Empirical use of growth hormone in IVF is useless: the largest randomized controlled trial.

Does adjuvant growth hormone (GH) therapy in GnRH antagonist cycles improve reproductive outcomes in the general IVF population? Empiric adjuvant GH therapy in GnRH antagonist cycles does not improve IVF stimulation results or reproductive outcomes, including implantation, miscarriage, and clinical pregnancy rates. Previous evidence regarding the benefits of GH therapy in IVF cycles has been inconclusive due to the lack of well-designed, large-scale randomized controlled trials (RCTs) in the general IVF population. This is a phase III open-label RCT involving 288 patients undergoing antagonist IVF cycles at the Ovo clinic in Montreal, Canada, between June 2014 and January 2020. Patients were randomly assigned at a 1:1 ratio to either the GH or control group. The intervention group received daily 2.5 mg subcutaneous injections of GH from Day 1 of ovarian stimulation until the day of oocyte retrieval, while the control group received standard ovarian stimulation without any adjuvant therapy. Patients were expected normal responders. All embryo transfers, both fresh and frozen, resulting from the studied IVF cycle were included in an intention-to-treat and per-protocol analyses. The primary outcome was the clinical pregnancy rate, while secondary outcomes included the number of retrieved oocytes, good-quality embryos, maturation, fertilization, implantation, and miscarriage rates. A total of 288 patients were recruited and randomly assigned at a 1:1 ratio to either the GH or the control group. After excluding cycle cancellations and patients who did not undergo transfer, 105 patients remained in each group. The overall mean age was 38.0 years, the mean BMI was 25.11 kg/m2 and the mean anti-Müllerian hormone was 2.51 ng/ml. The cycle characteristics were similar between both groups. No differences were observed regarding the total dose of gonadotropins (4600 versus 4660 IU for the GH and control groups, respectively, P = 0.752), days of stimulation (11.4 versus 11.7 days, P = 0.118), and endometrial thickness (10.63 versus 10.94 mm, P = 0.372). Both the intention to treat (ITT) and per protocol analyses yielded similar results for stimulation outcomes. In the ITT analysis, no differences were found in the number of follicles ≥15 mm (7.8 versus 7.1, P = 0.212), retrieved oocytes (11.7 versus 11.2, P = 0.613), mature oocytes (8.5 versus 8.6, P = 0.851), maturation rate (73.8 versus 78.4%, P = 0.060), fertilization rate (64.3 versus 67.2%, P = 0.388), and good quality embryos (2.5 versus 2.6, P = 0.767). Reproductive outcomes in fresh embryo transfer showed no difference for implantation rate (38.2 versus 39.5%, P = 0.829), miscarriage rate (26.5 versus 31.1%, P = 0.653), clinical pregnancy rate (43.6 versus 50.0%, P = 0.406, rate difference, 95% CI: -0.06 [-0.22, 0.09]), and live birth rate (32.1 versus 33.3%, P = 0.860). The number of embryos needed to achieve a clinical pregnancy was 3.0 versus 2.5 in the GH and control groups, respectively. Similarly, reproductive outcomes in first frozen embryo transfer showed no difference for implantation rate (31.6 versus 45.3%, P = 0.178), miscarriage rate (28.6 versus 26.3%, P = 0.873), clinical pregnancy rate (35.1 versus 44.2%, P = 0.406, P = 0.356, rate difference, 95% CI: -0.09 [-0.28, 0.10]), and live birth rate (22.8 versus 32.6%, P = 0.277). The number of embryos needed to achieve a clinical pregnancy was 3.1 versus 2.4 in the GH and control groups, respectively. The study focused on expected normal responders, limiting its applicability to other patient populations such as poor responders. These findings suggest that adding GH therapy to ovarian stimulation in GnRH antagonist cycles may not benefit the general IVF population. Additional high-quality RCTs are warranted to identify subgroups of patients who might benefit from this treatment. EMD Serono Inc., Mississauga, Canada, supplied Saizen® for the study, free of charge. In addition, they provided funding for the statistical analysis. I-J.K. declares grants or contracts from Ferring Pharmaceuticals, consulting fees from Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals and EMD Serono, support for attending meetings or travel from Ferring Pharmaceuticals and EMD Serono, participation on a Data Safety Monitoring Board or Advisory Board for Ferring Pharmaceuticals, and stock or stock options from The Fertility Partners; W.J. declares support for attending meetings or travel from EMD Serono; and S.P. declares stock or stock options from The Fertility Partners. All other authors have no conflicts of interest to disclose. NCT01715324. 25 October 2012. 25 June 2014.

Mourad A ，Jamal W ，Hemmings R ，Tadevosyan A ，Phillips S ，Kadoch IJ ... -  《-》

Psychosocial and physical wellbeing in women and male partners undergoing immediate versus postponed modified natural cycle frozen embryo transfer after ovarian stimulation and oocyte pick-up: a sub-study of a randomized controlled trial.

Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)? Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing. Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress. Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024. Questionnaires were distributed to all randomized women and their male partners on cycle day 2-5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed. Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P = 0.014), but the results were not significant after adjustment for multiple testing (P = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P < 0.001) in the immediate group. All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group. If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles. The RCT was supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. ClinicalTrials.gov NCT04748874.

Bergenheim S ，Saupstad M ，Colombo C ，Møller JE ，Bogstad JW ，Freiesleben NC ，Behrendt-Møller I ，Prætorius L ，Oxlund B ，Nøhr B ，Husth M ，Løkkegaard E ，Sopa N ，Pinborg A ，Løssl K ，Schmidt L ... -  《-》

Particulate air pollution at the time of oocyte retrieval is independently associated with reduced odds of live birth in subsequent frozen embryo transfers.

Does exposure to particulate matter (PM) air pollution prior to oocyte retrieval or subsequent frozen embryo transfer (FET) affect the odds of live birth? Live birth rates are lower when particulate matter (PM2.5 and PM10) levels are higher prior to oocyte retrieval, regardless of the conditions at the time of embryo transfer. Exposure to air pollution is associated with adverse reproductive outcomes, including reduced fecundity and ovarian reserve, and an increased risk of infertility and pregnancy loss. It is uncertain whether the effect on ART outcomes is due to the effects of pollution on oogenesis or on early pregnancy. This retrospective cohort study included 3659 FETs in 1835 patients between January 2013 and December 2021, accounting for all FETs performed at a single clinic over the study period. The primary outcome was the live birth rate per FET. Outcome data were missing for two embryo transfers which were excluded. Daily levels of PM2.5, PM10, nitric oxide, nitrogen dioxide, sulphur dioxide, ozone and carbon monoxide were collected during the study period and calculated for the day of oocyte retrieval and the day of embryo transfer, and during the preceding 2-week, 4-week, and 3-month periods. Clinical and embryological outcomes were analysed for their association with pollution over 24 hours, 2 weeks, 4 weeks, and 3 months, with adjustment for repeated cycles per participant, age at the time of oocyte retrieval, a quadratic age term, meteorological season, year, and co-exposure to air pollutants. Multi-pollutant models were constructed to adjust for co-exposures to other pollutants. Median concentrations in pollutant quartiles were modelled as continuous variables to test for overall linear trends; a Bonferroni correction was applied to maintain an overall alpha of 0.05 across the four exposure periods tested. Increased PM2.5 exposure in the 3 months prior to oocyte retrieval was associated with decreased odds of live birth (linear trend P = 0.011); the odds of live birth when PM2.5 concentrations were in the highest quartile were reduced by 34% (OR 0.66, 95% CI 0.47-0.92) when compared to the lowest quartile. A consistent direction of effect was seen across other exposure periods prior to oocyte retrieval, with an apparent dose-dependent relationship. Increased exposure to PM10 particulate matter in the 2 weeks prior to oocyte retrieval was associated with decreased odds of live birth (linear trend P = 0.009); the odds of live birth were decreased by 38% (OR 0.62, 95% CI 0.43-0.89, P = 0.010) when PM10 concentrations were in the highest quartile compared with the lowest quartile. Consistent trends were not seen across other exposure periods. None of the gaseous pollutants had consistent effects, prior to either oocyte retrieval or embryo transfer. This was a retrospective cohort study, however, all FETs during the study period were included and data were missing for only two FETs. The results are based on city-level pollution exposures, and we were not able to adjust for all possible factors that may affect live birth rates. Results were not stratified based on specific patient populations, and it was not possible to calculate the cumulative live birth rate per commenced cycle. This is the first study to specifically analyse FETs to separate the effects of environmental exposures prior to oocyte retrieval from those around the time of embryo transfer. Our findings suggest that increased PM exposure prior to oocyte retrieval is associated with reduced live birth rate following FET, independent of the conditions at the time of embryo transfer. Importantly, the air quality during the study period was excellent, suggesting that even 'acceptable' levels of air pollution have detrimental reproductive effects during gametogenesis. At the low pollution levels in our study, exposure to gaseous pollutants did not appear to affect live birth rates. This has important implications for our understanding of the effects of pollution on reproduction, and highlights the urgent need for effective policies limiting pollution exposure to protect human health and reproduction. No funding was provided for this study. S.J.L. is supported by the Jean Murray Jones Scholarship from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, has received educational sponsorship from Besins, Ferring, Merck, and Organon, honoraria from Hologic and Organon, consulting fees from Merck unrelated to the current study, and is a member of the Reproductive Technology Council of Western Australia. S.J.L. and R.J.H. are board members of Menopause Alliance Australia. C.S.R., M.W., and E.N. have no conflicts of interest to declare. R.J.H. is the Medical Director of Fertility Specialists of Western Australia, the National Medical Director of City Fertility Australia, and a shareholder in CHA SMG. He chairs the Western Australian Minister's Expert Panel on ART and Surrogacy. R.J.H. has made presentations for and received honoraria from Merck, Merck-Serono, Origio, Igenomix, Gideon-Richter, and Ferring, and has received support for attending meetings from Merck, Organon, and Ferring. N/A.

Leathersich SJ ，Roche CS ，Walls M ，Nathan E ，Hart RJ ... -  《-》

Flexible progestin-primed ovarian stimulation versus a GnRH antagonist protocol in predicted suboptimal responders undergoing freeze-all cycles: a randomized non-inferiority trial.

Are live birth rates (LBRs) per woman following flexible progestin-primed ovarian stimulation (fPPOS) treatment non-inferior to LBRs per woman following the conventional GnRH-antagonist protocol in expected suboptimal responders undergoing freeze-all cycles in assisted reproduction treatment? In women expected to have a suboptimal response, the 12-month likelihood of live birth with the fPPOS treatment did not achieve the non-inferiority criteria when compared to the standard GnRH antagonist protocol for IVF/ICSI treatment with a freeze-all strategy. The standard PPOS protocol is effective for ovarian stimulation, where medroxyprogesterone acetate (MPA) is conventionally administered in the early follicular phase for ovulatory suppression. Recent retrospective cohort studies on donor cycles have shown the potential to prevent premature ovulation and maintain oocyte yields by delaying the administration of MPA until the midcycle (referred to as fPPOS), similar to GnRH antagonist injections. With milder pituitary suppression, the fPPOS protocol may be a less costly option for women expected to have a low or suboptimal response if a fresh embryo transfer is not intended. This was a non-inferiority, open-label randomized controlled trial conducted at a tertiary assisted reproduction center. A total of 484 participants were randomized in the study between July 2020 and June 2023 with a 1:1 allocation. Infertile women with a predicted suboptimal ovarian response (<40 years old, antral follicle count <10, and basal serum FSH < 12 mIU/ml) were randomly assigned to receive either fPPOS treatment or GnRH antagonist treatment. MPA (10 mg) or GnRH antagonist (0.25 mg) was administered daily once the leading follicle reached 14 mm and continued until the day of trigger. All viable embryos were cryopreserved for subsequent frozen-thawed embryo transfer in both groups. The primary endpoint was the proportion of live births per woman within 12 months post-randomization (with a non-inferiority margin of -12.5%). The analysis was assessed in the per-protocol population. Twenty-two women withdrew at the beginning of the stimulation phase due to COVID-19. Eight women did not proceed with the assigned frozen embryo transfer, and six switched from the fPPOS to the antagonist protocol. Overall, 449 women were included in the per-protocol analysis, with 216 in the fPPOS group and 233 in the GnRH antagonist group. The LBRs per woman were 44.4% (96/216) for participants in the fPPOS group and 48.9% (114/233) for participants in the GnRH antagonist group [risk ratio (RR) 0.91 (95% CI, 0.74, 1.11), risk difference (RD) -4.5% (95% CI, -13.7, 4.7)], which did not meet the non-inferiority criterion (-12.5%). Oocyte and embryonic parameters were not significantly different between the two groups. Nine women (4.17%) in the fPPOS group experienced a premature luteinizing hormone surge, compared to five women (2.15%) in the antagonist group. Only one woman in the fPPOS group ovulated before oocyte retrieval. The distinct routes of administration for the medications precluded blinding in this open-label trial, potentially influencing outcome assessments. All participants were recruited in a single center from one country, limiting the generalizability. While MPA is considered a patient-friendly alternative to antagonists for women undergoing scheduled freeze-all cycles, the GnRH antagonist protocol should still be the preferred treatment for anticipated suboptimal responders in terms of LBR. This trial was funded by Science and Technology Department of Shaanxi Province, China (2021SF-210). Innovation Team of Shaanxi Provincial Health and Reproductive Medicine Research (2023TD-04); Key Industrial Chain Projects in Shaanxi Province: Research on Assisted Reproductive Technologies and Precision Prevention System for Genetic Diseases Preconception (2023-ZDLSF-48). Science and Technology Department of Shaanxi Province, China (2022SF-564). B.W.M. reports consultancy, travel support and research funding from Merck KGaA and consultancy for Organon and Norgine; owning stock in ObsEva; and holding an NHMRC Investigator Grant (GNT1176437). Other authors declare no conflicts of interest. All other authors have nothing to declare. Registered at Chinese clinical trial registry (www.chictr.org.cn). Registry Identifier: ChiCTR2000030356. 29 February 2020. 11 March 2020.

Cai H ，Shi Z ，Liu D ，Bai H ，Zhou H ，Xue X ，Li W ，Li M ，Zhao X ，Ma C ，Wang H ，Wang T ，Li N ，Wen W ，Wang M ，Zhang D ，Mol BW ，Shi J ，Tian L ... -  《-》

Biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART: a systematic review and meta-analysis.

Is the probability of pregnancy different between women using biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART? Meta-analysis of eight randomized clinical trials (RCTs) suggests that live birth, clinical, and ongoing pregnancy rates are significantly lower with biosimilars of follitropin alfa compared to the originator. All biosimilars of follitropin alfa have received regulatory approval by demonstrating non-inferiority in the number of retrieved oocytes compared to the originator. Nevertheless, the most clinically relevant outcome in ART for both clinicians and patients is live birth. A meta-analysis published in 2021 suggested that biosimilars of follitropin alfa are associated with lower live birth rates compared to the originator. Since then, more relevant RCTs have been published, and thus an updated critical synthesis of the available evidence is urgently warranted. A systematic review and meta-analysis were performed to compare biosimilars versus the originator of follitropin alfa in women undergoing ovarian stimulation for ART. A literature search was conducted until January 2024 in MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science, WHO, Clinicaltrials.gov, and others to identify eligible RCTs. The primary outcome was live birth. Secondary outcomes included clinical and ongoing pregnancy, duration of gonadotrophin administration and total FSH dose, number of oocytes retrieved, and ovarian hyperstimulation syndrome (OHSS). Data were extracted independently by two reviewers. Quality was assessed using the RoB-2 Tool by Cochrane, and a sensitivity analysis was performed by excluding studies having high risk of bias. Meta-analysis was performed using the random or fixed effects model depending on the presence or not of significant (>50%) statistical heterogeneity (I2). Results were combined using the intention-to-treat principle and are reported as risk ratio (RR) or weighted-mean-difference (WMD) with 95% CIs. Eight RCTs (n = 2987) (published between 2015 and 2023) were identified, assessing seven biosimilar products of follitropin alfa. The number of patients included in the eligible studies ranged from 100 to 1100. Three of the RCTs were deemed to be at high risk of bias. The duration of gonadotrophin administration was shorter in the biosimilars group (WMD: -0.19 days, 95% CI: -0.34 to -0.05; I2 = 0%, 5 studies, n = 2081), while no difference was observed in the total dose of FSH (WMD: -34.69 IUs, 95% CI: -74.54 to 5.16; I2 = 15.53%, 5 studies, n = 2081). No difference was observed in the number of oocytes retrieved (WMD: 0.27, 95% CI: -0.43 to 0.96; I2 = 10.7%, 6 studies, n = 1527) and OHSS rates (RR: 1.17, 95% CI: 0.90-1.52; I2 = 0%, 8 studies, n = 2986) between the two groups. A significantly lower live birth rate was observed using the biosimilars of follitropin alfa compared to the originator in women undergoing ovarian stimulation for ART (RR: 0.83, 95% CI: 0.72-0.96; I2 = 0%, 6 studies, n = 2335; moderate certainty of evidence). Similarly, clinical pregnancy (RR: 0.82, 95% CI: 0.73-0.92; I2 = 0%, 7 studies, n = 2876; low certainty of evidence) and ongoing pregnancy rates (RR: 0.81, 95% CI: 0.70-0.94; I2 = 0%, 7 studies, n = 1886; low certainty of evidence) were lower in the biosimilars group. These results were not materially altered in the sensitivity analyses performed where studies deemed at high risk of bias were excluded. This meta-analysis included RCTs evaluating seven different biosimilars of follitropin alfa; however, pooled data appeared to be homogeneous. No data were available comparing biosimilars of follitropin alfa with the originator regarding cumulative live birth rate per aspiration or the probability of live birth in frozen thawed cycles. The population examined in the eligible RCTs includes mainly normal responders and no RCTs were identified focusing on poor or high responders. Clinicians should be informed that although biosimilars of follitropin alfa produce similar number of oocytes with the originator, pregnancy rates after a fresh transfer are likely to be lower. Future research should focus on optimizing the production and use of biosimilars of follitropin alfa, so that they lead to pregnancy rates comparable to the originator. No external funding was used for this study. K.I.K. and A.S. have no competing interest to disclose. E.M.K. reports personal fees and non-financial support from Merck, Ferring, IBSA, and Vianex. B.W.M. has been supported by an investigator grant from NHMRC, has received consulting fees from Organon, Merck, and Norgine, research support and non-financial support from Merck KGaA, Darmstadt, Germany. B.W.M. also reports having stocks from OBsEva. C.A.V. reports grants, personal fees, and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees, and non-financial support from Merck, Sharpe and Dohme, personal fees and non-financial support from Organon, grants and non-financial support from Ferring, personal fees from IBSA, and personal fees and non-financial support from Gedeon Richter and Vianex. Protocol for the systematic review registered in The International Prospective Register of Systematic Reviews (PROSPERO; CRD42024498237).

Kiose KI ，Storr A ，Kolibianakis EM ，Mol BW ，Venetis CA ... -  《-》