. Implantation defects
7. Metabolic disorders, immunological and genetic factors
Potential contributing factors 8. Endometriosis
The diagnosis of unexplained subfertility is made by 9. Fibroids
10. Adenomyosis
exclusion. However, there are various potential

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 Unexplained subfertility: diagnosis and management

which leads to nonimplantation and subfertility.10,11 A cancellation caused by poor oocyte yield in in vitro
study by Maheshwari et al.12 showed that women over 35 fertilisation (IVF), but once oocytes are retrieved they
years of age were more likely to have unexplained have almost normal pregnancy rates.25
subfertility than their younger counterparts (OR 1.8, 95%
CI 1.4–2.2). Tubal function defects
In addition to tubal patency, tubal function is important to
Lifestyle factors and unexplained subfertility achieve successful pregnancy. Optimal tubal functions, such
as adequate ciliary motion and muscular activity, are
Smoking required for sperm–oocyte interaction and transport of the
Both active and passive smoking can adversely affect the embryo to the uterine cavity for implantation.26 Milder forms
potential to conceive by reducing the ovarian reserve and by of gonorrhoea and chlamydia infection can cause tubal
altering the tubal function and the uterine environment.13 In function defect without causing overt occlusion.27 Impaired
men, smoking impairs the fertilising capacity of the sperm by tubal function in otherwise patent tubes can lead
reducing the mitochondrial activity and increasing the to subfertility.
DNA damage.14
Fertilisation defects
Weight Subtle defects in oocyte and sperm leading to defective
Both obesity (defined as a body mass index above 30) and fertilisation are possible causes of unexplained subfertility.
being underweight (defined as a body mass index below 19) Sperm defects, such as abnormal acrosomes resulting in
can impair fertility even in young and regularly ovulating poor or no zona pellucida binding28 and defects in
women.15 Obesity can alter the follicular environment and acrosome reaction resulting in failure of sperm–zona
lead to oocyte incompetence and suboptimal embryo pellucida penetration, are possible factors leading to
quality,16 impairing implantation by negatively influencing subfertility.29 Sperm DNA integrity may be a prerequisite
the endometrium.17 Obesity in men can contribute to for normal fertilisation.30 An otherwise normal semen
subfertility by causing DNA damage to sperm,18 decreased analysis (as per the World Health Organization criteria)
libido and erectile dysfunction.19 may include sperm with altered genetic material induced by
various factors, such as defects in chromatin remodelling at
Excessive alcohol intake the time of meiotic division, post-testicular oxidative stress,
In men, even habitual consumption of over 5 units per week various environmental factors or advanced male age.31 High
has an adverse effect on sperm quality,20 although the true levels of sperm DNA fragmentation can lead to reduced
impact on male fertility is unclear. Similarly, excessive fertilisation and increased miscarriage rates.32 A variety of
alcohol consumption in women may affect fertility by in vitro tests are available to detect sperm function defects,
decreasing the implantation rate, and causing luteal phase such as the ability of sperm to penetrate cervical mucus
dysfunction and abnormal embryo development.21 However, surrogate, quantification of sperm–zona binding
there is still no universal agreement on the safe limit of using hemizona pellucidae and hyaluronan binding
alcohol consumption.22 assay.33 The methods used to detect sperm DNA
fragmentation include the sperm chromatin structure
Other factors assay, the single-cell gel electrophoresis assay and the
Other factors that may have an impact on fecundity are terminal uridine nick-end labelling assay.34 However, the
psychological stress, environmental exposure to pollutants clinical utility of these tests has been undermined by
and use of illicit drugs and caffeine.23 the introduction of intracytoplasmic sperm injection
(ICSI).32 Hence, these tests do not form a part of
Ovarian reserve routine investigations.2,35
Ovarian reserve is the size of the remaining follicle pool in
the ovary at any given time. This often indicates the Implantation defects
capacity of the ovary to produce an oocyte that can be A receptive endometrium is undoubtedly essential for
fertilised and that results in a successful pregnancy. The rate successful implantation and pregnancy. Various
of follicular depletion varies between individuals, hence the biochemical factors like cytokines, leukemia inhibitory
ovarian reserve.1 A woman’s age remains the single most factor, interleukin-1 and some chemokines (e.g. CX3CL1,
important factor in determining reproductive outcome; CCL14) may be involved in endometrial receptivity.36,37
ovarian reserve can only predict ovarian response in an Alterations of these factors in the endometrium can cause
assisted reproductive technology cycle.24 Younger women subfertility. There are no standard tests to detect
with low ovarian reserve are more likely to have cycle these defects.

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 Nandi and Homburg

Investigations for unexplained subfertility

Immunological, metabolic and genetic factors
Dysregulation of the immune system and increased Box 2 lists the tests performed to diagnose unexplained
production of autoantibodies have been suggested as subfertility. However, they have limitations and even the
possible causes of unexplained subfertility. Autoimmune most sophisticated tests can fail to detect subtle causes
antibodies like anti-thyroid, anti-ovarian, antinuclear, of subfertility.
antiphospholipid and anti-smooth muscle antibodies have
been associated with unexplained subfertility.38 Although the Detection of ovulation
exact role of these autoantibodies in the pathogenesis of Although there are various strategies to detect ovulation,
unexplained subfertility is unclear, various theories have been none of these tests can detect the quality of the oocyte. Tests
proposed, such as the reduction of fertilisation rate, like urinary luteinising hormone estimation, midluteal phase
interference with early implantation and modulation of progesterone levels and ultrasound monitoring of follicular
follicle-stimulating hormone (FSH) function, thereby growth might detect ovulation; however, they may fail to do
influencing ovarian function.39 In addition to altered so if not performed at the right time of the menstrual
immune response, thrombophilic gene polymorphisms cycle.2,52 The presence of a regular menstrual cycle in itself is
(e.g. methylenetetrahydrofolate reductase gene a fair indicator of regular ovulation, and the chances of
polymorphism) could be a cause of unexplained anovulation in a woman with a regular menstrual cycle
subfertility.40 The possible mechanism could be the are low.2,53
causation of early implantation failure; however, more
evidence is needed to confirm this.41 Tubal patency test
Oxidative stress owing to an imbalance between reactive Assessment of tubal patency can be achieved by various
oxygen species and antioxidants can be caused by factors methods, such as hysterosalpingogram, hysterocontrast
such as obesity, smoking, alcohol, recreational drug use and sonosalpingography and laparoscopy and dye tests. None
environmental exposure to various toxins. Oxidative stress of these methods, however, can detect tubal function
has been linked both with male subfertility (as it causes defects, which can potentially contribute to a
damaged sperm42) and with female subfertility, although the couple’s subfertility.
mechanism of its action in females is not clear.43
Semen analysis
Endometriosis This remains the most important investigation of the male
About 30% of asymptomatic women with otherwise partner. In 2010, new World Health Organization criteria for
unexplained subfertility will be diagnosed with mild semen analysis using lower reference limits were released
endometriosis if laparoscopy is undertaken.44 The fecundity (Table 1).2,54 Although semen analysis results provide
of women with mild endometriosis is similar to that of evidence of the concentration, motility and morphology of
women with unexplained subfertility.45 There is no evidence
that medical treatment of mild endometriosis improves
fertility, and laparoscopic ablation can improve the live birth
rate only minimally.46–48 Hence, it is debatable whether mild Box 2. Investigations for unexplained subfertility
endometriosis in women with unexplained subfertility is
responsible for their subfertility. 1. Detection of ovulation

a. Urinary luteinising hormone estimation

Fibroids b. Midluteal progesterone
c. Ultrasound monitoring of follicular growth and confirmation of
The role of fibroids in causing subfertility is unclear. The
follicular rupture.
submucosal component of fibroids could be associated with
reduced conception but evidence remains scarce.49 There is 2. Tubal patency test

insufficient evidence that myomectomy for intramural or a. Hysterosalpingogram

subserous fibroids improves pregnancy rates.50 b. Hysterocontrast sonosalpingography
c. Laparoscopy and dye test

Adenomyosis 3. Semen analysis

The impact of adenomyosis or its treatment on fertility 4. Pelvic ultrasound and saline infusion sonography
5. Ovarian reserve testing
remains unsubstantiated because of a paucity of data.51 6. Laparoscopy in symptomatic women
Therefore, subfertility in women with adenomyosis remains 7. Hysteroscopy in known uterine anomaly or pathology
unexplained for now.

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 Unexplained subfertility: diagnosis and management

reasonable to postpone laparoscopy in asymptomatic

Table 1. World Health Organization 2010 criteria for normal semen
analysis women with normal hysterosalpingogram and no previous
history of pelvic infection or surgery, it might be useful in
Criteria Parameters selected women with multiple failed ovarian stimulation with
or without intrauterine insemination (IUI).64,65
Volume ≥1.5 ml
pH ≥7.2
Sperm concentration ≥15 9 106/mL spermatozoa Hysteroscopy
Total sperm count ≥39 9 106 spermatozoa Hysteroscopy is a reliable way to diagnose and treat uterine
Total motility ≥40% cavity anomalies like fibroids, polyps, septum and
Progressive motility ≥32%
Vitality ≥58% live spermatozoa adhesions.66 Women with unexplained subfertility might
Morphology ≥4% with normal morphology benefit from hysteroscopic removal of submucous fibroids
and polyps to improve their chances of conceiving.67 Where
facilities are available, saline infusion sonography together
with 3D ultrasound can offer a less invasive outpatient
sperm, they do not assess sperm function,55 which potentially method to assess the uterine cavity with accuracy similar to
affects fertility. that of hysteroscopy.68

Ovarian reserve tests

Tests available for ovarian reserve estimate basal FSH (early Treatment options for unexplained
follicular phase: day 2–5 of the menstrual cycle), inhibin A subfertility
and B, anti-m€ ullerian hormone, antral follicle count and In the absence of a definitive diagnosis, the treatment of
ovarian volume. The clomiphene citrate challenge test and unexplained subfertility remains empirical.4 Although
the exogenous FSH ovarian reserve test56 are also used. various treatment strategies are available, evidence is
Although the basal FSH test is the most frequently used, it lacking to confirm the superiority of one over the
has significant intra- and intercycle variability, which limits other (Box 3).
its reliability. In contrast, the anti-m€
ullerian hormone test
can be applied at any time during the menstrual cycle and Expectant management
both this test and the antral follicle count have good The chances of spontaneous conception remain high in
predictive value for ovarian stimulation response.57 Although couples with unexplained subfertility. In a multicentre
these tests predict the response to ovarian stimulation during cohort study of 437 couples with unexplained subfertility,
IVF, they are quite limited in their accuracy to predict the 74% of couples conceived spontaneously.7 A Dutch
chances of spontaneous conception.58,59 According to the multicentre trial randomised 253 couples with unexplained
American College of Obstetricians and Gynecologists, it is subfertility and intermediate prognosis of natural conception
reasonable to encourage a woman to attempt to conceive within 12 months, into an expectant management group and
sooner rather than later if her ovarian reserve is found to be an intervention group receiving IUI with controlled ovarian
diminished, as her window of opportunity to conceive might hyperstimulation (COH) for 6 months. Similar continuing
be shorter than anticipated.60 pregnancy rates between the two groups were found (23% for
the intervention group and 27% for the expectant management
Diagnostic laparoscopy group)69 and there was a saving of €2,616 per couple in favour
Women with unexplained subfertility with tubal patency of expectant management.70 Although expectant management
confirmed by normal hysterosalpingogram findings can still is a valid option for couples with a favourable prognosis, it
have peritubal adhesions and/or endometriosis, which can
lower the chances of spontaneous conception.61 However, it
is difficult to predict which women would benefit most from
Box 3. Treatments for unexplained subfertility
surgery and the concerns are increased cost, surgical risks and
women’s anxiety about potential surgery. Both the American
1. Expectant management
Society for Reproductive Medicine and the National Institute 2. Ovulation induction (clomiphene citrate, letrozole, gonadotrophins)
for Health and Care Excellence (NICE) suggest laparoscopy 3. Intrauterine insemination (IUI) with or without ovarian stimulation
only in women with symptoms of comorbidities.2,62 In 2010, 4. In vitro fertilisation (IVF)
Badawy et al.63 showed in a prospective randomised NICE Guideline recommendations 2013: Do not offer IUI routinely
controlled trial that diagnostic laparoscopy could be for people with unexplained subfertility who have regular
postponed until after 3–6 failed cycles of ovarian unprotected sexual intercourse. Consider IVF after 2 years of expectant
management.
stimulation and timed sexual intercourse. While it is

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 Nandi and Homburg

remains challenging for clinicians to choose the best candidates expectant management in terms of live birth rates in couples
for this treatment. Twenty-nine prediction models have been with unexplained subfertility.69,76 A 2012 Cochrane review
developed to help clinicians in this regard. However, they have demonstrated that IUI plus COH increases the live birth rate
been developed for different patient profiles and lack thorough more than two-fold compared with IUI in a natural cycle
external validation.71 Although these models can be used for (OR 2.07, 95% CI 1.22–3.5).78 COH may correct subtle
decision making in couples similar to the populations they ovulation problems and slightly increase the number of
were developed for, there remain concerns regarding their oocytes available for fertilisation, thereby increasing the
generalisability across different patient profiles. Moreover, chances of pregnancy.79 However, a major concern with
expectant management might not be acceptable to many multiple follicle development in IUI plus COH is multiple
couples, as further attempts of natural conception add to pregnancies.80 It has been demonstrated that by using mild
already existing stress and frustration.72 This leads to ovarian hyperstimulation and strict cancellation policies,
overtreatment in many of these cases.73 multiple pregnancy rates can be kept to approximately 10%
without reducing pregnancy rates.81 The 2013 NICE fertility
Tubal flushing or perturbation guideline recommends not routinely offering IUI to couples
A possible therapeutic benefit of tubal flushing during with unexplained subfertility but proceeding directly to IVF
hysterosalpingogram has been known to gynaecologists for after 2 years of subfertility2. However, the success of IUI
over half a century. A range of oil-soluble and water-soluble depends on multiple factors82 and many clinics continue to
contrast media have been used for hysterosalpingogram and provide IUI plus COH for patients with unexplained
have been linked to an increased chance of pregnancy. A subfertility despite the NICE recommendation.83
2007 Cochrane review summarised 12 trials involving 2079
participants and concluded that oil-soluble contrast media In vitro fertilisation
increase the odds of live birth in comparison with no With advances in assisted reproductive techniques, IVF has
treatment (Peto OR 2.98, 95% CI 1.40–6.37), but could not emerged as a safe and successful treatment option. However,
confirm any benefit of oil-soluble versus water-soluble debate continues about whether it should be the sole
media because of the lack of an appropriate trial.74 treatment for couples with unexplained subfertility.
Possible mechanisms of action are mechanical (removal of The first randomised controlled trial by Goverde et al.84 in
tubal debris), immunological (affecting peritoneal cytokines 2000, compared six cycles of IUI in a natural cycle versus six
and preventing peritoneal mast cell phagocytosis of cycles of IUI plus COH versus six cycles of IVF in 258 couples
spermatozoa) or an effect on the endometrium to promote with unexplained and mild male factor subfertility. They
implantation.75 Oil-soluble contrast media have now been found that although pregnancy rate per cycle was better with
widely replaced by water-soluble contrast media because of IVF compared with IUI in natural cycle or IUI plus COH
better image quality, early dissipation that removes the need (12.2% versus 7.45% and 8.7%, respectively), there was no
for delayed films and the possibility of granuloma formation difference in cumulative pregnancy rates (38% versus 31%
with oil-soluble media. and 37%, respectively). However, pregnancy rates from IVF
have continued to improve and the current UK IVF success
Clomiphene citrate with or without intrauterine rates are 27–32% for women under 37 years of age.85 One
insemination might argue that the pregnancy rate reported by Goverde
Clomiphene citrate acts as an anti-estrogen; it increases et al.84 is outdated.
endogenous FSH and thereby stimulates multiple follicular Reindollar et al.,86 in a large randomised controlled trial in
developments. Although its effectiveness has been described 2010, demonstrated the effectiveness of moving to IVF after a
in cases of oligo-ovulation, questions have been raised course of clomiphene citrate and IUI compared with
regarding its usefulness in otherwise ovulatory women.76 A conventional treatments of clomiphene citrate and IUI,
Cochrane review that summarised 14 clinical trials (1159 followed by FSH and IUI, followed by IVF. Pregnancy rates
participants) found no clinical benefit of clomiphene citrate were not only higher, but moving to IVF sooner allowed
for unexplained subfertility.77 women to conceive 3 months earlier. However, the use of
clomiphene citrate and IUI prior to IVF in this trial can be
Intrauterine insemination questioned, as there is much evidence against the use of
IUI plus COH is widely used in cases of unexplained clomiphene citrate in ovulating women.77 The same group
subfertility before resorting to more invasive options like compared two cycles of clomiphene citrate and IUI versus
IVF. It involves placement of washed sperms into the uterine two cycles of FSH and IUI versus immediate IVF in 154
cavity around the time of ovulation. It has been used both couples with older women (38–42 years) and demonstrated
with and without ovarian stimulation. Two studies have superior pregnancy rates and fewer treatment cycles with
failed to show any benefit of IUI with or without COH over immediate IVF.87

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 Unexplained subfertility: diagnosis and management

In 2011, Custers et al.88 randomised 116 couples with multiple pregnancy rates (6% versus 5% and 7%,
unexplained and mild male factor subfertility and respectively) between the treatment arms.
unfavourable prognosis of natural conception, to one cycle The literature indicates that although the per-cycle success
of IVF-eSET (elective single embryo transfer) and three cycles rate of IUI is lower than that of IVF (9% versus 22%),92
of IUI plus COH. They found similar live birth rates: 24% in the cumulative IUI success rates are comparable to those of IVF.91
IVF-eSET group and 21% in the IUI plus COH group (relative From the perspective of couples, IUI remains less invasive, less
ratio 1.17; 95% CI 0.60–2.30). Custers and colleagues have also stressful and less time consuming than IVF. Perinatal outcome
found IUI plus COH to be more cost effective.89 for singletons is better with IUI than with IVF.93 Hence, IUI
In 2012, a Cochrane review summarised the trials for plus COH remains a very realistic treatment option.
unexplained subfertility treatment and found no evidence for
the effectiveness of IVF over IUI as a first line treatment. No Intracytoplasmic sperm injection
significant differences in multiple pregnancy or ovarian In 5–25% of cases of unexplained subfertility, no fertilisation
hyperstimulation syndrome rate between the two treatments has been reported with conventional IVF procedures.94 This
were found.90 could be due to occult abnormalities in sperm or oocytes.95,96
Bensdorp et al.91 shed new light on the effectiveness of ICSI has been advocated for these couples.97 However,
IUI and IVF for couples with subfertility in their 2015 studies have failed to show any benefits of ICSI over IVF in
study. In this multicentre randomised controlled trial terms of clinical pregnancy rates (33% IVF versus 26%
involving 17 centres in The Netherlands, 602 couples with ICSI)98 or live birth rates (46.7% IVF versus 50% ICSI).99 A
unexplained and mild male factor subfertility and 2013 systematic review summarised 11 studies with a total of
unfavourable prognosis for natural conception were 901 couples and showed a higher fertilisation rate with ICSI
randomised to three groups: three cycles of IVF and compared with IVF (RR 1.49, 95% CI 1.35–1.65) and the
single embryo transfer, six cycles of IVF in a modified need to treat five participants with ICSI to prevent one case
natural cycle, and six cycles of IUI plus COH. The of fertilisation failure.100 Because of the paucity of data, the
researchers found comparable singleton live birth rates review authors could not analyse the pregnancy outcome
(52% versus 43% and 47%, respectively) and comparable from ICSI compared with IVF. Both the American Society for

Figure 1. The authors’ suggested algorithm on the best treatments for unexplained subfertility. FSH = follicle-stimulating
hormone, IUI = intrauterine insemination, IVF = in vitro fertilisation.

112 ª 2016 Royal College of Obstetricians and Gynaecologists

 Nandi and Homburg

Reproductive Medicine and the NICE practice committees Contribution to authorship

do not recommend routine ICSI for unexplained AN carried out the literature search and wrote the draft
subfertility.2,101 However, use of ICSI for at least some article. RH contributed to the final version of the article.
oocytes (split IVF–ICSI) offers several benefits. It allows
detection of fertilisation defects, reduces the risk of failure to
fertilise and identifies couples that would need ICSI in
Supporting Information
subsequent cycles. Single Best Answer questions are available for this article at
https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
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