Ovarian stimulation strategies for intrauterine insemination in couples with unexplained infertility: a systematic review and individual participant data meta-analysis.

BACKGROUND: Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for unexplained infertility. Gonadotrophins, letrozole and clomiphene citrate (CC) are commonly used agents during IUI-OS and have been compared in multiple aggregate data meta-analyses, with substantial heterogeneity and no analysis on time-to-event outcomes. Individual participant data meta-analysis (IPD-MA) is considered the gold standard for evidence synthesis as it can offset inadequate reporting of individual studies by obtaining the IPD, and allows analyses on treatment-covariate interactions to identify couples who benefit most from a particular treatment. OBJECTIVE AND RATIONALE: We performed this IPD-MA to compare the effectiveness and safety of ovarian stimulation with gonadotrophins, letrozole and CC and to explore treatment-covariate interactions for important baseline characteristics in couples undergoing IUI. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO from their inception to 28 June 2021. We included randomized controlled trials (RCTs) comparing IUI-OS with gonadotrophins, letrozole and CC among couples with unexplained infertility. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA Collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Secondary outcomes were other reproductive outcomes, including time to conception leading to live birth. We performed a one-stage random effects IPD-MA. OUTCOMES: Seven of 22 (31.8%) eligible RCTs provided IPD of 2495 couples (62.4% of the 3997 couples participating in 22 RCTs), of which 2411 had unexplained infertility and were included in this IPD-MA. Six RCTs (n = 1511) compared gonadotrophins with CC, and one (n = 900) compared gonadotrophins, letrozole and CC. Moderate-certainty evidence showed that gonadotrophins increased the live birth rate compared to CC (6 RCTs, 2058 women, RR 1.30, 95% CI 1.12-1.51, I2 = 26%). Low-certainty evidence showed that gonadotrophins may also increase the multiple pregnancy rate compared to CC (6 RCTs, 2058 women, RR 2.17, 95% CI 1.33-3.54, I2 = 69%). Heterogeneity on multiple pregnancy could be explained by differences in gonadotrophin starting dose and choice of cancellation criteria. Post-hoc sensitivity analysis on RCTs with a low starting dose of gonadotrophins (≤75 IU) confirmed increased live birth rates compared to CC (5 RCTs, 1457 women, RR 1.26, 95% CI 1.05-1.51), but analysis on only RCTs with stricter cancellation criteria showed inconclusive evidence on live birth (4 RCTs, 1238 women, RR 1.15, 95% CI 0.94-1.41). For multiple pregnancy, both sensitivity analyses showed inconclusive findings between gonadotrophins and CC (RR 0.94, 95% CI 0.45-1.96; RR 0.81, 95% CI 0.32-2.03, respectively). Moderate certainty evidence showed that gonadotrophins reduced the time to conception leading to a live birth when compared to CC (6 RCTs, 2058 women, HR 1.37, 95% CI 1.15-1.63, I2 = 22%). No strong evidence on the treatment-covariate (female age, BMI or primary versus secondary infertility) interactions was found. WIDER IMPLICATIONS: In couples with unexplained infertility undergoing IUI-OS, gonadotrophins increased the chance of a live birth and reduced the time to conception compared to CC, at the cost of a higher multiple pregnancy rate, when not differentiating strategies on cancellation criteria or the starting dose. The treatment effects did not seem to differ in women of different age, BMI or primary versus secondary infertility. In a modern practice where a lower starting dose and stricter cancellation criteria are in place, effectiveness and safety of different agents seem both acceptable, and therefore intervention availability, cost and patients' preferences should factor in the clinical decision-making. As the evidence for comparisons to letrozole is based on one RCT providing IPD, further RCTs comparing letrozole and other interventions for unexplained infertility are needed.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Cost-effectiveness of ovarian stimulation agents for IUI in couples with unexplained subfertility.

STUDY QUESTION: Which agent for ovarian stimulation (OS) is the most cost-effective option in terms of net benefit for couples with unexplained subfertility undergoing IUI? SUMMARY ANSWER: In settings where a live birth is valued at €3000 or less, between €3000 and €55 000 and above €55 000, clomiphene citrate (CC), Letrozole and gonadotrophins were the most cost-effective option in terms of net benefit, respectively. WHAT IS KNOWN ALREADY: IUI-OS is a common first-line treatment for couples with unexplained subfertility and its increased uptake over the past decades and related personal or reimbursed costs are pressing concerns to patients and health service providers. However, there is no consensus on a protocol for conducting IUI-OS, with differences between countries, clinics and settings in the number of cycles, success rates, the agent for OS and the maximum number of dominant follicles in order to minimise the risk of a multiple pregnancy. In view of this uncertainty and the association with costs, guidance is needed on the cost-effectiveness of OS agents for IUI-OS. STUDY DESIGN, SIZE, DURATION: We developed a decision-analytic model based on a decision tree that follows couples with unexplained subfertility from the start of IUI-OS to a protocoled maximum of six cycles, assuming couples receive four cycles on average within one year. We chose the societal perspective, which coincides with other perspectives such as that from health care providers, as the treatments are identical except for the stimulation agent. We based our model on parameters from a network meta-analysis of randomised controlled trials for IUI-OS. We compared the following three agents: CC (oral medication), Letrozole (oral medication) and gonadotrophins (subcutaneous injection). PARTICIPANTS/MATERIALS, SETTING, METHODS: The main health outcomes were cumulative live birth and multiple pregnancy. As the procedures are identical except for the agent used, we only considered direct medical costs of the agent during four cycles. The main cost-effectiveness measures were the differences in costs divided by the differences in cumulative live birth (incremental cost-effectiveness ratio, ICER) and the probability of the highest net monetary benefit in which costs for an agent were deducted from the live births gained. The live birth rate for IUI using CC was taken from trials adhering to strict cancellation criteria included in a network meta-analysis and extrapolated to four cycles. We took the relative risks for the live birth rate after Letrozole and gonadotrophins versus CC from that same network meta-analysis to estimate the remaining absolute live birth rates. The uncertainty around live birth rates, relative effectiveness and costs was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE: The agent with the lowest cumulative live birth rate over 4 IUI-OS cycles conducted within one year was CC (29.4%), followed by Letrozole (32.0%) and gonadotrophins (34.5%). The average costs per four cycles were €362, €434 and €1809, respectively. The ICER of Letrozole versus CC was €2809 per additional live birth, whereas the ICER of gonadotrophins versus Letrozole was €53 831 per additional live birth. When we assume a live birth is valued at €3000 or less, CC had the highest probability of maximally 65% to achieve the highest net benefit. Between €3000 and €55 000, Letrozole had the highest probability of maximally 62% to achieve the highest net benefit. Assuming a monetary value of €55 000 or more, gonadotrophins had the highest probability of maximally 56% to achieve the highest net benefit. LIMITATIONS, REASONS FOR CAUTION: Our model focused on population level and was thus based on average costs for the average number of four cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. WIDER IMPLICATIONS OF THE FINDINGS: The high uncertainty surrounding our results indicate that more research is necessary on the relative effectiveness of using CC, Letrozole or gonadotrophins for IUI-OS in terms of the cumulative live birth rate. We suggest that in the meantime, CC or Letrozole are the preferred choice of agent. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by ZonMw Doelmatigheidsonderzoek, grant 80-85200-98-91072. The funder had no role in the design, conduct or reporting of this work. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. All other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?

STUDY QUESTION: Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years? SUMMARY ANSWER: If a live birth is considered worth €32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above €32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF. WHAT IS KNOWN ALREADY: IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM. STUDY DESIGN, SIZE, DURATION: We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE: From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54-64% and the average costs from approximately €4000 to €9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately €31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately €20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between €20 000 and €50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of €32 000. When we assume a monetary value per live birth over €50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth. LIMITATIONS, REASONS FOR CAUTION: Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation. WIDER IMPLICATIONS OF THE FINDINGS: EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. TRIAL REGISTRATION NUMBER: N/A.

Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis.

STUDY QUESTION: What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6-12 months for infertile women of age ≥35 years? SUMMARY ANSWER: Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY: In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION: A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms 'fertility service', 'waiting list', 'treatment-independent' and 'spontaneous conception'. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle-Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE: We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5-8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35-42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11-0.19) after 6 months and 0.24 (95% CI 0.17-0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04-0.11) after 6 months and 0.13 (95% CI 0.07-0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION: In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS: Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility. STUDY FUNDING/COMPETING INTEREST(S): S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet. PROSPERO REGISTRATION NUMBER: CRD42018096552.

Endometrial thickness as a biomarker for ongoing pregnancy in IUI for unexplained subfertility: a secondary analysis.

STUDY QUESTION: What is, in couples with unexplained subfertility undergoing IUI, the impact of gonadotrophins compared to clomiphene citrate (CC) on endometrial thickness (EMT) in relation to ongoing pregnancy? SUMMARY ANSWER: In women with unexplained subfertility undergoing IUI with ovarian stimulation, gonadotrophins lead to a thicker endometrium compared to CC, but this does not affect ongoing pregnancy rates. WHAT IS KNOWN ALREADY: A systematic review and meta-analysis among couples with unexplained subfertility undergoing IUI with ovarian stimulation showed that women who conceived had, on average, a thicker endometrium than women who did not conceive, but this evidence is not robust due to a high level of heterogeneity. There was insufficient data to draw any conclusions on EMT and the effect on pregnancy outcomes. STUDY DESIGN SIZE DURATION: We performed a secondary analysis of a multicentre randomized controlled superiority trial in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria. In total, 738 couples recruited between July 2013 and March 2016 were allocated to ovarian stimulation with gonadotrophins (n = 369) or with CC (n = 369) for a maximum of four IUI cycles. According to local protocol, recombinant FSH, urinary FSH or hMG was used. Natural conceptions and cancelled cycles were removed from this secondary analysis, as they do not provide any information on pregnancy in relation to stimulation after IUI. Ongoing pregnancy was defined as a positive heartbeat at or beyond 12 weeks of gestation. PARTICIPANTS/MATERIALS SETTING METHODS: We first determined the difference in EMT between women randomized to gonadotrophins (75 IU) and CC (100 mg) over all cycles using a linear mixed model. We then investigated the association between EMT and ongoing pregnancy after IUI using a logistic regression model, adjusted for the allocated drug, number of dominant follicles, female age, BMI, duration of subfertility, primary or secondary subfertility, referral status, smoking status, cycle number and total motile sperm count. To conclude, we investigated the association between EMT and ongoing pregnancy by logistic regression separately in women allocated to gonadotrophins and in women allocated to CC. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 666 couples underwent 1968 IUI cycles. Of these, 330 couples were allocated to gonadotrophins, of which 85 conceived leading to ongoing pregnancy (rate per cycle 8.9%) and 336 couples were allocated to CC, of which 71 conceived leading to ongoing pregnancy (rate per cycle 7.0%) (relative risk (RR) 1.22, 95% CI 0.92 to 1.61). The mean EMT was 8.9 mm (SD 2.1) in women treated with gonadotrophins and 7.5 mm (SD 2.1) in women treated with CC (adjusted mean difference 1.4 mm; 95% CI: 1.1-1.7). The overall mean EMT was 8.4 mm (SD 2.2) in women that conceived leading to ongoing pregnancy and 8.2 mm (SD 2.2) in women that did not conceive (adjusted odds ratio (OR): 1.03 per 1 mm increase, 95% CI 0.95-1.12). There was no association between EMT and ongoing pregnancy in women treated with gonadotrophins or CC (OR: 1.01 per 1 mm increase, 95% CI 0.90-1.13, and 1.10 per 1 mm increase, 95% CI 0.99-1.23, respectively). LIMITATIONS REASON FOR CAUTION: Since this is a secondary analysis, the data should be interpreted prudently as secondary analyses are prone to false-positive findings or could be underpowered to show associations that the study is not primarily set up for. WIDER IMPLICATIONS OF THE FINDINGS: In women with unexplained subfertility and treated with IUI, gonadotrophins lead to a significantly thicker endometrium compared to CC, but there was no evidence of a consistent association between EMT in women treated with gonadotrophins or CC and the ongoing pregnancy rate. A relatively thin endometrium after CC is therefore not a valid reason to prefer gonadotrophins as the stimulation agent in IUI for unexplained subfertility. STUDY FUNDING/COMPETING INTERESTS: The initial trial was funded by the Netherlands Organization for Health Research and Development (ZonMw) (Health Care Efficiency Research; project number: 80-83600-98-10 192). The EudraCT number for this trial was 2013-001034-18. Prof. Dr B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NTR 4057.

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

STUDY QUESTION: 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? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN SIZE DURATION: 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. PARTICIPANTS/MATERIALS SETTING METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTERESTS: 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.

IVF for unexplained subfertility; whom should we treat?

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.

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

STUDY QUESTION: 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? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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.

Follicle stimulating hormone or clomiphene citrate in intrauterine insemination with ovarian stimulation for unexplained subfertility: a role for treatment selection markers?

RESEARCH QUESTION: Can women be identified, on the basis of baseline patient characteristics, as having better chances of an ongoing pregnancy with FSH instead of clomiphene citrate as stimulation agent in intrauterine insemination for unexplained subfertility? DESIGN: A secondary analysis of a multicentre randomized controlled superiority trial; the SUPER study. Between July 2013 and March 2016, couples with unexplained subfertility undergoing intrauterine inemination (IUI) were allocated to an FSH or clomiphene citrate group. Female age, body mass index, duration of subfertility, primary versus secondary subfertility, antral follicle count and total motile count were assessed. For each of these factors, a logistic regression model was developed to assess if different estimated effects of FSH versus clomiphene citrate on ongoing pregnancy occurred within strata of each factor. RESULTS: A total of 684 couples received 2259 IUI cycles; 338 couples were allocated to FSH, of which 84 conceived leading to ongoing pregnancy and 346 couples were allocated to clomiphene citrate, of which 71 conceived leading to ongoing pregnancy. None of the treatment selection markers was associated with better ongoing pregnancy chances after IUI with FSH compared with clomiphene citrate. CONCLUSION: In couples with unexplained subfertility undergoing IUI, no baseline treatment selection markers could be identified to determine whether ovaries should be stimulated with FSH or clomiphene citrate.

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

STUDY QUESTION: Does starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management in couples with unexplained subfertility? SUMMARY ANSWER: IUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year. WHAT IS KNOWN ALREADY: IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI-OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple's prognosis of natural conception. STUDY DESIGN, SIZE, DURATION: A prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month 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. MAIN RESULTS AND THE ROLE OF CHANCE: Data from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47-2.62) compared to expectant management. The effect of treatment was modified by a couple's prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21-28%) for expectant management and 24% (95% CI: 9-36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15-19%) for expectant management and 24% (95% CI: 15-32%) for starting IUI-OS. LIMITATIONS, REASONS FOR CAUTION: The effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets. WIDER IMPLICATIONS OF THE FINDINGS: These results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost-)effective. STUDY FUNDING/COMPETING INTEREST(S): This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest.

The therapeutic effect of hysterosalpingography in couples with unexplained subfertility: a post-hoc analysis of a prospective multi-centre cohort study.

RESEARCH QUESTION: Hysterosalpingography (HSG) with an oil-based contrast has been shown to increase ongoing pregnancy rates compared with HSG with water-based contrast, but it remains unclear if an effect of HSG occurs compared with no HSG. DESIGN: A secondary data-analysis of a prospective cohort study among 4556 couples that presented with unexplained subfertility in 38 clinics in the Netherlands between January 2002 and December 2004. A time-varying Cox regression with inverse probability of treatment weighing was used to analyse ongoing pregnancy rates in women after undergoing the HSG procedure (with the use of either water- or oil-based contrast media) compared with women who did not undergo HSG. RESULTS: The probability of natural conception within 24 months after first presentation at the fertility clinic was increased after HSG, regardless of the type of contrast medium used, compared with no HSG (adjusted hazard ratio 1.48, 95% CI 1.26 to 1.73, corresponding to an absolute increase in 6-month pregnancy rate of +6%). When this analysis was limited to HSGs that were made with water-contrast, the treatment effect remained (adjusted hazard ratio 1.40, 95% CI 1.16 to 1.70). CONCLUSIONS: HSG increases the ongoing pregnancy rate of couples with unexplained subfertility compared with no HSG, regardless of the contrast medium used. Results need to be validated in future, preferably randomized, studies.

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

STUDY QUESTION: How well does a previously developed dynamic prediction model perform in an external, geographical validation in terms of predicting the chances of natural conception at various points in time? SUMMARY ANSWER: The dynamic prediction model performs well in an external validation on a Scottish cohort. WHAT IS KNOWN ALREADY: Prediction models provide information that can aid evidence-based management of unexplained subfertile couples. We developed a dynamic prediction model for natural conception (van Eekelen model) that is able to update predictions of natural conception when couples return to their clinician after a period of unsuccessful expectant management. It is not known how well this model performs in an external population. STUDY DESIGN, SIZE, DURATION: A record-linked registry study including the long-term follow-up of all couples who were considered unexplained subfertile following a fertility workup at a Scottish fertility clinic between 1998 and 2011. Couples with anovulation, uni/bilateral tubal occlusion, mild/severe endometriosis or impaired semen quality according to World Health Organization criteria were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endpoint was time to natural conception, leading to an ongoing pregnancy (defined as reaching a gestational age of at least 12 weeks). Follow-up was censored at the start of treatment, at the change of partner or at the end of study (31 March 2012). The performance of the van Eekelen model was evaluated in terms of calibration and discrimination at various points in time. Additionally, we assessed the clinical utility of the model in terms of the range of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE: Of a total of 1203 couples with a median follow-up of 1 year and 3 months after the fertility workup, 398 (33%) couples conceived naturally leading to an ongoing pregnancy. Using the dynamic prediction model, the mean probability of natural conception over the course of the first year after the fertility workup was estimated at 25% (observed: 23%). After 0.5, 1 and 1.5 years of expectant management after the completion of the fertility workup, the average probability of conceiving naturally over the next year was estimated at 18% (observed: 15%), 14% (observed: 14%) and 12% (observed: 12%). Calibration plots showed good agreement between predicted chances and the observed fraction of ongoing pregnancy within risk groups. Discrimination was moderate with c statistics similar to those in the internal validation, ranging from 0.60 to 0.64. The range of predicted chances was sufficiently wide to distinguish between couples having a good and poor prognosis with a minimum of zero at all times and a maximum of 55% over the first year after the workup, which decreased to maxima of 43% after 0.5 years, 34% after 1 year and 29% after 1.5 years after the fertility workup. LIMITATIONS, REASONS FOR CAUTION: The model slightly overestimated the chances of conception by ~2-3% points on group level in the first-year post-fertility workup and after 0.5 years of expectant management, respectively. This is likely attributable to the fact that the exact dates of completion of the fertility workup for couples were missing and had to be estimated. WIDER IMPLICATIONS OF THE FINDINGS: The van Eekelen model is a valid and robust tool that is ready to use in clinical practice to counsel couples with unexplained subfertility on their individualized chances of natural conception at various points in time, notably when couples return to the clinic after a period of unsuccessful expectant management. STUDY FUNDING/COMPETING INTEREST(S): 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). There are no conflicts of interest.

Natural conception rates in couples with unexplained or mild male subfertility scheduled for fertility treatment: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception? SUMMARY ANSWER: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%). WHAT IS KNOWN ALREADY: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable. STUDY DESIGN, SIZE, DURATION: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%. LIMITATIONS, REASONS FOR CAUTION: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive. WIDER IMPLICATIONS OF THE FINDINGS: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts. STUDY FUNDING/COMPETING INTEREST(S): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported. TRIAL REGISTRATION NUMBER: The INeS trial was registered at the Dutch trial registry (NTR 939).

Constructing the crystal ball: how to get reliable prognostic information for the management of subfertile couples.

Couples in whom the results of an initial fertility workup fail to identify the presence of any obvious barriers to conception are diagnosed with unexplained subfertility. Couples who have tried to conceive for a relatively short time have a good chance of natural conception and thus may not benefit from immediate access to ART. As fertility decreases over time, the main dilemma that clinicians and couples face is when to abandon an expectant approach in favour of active treatment. Several prognostic or predictive models have been used to try to discriminate between couples with high and low chances of conception but have been unable to compare individualized chances of conception associated with ART relative to chances of natural conception at various time points. These models are also unable to recalculate the chances of pregnancy at subsequent time points in those who return after a period of unsuccessful expectant management. In this paper, we discuss currently available models. We conclude that in order to provide accurate, individualized and dynamic fertility prognoses associated with and without treatment at different points in time, we need to develop, validate and update clinical prediction models which are fit for purpose. We suggest several steps to move the field forwards.

Natural conception: repeated predictions over time.

STUDY QUESTION: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility? SUMMARY ANSWER: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic. WHAT IS KNOWN ALREADY: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management. STUDY DESIGN, SIZE, DURATION: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup. LIMITATIONS, REASONS FOR CAUTION: The dynamic prediction model needs to be validated in an external population. WIDER IMPLICATIONS OF THE FINDINGS: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup. STUDY FUNDING/COMPETING INTERESTS: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.