Evaluation of costs associated with fertility treatment leading to a live birth after one fresh transfer: A global perspective.

Considerable costs are associated with infertility treatment, but little evidence is available on the main drivers of treatment costs. This cost analysis investigated key costs for treatment with assisted reproductive technology (ART) and the proportion of costs attributed to the acquisition of recombinant human follicle-stimulating hormone (r-hFSH) alfa originator for one fresh embryo transfer (ET) leading to a live birth in Spain, Norway, the UK, Germany, Denmark, South Korea, Australia, and New Zealand. The total costs for one ART cycle with a fresh ET leading to a live birth varied between countries (€4108-€12,314). Costs for pregnancy and live birth were the major contributors in European countries, and the costs of oocyte retrieval, monitoring during ovarian stimulation, pregnancy, and live birth were the top contributors in the Asia-Pacific countries, included in this analysis. Acquisition costs for r-hFSH alfa originator contributed to only 5%-17% of the total costs of one ART cycle with one fresh ET leading to a live birth.

Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35-40 years: A German database study.

This non-interventional study compared the effectiveness of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) (2:1 ratio) versus r-hFSH alone for ovarian stimulation (OS) during assisted reproductive technology treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register (D·I·R). Numerically higher clinical pregnancy (29.8% [95% CI 28.2, 31.6] vs. 27.8% [26.5, 29.2]) and live birth (20.3% [18.7, 21.8] vs. 18.0% [16.6, 19.4]) rates were observed with r-hFSH:r-hLH versus r-hFSH alone. The treatment effect was consistently higher for r-hFSH:r-hLH compared with r-hFSH alone in terms of clinical pregnancy (relative risk [RR] 1.16 [1.05, 1.26]) and live birth (RR 1.16 [1.02, 1.31]) in a post-hoc analysis of women with 5-14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of r-hFSH:r-hLH for OS in women aged 35-40 years with normal ovarian reserve.

The need for longitudinal data on the value of fertility treatment for infertile patients' quality of life: A review and pilot study.

Infertility threatens the life goal of parenthood and, hence, quality of life (QoL) of (wo)men, but the fertility clinic trajectory might be burdensome. This review of longitudinal studies and pilot longitudinal study examines the impact of the pre-in vitro fertilization (IVF) fertility clinic trajectory on patient-reported outcome measures (PROMs) for emotional well-being, including QoL. A publication found that the diagnostic workup decreases men's infertility-specific distress while publications disagree whether it decreases (wo)men's anxious and depressive reactions. Intrauterine insemination (IUI) was found to increase (wo)men's depressive reactions. Publications on infertility-specific, health-related, and overall QoL were missing. The pilot indicated that (wo)men's overall QoL is not affected by the diagnostic workup but is decreased by the time of the third IUI. Longitudinal studies on the impact of starting the fertility clinic trajectory on PROMs are needed as they are essential for patient-centered clinical decision-making and patient-centered policy-level decision-making.

What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis.

BACKGROUND: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE: A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS: The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES: The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS: Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

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.

Great expectations of IVF patients: the role of gender, dispositional optimism and shared IVF prognoses.

STUDY QUESTION: Which success rates do female and male IVF patients expect, what determines their expectations and do patients reconsider their expectations after receiving a personal IVF prognosis at the expense of anxious reactions? SUMMARY ANSWER: Female and male IVF patients have unrealistic high expectations which are positively associated with their dispositional optimism, and which are only reconsidered by patients receiving a less than average IVF prognosis, which leads to more anxious reactions in females. WHAT IS KNOWN ALREADY: Female patients undergoing IVF are known to have unrealistic expectations of the success of their own IVF cycle. The available evidence suggests women expect above average performance of their fertility clinic and (family) reproductive systems. The association of gender and personality trait dispositional optimism, with expectations of IVF success and the impact of providing couples with their IVF prognosis have not been studied previously. STUDY DESIGN, SIZE, DURATION: A total of 148 partnered individuals participated in this prospective survey at two separate points in treatment: following oocyte aspiration (T1) and embryo transfer (T2) (2019-2020, participation rate = 85%). At the time of embryo transfer, gynaecologists provided couples with their IVF prognosis, calculated with the Adapted van Loendersloot model. Women and their male partners completed questionnaires independently and immediately following oocyte aspiration and embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Dispositional optimism ('LOT-R' questionnaire) and expectations of IVF success (numerical rating scale) were assessed in eligible couples commencing a 2nd-6th IVF cycle on T1. Expectations of IVF success and anxiety ('Spielberger State-Anxiety Inventory') were (re)assessed on T2. The inter-partner correlation of expectations of IVF success was examined. Linear mixed models examined hypothesized determinants of expectations of IVF success (T1) and explored (determinants of) whether participants reconsidered their expectations after receiving their IVF prognosis (T1-T2) and whether couple's IVF prognosis was associated with anxious reactions (T2). MAIN RESULTS AND THE ROLE OF CHANCE: The mean of the IVF success rates expected by patients immediately after oocyte aspiration was 59.1% (±20.0), irrespective of gender (P = 0.077). Partners expectations of IVF success were moderately correlated (r = 0.483; P < 0.001). Expectations of IVF success were positively associated with the participant's dispositional optimism (P < 0.001) but were not associated with their partner's dispositional optimism, women's age and their previous (un)successful IVF experiences. Gynaecologists gave couples their calculated IVF prognosis ranging from 4.8% to 69.2% (mean = 30.9%) at the time of embryo transfer. Gender did not influence whether participants reconsidered their expectations after receiving their prognosis. In contrast to the subgroup (n = 78), who received at least an average IVF prognosis and that did not reconsider their expectations of IVF success, the subgroup (n = 70) receiving a below average IVF prognosis lowered their expectations of IVF success (interaction effect: P < 0.001) from 55% to 46%. A below average IVF prognosis was associated with anxious reactions in women but not in men (interaction effect: P = 0.011). LIMITATIONS, REASONS FOR CAUTION: The study design and sample size were more optimal for examining hypothesized determinants of patient's expectations of IVF success than for studying the impact of sharing prognoses with patients. Whether (reconsidering) expectations influences IVF discontinuation rates and achieved live birth rates has yet to be followed-up. WIDER IMPLICATIONS OF THE FINDINGS: Clinics are advised to offer patients the opportunity of receiving their IVF prognosis. Providing prognoses is in line with patient preferences and tempers the unrealistic high expectations of both partners in couples with a less than average prognosis. A sensitive communication style is indicated, as lower prognoses are associated with mild anxious reactions in women. STUDY FUNDING/COMPETING INTEREST(S): E.A.F.D. holds a postdoctoral fellowship of the Research Foundation-Flanders (12H9819N) and this study was funded by the Research Council of the KU Leuven (C14/18/106; project of J.V., K.P. and E.A.F.D.) and as an investigator sponsored study of K.P. and E.A.F.D. by Merck nv/sa Belgium, an affiliate of Merck KGaA, Darmstadt, Germany. The authors declare no conflict of interest related to this study. TRIAL REGISTRATION NUMBER: N/A.

The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis.

STUDY QUESTION: Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle? SUMMARY ANSWER: Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination. WHAT IS KNOWN ALREADY: Administration of GnRH agonists for a period of 3-6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation. STUDY DESIGN, SIZE, DURATION: A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar in both groups. The primary outcome studied-CPHB after the initiated ART treatment-did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41-3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57-3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group. LIMITATIONS, REASONS FOR CAUTION: Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely. WIDER IMPLICATIONS OF THE FINDINGS: Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient's concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation-Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801. TRIAL REGISTRATION DATE: Registration for EudraCT on 1 March 2013. DATE OF FIRST PATIENT'S ENROLMENT: 4 September 2013.

Reduced FSH and LH action: implications for medically assisted reproduction.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play complementary roles in follicle development and ovulation via a complex interaction in the hypothalamus, anterior pituitary gland, reproductive organs, and oocytes. Impairment of the production or action of gonadotropins causes relative or absolute LH and FSH deficiency that compromises gametogenesis and gonadal steroid production, thereby reducing fertility. In women, LH and FSH deficiency is a spectrum of conditions with different functional or organic causes that are characterized by low or normal gonadotropin levels and low oestradiol levels. While the causes and effects of reduced LH and FSH production are very well known, the notion of reduced action has received less attention by researchers. Recent evidence shows that molecular characteristics, signalling as well as ageing, and some polymorphisms negatively affect gonadotropin action. These findings have important clinical implications, in particular for medically assisted reproduction in which diminished action determined by the afore-mentioned factors, combined with reduced endogenous gonadotropin production caused by GnRH analogue protocols, may lead to resistance to gonadotropins and, thus, to an unexpected hypo-response to ovarian stimulation. Indeed, the importance of LH and FSH action has been highlighted by the International Committee for Monitoring Assisted Reproduction Technologies (ICMART) in their definition of hypogonadotropic hypogonadism as gonadal failure associated with reduced gametogenesis and gonadal steroid production due to reduced gonadotropin production or action. The aim of this review is to provide an overview of determinants of reduced FSH and LH action that are associated with a reduced response to ovarian stimulation.

A large observational data study supporting the PROsPeR score classification in poor ovarian responders according to live birth outcome.

STUDY QUESTION: Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? SUMMARY ANSWER: The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. WHAT IS KNOWN ALREADY: Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). STUDY DESIGN, SIZE, DURATION: The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer-Lemeshow test) were the two conditions required for evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS: The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. MAIN RESULTS AND THE ROLE OF CHANCE: The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was -0.0074 (95% CI: -0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer-Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer-Lemeshow test = 1.266688; P = 0.260). LIMITATIONS, REASONS FOR CAUTION: The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. WIDER IMPLICATIONS OF THE FINDINGS: This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. STUDY FUNDING/COMPETING INTEREST(S): This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Age-related miRNome landscape of cumulus oophorus cells during controlled ovarian stimulation protocols in IVF cycles.

STUDY QUESTION: Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy? SUMMARY ANSWER: Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy. WHAT IS KNOWN ALREADY: Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated. STUDY DESIGN, SIZE, DURATION: This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR). PARTICIPANTS/MATERIALS, SETTING, METHODS: COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value <0.05) of co-expressed miRNAs. MAIN RESULTS AND THE ROLE OF CHANCE: We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs. LIMITATIONS, REASONS FOR CAUTION: We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study. WIDER IMPLICATIONS OF THE FINDINGS: miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women. STUDY FUNDING/COMPETING INTEREST: This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA. TRIAL REGISTRATION NUMBER: N/A.

Estimation of the Endometriosis Fertility Index prior to operative laparoscopy.

STUDY QUESTION: Can the Endometriosis Fertility Index (EFI) be estimated accurately before surgery? SUMMARY ANSWER: The EFI can be estimated accurately based on mere clinical/ultrasound information, with some improvement after adding data from diagnostic laparoscopy. WHAT IS KNOWN ALREADY: The EFI is a validated clinical instrument predicting the probability of pregnancy after endometriosis surgery without the use of ART. Being an end-of-surgery-score, it implies the decision for operative laparoscopy to be made in advance-hence, its role in the pre-surgical decision-making process remains to be established. STUDY DESIGN, SIZE, DURATION: Single-cohort prospective observational study in 82 patients undergoing complete endometriosis excision (between June and December 2016). Two methods were used to estimate the final EFI: type A based on non-surgical clinical/ultrasound findings only, and type B based on the combination of non-surgical clinical/ultrasound findings and diagnostic laparoscopy data. To calculate EFI type A, an algorithm was created to translate non-surgical clinical/imaging information into rASRM (revised American Society of Reproductive Medicine)-and EFI points. EFI type A and type B estimates were assessed for their clinical and numerical agreement with the final EFI score. Agreement was defined as clinical if EFI scores were within the same range (0-4, 5-6, 7-10), and numerical if their difference was ≤1. PARTICIPANTS/MATERIALS, SETTING, METHODS: All 82 patients underwent complete laparoscopic CO2-laser excision of any rASRM stage of endometriosis in the Leuven University Fertility Centre (LUFC) of University Hospitals Leuven, a tertiary referral centre for both endometriosis and infertility. An anonymized clinical research file was created. For each patient, three different data sets were created, in order to allow the estimation of the (surgical part) EFI and of the rASRM scores, defined as follows: 'Estimated type A' contained only non-surgical clinical/imaging data, 'Estimated type B' included type A information plus the information of the diagnostic laparoscopy and 'Final EFI' included information of type A, type B and all intra-operative information required to calculate the final EFI. To calculate EFI type A without surgical information, a set of rules was used to translate pre-surgical clinical/imaging information into (rASRM and EFI points). Scoring was done by one person (C.T.), with a time interval of 4 weeks between sessions for each EFI type. Next to the EFI, also rASRM score and stage were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: Agreement rate between estimated EFI type A and final EFI was high for both the clinical (0.915; 95% CI 0.832-0.965) and numerical definition (0.878; 95% CI 0.787-0.940). Agreement rates between estimated EFI type B and final EFI were even higher (clinical (0.988; 95% CI 0.934-1.000), numerical (0.963; 95% CI 0.897-0.992)). LIMITATIONS, REASONS FOR CAUTION: Type A estimation is dependent on high-level gynaecological ultrasound expertise, which may not be available in all clinics. A small number of patients had no prior clinical, ultrasound (hard markers) or surgical confirmation of the diagnosis of endometriosis. When applying the estimated EFI type A in clinical practice, a priori assumptions of the presence or absence of endometriosis will need to be made in adjunct to the estimation of the estimated type A EFI when counselling patients on the potential benefit of an (at least diagnostic) laparoscopy. The level of agreement for type A or B should also be taken into account when counselling patients on the type of efforts undertaken to attempt to diagnose or rule out endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: As this study reports, the EFI can be estimated accurately based on clinical/ultrasound data only without the need for any surgical data. This means that the EFI could be used as an instrument to guide joint physician-patient decision-making between surgery, ART or other fertility management options for the individualized treatment of women with endometriosis-related infertility. STUDY FUNDING/COMPETING INTEREST(S): During this study period, C.T. was supported by FWO (Research Fund Flanders, Grant number 1700816N) and UZ Leuven KOF (University Hospitals Leuven, Klinisch Onderzoeksfonds).The LUFC received unrestricted research grants from Ferring Pharmaceuticals and Merck SA. Gedeon Richter and MSD sponsored travel to and attendance at scientific meetings. C.M. received consultancy fees from Lumenis (paid to KU Leuven, no private revenue). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since 1 October 2015. He continues his academic appointment on a part-time basis as Professor of Reproductive Medicine at the University of Leuven (KU Leuven). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since October 2015. He is also a Guest Professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium, and an Adjunct Professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. This work was initiated before he joined Merck KGaA in October 2015, and completed during the subsequent years. TRIAL REGISTRATION NUMBER: study registration number at UZ Leuven Clinical Trial Centre: S59221.

The stepwise development of an interactive web-based sex education programme for subfertile couples: the Pleasure & Pregnancy programme.

STUDY QUESTION: Can we develop a web-based sex education programme (programme running in a web browser) that addresses the needs of subfertile couples who are advised expectant management for at least 6 months? SUMMARY ANSWER: The 'Pleasure & Pregnancy' programme addresses couples' needs, is likely to improve couples' sexual functioning, and is subsequently hypothesised to improve the chance of natural pregnancy. WHAT IS KNOWN ALREADY: According to professional guidelines (e.g. the Netherlands and UK) couples with unexplained subfertility and a good chance of natural pregnancy, should be advised at least 6 months of expectant management. Adherence to expectant management is challenging as couples and gynaecologist prefer a more active approach. Targeting sexuality may be useful as subfertility is a risk factor for decreased sexual functioning. STUDY DESIGN, SIZE, DURATION: A novel programme was developed according to the three steps of the Medical Research Councils' (MRC) framework. First, relevant literature was explored. Second, an interdisciplinary expert panel developed a theory (based on a systematic literature review and patient interviews) on how the chance of natural conception can be improved. Third, the expected process and outcomes were modelled. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two licenced clinical sexologists, two gynaecologists, a clinical embryologist and two midwife-researchers, all from Belgium and the Netherlands, proposed components for the sex education programme. PubMed was searched systematically for randomised controlled trials (RCTs) evaluating the proposed components in different patient populations. The needs of 12 heterosexual Dutch or Belgian couples who were advised expectant management were explored with in-depth interviews. The content and delivery characteristics of the novel programme were described in detail with the aid of 'Intervention Taxonomy'. To model the outcomes, a protocol for an RCT was designed, registered and submitted for publication. MAIN RESULTS AND THE ROLE OF CHANCE: To help maintain or improve sexual functioning, mainly pleasure, and hence increase pregnancy rates, the web-based Pleasure & Pregnancy programme contains a combination of psychosexual education and couple communication, mindfulness and sensate focus exercises. Information on the biology of conception and interaction with fertility clinic staff and peers were added based on couples' needs to increase potential acceptability. LIMITATIONS AND REASON FOR CAUTION: This paper outlines the development phase of a sex education programme according to the MRC-framework. Whether the Pleasure & Pregnancy programme actually is acceptable, improves sexual functioning, increases pregnancy rates and is cost-effective remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: No previous interactive web-based sex education programme has aimed to increase the natural pregnancy rate of subfertile couples by targeting their sexual pleasure. The Pleasure & Pregnancy programme addresses couples' needs and its effect on sexual functioning and pregnancy rate is plausible but remains to be demonstrated by an RCT which is currently ongoing. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by The Netherlands Organisation for Health Research and Development (ZonMw), Flanders Research Foundation and the University of Amsterdam. C.B.L. is editor-in-chief of Human Reproductionbut was blinded to all parts of the peer review process. The remaining authors have no conflict of interest to report. TRIAL REGISTRATION NUMBER: Not applicable.

Reproducibility of the Endometriosis Fertility Index: a prospective inter-/intra-rater agreement study.

OBJECTIVE: To evaluate the reproducibility of the Endometriosis Fertility Index (EFI). DESIGN: Single-cohort prospective observational study. SETTING: University hospital. POPULATION: Women undergoing laparoscopic resection of any rASRM-stage endometriosis. METHODS: Details of pre- and peroperative findings were collected into a coded research file. EFI scoring was performed en-bloc by three different raters (expert-1 [C.T.], expert-2 [C.M.], junior [C.B.]). Required sample size: 71. Definitions used for agreement: clinical (scores within same range: 0-4, 5-6, 7-10) and numerical (difference ≤1 EFI point). MAIN OUTCOME MEASURES: Primary outcome: rate of clinical agreement between two experts. SECONDARY OUTCOMES: expert numerical agreement, clinical and numerical agreement between expert-1 and junior, and within expert-1 (intra-observer), agreement of rASRM score and -stage. RESULTS: A near 'inter-expert' clinical agreement rate (1.000, 95% CI 0.956-1.000; P = 0.0149) was observed. The numerical agreement between two experts was also high (0.988, 95% CI 0.934-1.000); similarly, high agreement rates were observed for both 'junior-expert' comparisons (clinical 0 .963, 95% CI 0.897-0.992; numerical 0.988, 95% CI 0.934-1.000) and 'intra-expert' comparisons (clinical 0.988, 95% CI 0.934-1.000; numerical 1.000, 95% CI 0.956-1.000). Reasons for disagreements were different scoring of the least-function score and disagreements in rASRM scores. The reproducibility of the rASRM score was clearly inferior to that of the EFI for all comparisons. CONCLUSION: The EFI can be reproduced reliably by different raters, further supporting its use in daily clinical practice as the principal clinical tool for postoperative fertility counselling/management of women with endometriosis. TWEETABLE ABSTRACT: A study confirming the high reproducibility of the EFI substantiates its use in daily clinical practice.

Clinical performance of a specific granulocyte colony stimulating factor ELISA to determine its concentration in follicular fluid as a predictor of implantation success during in vitro fertilization.

This study aimed to demonstrate the clinical performance of an ultra-sensitive follicular fluid (FF) granulocyte colony stimulating factor (G-CSF) immunoassay to confirm previous work, indicating a correlation between FF G-CSF concentration and live birth potential of the corresponding embryo after in vitro fertilization. This study was a noninterventional, prospective, diagnostic clinical multicentric study conducted between August 2012 and January 2014 with 396 single embryo transfers (SETs) from 278 subjects. During oocyte retrieval, FF was individually collected. Embryo morphology and implantation success were evaluated. The implantation success rate in the high G-CSF group (32.3%) was higher than the overall rate (27.5%). Similarly, for embryos with optimal morphology, implantation success rates were highest among those in the high G-CSF concentration category (34.5%) compared with low (19.6%) and intermediate (29.8%) G-CSF concentration categories. Significant differences in mean G-CSF concentrations were observed between the study sites. To minimize bias, analyses were repeated using data from the center with the largest number of SETs. In alignment with the overall analysis, this center demonstrated a 43% greater probability of implantation for optimal embryos with high G-CSF compared to the general implantation rate among optimal embryos and a 327% increase compared with the implantation rate of optimal embryos with low G-CSF.

IDEAL study: magnetic resonance imaging for suspected deep endometriosis assessment prior to laparoscopy is as reliable as radiological imaging as a complement to transvaginal ultrasonography.

OBJECTIVE: To compare the value of using one-stop magnetic resonance imaging (MRI) vs standard radiological imaging as a supplement to transvaginal ultrasonography (TVS) for the preoperative assessment of patients with endometriosis referred for surgery in a tertiary care academic center. METHODS: This prospective observational study compared the diagnostic value of the standard preoperative imaging practice of our center, which involves expert TVS complemented by intravenous urography (IVU) for the evaluation of the ureters and double-contrast barium enema (DCBE) for the evaluation of the rectum, sigmoid and cecum, with that of expert TVS complemented by a 'one-stop' MRI examination evaluating the upper abdomen, pelvis, kidneys and ureters as well as rectum and sigmoid on the same day, for the preoperative triaging of 74 women with clinically suspected deep endometriosis. The findings at laparoscopy were considered the reference standard. Patients were stratified according to their need for monodisciplinary surgical approach, carried out by gynecologists only, or multidisciplinary surgical approach, involving abdominal surgeons and/or urologists, based on the extent to which endometriosis affected the reproductive organs, bowel, ureters, bladder or other abdominal organs. RESULTS: Our standard preoperative imaging approach and the combined findings of TVS and MRI had similar diagnostic performance, resulting in correct stratification for a monodisciplinary or a multidisciplinary surgical approach of 67/74 (90.5%) patients. However, there were differences between the estimation of the severity of disease by DCBE and MRI. The severity of rectal involvement was underestimated in 2.7% of the patients by both TVS and DCBE, whereas it was overestimated in 6.8% of the patients by TVS and/or DCBE. CONCLUSIONS: Complementary to expert TVS, 'one-stop' MRI can predict intraoperative findings equally well as standard radiological imaging (IVU and DCBE) in patients referred for endometriosis surgery in a tertiary care academic center. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Plasma miRNAs as biomarkers for endometriosis.

STUDY QUESTION: Can plasma miRNAs be used for the non-invasive diagnosis of endometriosis in infertile women? SUMMARY ANSWER: miRNA-based diagnostic models for endometriosis failed the test of independent validation. WHAT IS KNOWN ALREADY: Circulating miRNAs have been described to be differentially expressed in patients with endometriosis compared with women without endometriosis, suggesting that they could be used for the non-invasive diagnosis of endometriosis. However, these studies have shown limited consistency or conflicting results, and no miRNA-based diagnostic test has been validated in an independent patient cohort. STUDY DESIGN, SIZE, DURATION: We performed genome-wide miRNA expression profiling by small RNA sequencing to identify a set of plasma miRNAs with discriminative potential between patients with and without endometriosis. Expression of this set of miRNAs was confirmed by RT-qPCR. Diagnostic models were built using multivariate logistic regression with stepwise feature selection. In a final step, the models were tested for validation in an independent patient cohort. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Plasma of all patients was available in the biobank of the Leuven Endometriosis Centre of Excellence. Biomarker discovery and model development were performed in a discovery cohort of 120 patients (controls = 38, endometriosis = 82), and models were tested for validation in an independent cohort of 90 patients (controls = 30, endometriosis = 60). RNA was extracted with the miRNeasy Plasma Kit. Genome-wide miRNA expression analysis was done by small RNA sequencing using the NEBNext small RNA library prep kit and the NextSeq 500 System. cDNA synthesis and qPCR were performed using the Qiagen miScript technology. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a set of 42 miRNAs with discriminative power between patients with and without endometriosis based on genome-wide miRNA expression profiling. Expression of 41 miRNAs was confirmed by RT-qPCR, and 3 diagnostic models were built. Only the model for minimal-mild endometriosis (Model 2: hsa-miR-125b-5p, hsa-miR-28-5p and hsa-miR-29a-3p) had diagnostic power above chance performance in the independent validation (AUC = 60%) with an acceptable sensitivity (78%) but poor specificity (37%). LIMITATIONS, REASONS FOR CAUTION: The diagnostic models were built and tested for validation in two patient cohorts from a single tertiary endometriosis centre. Further validation tests in large cohorts with patients from multiple endometriosis centres are needed. WIDER IMPLICATION OF THE FINDINGS: Our study supports a possible biological link between certain miRNAs and endometriosis, but the potential of these miRNAs as clinically useful biomarkers is questionable in women with infertility. Large studies in well-described patient cohorts, with rigorous methodology for miRNA expression analysis, sufficient statistical power and an independent validation step, are necessary to answer the question of whether miRNAs can be used as diagnostics markers for endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by a grant from the Research Foundation - Flanders (FWO). A.V., D.F.O. and D.P. are PhD fellows from the FWO. T.D. is vice president and Head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Patient-centeredness and endometriosis: Definition, measurement, and current status.

The patient-centeredness of care is important for health care quality, especially because it was recently associated with health-related quality of life, which is increasingly being recognized as the ultimate outcome parameter of health care. Therefore, insight into the definition, measurement, and current status of the patient-centeredness of clinics is important for all health care professionals caring for patients with endometriosis. The definition of patient-centered endometriosis care is based on research into the most common preferences, needs, and values of patients with endometriosis and can be summarized in ten dimensions. One valid and reliable questionnaire exists, the ENDOCARE questionnaire, which allows measuring the patient-centeredness status of an endometriosis clinic. This questionnaire has been used to benchmark centers in different countries and has allowed the identification of ten targets for improving the patient-centeredness of endometriosis care. The next step would be to use the ENDOCARE questionnaire before and after an improvement project.

Efficacy and safety of follitropin alfa/lutropin alfa in ART: a randomized controlled trial in poor ovarian responders.

STUDY QUESTION: How does the efficacy and safety of a fixed-ratio combination of recombinant human FSH plus recombinant human LH (follitropin alfa plus lutropin alfa; r-hFSH/r-hLH) compare with that of r-hFSH monotherapy for controlled ovarian stimulation (COS) in patients with poor ovarian response (POR)? SUMMARY ANSWER: The primary and secondary efficacy endpoints were comparable between treatment groups and the safety profile of both treatment regimens was favourable. WHAT IS KNOWN ALREADY: Although meta-analyses of clinical trials have suggested some beneficial effect on reproductive outcomes with r-hLH supplementation in patients with POR, the definitions of POR were heterogeneous and limit the comparability across studies. STUDY DESIGN, SIZE, DURATION: Phase III, single-blind, active-comparator, randomized, parallel-group clinical trial. Patients were followed for a single ART cycle. A total of 939 women were randomized (1:1) to receive either r-hFSH/r-hLH or r-hFSH. Randomization, stratified by study site and participant age, was conducted via an interactive voice response system. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women classified as having POR, based on criteria incorporating the ESHRE Bologna criteria, were down-regulated with a long GnRH agonist protocol and following successful down-regulation were randomized (1:1) to COS with r-hFSH/r-hLH or r-hFSH alone. The primary efficacy endpoint was the number of oocytes retrieved following COS. Safety endpoints included the incidence of adverse events, including ovarian hyperstimulation syndrome (OHSS). Post hoc analyses investigated safety outcomes and correlations between live birth and baseline characteristics (age and number of oocytes retrieved in previous ART treatment cycles or serum anti-Müllerian hormone (AMH)). The significance of the treatment effect was tested by generalized linear models (Poisson regression for counts and logistic regression for binary endpoints) adjusting for age and country. MAIN RESULTS AND THE ROLE OF CHANCE: Of 949 subjects achieving down-regulation, 939 were randomized to r-hFSH/r-hLH (n = 477) or r-hFSH (n = 462) and received treatment. Efficacy assessment: In the intention-to-treat (ITT) population, the mean (SD) number of oocytes retrieved (primary endpoint) was 3.3 (2.71) in the r-hFSH/r-hLH group compared with 3.6 (2.82) in the r-hFSH group (between-group difference not statistically significant). The observed difference between treatment groups (r-hFSH/r-hLH and r-hFSH, respectively) for efficacy outcomes decreased over the course of pregnancy (biochemical pregnancy rate: 17.3% versus 23.9%; clinical pregnancy rate: 14.1% versus 16.8%; ongoing pregnancy rate: 11.0% versus 12.4%; and live birth rate: 10.6% versus 11.7%). An interaction (identified post hoc) between baseline characteristics related to POR and treatment effect was noted for live birth, with r-hFSH/r-hLH associated with a higher live birth rate for patients with moderate or severe POR, whereas r-hFSH was associated with a higher live birth rate for those with mild POR. A post hoc logistic regression analysis indicated that the incidence of total pregnancy outcome failure was lower in the r-hFSH/r-hLH group (6.7%) compared with the r-hFSH group (12.4%) with an odds ratio of 0.52 (95% CI 0.33, 0.82; P = 0.005). Safety assessment: The overall proportion of patients with treatment-emergent adverse events (TEAEs) occurring during or after r-hFSH/r-hLH or r-hFSH use (stimulation or post-stimulation phase) was 19.9% and 26.8%, respectively. There was no consistent pattern of TEAEs associated with either treatment. LIMITATIONS, REASONS FOR CAUTION: Despite using inclusion criteria for POR incorporating the ESHRE Bologna criteria, further investigation is needed to determine the impact of the heterogeneity of POR in the Bologna patient population. The observed correlation between baseline clinical characteristics related to POR and live birth rate, as well as the observed differences between groups regarding total pregnancy outcome failure were from post hoc analyses, and the study was not powered for these endpoints. In addition, the attrition rate for pregnancy outcomes in this trial may not reflect general medical practice. Furthermore, as the patient population was predominantly White these results might not be applicable to other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: In the population of women with POR investigated in this study, although the number of oocytes retrieved was similar following stimulation with either a fixed-ratio combination of r-hFSH/r-hLH or r-hFSH monotherapy, post hoc analyses showed that there was a lower rate of total pregnancy outcome failure in patients receiving r-hFSH/r-hLH, in addition to a higher live birth rate in patients with moderate and severe POR. These findings are clinically relevant and require additional investigation. The benefit:risk balance of treatment with either r-hFSH/r-hLH or r-hFSH remains positive. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Merck KGaA, Darmstadt, Germany. P.H. has received honoraria for lectures and unrestricted research grants from Ferring, Merck KGaA and MSD. D.R. is a former employee of EMD Serono, a business of Merck KGaA, Darmstadt, Germany. J.S., J.H. and W.C. are employees of EMD Serono Research and Development Institute, a business of Merck KGaA, Darmstadt, Germany. T.D.'H. and S.L. are employees of Merck KGaA, Darmstadt, Germany. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16. TRIAL REGISTRATION DATE: ClinicalTrials.gov: 24 January 2014; EudraCT: 19 December 2013. DATE OF FIRST PATIENT'S ENROLMENT: 30 January 2014.