Search

Donor sperm treatment is advised to be performed with frozen-thawed donor semen. A disadvantage of frozen-thawed semen is lower pregnancy rates compared to inseminations with fresh semen. Semen parameters affect ongoing pregnancy rates in intracervical inseminations with frozen-thawed donor semen. In an attempt to translate this into clinical relevance, cohort studies have tried to find cut-off values for semen parameters after thawing for intracervical insemination, but these studies assessed only one semen parameter per study, thereby overlooking the intricate interplay between all semen parameters. We performed a retrospective cohort study and tried to calculate thresholds for all semen parameters that lead to the best possible ongoing pregnancy rates in intracervical insemination with frozen-thawed donor semen. Between April 1999 and December 2015, data from 1,186 women who underwent 7,103 cycles of intracervical insemination with donor semen from 129 sperm donors were available for analysis. Our results showed that total motility and total motile count (TMC) after thawing were associated with ongoing pregnancy rate. The best possible ongoing pregnancy chances after intracervical insemination were obtained at a total motility of ≥20% and a total motile count (TMC) of ≥8 × 10 6 after thawing.

Research Question: What is the risk of hypogonadism in men with obstructive azoospermia, non-obstructive azoospermia (NOA) or Klinefelter syndrome after testicular sperm extraction (TESE)?, Design: This prospective longitudinal cohort study was carried out between 2007 and 2015., Results: Around 36% of men with Klinefelter syndrome, 4% of men with obstructive azoospermia and 3% of men with NOA needed testosterone replacement therapy (TRT). Klinefelter syndrome was strongly associated with TRT while no association was found between obstructive azoospermia or NOA and TRT. Irrespective of the pre-operative diagnosis, a higher testosterone concentration before TESE was associated with a lower chance of needing TRT., Conclusions: Men with obstructive azoospermia or NOA have a similar moderate risk of clinical hypogonadism after TESE, while this risk is much larger for men with Klinefelter syndrome. The risk of clinical hypogonadism is lower when testosterone concentrations are high before TESE., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Study Question: Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation?, Summary Answer: Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer., What Is Known Already: Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown., Study Design, Size, Duration: This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration., Participants/materials, Setting, Methods: During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle., Main Results and the Role of Chance: No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome., Limitations, Reasons for Caution: The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation., Wider Implications of the Findings: Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence., Study Funding/competing Interest(s): The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work., Trial Registration Number: NTR4108., Trial Registration Date: 6 August 2013., Date of First Patient’s Enrolment: 30 January 2014., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Research Question: Are unmet needs for psychosocial counselling, peer support and friends/family support in parents directly and/or indirectly related to the mental health of parents and their donor-children?, Design: A cross-sectional sample of 214 parents participated in this quantitative study via an online questionnaire. The sample comprised mothers and fathers in a heterosexual relationship (n = 85), mothers in a lesbian relationship (n = 67) and single mothers (n = 62). Parents were recruited via three Dutch fertility clinics and four network organizations. Unmet support needs were measured with an adapted version of the Unmet Needs for Parenting Support questionnaire, changing the original items into items about donor conception. The items were derived from a qualitative study and checked by experts in donor conception. The parents' mental health was measured with the Adult Self Report and the donor-children's mental health with the Child Behaviour Checklist. A multigroup mediation analysis was conducted to explore relationships between parents' unmet support needs and their child's mental health, with the parents' mental health as a possible mediator., Results: There were no direct relations between parents' unmet support needs and the mental health of donor-children. Unmet needs for psychosocial counselling, peer support and friends/family support for parents and children's mental health were indirectly related through the mental health of the parents: 0.074 (CI 95%  = 0.013-0.136; P = 0.017), 0.085 (CI 95% = 0.018-0.151; P = 0.036) and 0.063 (CI 95% = 0.019-0.106; P = 0.013), respectively., Conclusions: We recommend that fertility clinics, network organizations and authorities for infertility counsellors make their support available to parents for extended periods after their treatment. Further qualitative studies are necessary to assess how to relieve unmet support needs during donor sperm treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Research Question: What are the unmet needs after psychosocial counselling and mental health of women who opt for donor sperm treatment (DST), and are unmet counselling needs related to their mental health?, Design: This quantitative study included women in a heterosexual relationship (n = 19), women in a lesbian relationship (n = 25) and single women (n = 51) who opted for DST. Women were included if they had passed the DST intake procedure at a Dutch fertility clinic, were not pregnant and had no previous donor-child. Unmet needs were measured by a self-developed questionnaire based on specific topics identified in a previous qualitative study with added items from experts in the field of DST. The Adult Self Report was used to measure mental health. Relationships between unmet counselling needs and mental health were explored by multiple regression analyses., Results: Fifty-two women (55%) reported unmet counselling needs. Women in heterosexual relationships mostly had unmet counselling needs on the topics of the decision to opt for DST (n = 11, 58%) and non-genetic parenthood (n = 11, 58%); women in lesbian relationships (n = 10, 40%) and single women (n = 14, 27%) mostly had unmet needs on the topic of choosing a sperm donor. In general, women had good mental health, but 13 (14%) met the criteria for clinical mental health problems. Women with more unmet counselling needs also had more mental health problems., Conclusions: Evidence-based guidelines for psychosocial counselling in DST should be developed. Only then can counselling be improved and be fit for purpose., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Origin of human adult Leydig cells (ALCs) is not well understood. This might be partly due to limited data available on the identification and location of human precursor and stem Leydig cells (SLCs) which hampers the study on the development of ALCs., Objectives: The aim of the present study was to investigate whether described human (PDGFRα, NGFR) and rodent (NES, PDGFRα, THY1, NR2F2) SLC markers are expressed by a common cell population within human adult testicular interstitial cells in vivo and before and after in vitro propagation., Materials and Methods: Immunohistochemical analyses were used to identify localization of human adult testicular interstitial cells expressing described SLC markers. Next, interstitial cells were isolated and cultured. The percentage of cells expressing one or more SLC markers was determined before and after culture using flow cytometry., Results: NR2F2 and PDGFRα were present in peritubular, perivascular, and Leydig cells, while THY1 was expressed in peritubular and perivascular cells. Although NES and NGFR were expressed in endothelial cells, co-localization with PDGFRα was found for both in vitro, although for NGFR only after culture. All marker positive cells were able to undergo propagation in vitro., Discussion: The partly overlap in localization and overlap in expression in human testicular cells indicate that PDGFRα, NR2F2, and THY1 are expressed within the same ALC developmental lineage from SLCs. Based on the in vitro results, this is also true for NES and after in vitro propagation for NGFR., Conclusion: Our results that earlier described SLC markers are expressed in overlapping human interstitial cell population opens up further research strategies aiming for a better insight in the Leydig cell lineage and will be helpful for development of strategies to cure ALC dysfunction., (© 2020 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Research Question: Women who face age-related fertility decline have the option to safeguard future reproductive potential by banking oocytes or ovarian tissue. What are the methods that women prefer and what factors are important in their decision-making?, Design: Qualitative interview study, participants were recruited through monthly information sessions at a university hospital on oocyte banking, postings on social media, websites and newsletters and snowball sampling. Women had to be aged 35 years or older, single, childless and with a possible future desire for motherhood. Key concepts of the Health Belief Model were used as framework for the analyses., Results: In total, 15 women participated in this qualitative study. For oocyte banking, they mentioned chances of success, extra time and faith in the technique and healthcare professionals as benefits. Risks for themselves or future children and costs were considered to be barriers in decision making. For ovarian tissue banking, the chances of success, the possibility of natural conception, the time investment and effect on menopausal symptoms were seen as benefits, and lack of experience and lack of information were considered barriers for themselves or their future children. Overall, they considered the procedures involved in oocyte banking as relatively 'easy', whereas ovarian tissue banking was seen as a more invasive procedure., Conclusion: Most women preferred oocyte banking over ovarian tissue banking because of its relative convenience. Future quantitative research in a larger cohort is necessary to confirm the findings and provide more insight into the relative importance of the different factors influencing women's decision., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Research Question: What valid guideline-based quality indicators can measure quality of care in early pregnancy assessment units (EPAU)?, Design: The systematic RAND-modified Delphi method was used to develop an indicator set from four evidence-based guidelines. An international expert panel was assembled to extract recommendations from these guidelines to establish quality indicators., Results: A total of 119 recommendations were extracted. Eleven recommendations received a high median score and top five score above the 75th percentile and were selected as key recommendations. The expert panel reassessed 15 high score recommendations and top five score between the 50th and 75th percentile as well as one high score recommendation without consensus. Eight of these 16 recommendations were selected in the second round as key recommendations. The key recommendations were formulated into a set of 19 quality indicators, summarized as follows: women referred to an EPAU could be seen within 24 h and receive a clear explanation on treatment options; designated senior staff members could be responsible for the unit and staff could have had ultrasound training; protocols could be available for daily practice covering all treatment options for miscarriage and ectopic pregnancy; and an EPAU could have access to urine pregnancy testing and serum HCG assays., Conclusions: Nineteen quality indicators to measure early pregnancy care provided by EPAU were identified., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: What is the cost-effectiveness of gonadotrophins compared with clomiphene citrate in couples with unexplained subfertility undergoing intrauterine insemination (IUI) with ovarian stimulation under strict cancellation criteria?, Design: A cost-effectiveness analysis alongside a randomized controlled trial (RCT). Between July 2013 and March 2016, 738 couples were randomized to gonadotrophins (369) or clomiphene citrate (369) in a multicentre RCT in the Netherlands. The direct medical costs of both strategies were compared. Direct medical costs included costs of medication, cycle monitoring, insemination and, if applicable, pregnancy monitoring. Non-parametric bootstrap resampling was used to investigate the effect of uncertainty in estimates. The cost-effectiveness analysis was performed according to intention-to-treat. The incremental cost-effectiveness ratio (ICER) between gonadotrophins and clomiphene citrate for ongoing pregnancy and live birth was assessed., Results: The mean costs per couple were €1534 for gonadotrophins and €1067 for clomiphene citrate (mean difference of €468; 95% confidence interval [CI] €464-472). As ongoing pregnancy rates were 31% in women allocated to gonadotrophins and 26% in women allocated to clomiphene citrate (relative risk 1.16, 95% CI 0.93-1.47), the ICER was €21,804 (95% CI €11,628-31,980) per additional ongoing pregnancy with gonadotrophins and €17,044 (95% CI €8998-25,090) per additional live birth with gonadotrophins., Conclusions: Gonadotrophins are more expensive compared with clomiphene citrate in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria, without being significantly more effective., (Copyright © 2019. Published by Elsevier Ltd.)

When intended parents choose to have donor sperm treatment (DST), this may entail wide-ranging and long-lasting psychosocial implications related to the social parent not having a genetic tie with the child, how to disclose donor-conception and future donor contact. Counselling by qualified professionals is recommended to help intended parents cope with these implications. The objective of this study is to present findings and insights about how counsellors execute their counselling practices. We performed a qualitative study that included 13 counsellors working in the 11 clinics offering DST in the Netherlands. We held a focus group discussion and individual face-to-face semi-structured interviews, which were fully transcribed and analysed using thematic analysis. The counsellors combined screening for eligibility and guidance within one session. They acted according to their individual knowledge and clinical experience and had different opinions on the issues they discussed with intended parents, which resulted in large practice variations. The counsellors were dependent on the admission policies of the clinics, which were mainly limited to regulating access to psychosocial counselling, which also lead to a variety of counselling practices. This means that evidence-based guidelines on counselling in DST need to be developed to provide consistent counselling with less practice variation.

Background: Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI,  and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making., Objectives: To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility., Search Methods: We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials., Selection Criteria: We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI)., Data Collection and Analysis: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence., Main Results: We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%., Authors' Conclusions: There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.

Introduction: At present, studies comparing intrauterine insemination in the natural cycle versus intracervical insemination in the natural cycle in women undergoing artificial insemination with donor sperm are scarce., Methods and Analysis: We perform a randomised controlled non-inferiority trial among five secondary and tertiary fertility clinics in the Netherlands and one tertiary fertility clinic in Belgium. Women eligible for artificial insemination with donor sperm are included. We perform six cycles of artificial insemination with donor sperm within a time horizon of 8 months comparing intrauterine insemination in the natural cycle with intracervical insemination in the natural cycle. The primary outcome is ongoing pregnancy leading to live birth conceived within eight months after randomisation. Secondary outcomes are clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, pregnancy complications (preterm birth, birth weight <2500 g, pregnancy induced hypertension, (pre-) eclampsia, Hemolysis Elevated Liver enzymes Low Platelets (HELLP)), time to ongoing pregnancy, direct and indirect costs. To demonstrate the non-inferiority of intracervical insemination with a margin of 12%, we need 208 women per arm., Ethics and Dissemination: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on research involving human subjects (47330-018-13). The boards of the participating hospitals approved the study. Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings., Trial Registration Number: NTR4462., Competing Interests: Competing interests: No, there are no competing interests for any author., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objectives: We aimed at exploring the wishes of Dutch donor-conceived offspring for parental support, peer support and counseling and sought to contribute to the improvement of health care for all parties involved with assisted reproductive technologies., Methods: We held semi-structured in-depth interviews with 24 donor-conceived offspring (M age  = 26.9, range 17-41) born within father-mother, two-mother and single mother families. The majority of the donor offspring was conceived with semen of anonymous donors. All offspring were recruited by network organizations and snowball sampling. The interviews were fully transcribed and analyzed using the constant comparative method., Results: Donor-conceived offspring wished that their parents had talked openly about donor conception and had missed parental support. They wished that their parents would have received counseling before donor sperm treatment on how to talk with their children about donor conception in several stages of life. They valued the availability of peer contact to exchange stories with other donor-conceived offspring and would have liked assistance in getting access to trustworthy information about characteristics and identifying information of their donor. Donor-conceived offspring wished to know where to find specialist counseling when needed., Conclusions: Peer support and counseling by professionals for donor-conceived offspring should be available for those who need it. The findings also support professional counseling for intended parents before treatment to improve parental support for donor-children.

Background: Ovulation induction with follicle stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate., Objectives: To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS), and women who do not ovulate or conceive after clomiphene citrate., Search Methods: In January 2018, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, the World Health Organisation clinical trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and Google Scholar. We checked references of in all obtained studies. We had no language restrictions., Selection Criteria: All randomised controlled trials reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate, and undergoing ovulation induction with urinary-derived gonadotrophins, including urofollitropin (uFSH) in purified FSH (FSH-P) or highly purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotrophin (HP-HMG), or recombinant FSH (rFSH), or continuing clomiphene citrate. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinizing hormone, or letrozole., Data Collection and Analysis: Three review authors (NW, EK, and MvW) independently selected studies for inclusion, assessed risk of bias, and extracted study data. Primary outcomes were live birth rate per woman and multiple pregnancy per woman. Secondary outcomes were clinical pregnancy, miscarriage, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotrophin dose, and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the risk ratio (RR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria., Main Results: The review included 15 trials with 2387 women. Ten trials compared rFSH with urinary-derived gonadotrophins (three compared rFSH with human menopausal gonadotrophin, and seven compared rFSH with FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P. One trial compared FSH with continued clomiphene citrate.Recombinant FSH (rFSH) versus urinary-derived gonadotrophinsThere may be little or no difference in the birth rate between rFSH and urinary-derived gonadotrophins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; five trials, N = 505; I² = 9%; low-quality evidence). This suggests that for the observed average live birth per woman who used urinary-derived FSH of 16%, the chance of live birth with rFSH is between 13% and 28%. There may also be little or no difference between groups in incidence of multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; eight trials, N = 1368; I² = 0%; low-quality evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; eight trials, N = 1330; I² = 0; low-quality evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; seven trials, N = 970; I² = 0; low-quality evidence). We are uncertain whether rFSH reduces the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65, ten trials, n=1565, I² = 0%, very low-quality evidence).Human menopausal gonadotrophin (HMG) or HP-HMG versus uFSHWhen compared to uFSH, we are uncertain whether HMG or HP-HMG improves live birth rate (RR 1.28, 95% CI 0.65 to 2.52; three trials, N = 138; I² = 0%; very low quality evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51 to 8.91; four trials, N = 161; I² = 0%; very low quality evidence). We are also uncertain whether HMG or HP-HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; three trials, N = 102; I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; two trials, N = 98; I² = 0%; very low quality evidence), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; two trials, N = 53; very low quality evidence) when compared to uFSH.Gonadotrophins versus continued clomiphene citrateGonadotrophins resulted in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; one trial, N = 661; I² = 0%; moderate-quality evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with FSH was between 43% and 60%. There is probably little or no difference in the incidence of multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; one trial, N = 661; I² = 0%; moderate-quality evidence). Gonadotrophins resulted in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; one trial, N = 661; I² = 0%; moderate-quality evidence), and more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; one trial, N = 661; I² = 0%; moderate-quality evidence). None of the women developed OHSS., Authors' Conclusions: There may be little or no difference in live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate between urinary-derived gonadotrophins and recombinant follicle stimulating hormone in women with polycystic ovary syndrome. For human menopausal gonadotropin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone we are uncertain whether one or the other improves or lowers live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate. We are uncertain whether any of the interventions reduce the incidence of ovarian hyperstimulation syndrome. We suggest weighing costs and convenience in the decision to use one or the other gonadotrophin. In women with clomiphene citrate failure, gonadotrophins resulted in more live births than continued clomiphene citrate without increasing multiple pregnancies.

Research Question: What are the reproductive outcomes of women who bank oocytes for fertility preservation?, Design: A prospective follow-up study of a cohort of 327 women who banked their oocytes for fertility preservation was carried out between July 2009 and August 2015. The indications for oocyte banking and outcomes of ovarian stimulation were collected from medical files. Follow-up data were obtained from an additional questionnaire., Results: In total, 243 out of 327 women (74%) responded and 228 women (70%) consented to participate and returned the questionnaire. The median time to follow-up of these women was 31 months. A total of 101 women (44%) were trying, or had tried, to become pregnant after oocyte banking, of which 66 became pregnant (65%). Five women reported an unintended pregnancy. Of these, 71 women became pregnant, 76% conceived naturally, 7% through intracytoplasmic sperm injection with their vitrified-warmed oocytes and 17% by other medically assisted reproduction treatments. Six women attempted to achieve a pregnancy using their banked oocytes. Of the six pregnancies achieved in five women, two resulted in a live birth. A total of thirty-eight women reported a live birth at the time of follow-up., Conclusion: Oocyte banking can be considered a form of risk management or preventive medicine because it is not certain that the women will experience sterility in the future., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Testicular sperm extraction (TESE) is a surgical procedure to retrieve spermatozoa from the testes of men with azoospermia to help them achieve biological parenthood. Although effective, the surgical procedure is not without complications and haematoma, devascularization, inflammation and a decrease in testosterone levels have been described as such. The prevalence and duration of hypogonadism and associated symptoms after TESE have not been studied systematically., Objective and Rationale: In this systematic review we addressed the following research questions: Are serum testosterone levels decreased after TESE and, if so, do these levels recover over time? What is the prevalence of symptoms and signs related to hypogonadism after TESE and are they related to testosterone levels?, Search Methods: We searched the databases Pubmed and Embase from 1 January 1993 to 26 June 2017. We combined subject headings with terms in title and/or abstract for participants, intervention and outcomes. We included all studies that reported on TESE, regardless of the specific technique used, that measured testosterone and/or LH, and/or had information on signs or symptoms related to hypogonadism as defined by hypogonadism guidelines. An additional inclusion criterion was that studies described these measurements both before and after TESE. The quality of the included studies was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions tool., Outcomes: We identified 15 studies reporting on total testosterone levels of which five studies also reported on testicular volume and one study on erectile dysfunction. Men with Klinefelter syndrome and men with non-obstructive azoospermia had the strongest decrease in total testosterone levels 6 months after TESE, with a mean decrease of 4.1 and 2.7 nmol/l, respectively, which recovered again to baseline levels 26 and 18 months after TESE, respectively. At 6 months after TESE, some studies reported serum total testosterone concentrations below a cut-off value of 12 nmol/l, where symptoms and signs related to hypogonadism may appear. Furthermore, an increased prevalence of erectile dysfunction related to decreased total testosterone levels 6 months after TESE was reported. Also, in some men a decrease in testicular volume was reported. However, it is not clear if this is related to low testosterone levels., Wider Implications: The transient, but statistically significant, decrease in total testosterone levels indicates that men are at risk of developing a temporary hypogonadism after TESE, but there is insufficient evidence for whether patients actually experience clinical symptoms in case of decreased serum testosterone levels. To be able to properly counsel TESE patients, more large-scale monitoring on signs and symptoms of hypogonadism, in combination with testosterone measurements, needs to be performed in men undergoing TESE.

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.

Background: Obesity in women of reproductive age has deleterious effects on reproductive and offspring health. In this study, we aimed to evaluate the association between the magnitude of periconceptional body-mass index (BMI) change and maternal and neonatal outcomes in obese infertile women who participated in the LIFEstyle study. The LIFEstyle study was a randomized controlled trial, evaluating if a six-month lifestyle intervention program prior to infertility treatment in obese infertile women improved birth rates, compared to prompt infertility treatment., Methods and Findings: This is an exploratory post hoc analysis of the LIFEstyle study. We recorded periconceptional BMI change in women with an ongoing pregnancy, pooling data of all women, regardless of randomization arm. Periconceptional BMI change was calculated using weight at randomization and the periconceptional weight (measured in kilograms 12 weeks before or after conception and expressed as BMI change in units BMI (kg/m2)). Subsequently, women were categorized into quartiles according to the magnitude of their periconceptional change in BMI. The odds of maternal and neonatal outcomes were calculated using logistic regression analysis, comparing women in each of the first three weight change quartiles separately, and combined, to women in the fourth quartile. The fourth quartile was chosen as reference group, since these women had the least weight loss. We adjusted for periconceptional BMI, nulliparity and smoking status. In addition, we performed a subgroup analysis for singleton pregnancies. In the LIFEstyle study, 321 obese infertile women achieved an ongoing pregnancy which was conceived within 24 months after randomization. Periconceptional BMI change was available in 244 of these women (76%). Median BMI at randomization was 35.9 kg/m2. Women in the first quartile (Q1) had a periconceptional BMI change of <-2.1 kg/m2, women in the second quartile (Q2) -2.1 to -0.9 kg/m2, women in the third quartile (Q3) -0.9 to 0.1 kg/m2 and women in the fourth quartile (Q4) gained ≥0.1 kg/m2. There were no significant differences between women in the quartiles regarding rates of excessive gestational weight gain (in term pregnancies), gestational diabetes, preterm birth, induction of labor, spontaneous vaginal birth and Caesarean section. Compared to women in Q4, the adjusted odds ratios, aOR, and 95% confidence interval for a hypertensive complication were; 0.55 (0.22-1.42) for women in Q1, 0.30 (0.12-0.78) for women in Q2, 0.39 (0.16-0.96) for women in Q3 and 0.39 (0.19-0.82) for women in Q1 to Q3 combined. In the subgroup analysis, investigating singleton pregnancies only, the statistically significant decreased rate of a hypertensive complication remained in women in Q2 (aOR 0.27, 95% CI 0.10-0.72) and Q3 (aOR 0.39, 95%CI 0.16-0.98) and when comparing women in Q1 to Q3 together to women in Q4 (aOR 0.38, 95%CI 0.18-0.80). Furthermore, there was a significantly decreased aOR (95%CI) of preterm birth in women in Q2 (0.24, 0.06-0.98) and when combining women in Q1 to Q3 (0.37, 0.14-0.97) compared to women in Q4., Conclusions: These results suggest that a periconceptional decrease in BMI in obese infertile women could lead to a decrease of the rates of hypertensive pregnancy complications and preterm birth. The results are limited by the exploratory nature of the analyses and further evidence is necessary to provide more definitive conclusions.

Background: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse., Methods: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449., Findings: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins., Interpretation: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so., Funding: The Netherlands Organization for Health Research and Development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment., Design: A systematic review and meta-analysis of randomized controlled studies that evaluate the effectiveness of low dosing of gonadotropins alone or combined with oral compounds compared with high doses of gonadotropins in women with poor ovarian reserve undergoing IVF/ICSI treatment., Setting: Not applicable., Patient(s): Subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment., Intervention(s): We searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and the Clinical Trials Registry using medical subject headings and free text terms up to June 2016, without language or year restrictions. We included randomized controlled studies (RCTs) enrolling subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment and comparing low doses of gonadotropins and gonadotropins combined with oral compounds versus high doses of gonadotropins. We assessed the risk of bias using the criteria recommended by the Cochrane Collaboration. We pooled the results by meta-analysis using the fixed and random effects model., Main Outcomes Measure(s): The primary outcome was ongoing pregnancy rate (PR) per woman randomized., Result(s): We retrieved 787 records. Fourteen RCTs (N = 2,104 women) were included in the analysis. Five studies (N = 717 women) compared low doses of gonadotropins versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (2 RCTs: risk rate 0.98, 95% confidence interval 0.62-1.57, I 2 = 0). Nine studies (N = 1,387 women) compared ovarian stimulation using gonadotropins combined with the oral compounds letrozole (n = 6) or clomiphene citrate (CC) (n = 3) versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (3 RCTs: risk rate 0.90, 95% confidence interval 0.63-1.27, I 2 = 0)., Conclusion(s): We found no evidence of a difference in pregnancy outcomes between low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens. Whether low doses of gonadotropins or gonadotropins combined with oral compounds is to be preferred is unknown, as they have never been compared head to head. A health economic analysis to test the hypothesis that an ovarian stimulation with low dosing is more cost-effective than high doses of gonadotropins is needed., Prospero Registration Number: CRD42016041301., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The first-line treatment in donor sperm treatment consists of inseminations that can be done by intrauterine insemination (IUI) or by intracervical insemination (ICI)., Objectives: To compare the effectiveness and safety of intrauterine insemination (IUI) and intracervical insemination (ICI) in women who start donor sperm treatment., Search Methods: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL in October 2016, checked references of relevant studies, and contacted study authors and experts in the field to identify additional studies. We searched PubMed, Google Scholar, the Grey literature, and five trials registers on 15 December 2017., Selection Criteria: We included randomised controlled trials (RCTs) reporting on IUI versus ICI in natural cycles or with ovarian stimulation, and RCTs comparing different cointerventions in IUI and ICI. We included cross-over studies if pre-cross-over data were available., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. We collected data on primary outcomes of live birth and multiple pregnancy rates, and on secondary outcomes of clinical pregnancy, miscarriage, and cancellation rates., Main Results: We included six RCTs (708 women analysed) on ICI and IUI in donor sperm treatment. Two studies compared IUI and ICI in natural cycles, two studies compared IUI and ICI in gonadotrophin-stimulated cycles, and two studies compared timing of IUI and ICI. There was very low-quality evidence; the main limitations were risk of bias due to poor reporting of study methods, and serious imprecision.IUI versus ICI in natural cyclesThere was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in natural cycles (odds ratio (OR) 3.24, 95% confidence interval (CI) 0.12 to 87.13; 1 RCT, 26 women; very low-quality evidence). There was only one live birth in this study (in the IUI group). IUI resulted in higher clinical pregnancy rates (OR 6.18, 95% CI 1.91 to 20.03; 2 RCTs, 76 women; I² = 48%; very low-quality evidence).No multiple pregnancies or miscarriages occurred in this study.IUI versus ICI in gonadotrophin-stimulated cyclesThere was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in gonadotrophin-stimulated cycles (OR 2.55, 95% CI 0.72 to 8.96; 1 RCT, 43 women; very low-quality evidence). This suggested that if the chance of a live birth following ICI in gonadotrophin-stimulated cycles was assumed to be 30%, the chance following IUI in gonadotrophin-stimulated cycles would be between 24% and 80%. IUI may result in higher clinical pregnancy rates than ICI (OR 2.83, 95% CI 1.38 to 5.78; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). IUI may be associated with higher multiple pregnancy rates than ICI (OR 2.77, 95% CI 1.00 to 7.69; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). This suggested that if the risk of multiple pregnancy following ICI in gonadotrophin-stimulated cycles was assumed to be 10%, the risk following IUI would be between 10% and 46%.We found insufficient evidence to determine whether there was any clear difference between the groups in miscarriage rates in gonadotrophin-stimulated cycles (OR 1.97, 95% CI 0.43 to 9.04; 2 RCTs, overall 67 pregnancies; I² = 50%; very low-quality evidence).Timing of IUI and ICIWe found no studies that reported on live birth rates.We found a higher clinical pregnancy rate when IUI was timed one day after a rise in blood levels of luteinising hormone (LH) compared to IUI two days after a rise in blood levels of LH (OR 2.00, 95% CI 1.14 to 3.53; 1 RCT, 351 women; low-quality evidence). We found insufficient evidence to determine whether there was any clear difference in clinical pregnancy rates between ICI timed after a rise in urinary levels of LH versus a rise in basal temperature plus cervical mucus scores (OR 1.31, 95% CI 0.42 to 4.11; 1 RCT, 56 women; very low-quality evidence).Neither of these studies reported multiple pregnancy or miscarriage rates as outcomes., Authors' Conclusions: There was insufficient evidence to determine whether there was a clear difference in live birth rates between IUI and ICI in natural or gonadotrophin-stimulated cycles in women who started with donor sperm treatment. There was insufficient evidence available for the effect of timing of IUI or ICI on live birth rates. Very low-quality data suggested that in gonadotrophin-stimulated cycles, ICI may be associated with a higher clinical pregnancy rate than IUI, but also with a higher risk of multiple pregnancy rate. We concluded that the current evidence was too limited to choose between IUI or ICI, in natural cycles or with ovarian stimulation, in donor sperm treatment.

Objective: To evaluate the cost-effectiveness of single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available, as compared to double embryo transfer in relation to female age., Study Design: We used a decision tree model to evaluate the costs from a healthcare provider perspective and the pregnancy rates of two embryo transfer policies: one fresh single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available (strategy I), and double embryo transfer (strategy II). The analysis was performed on an intention-to-treat basis. Sensitivity analyses were carried out to evaluate the robustness of our model and to identify which model parameters had the strongest impact on the results., Results: SET followed by an additional frozen-thawed single embryo transfer if available was dominant, less costly and more effective, over DET in women under 32 years. In women aged 32 or older DET was more effective than SET followed by an additional frozen-thawed single embryo transfer if available but also more costly., Conclusion: SET followed by an additional frozen-thawed single embryo transfer should be the preferred strategy in women under 32 undergoing IVF. The choice for SET followed by an additional frozen-thawed single embryo transfer or DET in women aged 32 or older depends on individual patient preferences and on how much society is willing to pay for an extra child. There is a strong need for a randomized clinical trial comparing the cost and effects of SET followed by an additional frozen-thawed single embryo transfer and DET in the latter category of women., (Copyright © 2017 Elsevier B.V. All rights reserved.)

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61)., (Copyright © 2017. Published by Elsevier Ltd.)

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

Objective: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception., Study Design: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment., Results: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p=0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p=0.86)., Conclusions: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Clomiphene citrate (CC) is generally considered first-line treatment in women with anovulation due to polycystic ovary syndrome (PCOS). Ovulation induction with follicle-stimulating hormone (FSH; gonadotrophins) is second-line treatment for women who do not ovulate or conceive while taking CC. Metformin may increase the effectiveness of ovulation induction with gonadotrophins and may promote safety by preventing multiple pregnancy., Objectives: To determine the effectiveness and safety of metformin co-treatment during ovulation induction with gonadotrophins with respect to rates of live birth and multiple pregnancy in women with PCOS., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and the Cumulative Index to Nursing and Allied Health Literature (CINAH) on 8 June 2016, and the reference lists of included and other relevant studies. We searched ongoing trials registries in the World Health Organization (WHO) portal and on clinicaltrials.gov on 4 September 2016., Selection Criteria: We included randomised controlled trials (RCTs) reporting data on comparison of clinical outcomes in women with PCOS undergoing ovulation induction with gonadotrophins plus metformin versus gonadotrophins alone or gonadotrophins plus placebo., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth rate and multiple pregnancy rate. Secondary outcomes were ovulation rate, clinical pregnancy rate, ovarian hyperstimulation syndrome (OHSS) rate, miscarriage rate, cycle cancellation rate and adverse effects., Main Results: We included five RCTs (with 264 women) comparing gonadotrophins plus metformin versus gonadotrophins. The gonadotrophin used was recombinant FSH in four studies and highly purified FSH in one study. Evidence was of low quality: The main limitations were serious risk of bias due to poor reporting of study methods and blinding of participants and outcome assessors. Live birth Metformin plus FSH was associated with a higher cumulative live birth rate when compared with FSH (odds ratio (OR) 2.31, 95% confidence interval (CI) 1.23 to 4.34; two RCTs, n = 180; I 2 = 0%; low-quality evidence). This suggests that if the chance of live birth after FSH is assumed to be 27%, then the chance after addition of metformin would be between 32% and 60%. Other pregnancy outcomes Metformin use was associated with a higher ongoing pregnancy rate (OR 2.46, 95% CI 1.36 to 4.46; four RCTs, n = 232; I 2 = 0%; low-quality evidence) and a higher clinical pregnancy rate (OR 2.51, 95% CI 1.46 to 4.31; five RCTs, n = 264; I 2 = 0%; low-quality evidence). Multiple pregnancy Results showed no evidence of a difference in multiple pregnancy rates between metformin plus FSH and FSH (OR 0.55, 95% CI 0.15 to 1.95; four RCTs, n = 232; I 2 = 0%; low-quality evidence) and no evidence of a difference in rates of miscarriage or OHSS. Other adverse effects Evidence was inadequate as the result of limited available data on adverse events after metformin compared with after no metformin (OR 1.78, 95% CI 0.39 to 8.09; two RCTs, n = 91; I 2 = 0%; very low-quality evidence)., Authors' Conclusions: Preliminary evidence suggests that metformin may increase the live birth rate among women undergoing ovulation induction with gonadotrophins. At this moment, evidence is insufficient to show an effect of metformin on multiple pregnancy rates and adverse events. Additional trials are necessary before we can provide further conclusions that may affect clinical practice.

Background: Women with a septate uterus are at increased risk for subfertility, recurrent miscarriage, and preterm birth. Restoration of the anatomy of the uterus by hysteroscopic septum resection is an established intervention. This treatment has been assessed mainly in retrospective cohort studies, which suggested a positive effect on pregnancy outcomes. The major flaw in these studies is the before/after design, which will always favour the tested intervention., Objectives: To determine whether hysteroscopic septum resection in women of reproductive age with a septate uterus improves live birth rates and to assess the safety of this procedure., Search Methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (inception to May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL CRSO) (inception to May 2016), MEDLINE (1946 to May 2016), Embase (1974 to May 2016), PsycINFO (1806 to May 2016), and CINAHL database (1982 to May 2016). We also searched trial registers for ongoing and registered trials, reference lists, the Cochrane Library, unpublished dissertations and theses, conference abstracts, OpenGrey, LILACS, PubMed, and Google., Selection Criteria: We planned to include randomised controlled trials that assessed the effect on reproductive outcomes and the safety of hysteroscopic septum resection in women of reproductive age with a septate uterus., Data Collection and Analysis: If there had been studies to include, two review authors would have independently selected studies, assessed trial risk of bias, and extracted data. They would also have contacted study authors for additional information., Main Results: As in the 2011 version of this review, we identified no randomised controlled trials for inclusion in this update., Authors' Conclusions: Hysteroscopic septum resection in women of reproductive age with a septate uterus is performed worldwide to improve reproductive outcomes. At present, there is no evidence to support the surgical procedure in these women. Randomised controlled trials are urgently needed. Two trials are currently underway.

Introduction: Women can now opt to bank their oocytes with the intention of increasing their chances of achieving a pregnancy after their fertility has declined. This exploratory study aimed to gain insight into how women, considering oocyte banking to circumvent age-related fertility decline, perceive this intervention., Material and Methods: We conducted a qualitative study in a Dutch university medical center and held in-depth interviews with women on the waiting list for oocyte banking. We recorded the interviews, transcribed them verbatim and used thematic analysis., Results: All women were financially independent and lived in single-person urban households. They opted for oocyte banking because they wished to share parenthood with a future partner rather than becoming a single parent. This strong desire was key in their interpretation of all aspects of the intervention. Women set aside information about the limited success rates and potential risks, as they were optimistic about their own prognosis, thought that the chances for success were equally likely as the chances it would fail, and because of "anticipatory regret". They perceived oocyte banking as a "helping hand" to achieve shared parenthood. Although women found the costs of the intervention high, they were willing to invest their money to increase their chances for shared parenthood., Conclusions: Oocyte banking allows women to circumvent age-related fertility decline. The prospect of potential shared parenthood overrules the perceived health risks and burden. Health professionals should take this into account when informing potential users of oocyte banking., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To collect published data on spermatogonial quantity in the testes of healthy children and calculate the reference values of spermatogonial quantities throughout prepuberty., Design: Systematic literature search in PubMed and EMBASE focusing on the number of spermatogonia per transverse tubular cross section (S/T) and spermatogonial density per cubic centimeter (cm 3 ) of testicular volume (S/V) throughout prepuberty., Setting: None., Patient(s): None., Intervention(s): None., Main Outcome Measure(s): Polynomial meta-regression analyses of S/T and S/V of healthy boys from the ages of 0 to 14 years., Result(s): We found six papers describing original quantitative data on S/T and S/V of healthy boys (total n = 334 and 62, respectively) that were suitable for meta-analysis. Polynomial meta-regression analyses of S/T and S/V demonstrated a clear pattern of spermatogonial quantity throughout prepubertal life. This consisted of a decline during the first 3 years of life, a gradual increase until the ages of 6 to 7 years, a plateau until the age of 11 years, and a sharp incline reaching pubertal numbers at 13 to 14 years of age. The association between S/T and S/V allowed us to perform S/T to S/V extrapolation, creating reference S/V (rS/V) values throughout prepubertal life from a cohort of 372 boys., Conclusion(s): Spermatogonial quantity varies during testicular development toward puberty. The values found in this study may serve as a baseline clinical reference to study the impact of diseases and adverse effects of gonadotoxic treatments on spermatogonial quantity in prepubertal testes. Spermatogonial quantity reference values may also help to evaluate the quality of testicular biopsy samples acquired for fertility preservation of prepubertal boys., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: How do parents feel about psychosocial counseling during donor sperm treatment?, Methods: We performed a qualitative study based on semi-structured in-depth interviews, conducted from July 2012 until August 2013, with 24 Dutch parents who had had children through donor sperm treatment between 2000 and 2012., Results: During counseling, parents sometimes felt screened for their eligibility for parenthood rather than guided, and therefore felt discouraged about bringing up topics that were important for them. Parents of all family types would value extended psychological counseling before and after successful donor sperm treatment, that is in several stages of parenthood. Only after childbirth topics such as disclosure, fear of rejection of the social parent and future contact of the child with the sperm donor became more pertinent., Conclusions: Both before and after childbirth, parents of all family types would value expert advice on when and how to disclose. Psychosocial guidance should be offered separately from psychosocial screening for treatment eligibility and should be offered in several stages of parenthood.

Trials assessing effectiveness in medically assisted reproduction (MAR) should aim to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess the extent to which multiple cycles are reported in MAR trials. A sample of randomized controlled trials (RCT) was collected on MAR, published in four time periods, in 11 pre-specified peer-reviewed journals; 253 trials were included: 196 on IVF, 37 on intrauterine insemination and 20 on ovulation induction. Forty-eight (19%) reported on multiple cycles, which was significantly more common in trials on intrauterine insemination and ovulation induction compared with trials on IVF (P < 0.01). Both trials on IVF were multi-centre trials, and those using live birth as primary outcome, reported significantly more often on multiple cycles (OR 3.7 CI 1.1 to 12.5) and (OR 8.7 CI 1.8 to 40.3), respectively. Trials designed to compare protocol variations reported multiple cycles less often (OR 0.07 CI 0.01 to 0.74). Most RCT on MAR, especially those on IVF, do not report cumulative pregnancy rates. As not all women become pregnant in their first cycle, the clinical significance of these trials is limited., (Copyright © 2016 Reproductive Healthcare Ltd. All rights reserved.)

Objective: To compare dropout rates in couples undergoing conventional in vitro fertilization with single embryo transfer (IVF-SET), in vitro fertilization in a modified natural cycle (IVF-MNC) or intrauterine insemination with ovarian stimulation (IUI-OS)., Study Design: Secondary analysis of a multicentre randomized controlled trial between January 2009 and February 2012. 602 couples with unexplained or mild male subfertility, allocated to IVF-SET (N=201), IVF-MNC (N=194) and IUI-OS (N=207)., Main Outcome Measures: Dropouts, defined as couples who discontinued their allocated three cycles of IVF-SET, six cycles of IVF-MNC or IUI-OS, without having achieved a pregnancy. We classified dropouts as "following medical advice" or "patient initiated"., Result(s): Thirty couples (15%) allocated to IVF-SET dropped out and 45 couples (23%) allocated to IVF-MNC, compared to 26 couples (13%) allocated to IUI-OS; relative risk (RR) 1.2 (95%CI; 0.73-1.9) for IVF-SET and 1.9 (95%CI; 1.2-2.9) for IVF-MNC, both compared to IUI-OS. Nine couples (4.5%) allocated to IVF-SET, 14 (7.2%) allocated to IVF-MNC and 14 (6.8%) allocated to IUI-OS dropped out following medical advice; RR of 0.51 (95%CI; 0.21-1.2) for IVF-SET and 0.84 (95%CI; 0.39-1.80) for IVF-MNC, both versus IUI-OS. Twenty-one couples (10%) allocated to IVF-SET were patient initiated dropouts, as were 31 (16%) allocated to IVF-MNC and 12 (5.8%) allocated to IUI-COS; RR 1.8 (95%CI; 0.91-3.6) for IVF-SET and 2.8 (95%CI; 1.5-5.2) for IVF-MNC both versus IUI-OS., Conclusion(s): IVF-SET and IUI-OS result in comparable drop-out rates, while drop-out rates after IVF-MNC are almost twice as high, mainly driven by patient preferences., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To compare maternal and perinatal outcomes in dizygotic twin pregnancies conceived after medically assisted reproduction (MAR) with outcomes after natural conception (NC)., Design: Nationwide registry based study., Setting: Academic medical center., Patient(s): Primiparous women who delivered opposite sex twins between January 2000 and December 2012 in the Netherlands, comprising dizygotic twin pregnancies: 6,694 women, 470 after ovulation induction (OI), 511 after intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH), 2,437 after in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), and 3,276 after NC., Intervention(s): None., Main Outcome Measure(s): Multivariable logistic regression and generalized linear mixed models to evaluate differences in outcomes: maternal outcomes of hypertension, preeclampsia, preterm delivery, hemorrhage, and delivery mode, perinatal outcomes including small for gestational age (SGA) with birth weight <10th percentile, birth weight <1,500 g, 5-minute Apgar score <7, admission to neonatal intensive care unit, congenital anomalies, and perinatal mortality., Result(s): We found no statistically significant differences in maternal or perinatal outcomes after OI compared with NC. Women pregnant after IVF-ICSI had a lower risk for hypertension (adjusted odds ratio [aOR] 0.74; 95% confidence interval [CI], 0.66-0.83) compared with women pregnant after NC. After IUI-COH more children had Apgar scores <7 (adjusted odds ratio (aOR) 1.38; 95% confidence interval (CI) 1.05-1.81) and perinatal mortality rates were higher (aOR 1.56; 95% CI, 1.04-2.33) compared with NC. We found no differences in perinatal outcomes after IVF-ICSI compared with NC., Conclusion(s): Overall, maternal and perinatal risks other than those due to multiplicity are similar for twin pregnancies conceived after MAR and after NC., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Available treatment options in couples with unexplained or mild male subfertility are intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) and in vitro fertilisation (IVF). IUI-COH is a less invasive treatment that is often used before proceeding with IVF. Yet as the IVF success rates might be higher and time to pregnancy shorter, expedited access to IVF might be the preferred option. To identify couples that could benefit from immediate IVF over IUI-COH, we assessed whether female age, duration of subfertility or prewash total motile count (TMC) can help to identify couples that would benefit from IVF over IUI-COH., Study Design: We performed a secondary data-analysis of a multicentre open-label randomised controlled trial in three university and six teaching hospitals in the Netherlands. 116 couples with unexplained or mild male subfertility were randomised to one cycle of IVF with elective single embryo transfer with subsequent frozen-thawed embryo transfers or 3 cycles of IUI-COH. The primary outcome was an ongoing pregnancy within 4 months after randomisation. Our aim was to explore a possible differential effect of specific markers on the effectiveness of treatment. We chose to therefore assess female age, duration of subfertility and TMC as these have previously been identified as predictors. For each prognostic factor we developed a logistic regression model to predict ongoing pregnancy with that prognostic factor, treatment and a factor-by-treatment interaction term., Results: Female age and duration of subfertility were not associated with better ongoing pregnancy chances after IVF compared to IUI-COH (p-value for interaction=0.65 and 0.26, respectively). Only when TMC was lower than 110 (×10(6)spermatozoa/mL), the probability of ongoing pregnancy was higher in women allocated to IVF (p-value for interaction=0.06)., Conclusion: In couples with unexplained or mild male subfertility, a low TMC might lead to higher pregnancy rates after IVF than after IUI-COH. This finding needs to be validated in a larger trial before it can be applied in clinical practice., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Small lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking., Methods: We randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization., Results: We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P<0.001). The primary outcome occurred in 27.1% of the women in the intervention group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99)., Conclusions: In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.).

Objective: To assess the capacity of the postcoital test (PCT) to predict pregnancy in WHO II anovulatory women who are ovulatory on clomiphene citrate (CC). In these women, an abnormal PCT result could be associated with lower pregnancy chances, but this has never been proven or refuted., Study Design: Prospective cohort study was performed between December 2009 and September 2012 for all women who started ovulation induction with CC in one university clinic and two teaching hospitals in the Netherlands. A PCT was performed in one of the first three ovulatory cycles. Ovulation induction with CC was continued for at least six cycles. The PCT was judged to be positive if at least one progressive motile spermatozo was seen in one of five high power fields at 400× magnification. The primary outcome was time to ongoing pregnancy, within six ovulatory cycles., Results: In 152 women the PCT was performed. 135 women had a reliable, well-timed PCT. The ongoing pregnancy rate was 44/107 (41%) for a positive and 10/28 (36%) for a negative PCT. The hazard rate for ongoing pregnancy was 1.3 (95% CI 0.64-2.5) for a positive versus a negative PCT. Thirty five of 77 (46%) women with clear mucus had an ongoing pregnancy versus 12 of 45 (27%) women in whom the mucus was not clear (HR 2.0; 95% CI 1.02-3.84, p=0.04)., Conclusion: The present study suggests that the outcome of the postcoital test in women with WHO-II anovulation that undergo ovulation induction with CC does not have a large effect on ongoing pregnancy chances over time., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Standardization of the semen analysis may improve reproducibility. We assessed variability between laboratories in semen analyses and evaluated whether a transformation using Z scores and regression statistics was able to reduce this variability., Materials and Methods: We performed a retrospective cohort study. We calculated between-laboratory coefficients of variation (CVB) for sperm concentration and for morphology. Subsequently, we standardized the semen analysis results by calculating laboratory specific Z scores, and by using regression. We used analysis of variance for four semen parameters to assess systematic differences between laboratories before and after the transformations, both in the circulation samples and in the samples obtained in the prospective cohort study in the Netherlands between January 2002 and February 2004., Results: The mean CVBwas 7% for sperm concentration (range 3 to 13%) and 32% for sperm morphology (range 18 to 51%). The differences between the laboratories were statistically significant for all semen parameters (all P<0.001). Standardization using Z scores did not reduce the differences in semen analysis results between the laboratories (all P<0.001)., Conclusion: There exists large between-laboratory variability for sperm morphology and small, but statistically significant, between-laboratory variation for sperm concentration. Standardization using Z scores does not eliminate between-laboratory variability.

Background: Many media are commercially available for culturing pre-implantation human embryos in assisted reproductive technology (ART) cycles. It is unknown which culture medium leads to the best success rates after ART., Objectives: To evaluate the safety and effectiveness of different human pre-implantation embryo culture media in used for in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles., Search Methods: We searched the Cochrane Menstrual Disorders and Subfertility Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the National Research Register, the Medical Research Council's Clinical Trials Register and the NHS Center for Reviews and Dissemination databases from January 1985 to March 2015. We also examined the reference lists of all known primary studies, review articles, citation lists of relevant publications and abstracts of major scientific meetings., Selection Criteria: We included all randomised controlled trials which randomised women, oocytes or embryos and compared any two commercially available culture media for human pre-implantation embryos in an IVF or ICSI programme., Data Collection and Analysis: Two review authors independently selected the studies, assessed their risk of bias and extracted data. We sought additional information from the authors if necessary. We assessed the quality of the evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. The primary review outcome was live birth or ongoing pregnancy., Main Results: We included 32 studies in this review. Seventeen studies randomised women (total 3666), three randomised cycles (total 1018) and twelve randomised oocytes (over 15,230). It was not possible to pool any of the data because each study compared different culture media.Only seven studies reported live birth or ongoing pregnancy. Four of these studies found no evidence of a difference between the media compared, for either day three or day five embryo transfer. The data from the fifth study did not appear reliable.Six studies reported clinical pregnancy rate. One of these found a difference between the media compared, suggesting that for cleavage-stage embryo transfer, Quinn's Advantage was associated with higher clinical pregnancy rates than G5 (odds ratio (OR) 1.56; 95% confidence interval (CI) 1.12 to 2.16; 692 women). This study was available only as an abstract and the quality of the evidence was low.With regards to adverse effects, three studies reported multiple pregnancies and six studies reported miscarriage. None of them found any evidence of a difference between the culture media used. None of the studies reported on the health of offspring.Most studies (22/32) failed to report their source of funding and none described their methodology in adequate detail. The overall quality of the evidence was rated as very low for nearly all comparisons, the main limitations being imprecision and poor reporting of study methods., Authors' Conclusions: An optimal embryo culture medium is important for embryonic development and subsequently the success of IVF or ICSI treatment. There has been much controversy about the most appropriate embryo culture medium. Numerous studies have been performed, but no two studies compared the same culture media and none of them found any evidence of a difference between the culture media used. We conclude that there is insufficient evidence to support or refute the use of any specific culture medium. Properly designed and executed randomised trials are necessary.

Objective: Acute fertility preservation for women is an interdisciplinary treatment that requires adequate information provision and early referral. This quality management project aimed to improve fertility preservation care by using a practical tool: Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis., Study Design: Quality management project was executed between May 2011 and July 2013. This project has been executed in a university affiliated IVF-clinic in cooperation with two oncological sites and used a four-step strategy: (1) monitoring baseline referral process, (2) exploring baseline fertility preservation program by Strengths, Weaknesses, Opportunities and Threats' (SWOT)-analysis, (3) setting up a new fertility preservation program and (4) evaluating the new fertility preservation program by means of SWOT-analysis., Results: During the three-months monitoring period, fertility preservation was requested for a total of 126 women. The mean age of the women was 33.8 years old (range 1-42 years old). Most requests came from women who wanted to cryopreserve oocytes because of age-related decline of fertility (n=90; 71%). Most requests for acute fertility preservation concerned women with breast cancer (n=16; 57%). Information leaflets and pre-consultation questionnaires for women improved the quality of first fertility preservation consultation as evaluated by final SWOT-analysis. Collaboration with oncological centres and information about fertility preservation improved the referral process., Conclusions: SWOT-analysis proved useful for setting up a new fertility preservation-program and can be recommended as a tool to improve the management and organisation of new types of reproductive care., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Ovulation induction with follicle stimulating hormone (FSH) is the second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate (CC)., Objectives: To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with CC-resistant PCOS., Search Methods: We searched the Menstrual Disorders & Subfertility Group's Specialist Register of controlled trials, the Cochrane Central Register of Controlled Trials, MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014), CINAHL (1982 to October 2014), National Research Register and web-based trials databases such as Current Controlled Trials. There was no language restriction., Selection Criteria: All randomised controlled trials reporting data on comparing clinical outcomes in women with PCOS who did not ovulate or conceive on CC, and undergoing ovulation induction with urinary FSH (uFSH: FSH-P or FSH-HP), HMG/HP-HMG or recombinant FSH. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that used co-treatment with CC, metformin, LH or letrozole., Data Collection and Analysis: Three review authors (NW, MN and MvW) independently selected studies for inclusion, assessed study quality and extracted study data. Primary outcomes were live birth rate per woman (effectiveness outcome) and incidence of ovarian hyperstimulation syndrome (OHSS) per woman (safety outcome). Secondary outcomes were clinical pregnancy, miscarriage, multiple pregnancy, total gonadotrophin dose and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the odds ratio (OR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria., Main Results: The review includes 14 trials with 1726 women. Ten trials compared rFSH versus urinary-derived gonadotrophins (three rFSH versus HMG and seven rFSH versus FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P.We found no evidence of a difference in live birth for rFSH versus urinary-derived gonadotrophins (OR 1.26, 95% CI 0.80 to 1.99, 5 trials, 505 women, I² = 0%, low-quality evidence) or clinical pregnancy rate (OR 1.08, 95% CI 0.83 to 1.39, 8 trials, 1330 women, I² = 0, low-quality evidence). This suggests that for the observed average live birth per woman with urinary-derived FSH of 16%, the chance of live birth following rFSH is between 13% and 26%.For the comparison HMG or HP-HMG versus FSH-P there was also no difference in the evidence on live birth rate (OR 1.36, 95% CI 0.58 to 3.18, 3 trials, 138 women, I² = 0%, low-quality evidence). This suggests that for a woman with a live birth rate of 18% with HMG or HP-HMG, the chance of live birth following uFSH is between 9% and 37%.Trial authors used various definitions for OHSS. Pooling the data, we found no evidence of a difference for rFSH versus urinary-derived gonadotrophins (OR 1.52, 95% CI 0.81 to 2.84, 10 trials, 1565 women, I(2) = 0%, very low-quality evidence) and for HMG or HP-HMG versus FSH-P (OR 9.95, 95% CI 0.47 to 210.19, 2 trials, 53 women, I² = 0%, very low-quality evidence)., Authors' Conclusions: In women with PCOS and CC resistance or CC failure, we found no evidence of a difference in live birth and OHSS rates between urinary-derived gonadotrophins and rFSH or HMG/HP-HMG. Evidence for all outcomes was of low or very low quality. We suggest weighing costs and convenience in the decision to use one or the other.

Objective: To study the impact on health-related quality of life (HRQoL) of treatment with systemic methotrexate (MTX) or expectant management in women with ectopic pregnancy or pregnancy of unknown location (PUL) with low and plateauing serum hCG concentrations., Study Design: HRQoL was assessed alongside a randomized clinical trial (RCT) with the use of standard self-administered psychometric measure questionnaires., Patients and Setting: All women who participated in the multicenter RCT comparing treatment with systemic MTX to expectant management in women with ectopic pregnancy or persisting PUL were eligible for the HRQoL measurements., Main Outcome Measure: HRQoL measures of three standardized questionnaires (SF-36, RSCL, HADS)., Results: Data were available for 64 of 73 women (78%) randomized in the RCT. We found no difference in HRQoL between the two treatment groups. The need for additional treatment, i.e. additional MTX injections or surgical intervention, had no impact on HRQoL., Conclusion: Women treated with MTX or expectant management for an ectopic pregnancy or persisting PUL have comparable quality of life., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

In this observational study, the effect of the introduction of the first Early Pregnancy Assessment Unit (EPAU) in a university hospital in The Netherlands in 2008 on early pregnancy care is analysed. Derivatives of quality of care were measured before and after the establishment of the EPAU, with the aim of reducing unnecessary care. Care within three time periods was measured: 2006, 2009 and 2012. In 2006, 14% of women who had experienced a miscarriage were admitted to the hospital, whereas in 2009 and 2012 no women were admitted. The surgical management rate for miscarriage decreased from 79% (2006) to 6% (2009) and 28% (2012). Karyotyping of couples who had experienced recurrent miscarriage decreased from 100% (2006) to 17% (2009) and 33% (2012). The surgical management rate for ectopic pregnancy decreased from 50% (2006) to 25% (2009) and 29% (2012). The mean total cost per woman treated in 2006 was €1111 (95% CI €808 to 1426), €436 (95% CI €307 to 590) in 2009 and €633 (95% CI €586 to 788) in 2012. We can therefore conclude that an EPAU results in higher quality and cost-effective care, and has a positive effect on early pregnancy care., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To study risk of birth asphyxia and related morbidity among term singletons born after medically assisted reproduction (MAR)., Design: Population cohort study., Setting: Not applicable., Patient(s): A total of 1,953,932 term singleton pregnancies selected from a national registry for 1999-2011., Intervention(s): None., Main Outcome Measure(s): Primary outcome Apgar score <4; secondary outcomes Apgar score <7, intrauterine fetal death, perinatal mortality, congenital anomalies, small for gestational age, asphyxia related morbidity, and cesarean delivery., Result(s): The risks of birth asphyxia and related morbidity were calculated in women who conceived either through MAR or spontaneously (SC), with a subgroup analysis for in vitro fertilization (IVF). An additional propensity score matching analysis was performed with matching on multiple maternal baseline covariates (maternal age, ethnicity, socioeconomic status, parity, year of birth, and preexistent diseases). Each MAR pregnancy was matched to three SC controls. Relative to SC, the MAR singletons had an increased risk of adverse neonatal outcomes including Apgar score <4 (adjusted odds ratio [OR] 1.29; 95% CI, 1.14-1.46) and intrauterine fetal death (adjusted OR 1.61; 95% CI, 1.35-1.91). After propensity score matching, the risk of an Apgar score <4 was comparable between MAR and SC singletons (OR 0.99; 95% CI, 0.87-1.14). Cesarean delivery for both fetal distress and nonprogressive labor occurred more among MAR pregnancies compared with SC pregnancies., Conclusion(s): Term singletons conceived after MAR have an increased risk of morbidity related to birth asphyxia. Because this is mainly due to maternal characteristics, obstetric caregivers should be aware that the increased rates of cesareans reflect the behavior of women and physicians rather than increased perinatal complications., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Intrauterine insemination (IUI), with or without ovarian stimulation, IVF and intracytoplasmatic sperm injection (ICSI) are frequently used treatments for couples with male subfertility. No consensus has been reached on specific cut-off values for semen parameters, at which IVF would be advocated over IUI and ICSI over IVF. The aim of this study was to evaluate the cost-effectiveness of interventions for male subfertility according to total motile sperm count (TMSC). A computer-simulated cohort of subfertile women aged 30 years with a partner was analysed with a pre-wash TMSC of 0 to 10 million. Three treatments were evaluated: IUI with and without controlled ovarian stimulation; IVF; and ICSI. Main outcome was expected live birth; secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. The choice of IVF over IUI with ovarian stimulation and ICSI over IVF depends on the willingness to pay for an extra live birth. If only cost per live birth is considered for each treatment, above a pre-wash TMSC of 3 million, IUI is less costly than IVF and, below a pre-wash, TMSC of 3 million ICSI is less costly. Effectiveness needs to be confirmed in a large randomized controlled trial., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants., Design: Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilization and single-embryo transfer (SET) rates., Setting: Not applicable., Patient(s): Not applicable., Intervention(s): None., Main Outcome Measure(s): The contribution of ART multiple-gestation infants to the total number of multiple-gestation infants in a population was calculated in relation to utilization of ART and SET rates., Result(s): The number of ART treatments leading to embryo transfer varied from 304 per million inhabitants in the U.S. to 1,518 in Denmark. The percentage of ART cycles that utilized SET varied from 8.8% in South Korea to 53.3% in Australia. Reflecting both utilization rates and SET rates, the percentage of multiple-gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark., Conclusion(s): In seven countries, the contribution of ART multiple-gestation infants to all multiple-gestation infants varies from 14.7% to 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study the indications of oocyte vitrification in women who undergo this intervention., Design: Cross-sectional study., Method: We collected the indications of oocyte vitrification in women who underwent, or started ovarian stimulation for, this intervention between May 2006 and December 31st 2013. Indications were subcategorized into six groups: no sperm available during IVF or ICSI treatment, planned gonadotoxic therapy, ovarian surgery, risk on premature ovarian insufficiency , previous gonadotoxic therapy, and anticipated gamete exhaustion., Results: During the study period 298 women vitrified oocytes or started with ovarian stimulation for oocyte vitrification. The majority of the women (33%) vitrified oocytes because of anticipated gamete exhaustion. Planned gonadotoxic treatment was for 81 women (27%) the reason for oocyte vitrification., Conclusion: With oocyte vitrification women are able to extend the time at which they can conceive. The future will tell whether the benefits of oocyte vitrification outweigh the risks and costs.

Background: Human chorionic gonadotropin (HCG) is routinely used for final oocyte maturation triggering in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles, but the use of HCG for this purpose may have drawbacks. Gonadotropin-releasing hormone (GnRH) agonists present an alternative to HCG in controlled ovarian hyperstimulation (COH) treatment regimens in which the cycle has been down-regulated with a GnRH antagonist. This is an update of a review first published in 2010., Objectives: To evaluate the effectiveness and safety of GnRH agonists in comparison with HCG for triggering final oocyte maturation in IVF and ICSI for women undergoing COH in a GnRH antagonist protocol., Search Methods: We searched databases including the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and trial registers for published and unpublished articles (in any language) on randomised controlled trials (RCTs) of gonadotropin-releasing hormone agonists versus HCG for oocyte triggering in GnRH antagonist IVF/ICSI treatment cycles. The search is current to 8 September 2014., Selection Criteria: RCTs that compared the clinical outcomes of GnRH agonist triggers versus HCG for final oocyte maturation triggering in women undergoing GnRH antagonist IVF/ICSI treatment cycles were included., Data Collection and Analysis: Two or more review authors independently selected studies, extracted data and assessed study risk of bias. Treatment effects were summarised using a fixed-effect model, and subgroup analyses were conducted to explore potential sources of heterogeneity. Treatment effects were expressed as mean differences (MDs) for continuous outcomes and as odds ratios (ORs) for dichotomous outcomes, together with 95% confidence intervals (CIs). Primary outcomes were live birth and rate of ovarian hyperstimulation syndrome (OHSS) per women randomised. Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods were used to assess the quality of the evidence for each comparison., Main Results: We included 17 RCTs (n = 1847), of which 13 studies assessed fresh autologous cycles and four studies assessed donor-recipient cycles. In fresh autologous cycles, GnRH agonists were associated with a lower live birth rate than was seen with HCG (OR 0.47, 95% CI 0.31 to 0.70; five RCTs, 532 women, I(2) = 56%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving live birth with the use of HCG, the chance of a live birth with the use of an GnRH agonist would be between 12% and 24%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower incidence of mild, moderate or severe OHSS than was HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I² = 42%, moderate-quality evidence). This suggests that for a woman with a 5% risk of mild, moderate or severe OHSS with the use of HCG, the risk of OHSS with the use of a GnRH agonist would be between nil and 2%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower ongoing pregnancy rate than was seen with HCG (OR 0.70, 95% CI 0.54 to 0.91; 11 studies, 1198 women, I(2) = 59%, low-quality evidence) and a higher early miscarriage rate (OR 1.74, 95% CI 1.10 to 2.75; 11 RCTs, 1198 women, I² = 1%, moderate-quality evidence). However, the effect was dependent on the type of luteal phase support provided (with or without luteinising hormone (LH) activity); the higher rate of pregnancies in the HCG group applied only to the group that received luteal phase support without LH activity (OR 0.36, 95% CI 0.21 to 0.62; I(2) = 73%, five RCTs, 370 women). No evidence was found of a difference between groups in risk of multiple pregnancy (OR 3.00, 95% CI 0.30 to 30.47; two RCTs, 62 women, I(2) = 0%, low-quality evidence).In women with donor-recipient cycles, no evidence suggested a difference between groups in live birth rate (OR 0.92, 95% CI 0.53 to 1.61; one RCT, 212 women) or ongoing pregnancy rate (OR 0.88, 95% CI 0.58 to 1.32; three RCTs, 372 women, I² = 0%). We found evidence of a lower incidence of OHSS in the GnRH agonist group than in the HCG group (OR 0.05, 95% CI 0.01 to 0.28; three RCTs, 374 women, I² = 0%).The main limitation in the quality of the evidence was risk of bias associated with poor reporting of methods in the included studies., Authors' Conclusions: Final oocyte maturation triggering with GnRH agonist instead of HCG in fresh autologous GnRH antagonist IVF/ICSI treatment cycles prevents OHSS to the detriment of the live birth rate. In donor-recipient cycles, use of GnRH agonists instead of HCG resulted in a lower incidence of OHSS, with no evidence of a difference in live birth rate.Evidence suggests that GnRH agonist as a final oocyte maturation trigger in fresh autologous cycles is associated with a lower live birth rate, a lower ongoing pregnancy rate (pregnancy beyond 12 weeks) and a higher rate of early miscarriage (less than 12 weeks). GnRH agonist as an oocyte maturation trigger could be useful for women who choose to avoid fresh transfers (for whatever reason), women who donate oocytes to recipients or women who wish to freeze their eggs for later use in the context of fertility preservation.