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

Introduction

Potential contributing factors for subfertility
1. Low ovarian reserve
2. Increased age (over 35 years) and low oocyte quality
3. Lifestyle factors
4. Tubal function defects
5. Fertilisation defects
6. Implantation defects
7. Metabolic disorders, immunological and genetic factors
8. Endometriosis
9. Fibroids
10. Adenomyosis

Investigations for unexplained subfertility
1. Detection of ovulation
a. Urinary luteinising hormone estimation
b. Midluteal progesterone
c. Ultrasound monitoring of follicular growth and confirmation of
follicular rupture.
2. Tubal patency test
a. Hysterosalpingogram
b. Hysterocontrast sonosalpingography
c. Laparoscopy and dye test
3. Semen analysis
4. Pelvic ultrasound and saline infusion sonography
5. Ovarian reserve testing
6. Laparoscopy in symptomatic women
7. Hysteroscopy in known uterine anomaly or pathology

Treatments for unexplained subfertility
1. Expectant management
2. Ovulation induction (clomiphene citrate, letrozole, gonadotrophins)
3. Intrauterine insemination (IUI) with or without ovarian stimulation
4. In vitro fertilisation (IVF)
NICE Guideline recommendations 2013: Do not offer IUI routinely
for people with unexplained subfertility who have regular
unprotected sexual intercourse. Consider IVF after 2 years of expectant
management.

Conclusions
A range of treatment options is available for unexplained
subfertility; however, the right treatment strategy needs to be
tailored according to the individual circumstances. Factors
like the age of the female partner, duration of subfertility and
previous pregnancies should be considered in choosing the
optimal treatment protocol. One suggested algorithm is
presented in Figure 1. There is a lack of agreement between
clinicians regarding management and this is aggravated by a
lack of strong evidence, impatience on the part of
practitioners and couples and financial considerations. This
frequently leads to overtreatment in cases suitable for
expectant management or IUI with gonadotrophic ovarian
stimulation. While clomiphene with or without IUI is not
suitable for unexplained subfertility, 3–4 cycles of IUI and
ovarian stimulation with gonadotrophins could be beneficial
for many suitable couples. IVF should remain the first choice
of treatment only for those with a long duration of
subfertility, where ovarian reserve is deteriorating or when
conservative treatment has failed.