UNEXPLAINED INFERTILITY

The textbook definition and prevalence of unexplained infertility have changed little since the classic definitions of Michael Hull and colleagues in 1985.(1) Then, having studied a population of 708 couples during a single year, they found that 'infertility was unexplained in 28% and the chance of pregnancy (overall 72%) was mainly determined by duration of infertility'. NICE, in its latest (2013) infertility guidance concluded that unexplained infertility affects about 15% of couples seeking help, with some studies reporting a prevalence as high as 37%, especially in older age groups.(2) Incidence has also been found to vary according to definition and diagnosis, which, as an 'exclusion' diagnosis, seems dependent on the normal results of semen analysis, tubal patency and ovulation assessment. Female age and the duration of infertility are also reported as important variables in treatment.(3)

It is because of this inability to define a cause - and thus with no obvious explanation for non-conception - that expectant management as an empirical treatment has achieved high cumulative delivery rates in some studies, though a Cochrane review from 2019 was unable to calculate any difference in efficacy between expectant management and ovarian stimulation alone, IUI with stimulation, and IVF/ICSI.(4) However, despite the low quality of evidence, the review did report that 'compared to expectant management or IUI, OS [ovarian stimulation] may increase the odds of multiple pregnancy, and OS‐IUI probably increases the odds of multiple pregnancy'.

Now, a new meta-analysis, comprising almost 3000 patients, has concluded that the risk of multiple pregnancy in unexplained infertility patients treated with IUI and gonadotrophin stimulation is too great for routine use.(5) Indeed, the authors concluded, 'for every birth gained with the use of gonadotropins, a similar increased risk of multiple gestation occurs.' Analysis showed that the overall relative risk of live birth in the IUI-gonadotrophin patients was 1.09, with the RR of multiple pregnancy only little different at 1.06. This risk of multiples was found greater with higher gonadotrophin doses or 'with lax cancellation policies'.

The authors explain that this 'dichotomous' result was similarly evident in a recent trial (included in the meta-analysis) in which subjects randomised to gonadotrophins had a higher live birth (32%) than with clomiphene (22%) and letrozole (19%), but 32% of all the pregnancies achieved with gonadotrophins were multiple gestations (19% triplets).(6) It was because of such unacceptably high multiple rates, say the authors, that oral stimulation agents - clomiphene citrate and letrozole - became generally preferred as first-line therapy (and because of their lower cost).

The authors describe this latest study as the first meta-analysis to compare live birth rates after IUI with gonadotrophins and oral agents in unexplained infertility. And their results appear to confirm the minimal benefit from gonadotrophin stimulation seen in individual trials, especially with a tight cancellation policy designed to minimise the risk of multiples. Indeed, this analysis showed, when gonadotrophins were used in higher doses or with lax cancellation policies, there was an increased risk of multiple gestations which clearly exceeded the gains in pregnancy and birth.

This pattern was emphatically seen in a Dutch trial reported in 2018 comparing the effect of clomiphene and IUI with FSH and IUI in unexplained infertility.(7) Again, 'with adherence to strict cancellation criteria', stimulation with clomiphene prior to IUI produced comparable cumulative ongoing pregnancy rates as FSH, but with a low multiple pregnancy rate. The authors suggested that a strict cancellation policy was central to the results - and ' a successful solution to reduce the number of multiple pregnancies in IUI'.

The results are likely to strengthen the place of stimulated IUI in the treatment of unexplained infertility, but heighten the risk of multiple gestations with FSH. Certainly, as Danhof et al suggested in 2018, IUI is effective, and 'less invasive, less burdensome and less costly' than IVF, which controversially remains the treatment of choice for NICE in its guidance after two years of expectant management.

1. Hull MG, Glazener CM, Kelly NJ, et al. Population study of causes, treatment, and outcome of infertility. Br Med J 1985; 291: 1693-1697.

2. See https://www.nice.org.uk/guidance/cg156/chapter/Recommendations#unexplained-infertility.

3. Hunault CC, Habbema JD, Eijkemans MJ, et al. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Hum Reprod 2004; 19: 2019-2026.

4. Wang R, Danhof NA, Tjon-Kon-Fat R, et al. Interventions for unexplained infertility: a systematic review and network meta‐analysis. Cochrane Database of Systematic Reviews 2019, Issue 9. Art. No.: CD012692.

5. Zolton JR, Lindner PG, Terry N, et al. Gonadotropins versus oral ovarian stimulation agents for unexplained infertility: a systematic review and meta-analysis. Fertil Steril 2019; 0015-0282/$36.00.

6. Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, gonadotropin, or clomiphene for unexplained infertility. N Engl J Med 2015; 373: 1230–1240.

7. Danhof NA, Van Wely M, Repping S, et al. Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial. Hum Reprod 2018; 33: 1866-1874.