I-31: The Scientific Underpinning of ART in Unexplained Infertility

Although intra uterine insemination (IUI) and in vitro fertilization (IVF) are widely accepted treatments among doctors and patients and practiced on large scale, it is good to realize that they have rarely been evaluated properly in randomized clinical trials or even in comparative cohort studies. Although the first pregnancy after IUI was established in 1884, it was not until 2008 that the first and sofar only randomized clinical trial (RCT) comparing IUI versus natural conception was published. This trial found no evidence of a beneficial effect (RR: 1.4, 95%, CI: 0.90-2.0). Also the addition of superovulation by gonadotrophins to IUI -also only studied in one RCT- in the comparison with natural conception did not show any evidence of an effect (RR: 0.85, 95%, CI: 0.55-1.3) both on short and long term. The pooled data from the only two RCTs available on superovulation with IUI compared to superovulation and natural conception show a RR of 1.4, 95%, CI: 0.62-3.2. Unfortunately, the same lack of evidence applies to IVF. Bob Edwards and Edward Steptoe applied IVF successfully in the 29-year old Lesley Brown who had infertility from blocked tubes, resulting in the birth of Louise Brown, the first ‘‘test tube’’ baby in the world. Subsequently, IVF was applied more and more, also for women with unexplained infertility. From a pathofysiologic point of view it makes sense that IVF is an effective treatment in couples in whom the egg and the sperm do not meet - for instance due to tubal blockage- since it allows fertilisation, where this can not be expected after intercourse. In older women with any reproductive abnormalities, there is no biologic plausibility to assume that fertilization in vitro would be superior over fertilization in vivo. This in itself is worrisome, but even more so in view of the massive epidemic of delayed child wish, since all epidemiologic data available so far pinpoint advanced female age as the most important negative predictive factor for chances of pregnancy after IVF. IVF does not improve the natural decline in female fertility. Most doctors have assumed that expectant management is not acceptable for these women and have offered assisted reproductive technology (ART) as treatment of last resort. As a consequence more and more ‘subfertile’ couples in whom the woman is of advanced age turn to ART for conception. Indeed, the mean age of women undergoing IVF is increasing year after year. However, evidence of a beneficial effect of IVF is simply not there. Only two very small and underpowered RCTs compared IVF with natural conception and the pooled RR is 2.7 (95%. CI: 0.97-7.5). IVF was only compared in one trial and found no evidence of an effect (RR: 1.1, 95%, CI: 0.69-1.7) and IVF versus superovulation IUI was studied in two trials with a common RR of 1.1 (95%, CI: 0.75-1.5) It may be that better patient selection based upon prognosis may provide new data on effectiveness of ART, and provisional data will be given in the presentation. For the time being we can only conclude that we have no evidence whatsoever to justify our practice of ART in couples with unexplained infertility. Until evidence of the contrary becomes available, we should counsel our patients with socalled unexplained infertility that we have found no abnormalities after the fertility workup and that therefore there is no disease and thus no treatment.