IVF for unexplained subfertility; whom should we treat?

Abstract

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.

Keywords: Cox proportional hazards; IVF; cohort; expectant management; individual prognoses; matching; natural conception; survival analysis; treatment registry; unexplained subfertility.

Figure 1

Flowchart of recruitment and inclusion/exclusion in the three cohorts.

Figure 2

Overlap of patient characteristics for couples who received IVF and couples who underwent expectant management. (A) Distribution of female age per treatment group, depicted by relative frequency (density). (B) Distribution of duration of subfertility per treatment group, depicted as the proportion of couples per group who had a certain (rounded) duration.

Figure 3

Association between female age and the 1-year chance of conception after receiving IVF or pursuing expectant management for a primary subfertile couple who have been trying to conceive for 2 years. Grey bands are 95% confidence limits.

Figure 4

Association between duration of subfertility and the 1-year chance of conception receiving IVF or pursuing expectant management for a primary subfertile couple of which the woman is 35 years old. Grey bands are 95% confidence limits.