IVF for unexplained subfertility; whom should we treat?

Which couples with unexplained subfertility can expect increased chances of ongoing pregnancy with IVF compared to expectant management? For couples in which the woman is under 40 years of age, IVF is associated with higher chances of conception than expectant management. 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. 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. 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. 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. 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. 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. 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.

van Eekelen R ，van Geloven N ，van Wely M ，Bhattacharya S ，van der Veen F ，Eijkemans MJ ，McLernon DJ ... -  《-》

Is IUI with ovarian stimulation effective in couples with unexplained subfertility?

van Eekelen R ，van Geloven N ，van Wely M ，McLernon DJ ，Mol F ，Custers IM ，Steures P ，Bhattacharya S ，Mol BW ，van der Veen F ，Eijkemans MJ ... -  《-》

Does the effectiveness of IUI in couples with unexplained subfertility depend on their prognosis of natural conception? A replication of the H2Oil study.

Can we replicate the finding that the benefit of IUI-ovarian stimulation (IUI-OS) compared to expectant management for couples with unexplained subfertility depends on the prognosis of natural conception? The estimated benefit of IUI-OS did not depend on the prognosis of natural conception but did depend on when treatment was started after diagnosis, with starting IUI-OS later yielding a larger absolute and relative benefit of treatment. IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials (RCTs) compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found different results. In a previous study (a Dutch national cohort), it was found that the benefit of IUI-OS compared to expectant management seemed dependent on the prognosis of natural conception, but this finding warrants replication. We conducted a secondary analysis of the H2Oil study (n = 1119), a multicentre RCT that evaluated the effect of oil-based contrast versus water-based contrast during hysterosalpingography (HSG). Couples were randomized before HSG and followed up for 3-5 years. We selected couples with unexplained subfertility who received HSG and had follow-up or pregnancy data available. Follow-up was censored at the start of IVF, after the last IUI cycle or at last contact and was truncated at a maximum of 18 months after the fertility workup. The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month the ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting. Data from 975 couples were available. There were 587 couples who received at least one IUI-OS cycle within 18 months after HSG of whom 221 conceived leading to an ongoing pregnancy (rate: 0.74 per couple per year over a median follow-up for IUI of 5 months). The median period between HSG and starting IUI-OS was 4 months. Out of 388 untreated couples, 299 conceived naturally (rate: 0.56 per couple per year over a median follow-up of 4 months). After creating our mimicked trial datasets, starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.50 (95% CI: 1.19-1.89) compared to expectant management. We did not find strong evidence that the effect of treatment was modified by a couple's prognosis of achieving natural conception (Akaike's Information Criterion (AIC) decreased by 1 point). The effect of treatment was dependent on when couples started IUI-OS (AIC decreased by more than 2 points). The patterns of estimated absolute chances over time for couples with increasingly better prognoses were different from the previous study but the finding that starting later yields a larger benefit of treatment was similar. We found IUI-OS increased the absolute chance of pregnancy by at least 5% compared to expectant management. The absolute chance of pregnancy after IUI-OS seems less variable between couples and starting times of treatment than the absolute chance after expectant management. This is a secondary analysis, as the H2Oil trial was not designed with this research question in mind. Owing to sample size restrictions, it remained difficult to distinguish between the ranges of prognoses in which true benefit was found. We replicated the finding that starting IUI-OS later after diagnosis yields a larger absolute and relative benefit of treatment. We did not replicate the dependency of the effect of IUI-OS on the prognosis of natural conception and could not identify clear thresholds for the prognosis of natural conception when IUI-OS was and/or was not effective. Because many of these couples still have good chances of natural conception at the time of diagnosis, we suggest clinicians should advise couples to delay the start of IUI-OS for several months to avoid unnecessary treatment. The H2Oil study (NTR 3270) was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The follow-up study (NTR 6577) was also an investigator-initiated study with funding by Guerbet, France. The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by an Investigator grant (GNT1176437) from the Australian National Health and Medical Research Council (NHMRC). K.D. reports receiving travel and speaker fees from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. V.M. reports receiving travel- and speaker fees as well as research grants from Guerbet.

van Eekelen R ，Rosielle K ，van Welie N ，Dreyer K ，van Wely M ，Mol BW ，Eijkemans MJ ，Mijatovic V ，van Geloven N ... -  《-》

Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility.

Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility? Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis. Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations. A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011. A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands. A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment. We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort. For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey. This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.

McLernon DJ ，Lee AJ ，Maheshwari A ，van Eekelen R ，van Geloven N ，Putter H ，Eijkemans MJ ，van der Steeg JW ，van der Veen F ，Steyerberg EW ，Mol BW ，Bhattacharya S ... -  《-》

External validation of a dynamic prediction model for repeated predictions of natural conception over time.

van Eekelen R ，McLernon DJ ，van Wely M ，Eijkemans MJ ，Bhattacharya S ，van der Veen F ，van Geloven N ... -  《-》