IVF for Unexplained Subfertility; Whom Should We Treat?

R. van Eekelen; N. van Geloven; M. vanWely; S. Bhattacharya; F. van der Veen; M.J. Eijkemans; D.J. McLernon


Hum Reprod. 2019;34(7):1249-1259. 

In This Article

Abstract and Introduction


STUDY QUESTION: Which couples with unexplained subfertility can expect increased chances of ongoing pregnancy with IVF compared to expectant management?

SUMMARY ANSWER: For couples in which the woman is under 40 years of age, IVF is associated with higher chances of conception than expectant management.

WHAT IS KNOWN ALREADY: The clinical indications for IVF have expanded over time from bilateral tubal blockage to include unexplained subfertility in which there is no identifiable barrier to conception. Yet, there is little evidence from randomized controlled trials that IVF is effective in these couples.

STUDY DESIGN, SIZE, DURATION: We compared outcomes in British couples with unexplained subfertility undergoing IVF (n = 40 921) from registry data to couples with the same type of subfertility on expectant management. Those couples on expectant management (defined as no intervention aside from the advice to have intercourse) comprised a prospective nation-wide Dutch cohort (n = 4875) and a retrospective regional cohort from Aberdeen, Scotland (n = 975). We excluded couples who had tried for <1 year to conceive and also those with anovulation, uni- or bilateral tubal occlusion, mild or severe endometriosis or male subfertility i.e. impaired semen quality according to World Health Organization criteria.

PARTICIPANTS/MATERIALS, SETTING, METHODS: We matched couples who received IVF and couples on expectant management based on their characteristics to control for confounding. We fitted a Cox proportional hazards model including patient characteristics, IVF treatment and their interactions to estimate the individualized chance of conception over 1 year—either following IVF or expectant management for all combinations of patient characteristics. The endpoint was conception leading to ongoing pregnancy, defined as a foetus reaching a gestational age of at least 12 weeks.

MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted 1-year chance of conception was 47.9% (95% CI: 45.0–50.9) after IVF and 26.1% (95% CI: 24.2–28.0) after expectant management. The absolute difference in the average adjusted 1-year chances of conception was 21.8% (95%CI: 18.3–25.3) in favour of IVF. The effectiveness of IVF was influenced by female age, duration of subfertility and previous pregnancy. IVF was effective in women under 40 years, but the 1-year chance of an IVF conception declined sharply in women over 34 years. In contrast, in woman over 40 years of age, IVF was less effective, with an absolute difference in chance compared to expectant management of 10% or lower. Regardless of female age, IVF was also less effective in couples with a short period of secondary subfertility (1 year) who had chances of natural conception of 30% or above.

LIMITATIONS, REASONS FOR CAUTION: The 1-year chances of conception were based on three cohorts with different sampling mechanisms. Despite adjustment for the three most important prognostic patient characteristics, namely female age, duration of subfertility and primary or secondary subfertility, our estimates might not be free from residual confounding.

WIDER IMPLICATIONS OF THE FINDINGS: IVF should be used selectively based on judgements on gain compared to continuing expectant management for a given couple. Our results can be used by clinicians to counsel couples with unexplained subfertility, to inform their expectations and facilitate evidence-based, shared decision making.

STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Tenovus Scotland [grant G17.04]. Travel for RvE was supported by the Amsterdam Reproduction & Development Research Group [grant V.000296]. SB reports acting as editor-in-chief of HROpen. Other authors have no conflicts.


Subfertility is defined as not conceiving within 1 year of regular unprotected intercourse and this affects approximately one in nine heterosexual couples (Datta et al., 2016). Following standard investigations, no cause can be identified in one-third of these couples who are said to have unexplained subfertility. IVF with or without ICSI, is a commonly used treatment for couples with prolonged unresolved subfertility and over 470 000 treatment cycles were recorded in Europe in 2013 (Calhaz-Jorge et al., 2017). IVF is a burden to couples in terms of mental and physical stress, is associated with high expectations and considerable investment in terms of emotions, finances and time (Rooney and Domar, 2016). The number of IVF cycles conducted increases annually, posing an increasing burden on health services in countries where IVF is publicly funded (HFEA, 2004; Andersen et al., 2007; NVOG, 2010; NICE, 2013; Kamphuis et al., 2014; Calhaz-Jorge et al., 2017; HFEA, 2018). This increase is generally considered to be the consequence of the increasingly liberal utilization of IVF for a variety of indications, including unexplained subfertility (HFEA, 2004; Kamphuis et al., 2014; HFEA, 2015). Yet, there is little robust evidence supporting the effectiveness of IVF in couples with unexplained subfertility compared to a wait-and-see approach i.e. expectant management (Pandian et al., 2015; Tjon-Kon-Fat et al., 2016).

There is a single trial evaluating the effectiveness of IVF versus expectant management for couples with unexplained subfertility in terms of live birth which reported the chance of live birth following IVF (11 out of 24 couples) to be12 times that of expectant management (1 out of 27 couples) (Hughes et al., 2004). Although the results seem to support IVF, there is considerable uncertainty around this result based on very small numbers of participants and it is inappropriate for clinical practice across the globe to be based on this quality of evidence (Tjon-Kon-Fat et al., 2016).

Observational studies have separately quantified the predicted chances of conception after IVF and after a period of expectant management (Leushuis et al., 2009; McLernon et al., 2016; van Eekelen et al., 2017a). There are two problems that hamper the comparability of these predictions, which currently limit their clinical utility. First, the prognoses were derived from separate studies with dissimilar patient characteristics. For instance, women with unexplained subfertility who received IVF are generally older than women who pursued expectant management. Second, the prognosis after IVF is expressed per embryo transfer or per complete IVF cycle while the prognosis associated with expectant management is expressed in terms of calendar time, commonly over 1 year (Daya, 2005).

We can address these problems by adjusting for differences between couples who were treated with IVF and couples who pursued expectant management and expressing predicted chances over a uniform time horizon. To this end, we opted for a pragmatic approach by analysing data from three observational cohorts: the UK national IVF registry and two groups of couples (from the Netherlands and Scotland, respectively) who embarked on a variable period of expectant management.

Our aim was threefold. First, to use individual patient data from these three cohorts to compare the average absolute unadjusted 1-year chance of conception after IVF or expectant management. Second, to compare the adjusted 1-year chance of conception after IVF or expectant management and third, to estimate the effectiveness of IVF in individual patients based on their clinical characteristics.