Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Late reproduction is associated with extended female survival but not with familial longevity.

RESEARCH QUESTION: Are age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity? DESIGN: This observational study included 10,255 female participants from a multigenerational historical cohort, the LINKing System for historical family reconstruction (LINKS), and 1258 female participants from 651 long-lived families in the Leiden Longevity Study (LLS). Age at last childbirth and number of children, as outcomes of reproductive success, were compared with individual and familial longevity using the LINKS dataset. In addition, the genetic predisposition in the form of a polygenic risk score (PRS) for age at menopause was studied in relation to familial longevity using the LLS dataset. RESULTS: For each year increase in the age of the birth of the last child, a woman's lifespan increased by 0.06 years (22 days; P = 0.002). The yearly risk for having a last child was 9% lower in women who survived to the oldest 10% of their birth cohort (hazard ratio 0.91, 95% CI 0.86-0.95). Women who came from long-living families did not have a higher mean age of last childbirth. There was no significant association between familial longevity and genetic predisposition to age at menopause. CONCLUSIONS: Female reproductive health associates with a longer lifespan. Familial longevity does not associate to extended reproductive health. Other factors in somatic maintenance that support a longer lifespan are likely to have an impact on reproductive health.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

STUDY QUESTION: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? SUMMARY ANSWER: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. WHAT IS KNOWN ALREADY: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. LARGE SCALE DATA: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. WIDER IMPLICATIONS OF THE FINDINGS: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. STUDY FUNDING/COMPETING INTEREST(S): Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Ministère de l'Économie, de la Science et de l'Innovation du Québec' through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests.

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples? SUMMARY ANSWER: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy. STUDY DESIGN, SIZE, DURATION: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001). LIMITATIONS, REASONS FOR CAUTION: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn. WIDER IMPLICATIONS OF THE FINDINGS: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foam® kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports travel and speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: NTR4746/NL4587 (https://www.trialregister.nl). TRIAL REGISTRATION DATE: 19 August 2014. DATE OF FIRST PATIENT'S ENROLMENT: 7 May 2015.

Anti-Müllerian hormone levels and risk of type 2 diabetes in women.

AIMS/HYPOTHESIS: Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is considered to be a marker of reproductive ageing. Although accelerated reproductive ageing has been associated with a higher risk of type 2 diabetes, research on the relationship between AMH and type 2 diabetes risk is scarce. Therefore, we aimed to investigate whether age-specific AMH levels and age-related AMH trajectories are associated with type 2 diabetes risk in women. METHODS: We measured AMH in repeated plasma samples from 3293 female participants (12,460 samples in total), aged 20-59 years at recruitment, from the Doetinchem Cohort Study, a longitudinal study with follow-up visits every 5 years. We calculated age-specific AMH tertiles at baseline to account for the strong AMH-age correlation. Cox proportional hazards models adjusted for confounders were used to assess the association between baseline age-specific AMH tertiles and incident type 2 diabetes. We applied linear mixed models to compare age-related AMH trajectories for women who developed type 2 diabetes with trajectories for women who did not develop diabetes. RESULTS: During a median follow-up of 20 years, 163 women developed type 2 diabetes. Lower baseline age-specific AMH levels were associated with a higher type 2 diabetes risk (HRT2vsT3 1.24 [95% CI 0.81, 1.92]; HRT1vsT3 1.62 [95% CI 1.06, 2.48]; ptrend = 0.02). These findings seem to be supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages in women who developed type 2 diabetes compared with women who did not. The trajectories also suggested that AMH levels declined at a slower rate in women who developed type 2 diabetes, although differences in trajectories were not statistically significant. CONCLUSIONS/INTERPRETATION: We observed that lower age-specific AMH levels were associated with a higher risk of type 2 diabetes in women. Longitudinal analyses did not show clear evidence of differing AMH trajectories between women who developed type 2 diabetes compared with women who did not, possibly because these analyses were underpowered. Further research is needed to investigate whether AMH is part of the biological mechanism explaining the association between reproductive ageing and type 2 diabetes. Graphical abstract.

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?

RESEARCH QUESTION: What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. DESIGN: A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. RESULTS: Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. CONCLUSIONS: The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.

Individualized ovarian stimulation in IVF/ICSI treatment: it is time to stop using high FSH doses in predicted low responders.

In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes-on average one to two more oocytes in the high versus standard dose group-no beneficial impact on the probability of a live birth has been demonstrated (risk difference, -0.02; 95% CI, -0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in 'the more oocytes, the better'. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).

Organoids can be established reliably from cryopreserved biopsy catheter-derived endometrial tissue of infertile women.

RESEARCH QUESTION: Can organoids be established from endometrial tissue of infertile women and does tissue cryopreservation allow for establishment of organoids comparable to organoids derived from freshly biopsied endometrial tissue? DESIGN: Endometrial tissue was obtained from six infertile women through minimally invasive biopsy using a Pipelle catheter and subjected to organoid development, immediately after biopsy as well as after tissue cryopreservation. Organoid formation efficiency, morphology, expandability potential, endometrial marker expression (immunostaining and reverse transcription quantitative real-time polymerase chain reaction) and hormonal responsiveness (after oestradiol and progesterone treatment) were assessed. RESULTS: Organoids established from both fresh and frozen tissue at comparable efficiency could be passaged long-term and showed similar morphology, i.e. cystic with a central lumen lined by a single epithelial cell layer. They also exhibited comparable expression of endometrial markers and proliferative activity (Ki67 expression). Finally, organoids from freshly biopsied and cryopreserved endometrial tissue showed similar responses to oestradiol and progesterone treatment. CONCLUSIONS: Organoids can be established from cryopreserved endometrial tissue of infertile women and cryopreservation of the biopsy does not affect organoid formation and overall organoid characteristics. Cryopreservation of biopsies for later organoid development facilitates sample collection from any fertility clinic, not just the ones near an organoid laboratory.

Cumulative live birth rates in low-prognosis women.

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Low-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach. MAIN RESULTS AND THE ROLE OF CHANCE: The CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up. LIMITATIONS, REASONS FOR CAUTION: Small numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: The CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman's age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring, and Guerbet. K.F. received unrestricted research grants from Merck Serono, Ferring, and GoodLife. She also received fees for lectures and consultancy from Ferring and GoodLife. A.H. declares that the Department of Obstetrics and Gynaecology, University Medical Centre Groningen received an unrestricted research grant from Ferring Pharmaceuticals BV, the Netherlands. J.S.E.L. has received unrestricted research grants from Ferring, Zon-MW, and The Dutch Heart Association. He also received travel grants and consultancy fees from Danone, Euroscreen, Ferring, AnshLabs, and Titus Healthcare. B.W.J.M. is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, and Guerbet. He also received a research grant from Merck BV and travel support from Guerbet. F.J.M.B. received monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands) and Ferring Pharmaceuticals BV (the Netherlands) for advisory work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Do female age and body weight modify the effect of individualized FSH dosing in IVF/ICSI treatment? A secondary analysis of the OPTIMIST trial.

INTRODUCTION: The OPTIMIST trial revealed that for women starting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, no substantial differences exist in first cycle and cumulative live birth rates between an antral follicle count (AFC)-based individualized follicle-stimulating hormone (FSH) dose and a standard dose. Female age and body weight have been suggested to cause heterogeneity in the effect of FSH dose individualization. The objective of the current study is to evaluate whether these patient characteristics modify the effect of AFC-based individualized FSH dosing in IVF/ICSI treatment. MATERIAL AND METHODS: A secondary data-analysis of the OPTIMIST trial. Women initiating IVF/ICSI treatment were classified as predicted poor (AFC 0-7), suboptimal (AFC 8-10) or hyper responders (AFC >15), and randomly allocated to a standard FSH dose (150 IU/d) or an individualized FSH dose (450, 225 or 100 IU/d for predicted poor, suboptimal and hyper responders, respectively). In each predicted response category, logistic regression models with interaction terms were used to evaluate the presence of effect modification. The first cycle was analyzed, and the primary outcomes were first complete cycle live birth rate (including fresh plus frozen-thawed embryo transfers) and ovarian hyperstimulation syndrome (OHSS) risks. RESULTS: No effect modification was revealed in the predicted poor (n = 234) and suboptimal (n = 277) responders. In the predicted hyper responders (n = 521), the effect of the individualized FSH dose on the first cycle live birth rate was modified by female age (P = 0.02) and the effect on OHSS risks was modified by body weight (P = 0.02). A dose reduction from 150 to 100 IU/d generally decreased the OHSS risks in predicted hyper responders, but also reduced the chance of a live birth in young women, and had no beneficial impact on OHSS risks in women with a relatively low body weight. CONCLUSIONS: In women with a predicted hyper response undergoing IVF/ICSI treatment, female age and body weight seem to modify the effect of FSH dose individualization. Although a reduced FSH starting dose generally decreases the OHSS risks, it may also reduce the chance of a live birth, specifically for young women. Future studies could consider these findings when investigating the optimal approach to reduce OHSS risks while maintaining the probability of a live birth for predicted hyper responders in IVF/ICSI treatment.

Anti-Müllerian Hormone Trajectories Are Associated With Cardiovascular Disease in Women: Results From the Doetinchem Cohort Study.

BACKGROUND: Earlier age at menopause is widely considered to be associated with an increased risk of cardiovascular disease. However, the underlying mechanisms of this relationship remain undetermined. Indications suggest that anti-Müllerian hormone (AMH), an ovarian reserve marker, plays a physiological role outside of the reproductive system. Therefore, we investigated whether longitudinal AMH decline trajectories are associated with an increased risk of cardiovascular disease (CVD) occurrence. METHODS: This study included 3108 female participants between 20 and 60 years of age at baseline of the population-based Doetinchem Cohort. Participants completed ≥1 of 5 consecutive quinquennial visits between 1987 and 2010, resulting in a total follow-up time of 20 years. AMH was measured in 8507 stored plasma samples. Information on total CVD, stroke, and coronary heart disease was obtained through a hospital discharge registry linkage. The association of AMH trajectories with CVD was quantified with joint modeling, with adjustment for age, smoking, oral contraceptive use, body mass index, menopausal status, postmenopausal hormone therapy use, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and glucose levels. RESULTS: By the end of follow-up, 8.2% of the women had suffered from CVD, 4.9% had suffered from coronary heart disease, and 2.6% had experienced a stroke. After adjustment, each ng/mL lower logAMH level was associated with a 21% higher risk of CVD (hazard ratio, 1.21; 95% confidence interval, 1.07-1.36) and a 26% higher risk of coronary heart disease (hazard ratio, 1.25; 95% confidence interval, 1.08-1.46). Each additional ng/mL/year decrease of logAMH was associated with a significantly higher risk of CVD (hazard ratio, 1.46; 95% confidence interval, 1.14-1.87) and coronary heart disease (hazard ratio, 1.56; 95% confidence interval, 1.15-2.12). No association between AMH and stroke was found. CONCLUSIONS: These results indicate that AMH trajectories in women are independently associated with CVD risk. Therefore, we postulate that the decline of circulating AMH levels may be part of the pathophysiology of the increased cardiovascular risk of earlier menopause. Confirmation of this association and elucidation of its underlying mechanisms are needed to place these results in a clinical perspective.

Influence of endometrial thickness on pregnancy rates in modified natural cycle frozen-thawed embryo transfer.

INTRODUCTION: Pregnancy after frozen-thawed embryo transfer (FET) is a multifactorial process. Although embryo quality is a key factor in determining pregnancy, other factors, including maternal determinants, are also considered to be predictive. Even though an association between endometrial thickness measured by transvaginal ultrasound and pregnancy rates has been reported in patients undergoing various assisted reproductive technology treatments, whether endometrial thickness predicts achieving pregnancy after natural cycle FET (NC-FET) remains unclear. MATERIAL AND METHODS: In this cohort study, 463 patients allocated to the modified NC-FET (mNC-FET) arm of a previously published randomized controlled trial were included. Monitoring in mNC-FET cycles consisted of regular ultrasound scans, measuring both dominant follicle and endometrial thickness. When the dominant follicle reached a size of 16-20 mm, an injection of human chorionic gonadotrophin was administered and embryo thawing and transfer planned. No minimal endometrial thickness was defined below which transfer was to be deferred. The primary endpoint was ongoing pregnancy rate. RESULTS: Overall, the ongoing pregnancy rate per started FET cycle was 12.5%. Multivariate regression analyses showed that embryo quality was the only significant predictor for ongoing pregnancy. Mean endometrial thickness did not differ between patients achieving ongoing pregnancy and those who did not (9.0 vs. 8.8 mm, p = 0.4). Comparable results were obtained with regard to clinical pregnancy, live birth and miscarriage rates. The area under the receiver operator curve was 0.5, indicating little discriminatory value of endometrial thickness. CONCLUSIONS: Given that endometrial thickness was not found to be predictive of pregnancy after mNC-FET, cancellation based on endometrial thickness alone may not be justified.

The FOAM study: is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial.

BACKGROUND: Tubal pathology is a causative factor in 20% of subfertile couples. Traditionally, tubal testing during fertility work-up is performed by hysterosalpingography (HSG). Hysterosalpingo-foam sonography (HyFoSy) is a new technique that is thought to have comparable accuracy as HSG, while it is less expensive and more patient friendly. HyFoSy would be an acceptable alternative for HSG, provided it has similar effectiveness in terms of patient outcomes. METHODS/DESIGN: We aim to compare the effectiveness and costs of management guided by HyFoSy or by HSG. Consenting women will undergo tubal testing by both HyFoSy and HSG in a randomized order during fertility work-up. The study group will consist of 1163 subfertile women between 18 and 41 years old who are scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male subfertility or a known contrast (iodine) allergy will be excluded. We anticipate that 7 % (N = 82) of the participants will have discordant test results for HyFoSy and HSG. These participants will be randomly allocated to either a management strategy based on HyFoSy or a management strategy based on HSG, resulting in either a diagnostic laparoscopy with chromopertubation or a strategy that assumes tubal patency (intrauterine insemination or expectant management). The primary outcome is ongoing pregnancy leading to live birth within 12 months after randomization. Secondary outcomes are patient pain scores, time to pregnancy, clinical pregnancy, miscarriage rate, multiple pregnancy rate, preterm birth rate and number of additional treatments. Costs will be estimated by counting resource use and calculating unit prices. DISCUSSION: This trial will compare the effectiveness and costs of HyFoSy versus HSG in assessing tubal patency in subfertile women. TRIAL REGISTRATION: Dutch Trial Register (NTR 4746, http://www.trialregister.nl ). Date of registration: 19 August 2014.

Hysteroscopy before in-vitro fertilisation (inSIGHT): a multicentre, randomised controlled trial.

BACKGROUND: Hysteroscopy is often done in infertile women starting in-vitro fertilisation (IVF) to improve their chance of having a baby. However, no data are available from randomised controlled trials to support this practice. We aimed to assess whether routine hysteroscopy before the first IVF treatment cycle increases the rate of livebirths. METHODS: We did a pragmatic, multicentre, randomised controlled trial in seven university hospitals and 15 large general hospitals in the Netherlands. Women with a normal transvaginal ultrasound of the uterine cavity and no previous hysteroscopy who were scheduled for their first IVF treatment were randomly assigned (1:1) to either hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF (hysteroscopy group) or immediate start of the IVF treatment (immediate IVF group). Randomisation was done with web-based concealed allocation and was stratified by centre with variable block sizes. Participants, doctors, and outcome assessors were not masked to the assigned group. The primary outcome was ongoing pregnancy (detection of a fetal heartbeat at >12 weeks of gestation) within 18 months of randomisation and resulting in livebirth. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01242852. FINDINGS: Between May 25, 2011, and Aug 27, 2013, we randomly assigned 750 women to receive either hysteroscopy (n=373) or immediate IVF (n=377). 209 (57%) of 369 women eligible for assessment in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group had a livebirth from a pregnancy during the trial period (relative risk 1·06, 95% CI 0·93-1·20; p=0·41). One (<1%) woman in the hysteroscopy group developed endometritis after hysteroscopy. INTERPRETATION: Routine hysteroscopy does not improve livebirth rates in infertile women with a normal transvaginal ultrasound of the uterine cavity scheduled for a first IVF treatment. Women with a normal transvaginal ultrasound should not be offered routine hysteroscopy. FUNDING: The Dutch Organisation for Health Research and Development (ZonMW).

Ovarian response to controlled ovarian hyperstimulation: what does serum FSH say?

STUDY QUESTION: Do serum FSH levels on day of hCG trigger differ between women with a poor, normal or hyper response to a fixed daily dose of 150 IU recombinant FSH (rFSH)? SUMMARY ANSWER: There is no consistent relationship between ovarian response and serum FSH levels on day of hCG trigger in a 150 IU fixed dose treatment protocol. WHAT IS KNOWN ALREADY: When ovarian response to stimulation for IVF/ICSI is suboptimal, the FSH dose is often adjusted in a subsequent cycle, thereby assuming that serum FSH levels were inadequate for optimal stimulation. STUDY DESIGN, SIZE, DURATION: Nested cohort study within a randomized controlled trial conducted at the University Medical Centre Utrecht between March 2009 and July 2011. Blood was drawn from 124 women on cycle Day 2 and on day of hCG triggering. Serum FSH level was determined by the Beckman-Coulter Unicel DXi800 chemiluminescence assay. In order to detect a difference of 2 IU/L between poor, normal and hyper responders, a total of 64 participants (16 poor, 32 normal and 16 hyper responders) would provide 80% power, assuming a standard deviation of 2 and an alpha of 0.05. PARTICIPANTS, SETTING, METHODS: Women aged ≤39 years with a regular cycle and fixed FSH dose of 150 IU. Exclusion criteria: BMI > 32 kg/m2 and >2 previous unsuccessful IVF/ICSI cycles. The primary outcome measure was serum FSH level on day of triggering. MAIN RESULTS AND THE ROLE OF CHANCE: Median [range] body weight was 70.0 kg [55.0-85.6], 68.0 kg [52.0-94] and 60.6 kg [51.0-78.0] for poor (n = 16), normal (n = 94) and hyper (n = 17) responders, respectively. Mean (SD) serum FSH levels on day of triggering were 9.5 IU/L (2.4) in poor, 10.4 IU/L (2.3) in normal and 11.5 IU/L (2.2) in hyper responders. Serum FSH levels on day of hCG in poor responders differed significantly as compared to those in hyper responders (P = 0.03). LIMITATIONS, REASONS FOR CAUTION: The number of retrieved oocytes is only minimally determined by serum FSH level on the day of hCG trigger. After correction for age, body weight, basal serum FSH and basal anti-Mullerian hormone the correlation between serum FSH level on the day of hCG and ovarian response regarding the number of retrieved oocytes disappeared. WIDER IMPLICATIONS OF THE FINDINGS: The current study shows that a poor response is not related to inadequate serum FSH levels per se. One could therefore question whether increasing the rFSH dose in women with a suboptimal response is meaningful. In women with a hyper response, however, lowering the dose of rFSH in a subsequent IVF cycle may lead to lower serum FSH levels and thereby mitigate ovarian response and improve safety of the IVF treatment. As this was not a dose-response study, future research should assess whether dose adjustments benefit the poor and hyper responder. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. S.C.O, T.C.v.T., O.H., H.L.T., E.G.W.M.L., C.B.L. and M.J.C.E. have nothing to disclose. F.J.M.B. receives monetary compensation: member of the external advisory board for Merck Serono and Ferring, the Netherlands; educational activities for Ferring BV, the Netherlands; consultancy work for Gedeon Richter, Belgium; strategic cooperation with Roche on automated AMH assay development and research cooperation with Ansh Labs.

Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder.

STUDY QUESTION: Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? SUMMARY ANSWER: Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. WHAT IS KNOWN ALREADY: Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. STUDY DESIGN SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. WIDER IMPLICATIONS OF THE FINDINGS: In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT'S ENROLMENT: 12 May 2011.

Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder.

STUDY QUESTION: Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? SUMMARY ANSWER: In women with a predicted poor ovarian response (AFC < 11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). WHAT IS KNOWN ALREADY: In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC < 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8-10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8-10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78-1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562-1591)], standard FSH dosing was the dominant strategy in our economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. WIDER IMPLICATIONS OF THE FINDINGS: Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC < 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT'S ENROLMENT: 12 May 2011.

Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis.

STUDY QUESTION: Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? SUMMARY ANSWER: In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose. WHAT IS KNOWN ALREADY: In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping. PARTICIPANTS/MATERIALS, SETTING, METHODS: In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results. LIMITATIONS, REASONS FOR CAUTION: Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response. WIDER IMPLICATIONS OF THE FINDINGS: Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

Serum AMH levels in healthy women from BRCA1/2 mutated families: are they reduced?

STUDY QUESTION: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels? SUMMARY ANSWER: BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders. WHAT IS KNOWN ALREADY: It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHOD: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76). LIMITATIONS, REASONS FOR CAUTION: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. WIDER IMPLICATIONS OF THE FINDINGS: Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. STUDY FUNDING/COMPETING INTERESTS: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work. TRIAL REGISTRATION NUMBER: NTR no. 4324.

Semen cryopreservation and usage rate for assisted reproductive technology in 898 men with cancer.

An undesired side effect of cancer treatment is potential subfertility or infertility. Timely cryopreservation of semen is the best modality to ensure fertility. This retrospective data analysis established the usage rate of cryopreserved semen from cancer patients. Pubertal and post-pubertal patients who could become infertile as a result of cancer (treatment) were offered the option to cryopreserve semen prior to treatment. Of the 898 patients who cryopreserved their semen in our hospital, 96 (10.7%) used this for assisted reproductive technology. The live birth rates for intrauterine insemination, in-vitro fertilization, intracytoplasmic sperm injection and cryopreserved embryo transfer were 13%, 29%, 32% and 17%, respectively. Of all couples involved, 77% achieved parenthood, i.e. 60 of the 78 patients (with complete follow-up) fathered at least one child.