A recently published clinical trial of expectant management or stimulated IUI in unexplained infertility patients with a poor outlook for natural conception confirmed the superiority of IUI. A recent editorial has proposed all such treatment should be based on an individualised prognostic approach.
‘Unexplained’ infertility is one of few misnomers in reproductive medicine. There will, of course, be some explanation for this apparent mystery, but as yet the explanation has defied diagnosis. The other paradox of unexplained infertility is that some – even many – of those so diagnosed will become pregnant naturally, which is why ‘keep trying’ – expectant management – is a realistic first approach to treatment. However, patients beyond their mid-30s don’t have too much time to wait, and a more direct intervention is usually needed.
Unexplained infertility is commonly defined as an inability to conceive after 12 months of trying but with no abnormality evident on investigation. Estimates seem to put prevalence at around 10% of all infertility cases, with prospects for pregnancy (natural or assisted) varying according to the usual prognostic factors (female age, duration of infertility, sperm count and motility, previous pregnancy). However, whether the prognosis is good or poor, treatments tend to be from the usual playlist: expectant management, ovarian stimulation (clomiphene citrate, letrozole or gonadotrophins), IUI alone or with stimulation, or IVF/ICSI.
These treatments have been tested head-to-head in many studies, but, according to the background notes of a new reported trial, nearly always in good prognosis cases. However, a recent Cochrane review – after analysing more than 20 RCTs in more than 4000 couples – concluded that the ‘evidence of differences in live birth between expectant management and the other four treatments (OS, IUI, OS‐IUI, and IVF/ICSI) was insufficient’.(1) Thus, shifting the findings into everyday numbers, the Cochrane reviewers estimated that, if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS‐IUI and IVF would be 9-28%, 11-33%, 15-37% and 14-47%, respectively. However, when only couples with a poor prognosis of natural conception were included in the analysis, the Cochrane reviewers found that stimulated IUI and IVF/ICSI increased LBR much better than expectant management (OR 4.48). These results seemed confirmed in a New Zealand RCT reported at the same time (the ‘TUI’ trial) in which women randomised to IUI had a higher cumulative LBR than those assigned to expectant management (31% vs 9%).(2)
Now, this new RCT, of treating unexplained infertility in poor prognosis patients, appears to reaffirm the Cochrane and TUI study conclusions, similarly finding that LBR following stimulated IUI is higher than after an expectant management period of at least six months (33% vs 13%).(3) The study was a multicentre RCT performed in a consortium of Dutch clinics in couples deemed of poor prognosis according to the predictive model of Hunault and colleagues (ie, a prediction score of 30% or less for natural conception), first described in 2004.(4) Couples with diagnosed unexplained infertility and a poor prediction score were randomised to either six months expectant management (the experimental group) or a maximum of six cycles stimulated IUI within six months. Mean female age was 34 years in both groups.
The trial was started in 2016 with an intention to recruit 1091 couples, but by September 2020 only 178 couples had been randomised from an initial total of 360 deemed eligible, a rate of decline of around 50%. The trial was thus stopped early ‘because of a slow inclusion rate and resulting lack of funding’, partly attributed to the results (and slow progress) of the New Zealand TUI study. However, analysis plans based on intention-to-treat did go ahead in the Dutch trial, with results showing lower LBR in couples allocated to expectant management than in those allocated to IUI-OS (12/92, 13% vs 28/86, 33%). The difference remained after adjustments for age, BMI and other variables. However, a post-hoc analysis in women aged 38-43 years (albeit small numbers) found similar LBRs in the two groups (16% vs 18%), suggesting to the authors that IUI in this group ‘does not counteract the natural decline in fertility’.
The study report makes interesting comment on its slow rate of recruitment, particularly about the 182 eligible couples who declined to be randomised. Almost one half of them preferred to wait for IUI or IVF, without any ‘uncertainty’ of expectant management. Such arguments have been widely reported in the discussions about add-on treatments or indeed inclusion in other RCTs (especially in Europe), that patients – and their clinics – prefer the more active treatment. Indeed, Shingshetty et al said in a very recent commentary on treating unexplained infertility that many couples ‘are sceptical about an expectant approach and are keen to receive treatment’; and similarly with clinics that ‘this approach [expectant management] has never been popular with clinicians who have tended to favour a treatment pathway based on escalating degrees of invasiveness and/or expense’.(5)
The alternative approach favoured by the editorial is one based on individual prognosis ‘such that a decision to access treatment is based on the estimated chances of natural and treatment-related conception’, rather than a broadside approach of treating all couples with unexplained infertility as a homogeneous group. However, so far – as the HR Open editorial makes clear – the availability of reliable prognostic models is limited, thereby inhibiting the opportunity to ‘allow live predictions to be made at the time of consultation’. And that, they add, will need robust evidence from RCTs to demonstrate the benefit of these models in clinical practice.
Many such trials – many of them of head-to-head treatment studies – are now included in an upcoming ESHRE guideline on unexplained infertility, which is now open for stakeholder review.(6) Many of the recommendations so far listed are based on ‘strong’ evidence, notably that ‘IUI combined with ovarian stimulation is recommended over expectant management’ and ‘is recommended as a first-line treatment’. So far, but subject to stakeholder response, no ‘alternative approaches’ are recommended.
1. Wang R, Danhof NA, Tjon-Kon-Fat RI, et al. Interventions for unexplained infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2019; 9: CD012692.
2. Farquhar CM, Liu E, Armstrong S, et al. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial. Lancet 2018; 391: 441-450. doi.org/10.1016/S0140-6736(17)32406-6
3. Wessel JA, Mochtar MH, Besselink DE, et al. Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial. Hum Reprod 2022; 37: 2808–2816. https://doi.org/10.1093/humrep/deac236
4. 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. doi.org/10.1093/humrep/deh365
5. Shingshetty L, Maheshwari A, McLernon DJ, Bhattacharya S. Should we adopt a prognosis-based approach to unexplained infertility? Hum Reprod Open 2022; hoac046. doi.org/10.1093/hropen/hoac046
6. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Guidelines-in-development/Unexplained-infertility
