The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial.

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.

STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2017.

The cost-effectiveness of transvaginal hydrolaparoscopy versus hysterosalpingography in the work-up for subfertility.

STUDY QUESTION: Is a strategy starting with transvaginal hydrolaparoscopy (THL) cost-effective compared to a strategy starting with hysterosalpingography (HSG) in the work-up for subfertility? SUMMARY ANSWER: A strategy starting with THL is cost-effective compared to a strategy starting with HSG in the work-up for subfertile women. WHAT IS KNOWN ALREADY: Tubal pathology is a common cause of subfertility and tubal patency testing is one of the cornerstones of the fertility work-up. Both THL and HSG are safe procedures and can be used as a first-line tubal patency test. STUDY DESIGN, SIZE, DURATION: This economic evaluation was performed alongside a randomized clinical trial comparing THL and HSG in 300 subfertile women, between May 2013 and October 2016. For comparisons of THL and HSG, the unit costs were split into three main categories: costs of the diagnostic procedure, costs of fertility treatments and the costs for pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subfertile women scheduled for tubal patency testing were eligible. Women were randomized to a strategy starting with THL or a strategy starting with HSG. The primary outcome of the study was conception leading to a live birth within 24 months after randomization. The mean costs and outcomes for each treatment group were compared. We used a non-parametric bootstrap resampling of 1000 re-samples to investigate the effect of uncertainty and we created a cost-effectiveness plane and cost-effectiveness acceptability curves. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 149 women to THL and 151 to HSG, and we were able to achieve complete follow-up of 142 versus 148 women, respectively. After the fertility work-up women were treated according to the Dutch guidelines and based on a previously published prognostic model. In the THL group, 83 women (58.4%) conceived a live born child within 24 months after randomization compared to 82 women (55.4%) in the HSG group (difference 3.0% (95% CI: -8.3 to 14.4)). The mean total costs per woman were lower in the THL group compared to the HSG group (THL group €4991 versus €5262 in the HSG group, mean cost difference = -€271 (95% CI -€273 to -€269)). Although the costs of only the diagnostic procedure were higher in the THL group, in the HSG group more women underwent diagnostic and therapeutic laparoscopies and also had higher costs for fertility treatments. LIMITATIONS, REASONS FOR CAUTION: Our trial was conducted in women with a low risk of tubal pathology; therefore, the results of our study are not generalizable to women with high risk of tubal pathology. Furthermore, this economic analysis was based on the Dutch healthcare system, and possibly our results are not generalizable to countries with different strategies or costs for fertility treatments. WIDER IMPLICATIONS OF THE FINDINGS: After 2 years of follow-up, we found a live birth rate of 58.4% in the THL group versus 55.4% in the HSG group and a lower mean cost per woman in the THL group, with a cost difference of -€271. The findings of our trial suggest that a strategy starting with THL is cost-effective compared to a strategy starting with HSG in the workup for subfertile women. However, the cost difference between the two diagnostic strategies is limited compared to the total cost per woman in our study and before implementing THL as a first-line strategy for tubal patency testing, more research in other fields, such as patient preference and acceptance, is necessary. STUDY FUNDING/COMPETING INTEREST(S): The authors received no external financial support for the research. B.W.J.M. is supported by an NHMRC Investigator Grant (GNT1176437). B.W.J.M. reports consultancy for ObsEva, Merck KGaA, Guerbet. B.W.J.M. reports receiving travel support from Merck KGaA. C.T.P. reports consultancy for Guerbet, outside of this manuscript. All other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: NTR3462.

Tubal flushing with oil-based contrast during transvaginal hydro laparoscopy, a case report.

Background: Oil-based contrast has been shown to have a fertility-enhancing effect during hysterosalpingography (HSG) but is not yet used during transvaginal hydro laparoscopy (THL). Objective: To asses if additional tubal flushing with oil-based contrast during THL is feasible. Materials and Methods: Case report with video assessment. A healthy 29-year-old woman with primary unexplained subfertility, underwent a THL under local anaesthesia. First, chromopertubation was performed by methylene blue. Afterwards, tubal flushing with 3mL oil-based contrast (Lipiodol® UltraFluid, Guerbet) was performed. Main Outcome Measures: In this case report we evaluated the feasibility of additional tubal flushing with oil- based contrast during THL, in terms of; the visibility of the oil-based contrast at the tubal fimbriae, the pain and acceptability scores. Results: Both fallopian tubes were patent to methylene-blue as well as to oil-based contrast. Interestingly, the oil-based contrast came out of the fallopian tube in the form of free droplets with strong internal bonding. Furthermore, some residue of the droplets was visible on the surface of the peritoneal wall in the form of oily micro-droplets. Conclusions: We present the first sub-fertile woman, in which additional tubal flushing with oil-based contrast during THL was performed. It is likely, that the residue of oily micro-droplets is also present inside the fallopian tube, where it may enhance the cilia movement by introducing lubrication. These lubricating characteristics of the oil-based contrast may be important for its fertility-enhancing effect. More research is necessary to confirm this hypothesis and the feasibility of tubal flushing with oil-based contrast during THL in more women.

Fertility-related quality of life in subfertile women undergoing tubal testing with transvaginal hydrolaparoscopy or hysterosalpingography.

OBJECTIVE: Both subfertility and its management can have significant impact on quality of life (QoL). Tubal patency testing as part of the fertility work-up, is considered to cause more physical complaints and stress than other tests. Pain scores for HSG are higher than for THL, but acceptability of the procedures was found to be comparable. Fertility-related QoL has not yet been studied in women undergoing tubal patency testing. STUDY DESIGN: We performed a standardized questionnaire study alongside a previously reported randomized controlled trial comparing THL and HSG in subfertile women, in which 24-month live birth rates occurred in 58.5% versus 55.4%, respectively. We randomly assigned 300 subfertile women to THL or HSG between May 2013 and October 2016. Women were eligible if they were undergoing a fertility work-up with an indication for evaluation of tubal patency. Fertility-related QoL was measured six weeks after the procedure with the validated FertiQoL questionnaire. The scores for the Core scale and subscales between THL and HSG were compared using Mann-Whitney-U test and multiple linear regression analysis. RESULTS: The questionnaire was completed by 84 women in the THL group (56%) and 96 women in the HSG group (64%). Core scores were 74.6 ± 12.8 for THL and 73.4 ± 12.4 for HSG (p = 0.39). Scores for the Emotional domain were 64.5 ± 19.0 for THL versus 66.0 ± 16.3 (p = 0.67) for HSG. Scores for the 'Mind-body' domain for THL were 76.9 ± 15.6 versus 74.1 ± 18.0 for HSG (p = 0.42), while scores for the Relational domain were 79.2 ± 12.9 for THL and 76.9 ± 15.6 for HSG (p = 0.21). Scores for the Social domain for THL were 77.9 ± 15.1 versus 76.7 ± 14.1, (p = 0.42). The multiple linear regression analysis showed only a statistical significant positive effect of older age on the score for the Emotional domain (p = 0.015). CONCLUSION: In a preselected group of women with low risk for tubal pathology we did not find differences in fertility-related QoL between tubal patency testing with THL versus HSG.

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.

Intracervical insemination versus intrauterine insemination with cryopreserved donor sperm in the natural cycle: a randomized controlled trial.

STUDY QUESTION: Is intracervical insemination (ICI) non-inferior to IUI with cryopreserved donor sperm in the natural cycle in terms of live birth? SUMMARY ANSWER: ICI with cryopreserved donor sperm in the natural cycle was inferior to IUI in terms of live birth. WHAT IS KNOWN ALREADY: Both ICI and IUI in the natural cycle are performed as first-line treatments in women who are eligible for donor sperm treatment. High-quality data on the effectiveness of ICI versus IUI with cryopreserved donor sperm in the natural cycle in terms of live birth is lacking. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicentre randomized non-inferiority trial in the Netherlands and Belgium. PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomly allocated women who were eligible for donor sperm treatment with cryopreserved donor semen to six cycles of ICI in the natural cycle or six cycles of IUI in the natural cycle. The primary outcome was conception within 8 months after randomization leading to a live birth. Secondary outcomes were ongoing pregnancy, multiple pregnancy, clinical pregnancy, miscarriage and time to conception leading to live birth. We calculated relative risks (RRs) and risk differences (RDs) with 95% CI. Non-inferiority would be shown if the lower limit of the 95% RD CI was <-12%. MAIN RESULTS AND THE ROLE OF CHANCE: Between June 2014 and February 2019, we included 421 women, of whom 211 women were randomly allocated to ICI and 210 to IUI. Of the 211 women allocated to ICI, 2 women were excluded, 126 women completed treatment according to protocol and 75 women did not complete 6 treatment cycles. Of the 210 women allocated to IUI, 3 women were excluded, 140 women completed treatment according to protocol and 62 women did not complete 6 treatment cycles. Mean female age was 34 years (SD ±4) in both interventions. Conception leading to live birth occurred in 51 women (24%) allocated to ICI and in 81 women (39%) allocated to IUI (RR 0.63, 95% CI: 0.47 to 0.84). This corresponds to an absolute RD of -15%; 95% CI: -24% to -6.9%, suggesting inferiority of ICI. ICI also resulted in a lower live birth rate over time (hazard ratio 0.58, 95% CI: 0.41-0.82). Our per-protocol analysis showed that, within the 8 months treatment horizon, 48 women (38%) had live births after ICI and 79 women (56%) had live births after IUI (RR 0.68, 95% CI: 0.52-0.88; RD -18%, 95% CI: -30% to -6%). LIMITATIONS, REASONS FOR CAUTION: The study was non-blinded owing 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: Since ICI in the natural cycle was inferior to IUI in the natural cycle with cryopreserved donor sperm in terms of live birth rate, IUI is the preferred treatment. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw project number 837002407). B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437), reports consultancy for ObsEva and has received research funding from Guerbet, Ferring and Merck. The other authors do not declare a COI. TRIAL REGISTRATION NUMBER: NTR4462. TRIAL REGISTRATION DATE: 11 March 2014. DATE OF FIRST PATIENT'S ENROLMENT: 03 June 2014.

Oil-based versus water-based contrast media for hysterosalpingography in infertile women of advanced age, with ovulation disorders or a high risk for tubal pathology: study protocol of a randomized controlled trial (H2Oil2 study).

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. METHODS: We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. DISCUSSION: This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as 'H2Oil2' (reference number NL7925, https://www.trialregister.nl/trial/7925 ).

Consequences of cervical pessary for subsequent pregnancy: follow-up of randomized clinical trial (ProTWIN).

OBJECTIVE: To evaluate the effect of cervical pessary, as a strategy to prevent preterm birth (PTB), on the outcome of subsequent pregnancy and maternal quality of life 4 years after the index twin pregnancy. METHODS: Between 2009 and 2012, the ProTWIN trial randomized women with a multiple pregnancy to pessary use vs standard care for the prevention of PTB. The trial showed no benefit in unselected women with a twin pregnancy, but showed a 60% reduction in poor perinatal outcomes in favor of the pessary group in the subgroup of women with a mid-trimester short cervix (cervical length < 38 mm). All women were invited to participate in a follow-up study 4 years after their participation in the ProTWIN trial. In this follow-up study, maternal quality of life was assessed using the EQ-5D-3L questionnaire and women were asked separate questions about subsequent pregnancies. Results were compared between women who were randomized to the pessary vs the control group in the ProTWIN trial by calculating relative risk (RR) and 95% CI. Subgroup analysis was performed for women with a mid-trimester short cervix (cervical length < 38 mm). RESULTS: Of the 813 women included in the ProTWIN trial, 408 (50.2%) participated in this follow-up study, comprising 228 randomized to the pessary group and 180 to the control group in the original trial. The median interval between participation in the ProTWIN trial and participation in this follow-up study was 4.1 (interquartile range (IQR), 3.9-7.1) years. Ninety-eight (24.0%) participants tried to conceive after their participation in the ProTWIN trial. Of those, 22 (22.4%) women did not have a subsequent pregnancy (no difference between pessary and control groups), seven (7.1%) women had at least one miscarriage but no live birth, and 67 (68.4%) women had at least one live birth (35 in the pessary vs 32 in the control group; RR, 0.93 (95% CI, 0.8-1.07)). In two women, the pregnancy outcome was unknown. Preterm delivery (< 37 weeks of gestation) of the first live birth occurred in three women in the pessary vs one woman in the control group (all singleton; RR, 2.57 (95% CI, 0.28-23.44)). No differences were found between the pessary and control groups in the subgroup of women with mid-trimester short cervix, but the numbers analyzed were small. The median health state index score was 0.95 (IQR, 0.82-0.95), with no difference between the pessary and control groups. CONCLUSION: Our findings suggest that there are no long-term effects of pessary use on the outcome of subsequent pregnancies and maternal quality of life. Data on obstetric outcome were limited due to the small numbers. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The role of PCOS in mental health and sexual function in women with obesity and a history of infertility.

STUDY QUESTION: Do mental health and sexual function differ between women with or without polycystic ovary syndrome (PCOS) with comparable BMI and fertility characteristics? SUMMARY ANSWER: Women with PCOS have a poorer mental quality of life than women without PCOS, but there were no differences in symptoms of depression, anxiety, physical quality of life or sexual function. WHAT IS KNOWN ALREADY: Various studies suggest that women with PCOS have poorer mental health, such as higher symptoms of anxiety and depression with a lower quality of life, and have an impaired sexual function compared to women without PCOS. However, in most studies, BMI and infertility status differ between women with and without PCOS, which may hamper comparability. STUDY DESIGN SIZE DURATION: This study is a cross-sectional analysis of a 5-year follow-up of a randomized controlled trial (RCT) among women with obesity and a history of infertility. PARTICIPANTS/MATERIALS SETTING METHODS: Participants in this follow-up study of an RCT were women with obesity and infertility randomized to a lifestyle intervention followed by infertility treatment or prompt infertility treatment (control), stratified by ovulatory status and trial centre. In total, 173 (30.0%) women of the 577 women randomized in the initial trial participated in this follow-up study, with a mean follow-up of 5.5 years (range 3.7-7.0 years); of these women 73 had been diagnosed with PCOS and 100 did not have PCOS. Participants completed questionnaires on symptoms of anxiety and depression (Hospital Anxiety and Depression scale (HADS)), quality of life (36-item Short Form Health Survey (SF-36)) and sexual function (McCoy Female Sexuality Questionnaire (MFSQ)). We also compared quality of life subscale scores in women with and without PCOS and compared them to an age-matched Dutch reference population with average BMI. Effect sizes were calculated to assess the differences. MAIN RESULTS AND THE ROLE OF CHANCE: Symptoms of anxiety and depression, physical quality of life and sexual function did not differ significantly between obese women with and without PCOS. However, women with PCOS had a worse mental quality of life summary component score (-3.60 [95% CI -6.72 to -0.56]), mainly due to a lower score on the subscale 'role limitations due to emotional problems' (-12.41 [95% CI -22.78 to -2.28]), compared to women without PCOS. However, compared to an age-matched Dutch reference population, the obese infertile women with and without PCOS both scored lower on almost all physical and mental quality of life subscales. LIMITATIONS REASONS FOR CAUTION: These are secondary analyses of the follow-up study of the RCT. No power analysis was performed for the outcomes included in this analysis and, as our study had a relatively small sample size, the null findings could be based on insufficient power to detect small differences between the groups. Our study population had a high mean BMI (average total group 34.5 [SD ± 5.1]); therefore, our results may only be generalizable to women with obesity. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that PCOS status is associated with impaired mental quality of life. Anxiety and depression, physical quality of life and sexual function in obese infertile women with PCOS seem more related to the obesity than the PCOS status. STUDY FUNDING/COMPETING INTERESTS: The initial study and follow-up were supported by grants from: ZonMw (50-50110-96-518), the Dutch Heart Foundation (2013T085) and the European Commission (633595). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands, outside the submitted work. A.H. reports consultancy for Ferring pharmaceuticals. B.W.J.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.J.M. reports consultancy for ObsEva, Merck Merck KGaA, iGenomix and Guerbet. All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: The initial trial was registered on 16 November 2008 in the Dutch trial register; clinical trial registry number NTR1530.

Change in cervical length after arrested preterm labor and risk of preterm birth.

OBJECTIVE: To assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women. METHODS: In this post-hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of < 15 mm or a cervical length of 15-30 mm with a positive fetal fibronectin test. Logistic regression analysis was used to investigate the association of cervical length measured at least 48 h after admission and of the change in cervical length between admission and at least 48 h later, with preterm birth before 34 weeks' gestation and delivery within 7 days after admission. RESULTS: A total of 164 women were included in the analysis. Women whose cervical length increased between admission for threatened preterm labor and 48 h later (32%; n = 53) were found to have a lower risk of preterm birth before 34 weeks compared with women whose cervical length did not change (adjusted odds ratio (aOR), 0.24 (95% CI, 0.09-0.69)). The risk in women with a decrease in cervical length between the two timepoints was not different from that in women with no change in cervical length (aOR, 1.45 (95% CI, 0.62-3.41)). Moreover, greater absolute cervical length after 48 h was associated with a lower risk of preterm birth before 34 weeks (aOR, 0.90 (95% CI, 0.84-0.96)) and delivery within 7 days after admission (aOR, 0.91 (95% CI, 0.82-1.02)). Sensitivity analysis in women randomized to receive no intervention showed comparable results. CONCLUSION: Our study suggests that the risk of preterm birth before 34 weeks is lower in women whose cervical length increases between admission for threatened preterm labor and at least 48 h later when contractions had ceased compared with women in whom cervical length does not change or decreases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial.

STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus. WHAT IS KNOWN ALREADY: A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant. STUDY DESIGN, SIZE, DURATION: We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%). LIMITATIONS, REASONS FOR CAUTION: Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance. WIDER IMPLICATIONS OF THE FINDINGS: The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery. STUDY FUNDING/COMPETING INTEREST(S): There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: Dutch trial registry: NTR 1676. TRIAL REGISTRATION DATE: 18 February 2009. DATE OF FIRST PATIENT'S ENROLMENT: 20 October 2010.

Progesterone for prevention of preterm birth in women with short cervical length: 2-year infant outcomes.

OBJECTIVE: To evaluate the long-term outcomes of children born to women with a short cervix and otherwise low risk for preterm birth, after antenatal exposure to vaginal progesterone vs placebo. METHODS: This was a follow-up study of the Triple P trial, which randomized 80 low-risk women with a short cervix (≤ 30 mm) at 18-22 weeks' gestation to progesterone (n = 41) or placebo (n = 39). At 2 years of corrected age, children were invited for a neurodevelopmental assessment, using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), and a neurological and physical examination by an assessor blinded to the allocated treatment. Parents filled out the Ages and Stages Questionnaire, the Child Behavior Checklist (CBCL) and a general-health questionnaire. The main outcome of interest was mean BSID-III cognitive and motor scores. Additionally, a composite score of mortality and abnormal developmental outcome, including BSID-III ≤-1 SD, CBCL score in the clinical range and/or parental reported physical problems (at least two operations or at least two hospital admissions in the previous 2 years), was evaluated. Our sample size, dictated by the original sample of the Triple P trial, provided 80% power to detect a mean difference (MD) of 15 points (1 SD) between groups for the BSID-III tests. RESULTS: Of the 80 children born to the randomized women, one in the progesterone group and two in the placebo group died in the neonatal period. Follow-up data were obtained for 59/77 (77%) children and BSID-III outcomes in 57 children (n = 28 in the progesterone group and n = 29 in the placebo group) born at a median gestational age of 38 + 6 weeks (interquartile range (IQR), 37 + 3 to 40 + 1 weeks) with a median birth weight of 3240 g (IQR, 2785-3620 g). In the progesterone vs placebo groups, mean BSID-III cognitive development scores were 101.6 vs 105.0 (MD, -3.4 (95% CI, -9.3 to 2.6); P = 0.29) while mean motor scores were 102.4 vs 107.3 (MD, -4.9 (95% CI, -11.2 to 1.4); P = 0.13). No differences were seen between the two groups in physical (including genital and neurological examination), behavioral and health-related outcomes. CONCLUSION: In this sample of children born to low-risk women with a short cervix at screening, no relevant differences in neurodevelopmental, behavioral, health-related and physical outcomes were found between offspring exposed to vaginal progesterone and those exposed to placebo. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Developing a core outcome set for future infertility research: an international consensus development study.

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection, and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCT) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions, and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Ferility and Sterility, and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Annika Strandell reports consultancy fees from Guerbet. Ernest Ng reports research sponsorship from Merck. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Birthweight and other perinatal outcomes of singletons conceived after assisted reproduction compared to natural conceived singletons in couples with unexplained subfertility: follow-up of two randomized clinical trials.

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 75.8 g, 95% CI -102.0 to 253.7; IVF-SET -10.6 g, 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 -157.7 g, 95% CI -277.4 to -38.0). The IVF group had comparable birthweights with the naturally conceived group (adjusted difference 20.9 g, 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 FUNDING/COMPETING INTEREST(S): Both initial trials were supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (INeS 120620027, SUPER 80-83600-98-10192). The INeS study also had a grant from Zorgverzekeraars Nederland, the Dutch association of healthcare insurers (09-003). B.W.J.M. is supported by an NHMRC investigator Grant (GNT1176437) and reports consultancy for ObsEva, Merck Merck KGaA, Guerbet and iGenomix, outside the submitted work. A.H. reports grants from Ferring Pharmaceutical company (the Netherlands), outside the submitted work. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands), Ferring Pharmaceutics BV (the Netherlands) and Gedeon Richter (Belgium), he receives personal fees from educational activities for Ferring BV (the Netherlands) and for advisory and consultancy work for Roche and he receives research support grants from Merck Serono and Ferring Pharmaceutics BV, outside the submitted work. The remaining authors have nothing to disclose. TRIAL REGISTRATION NUMBER: INeS study Trial NL915 (NTR939); SUPER Trial NL3895 (NTR4057).

Developing a core outcome set for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

SOMA-trial: surgery or medication for women with an endometrioma? Study protocol for a randomised controlled trial and cohort study.

STUDY QUESTIONS: The objective of this study is to evaluate the effectiveness and cost-effectiveness of surgical treatment of women suffering from pain due to an ovarian endometrioma when compared to treatment with medication (analgesia and/or hormones). The primary outcome is defined as successful pain reduction (-30% reduction of pain) measured by the numeric rating scale (NRS) after 6 months. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life, affective symptoms, cost-effectiveness, recurrence rate, need of adjuvant medication after surgery, ovarian reserve, adjuvant surgery and budget impact. WHAT IS KNOWN ALREADY: Evidence suggests that both medication and surgical treatment of an ovarian endometrioma are effective in reducing pain and improving quality of life. However, there are no randomised studies that compare surgery to treatment with medication. STUDY DESIGN SIZE DURATION: This study will be performed in a research network of university and teaching hospitals in the Netherlands. A multicentre randomised controlled trial and parallel prospective cohort study in patients with an ovarian endometrioma, with the exclusion of patients with deep endometriosis, will be conducted. After obtaining informed consent, eligible patients will be randomly allocated to either treatment arm (medication or surgery) by using web-based block randomisation stratified per centre. A successful pain reduction is set at a 30% decrease on the NRS at 6 months after randomisation. Based on a power of 80% and an alpha of 5% and using a continuity correction, a sample size of 69 patients in each treatment arm is needed. Accounting for a drop-out rate of 25% (i.e. loss to follow up), we need to include 92 patients in each treatment arm, i.e. 184 in total. Simultaneously, a cohort study will be performed for eligible patients who are not willing to be randomised because of a distinct preference for one of the two treatment arms. We intend to include 100 women in each treatment arm to enable standardization by inverse probability weighting, which means 200 patients in total. The expected inclusion period is 24 months with a follow-up of 18 months. PARTICIPANTS/MATERIALS SETTING METHODS: Premenopausal women (age ≥ 18 years) with pain (dysmenorrhoea, pelvic pain or dyspareunia) and an ovarian endometrioma (cyst diameter ≥ 3 cm) who visit the outpatient clinic will make up the study population. Patients with signs of deep endometriosis will be excluded. The primary outcome is successful pain reduction, which is defined as a 30% decrease of pain on the NRS at 6 months after randomisation. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life and affective symptoms, cost-effectiveness (from a healthcare and societal perspective), number of participants needing additional surgery, need of adjuvant medication after surgery, ovarian reserve and recurrence rate of endometriomas. Measurements will be performed at baseline, 6 weeks and 6, 12 and 18 months after randomisation. STUDY FUNDING/COMPETING INTERESTS: This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-85200-98-91041. The Department of Reproductive Medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck KGaA and Ferring not related to the submitted work. B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck KGaA and Guerbet. V. Mijatovic reports grants from Guerbet, grants from Merck and grants from Ferring outside the submitted work. All authors declare that they have no competing interests concerning this publication. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NTR 7447, http://www.trialregister.nl). TRIAL REGISTRATION DATE: 2 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: First inclusion in randomised controlled trial October 4, 2019. First inclusion in cohort May 22, 2019.

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.