Background: Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. Aim: To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. Method: We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. 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. We used a one-stage approach using a random effects model. Results: Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Conclusion: Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

BACKGROUND: IUI for unexplained infertility can be performed in a natural cycle or in combination with ovarian stimulation. A disadvantage of ovarian stimulation is an increased risk of multiple pregnancies with its inherent maternal and neonatal complication risks. Stimulation agents for ovarian stimulation are clomiphene citrate (CC), Letrozole or gonadotrophins. Although studies have compared two or three of these drugs to each other in IUI, they have never been compared to one another in one analysis. OBJECTIVE AND RATIONALE: The objective of this network meta-analysis was to compare the effectiveness and safety of IUI with CC, Letrozole or gonadotrophins with each other and with natural cycle IUI. SEARCH METHODS: We searched PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL and the Clinical Trial Registration Database indexed up to 16 August 2018. We included randomized controlled trials that compared a stimulation regimen with CC, Letrozole or gonadotrophins to each other or to natural cycle IUI among couples with unexplained infertility. We performed the network meta-analysis within a multivariate random effects model. OUTCOMES: We identified 26 studies reporting on 5316 women. The relative risk (RR) for live birth/ongoing pregnancy rates comparing IUI with CC to natural cycle IUI was 1.05 (95% CI 0.63-1.77, low quality of evidence), while comparing IUI with Letrozole to natural cycle IUI was 1.15 (95% CI 0.63-2.08, low quality of evidence) and comparing IUI with gonadotrophins to natural cycle IUI was 1.46 (95% CI 0.92-2.30, low quality of evidence). The RR for live birth/ongoing pregnancy rates comparing gonadotrophins to CC was 1.39 (95% CI 1.09-1.76, moderate quality of evidence), comparing Letrozole to CC was 1.09 (95% CI 0.76-1.57, moderate quality of evidence) and comparing Letrozole to gonadotrophins was 0.79 (95% CI 0.54-1.15, moderate quality of evidence). We did not perform network meta-analysis on multiple pregnancy due to high inconsistency. Pairwise meta-analyses showed an RR for multiple pregnancy rates of 9.11(95% CI 1.18-70.32) comparing IUI with gonadotrophins to natural cycle IUI. There was no data available on multiple pregnancy rates following IUI with CC or Letrozole compared to natural cycle IUI. The RR for multiple pregnancy rates comparing gonadotrophins to CC was 1.42 (95% CI 0.68-2.97), comparing Letrozole to CC was 0.97 (95% CI 0.47-2.01) and comparing Letrozole to gonadotrophins was 0.29 (95% CI 0.14-0.58). In a meta-analysis among studies with adherence to strict cancellation criteria, the RR for live births/ongoing pregnancy rates comparing gonadotrophins to CC was 1.20 (95% CI 0.95-1.51) and the RR for multiple pregnancy rates comparing gonadotropins to CC was 0.80 (95% CI 0.38-1.68). WIDER IMPLICATIONS: Based on low to moderate quality of evidence in this network meta-analysis, IUI with gonadotrophins ranked highest on live birth/ongoing pregnancy rates, but women undergoing this treatment protocol were also at risk for multiple pregnancies with high complication rates. IUI regimens with adherence to strict cancellation criteria led to an acceptable multiple pregnancy rate without compromising the effectiveness. Within a protocol with adherence to strict cancellation criteria, gonadotrophins seem to improve live birth/ongoing pregnancy rates compared to CC. We, therefore, suggest performing IUI with ovarian stimulation using gonadotrophins within a protocol that includes strict cancellation criteria. Obviously, this ignores the impact of costs and patients preference.

STUDY QUESTION: Does assisted reproduction, such as ovarian stimulation and/or laboratory procedures, have impact on perinatal outcomes of singleton live births compared to natural conception in couples with unexplained subfertility? SUMMARY ANSWER: Compared to natural conception, singletons born after intrauterine insemination with ovarian stimulation (IUI-OS) had a lower birthweight, while singletons born after IVF had comparable birthweights, in couples with unexplained subfertility. WHAT IS KNOWN ALREADY: Singletons conceived by assisted reproduction have different perinatal outcomes such as low birthweight and a higher risk of premature birth than naturally conceived singletons. This might be due to the assisted reproduction, such as laboratory procedures or the ovarian stimulation, or to an intrinsic factor in couples with subfertility. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study using the follow-up data of two randomized clinical trials performed in couples with unexplained subfertility. We evaluated perinatal outcomes of 472 live birth singletons conceived after assisted reproduction or after natural conception within the time horizon of the studies. PARTICIPANTS/MATERIALS, SETTING, METHODS: To assess the possible impact of ovarian stimulation we compared the singletons conceived after IUI with FSH or clomiphene citrate (CC) and IVF in a modified natural cycle (IVF-MNC) or standard IVF with single embryo transfer (IVF-SET) to naturally conceived singletons in the same cohorts. To further look into the possible effect of the laboratory procedures, we put both IUI and IVF groups together into IUI-OS and IVF and compared both to singletons born after natural conception. We only included singletons conceived after fresh embryo transfers. The main outcome was birthweight presented as absolute weight in grams and gestational age- and gender-adjusted percentiles. We calculated differences in birthweight using regression analyses adjusted for maternal age, BMI, smoking, parity, duration of subfertility and child gender. MAIN RESULTS AND THE ROLE OF CHANCE: In total, there were 472 live birth singletons. Of the 472 singleton pregnancies, 209 were conceived after IUI-OS (136 with FSH and 73 with CC as ovarian stimulation), 138 after IVF (50 after IVF-MNC and 88 after IVF SET) and 125 were conceived naturally. Singletons conceived following IUI-FSH and IUI-CC both had lower birthweights compared to naturally conceived singletons (adjusted difference IUI-FSH -156.3 g, 95% CI -287.9 to -24.7; IUI-CC -160.3 g, 95% CI -316.7 to -3.8). When we compared IVF-MNC and IVF-SET to naturally conceived singletons, no significant difference was found (adjusted difference IVF-MNC 75.8g, 95% CI -102.0 to 253.7; IVF-SET - I 0.6g, 95% CI -159.2 to 138.1). The mean birthweight percentile was only significantly lower in the IUI-FSH group (-7.0 percentile, 95% CI -13.9 to -0.2). The IUI-CC and IVF-SET group had a lower mean percentile and the IVF-MNC group a higher mean percentile, but these groups were not significant different compared to the naturally conceived group (IUI-CC -5.1 percentile, 95% CI -13.3 to 3.0; IVF-MNC 4.4 percentile, 95% CI -4.9 to 13.6; IVF-SET -1.3 percentile, 95% CI -9.1 to 6.4). Looking at the laboratory process that took place, singletons conceived following IUI-OS had lower birthweights than naturally conceived singletons (adjusted difference - I 57.7 g, 95% CI -277.4 to -38.0). The IVF group had comparable birthweights with the naturally conceived group (adjusted difference 20.9g, 95% CI -110.8 to 152.6). The mean birthweight percentile was significantly lower in the IUI-OS group compared to the natural group (-6.4 percentile, 95% CI -12.6 to -0.1). The IVF group was comparable (0.7 percentile, 95% CI -6.1 to 7.6). LIMITATIONS, REASONS FOR CAUTION: The results are limited by the number of cases. The data were collected prospectively alongside the randomized controlled trials, but analyzed as treated. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest IUI in a stimulated cycle may have a negative impact on the birthweight of the child and possibly on pre-eclampsia. Further research should look into the effect of different methods of ovarian stimulation on placenta pathology and pre-eclampsia in couples with unexplained subfertility using naturally conceived singletons in the unexplained population as a reference.

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.

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . Corrigendum. IUI for unexplained infertility—a network meta-analysis N.A. Danhof, R. Wang, M. van Wely, F. van der Veen, B.W.J. Mol, and M.H. Mochtar * Center for Reproductive Medicine, AmsterdamUMC, Amsterdam, The Netherlands Department of Obstetrics and Gynaecology, Monash University Obstetrics and Gynaecology, AmsterdamUMC, Amsterdam, The Netherlands Monash University

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 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.

BACKGROUND:Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI,  and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making. OBJECTIVES:To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility. SEARCH METHODS:We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials. SELECTION CRITERIA:We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI). DATA COLLECTION AND ANALYSIS:Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence. MAIN RESULTS:We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests 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% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. AUTHORS' CONCLUSIONS:There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.

STUDY QUESTION:Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER:In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN:FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION:We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS:We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE:Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION:We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS:We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S):This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER:Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE:1 July 2013. DATE OF FIRST PATIENT’S ENROLMENT:The first patient was randomized at 27 August 2013.

Objective To study the effectiveness of four cycles of intrauterine insemination (IUI) with ovarian stimulation (OS) by follicle-stimulating hormone (FSH) or by clomiphene citrate (CC), and adherence to strict cancellation criteria.Setting Randomised controlled trial among 22 secondary and tertiary fertility clinics in the Netherlands.Participants 732 women from couples diagnosed with unexplained or mild male subfertility and an unfavourable prognosis according to the model of Hunault of natural conception.Interventions Four cycles of IUI-OS within a time horizon of 6 months comparing FSH 75 IU with CC 100 mg. The primary outcome is ongoing pregnancy conceived within 6 months after randomisation, defined as a positive heartbeat at 12 weeks of gestation. Secondary outcomes are cancellation rates, number of cycles with a monofollicular or with multifollicular growth, number of follicles > 14 mm at the time of ovulation triggering, time to ongoing pregnancy, clinical pregnancy, miscarriage, live birth and multiple pregnancy. We will also assess if biomarkers such as female age, body mass index, smoking status, antral follicle count and endometrial aspect and thickness can be used as treatment selection markers.Ethics and dissemination The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on Research involving Human Subjects (CCMO NL 43131-018-13). Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings.

BackgroundOne of the various ovarian stimulation regimens used for in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles is the use of recombinant follicle-stimulating hormone (rFSH) in combination with a gonadotrophin-releasing hormone (GnRH) analogue. GnRH analogues prevent premature luteinizing hormone (LH) surges. Since they deprive the growing follicles of LH, the question arises as to whether supplementation with recombinant LH (rLH) would increase live birth rates. This is an updated Cochrane Review; the original version was published in 2007.ObjectivesTo compare the effectiveness and safety of recombinant luteinizing hormone (rLH) combined with recombinant follicle-stimulating hormone (rFSH) for ovarian stimulation compared to rFSH alone in women undergoing in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI).Search methodsFor this update we searched the following databases in June 2016: the Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and ongoing trials registers, and checked the references of retrieved articles.Selection criteriaWe included randomised controlled trials (RCTs) comparing rLH combined with rFSH versus rFSH alone in IVF/ISCI cycles.Data collection and analysisTwo review authors independently selected studies, assessed risk of bias, and extracted data. We combined data to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I-2 statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. Our primary outcomes were live birth rate and incidence of ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included ongoing pregnancy rate, miscarriage rate and cancellation rates (for poor response or imminent OHSS).Main resultsWe included 36 RCTs (8125 women). The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias (associated with poor reporting of methods) and imprecision.Live birth rates: There was insufficient evidence to determine whether there was a difference between rLH combined with rFSH versus rFSH alone in live birth rates (OR 1.32, 95% CI 0.85 to 2.06; n = 499; studies = 4; I-2 = 63%, very low-quality evidence). The evidence suggests that if the live birth rate following treatment with rFSH alone is 17% it will be between 15% and 30% using rLH combined with rFSH.OHSS: There may be little or no difference between rLH combined with rFSH versus rFSH alone in OHSS rates (OR 0.38, 95% CI 0.14 to 1.01; n = 2178; studies = 6; I-2 = 10%, low-quality evidence). The evidence suggests that if the rate of OHSS following treatment with rFSH alone is 1%, it will be between 0% and 1% using rLH combined with rFSH.Ongoing pregnancy rate: The use of rLH combined with rFSH probably improves ongoing pregnancy rates, compared to rFSH alone (OR 1.20, 95% CI 1.01 to 1.42; participants = 3129; studies = 19; I-2 = 2%, moderate-quality evidence). The evidence suggests that if the ongoing pregnancy rate following treatment with rFSH alone is 21%, it will be between 21% and 27% using rLH combined with rFSH.Miscarriage rate: The use of rLH combined with rFSH probably makes little or no difference to miscarriage rates, compared to rFSH alone (OR 0.93, 95% CI 0.63 to 1.36; n = 1711; studies = 13; I-2 = 0%, moderate-quality evidence). The evidence suggests that if the miscarriage rate following treatment with rFSH alone is 7%, the miscarriage rate following treatment with rLH combined with rFSH will be between 4% and 9%.Cancellation rates: There may be little or no difference between rLH combined with rFSH versus rFSH alone in rates of cancellation due to low response (OR 0.77, 95% CI 0.54 to 1.10; n = 2251; studies = 11; I-2 = 16%, low quality evidence). The evidence suggests that if the risk of cancellation due to low response following treatment with rFSH alone is 7%, it will be between 4% and 7% using rLH combined with rFSH.We are uncertain whether use of rLH combined with rFSH improves rates of cancellation due to imminent OHSS compared to rFSH alone. Use of a fixed effect model suggested a benefit in the combination group (OR 0.60, 95% CI 0.40 to 0.89; n = 2976; studies = 8; I-2 = 60%, very low quality evidence) but use of a random effects model did not support the conclusion that there was a difference between the groups (OR 0.82, 95% CI 0.34 to 1.97).Authors' conclusions We found no clear evidence of a difference between rLH combined with rFSH and rFSH alone in rates of live birth or OHSS. The evidence for these comparisons was of very low-quality for live birth and low quality for OHSS. We found moderate quality evidence that the use of rLH combined with rFSH may lead to more ongoing pregnancies than rFSH alone. There was also moderate-quality evidence suggesting little or no difference between the groups in rates of miscarriage. There was no clear evidence of a difference between the groups in rates of cancellation due to low response or imminent OHSS, but the evidence for these outcomes was of low or very low quality.We conclude that the evidence is insufficient to encourage or discourage stimulation regimens that include rLH combined with rFSH in IVF/ICSI cycles.

Cervical surgery is associated with preterm birth (PTB) and neonatal morbidity. However, it is unknown whether this increased risk is due to the surgery itself or to the cervical intraepithelial neoplasia (CIN) underlying the surgery. Our objective was to assess the risk for PTB in women with treated and untreated CIN. We performed an electronic literature search in MEDLINE, Embase and CENTRAL for studies that reported on pregnancy outcome after treated and untreated CIN. The methodological quality was scored using the STROBE combined checklist for observational studies. We extracted data on PTB<37 weeks, very PTB<32 weeks, spontaneous PTB<37 weeks, (preterm) premature rupture of membranes ((P)PROM), perinatal mortality and section caesarean each before and after treatment for CIN. We used the Mantel-Haenszel method to estimate summarizing odds ratios. Our search identified 620 studies, of which 20 were reporting on pregnancy outcome for a total of 12,159,293 women. There were 20,832 women who gave birth after treatment for CIN before pregnancy, 52 women who gave birth after treatment for CIN during pregnancy, 64,237 women with CIN who gave birth before treatment, and 8,902,865 women who gave birth without CIN. Compared to women with untreated CIN, women treated for CIN before or during pregnancy, had a significantly higher risk of PTB<37 weeks (OR 1.7, 95% CI 1.0-2.7). When comparing women treated for CIN before pregnancy (n=20,832) to women with untreated CIN (n=64,162), we found an OR of 1.4 with a 95% confidence interval of 0.85-2.3. Women treated during pregnancy had a clearly increased risk for PTB (OR 6.5, 95% CI 1.1-37), and (P)PROM (OR 1.8, 95% CI 1.4-2.2). In women with cervical surgery, the risks for spontaneous PTB<37 weeks (OR 0.87, 95% CI 0.54-1.4), caesarean section (OR 1.0, 95% CI 0.71-1.5) and perinatal mortality (OR 1.0, 95% CI 0.38-2.8) were not increased. The increased risk of PTB in women who underwent cervical surgery for CIN is especially increased when performed during pregnancy. When performed before pregnancy the risk of PTB is increased, although insignificant.

In the United States, ∼12% of all neonates are born preterm. Prior excisional procedures to diagnose and treat cervical dysplasia are a risk factor of preterm delivery. Studies on the risk for preterm birth in women after cold knife conization, laser cone, or loop electrosurgical excision procedure (LEEP) have provided conflicting results. One consideration is whether the increased risk for preterm birth is attributable to the cervical excision procedure itself or secondary to risk factors associated with cervical dysplasia. This review was performed to assess whether LEEP increases the risk for preterm birth before 37 weeks’ gestation and to clarify whether the increased risk for preterm birth is attributable to the procedure or to risk factors associated with cervical dysplasia. The review and meta-analysis were based on a predesigned protocol; PubMed, EMBASE, SCOPUS, CENTRAL, and ClinicalTrials.gov databases were searched. The review included cohort and case-control studies that compared rates of preterm birth in women with prior LEEP and women with no history of cervical excision. The primary outcome was preterm birth at less than 37 weeks. Secondary outcomes were preterm birth at less than 34 weeks, spontaneous preterm birth, preterm premature rupture of membranes, and perinatal mortality. The exposure was a history of LEEP for treatment of cervical dysplasia. Two unexposed categories included women with no or unknown history of cervical dysplasia and women with a history of cervical dysplasia but no excisional procedure. Data were analyzed using Stata 12.0 with METAN software. From 559 publications, 47 studies were examined; the final analysis included 16 retrospective cohort and 2 prospective cohort studies and 1 case-control study. These reports comprised 6589 patients with a history of LEEP (exposed) and 1,415,015 without a history of LEEP (unexposed). All studies reported preterm birth at less than 37 weeks’ gestation as an outcome. Loop electrosurgical excision procedure was associated with a higher risk for preterm birth at less than 37 weeks (8.8% vs 5.1%; pooled relative risk (RR) 1.61; 95% confidence interval [CI], 1.35–1.92; P = 0.001). No statistically significant difference was found in the risk for preterm birth when the prior LEEP group was compared with women with a history of cervical dysplasia but no excision procedure (4 studies: 10.0% vs 7.2%; pooled RR, 1.08; 95% CI, 0.88–1.33; P = 0.654). The association between LEEP and preterm birth persisted when the comparison group was women with either no history or unknown history of dysplasia (15 studies: 8.6% vs 4.6%; pooled RR, 1.86; 95% CI, 1.58–2.21; P = 0.69). In 8 studies, spontaneous preterm birth at less than 37 weeks could specifically be assessed. Although a similar magnitude of increase in risk was found, it was not statistically significant (8 studies: 6.8% vs 3.4%; pooled RR, 1.60; 95% CI, 0.99–2.55). The risk for preterm premature rupture of membranes was increased greater than 2-fold in women with a history of LEEP (6 studies: 5.1% vs 2.5%; pooled RR, 2.37; 95% CI, 1.64–3.44), as was the risk for preterm birth at less than 34 weeks (5 studies: 2.9% vs 2.3%; pooled RR, 2.21; 95% CI, 1.33–3.67). The perinatal mortality risk was elevated in women with a prior LEEP but was not statistically significant (1.0% vs0.8%; pooled RR, 1.63; 95% CI, 0.95–2.80; P = 0.911). Women with a prior LEEP are at increased risk for preterm birth before 37 weeks, but the risk was not significantly different when compared with women with prior dysplasia but no cervical excision. Risk factors of dysplasia and preterm birth are shared, and LEEP itself may not be an independent risk factor of preterm birth. If LEEP is not an independent risk factor of preterm birth, the risk and benefits of LEEP or expectant management might be altered, thus ensuring optimal therapy without fear of increasing the risk for preterm birth.

Objective To determine whether neonatal intensive care unit (NICU) admission is a valid surrogate outcome measure to assess neonatal condition in clinical studies. Design Retrospective study. Setting Tertiary hospital in the Netherlands. Population Neonates admitted to NICU during a 10-year period. Inclusion was restricted to singletons born beyond 37weeks of gestation, and admitted to NICU in the first 24h for delivery-related morbidity. Methods Patient characteristics and admission data were compared for four groups based on the line of care during delivery, i.e. home birth (Ia), midwife-led hospital delivery (Ib), secondary care (II), tertiary care (III). Main outcome measures Percentage of neonates/infants that died during NICU admission, diagnosis on admission, treatment received and a Neonatal Therapeutic Intervention Score System (NTISS). Results We studied 776 newborns (Ia 52, Ib 25, II 160, III 512, 27 unknown). The mortality rate differed significantly (Ia 15%, Ib 12%, II 22%, III 1%, p<0.01), as did the NTISS morbidity scores at admission [Ia 12.0 (6.0-23.0), Ib 8.5 (6.3-10.0), II 21.0 (15.0-30.0), III 6.0 (4.0-9.0); p<0.01], diagnosis at admission, received treatment and the duration of admission. Conclusions The severity of neonatal illness after 37weeks of gestation differed depending on the line of care in which they were born, with neonates born in secondary care consistently having the highest morbidity, and those born in tertiary care having the lowest. NICU admission should not be used as an outcome measure for neonatal morbidity, specifically not when comparing different birth settings.