Hum. Reprod. [JOURNAL]
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200 papers
Cleavage stage versus blastocyst stage transfers in patients with a single zygote: an emulated target trial.
Fitzgerald O, Li W, Vallence C … +2 more , Chambers GM, Rombauts L
Hum Reprod · 2026 May · PMID 42213867 · Publisher ↗
STUDY QUESTION: Is the live birth rate higher for cleavage stage embryos compared to blastocysts in patients with a single zygote following oocyte fertilization using IVF or ICSI? SUMMARY ANSWER: Among patients with only...
STUDY QUESTION: Is the live birth rate higher for cleavage stage embryos compared to blastocysts in patients with a single zygote following oocyte fertilization using IVF or ICSI? SUMMARY ANSWER: Among patients with only a single zygote, transfer at cleavage stage was observed to result in a higher live birth rate than transfer at blastocyst stage. WHAT IS KNOWN ALREADY: Existing evidence suggests that blastocyst transfer is superior to cleavage stage in terms of live birth rate per embryo transfer, cumulative live birth rate, and time to pregnancy with three or more zygotes. However, whether these findings generalize to cohorts with less than three zygotes remains unclear. STUDY DESIGN, SIZE, DURATION: This target trial emulation, with live birth as the primary outcome, involved a retrospective analysis of 11 163 nulliparous patients who undertook ART in Australia and New Zealand between 2009 and 2022. Participants were included in the study if they were undergoing their first-ever stimulated ART cycle resulting in a single zygote following fertilization using IVF or ICSI. In this cohort, there were 6505 patients who received a cleavage stage transfer, 2216 who received a blastocyst stage transfer, and 2442 who had no embryo available for transfer following embryo culture, with the intended day of transfer unknown for these patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: We modelled a comparison of intended transfer of a cleavage or blastocyst using g-computation within the target trial emulation framework. This involved fitting models that estimated the chance that embryo would survive to cleavage or blastocyst stage based on patient characteristics, and if it did so, the chance of a live birth when it is transferred. These models were used to simulate an idealized randomized controlled trial (target trial) on our retrospective cohort. MAIN RESULTS AND THE ROLE OF CHANCE: We found that compared to blastocyst transfers, cleavage stage transfers were associated with a higher live birth rate per couple in this cohort (12.5% vs 10.1%), with an adjusted relative risk of 1.24 (95% CI: 1.15-1.50). This effect increased with female age from 35 years, with a relative risk of 1.34 (95% CI: 1.15-1.57) in a 35-year-old and 1.51 (95% CI: 1.25-1.80) in a 40-year-old woman. This is likely due to the high rate of embryo attrition between the cleavage and blastocyst stages; our models predict that on average 92.0% of zygotes would survive to cleavage stage, compared to 58.9% and 49.9% surviving to the blastocyst stage at ages 35 and 40 years. LIMITATIONS, REASONS FOR CAUTION: The originally intended/planned day of embryo transfer, i.e. cleavage stage or blastocyst, is not recorded in the data source, only the actual day of transfer. This required utilization of a multinomial mixture model that estimates the cleavage and blastocyst embryo development rates as a sub-model, using the year of treatment as an external source of variation (in additional to patient factors) for predicting the intended treatment group. As with any causal analysis using retrospectively collected observational data, the results are dependent on the accuracy of our modelling assumptions which cannot be verified. Additionally, the potential confounder of embryo quality on the day of transfer was not available. WIDER IMPLICATIONS OF THE FINDINGS: These results highlight the role target trial emulation can play in filling evidence gaps for patient cohorts excluded from existing RCTs, and where the prospect for future RCTs is limited due to sample size constraints or ethical considerations. Further, the assessment of new ART technologies and procedures needs to be stratified by markers of patient prognosis (in this case, female age and number of available zygotes), and there should be caution in generalizing the findings to a different group. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the 2024 Ferring Australia Reproductive Medicine Research Grant Scheme. O.F., G.M.C., and L.R. are the listed investigators on this grant paid to UNSW Sydney. Ferring had no role in designing, analysing, interpreting, or reviewing the study. W.L. declares that they are a Human Reproduction Deputy Editor. L.R. declares consulting fees from Besins, Merck, and Organon, speaker's fees from Besins, travel support from Gedeon Richter, and shares in Monash IVF Group (ASX: MVF). C.V. declares receipt of gift vouchers as honorarium for consumer input to the study as part of their membership of UNSW YourIVFSuccess/National Perinatal Epidemiology and the Statistics Unit Consumer Advisory Group. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Correction to: Decoding serotonin in endometriosis: unveiling its role in disease pathogenesis via the gut-reproductive microbiota axis.
Hum Reprod · 2026 May · PMID 42213860 · Publisher ↗
Abstract loading — click title to view on PubMed.
ABHD2 activity is not required for the non-genomic action of progesterone on human sperm.
Edwards M, Amaral A, Carter EM … +27 more , Arnolds O, Vester K, Thrun A, Wigren E, Homan E, Ribera P, Bentley K, Haraldsson M, Theo-Emegano N, Loppnau P, Szewczyk MM, Cao MA, Barsyte-Lovejoy D, Dittmar N, Hans A, Weber M, Münchow J, Zhu WF, Temme L, Brenker C, Strünker T, Sundström M, Todd MH, Edwards AM, Lesche R, Gileadi O, Tredup C
Hum Reprod · 2026 May · PMID 42212558 · Publisher ↗
STUDY QUESTION: Is the hydrolase ABHD2 required for progesterone-induced Ca2+ influx via CatSper and the resulting motility responses in human sperm? SUMMARY ANSWER: Progesterone-induced Ca2+ influx via CatSper and the r...
STUDY QUESTION: Is the hydrolase ABHD2 required for progesterone-induced Ca2+ influx via CatSper and the resulting motility responses in human sperm? SUMMARY ANSWER: Progesterone-induced Ca2+ influx via CatSper and the resulting motility responses in human sperm do not require ABHD2 activity. WHAT IS KNOWN ALREADY: Sperm motility is tightly regulated by signalling pathways that are activated as sperm ascend the female reproductive tract, including progesterone triggering Ca2+ influx via the CatSper channel and inducing hyperactivated motility needed for fertilization. This process is thought to involve ABHD2, which may hydrolyze the endogenous CatSper inhibitor 2-arachidonoylglycerol (2-AG), thereby relieving inhibition and enabling calcium entry into the flagellum. STUDY DESIGN, SIZE, DURATION: Potent small molecule inhibitors of ABHD2 activity were synthesized, characterized, and used as tools to scrutinize the role of ABHD2 in activation of CatSper and regulation of sperm motility. PARTICIPANTS/MATERIALS, SETTING, METHODS: Derivatives of published ABHD2 inhibitors were optimized for in vitro potency and cellular activity and subsequently tested in human sperm motility and Ca2+ influx assays. MAIN RESULTS AND THE ROLE OF CHANCE: Progesterone does not activate ABHD2 in vitro. In addition, inhibition of ABHD2 in human sperm has no effect on progesterone-induced Ca2+ influx through CatSper nor on basal or progesterone-induced hyperactivated motility. This demonstrates that ABHD2 activity is, in fact, not required for the non-genomic action of progesterone on human sperm. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: We examined the effects of inhibition of the enzymatic activity of ABHD2. We cannot exclude that ABHD2 functions as a part of a larger multiprotein complex, in which it may play a structural role independent of its hydrolase activity. WIDER IMPLICATIONS OF THE FINDINGS: This study presents conclusive evidence that ABHD2 does not bind progesterone and that its hydrolase activity is not required for progesterone activation of CatSper and resulting changes in motility of human sperm. These results highlight the need for further research to elucidate the mechanism underlying the non-genomic action of progesterone on human sperm. STUDY FUNDING/COMPETING INTEREST(S): This publication is based on research funded by the Gates Foundation, reference IDs INV-040467 and ID INV-072213. The findings and conclusions contained within are those of the authors and do not necessarily reflect the positions or policies of the Gates Foundation. LT, CB, and TS were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-project numbers 329621271 (CRU326; CB, TS), and 404595355 (Research Training Group 'Chemical biology of ion channels (Chembion)'; LT, TS). This work was funded by the German Federal Ministry of Education and Research (BMBF) within the framework of Contraception Research, grant numbers 01GR2501A and 01GR2502A. A.A., K.V., A.T., N.D., A.H., M.W., and R.L. are employees of Nuvisan ICB GMBH, Berlin, Germany. Nuvisan is a recipient of a Gates Foundation grant. A.A. is associate editor of Human Reproduction Open.
Donor-conceived adolescents' interest in obtaining information about their identity-release oocyte or sperm donor-results from the Swedish Study on Gamete Donation.
Groundstroem H, Paulin J, Thorup E … +2 more , Sydsjö G, Lampic C
Hum Reprod · 2026 May · PMID 42204656 · Publisher ↗
STUDY QUESTION: Do donor-conceived adolescents in lesbian- and heterosexual-couple families intend to request information about their identity-release oocyte or sperm donor? SUMMARY ANSWER: While more than half of adoles...
STUDY QUESTION: Do donor-conceived adolescents in lesbian- and heterosexual-couple families intend to request information about their identity-release oocyte or sperm donor? SUMMARY ANSWER: While more than half of adolescents intended to request donor information, being uncertain about making such requests was quite common, particularly among adolescents reporting better family functioning and those conceived with donor sperm in heterosexual-couple families. WHAT IS KNOWN ALREADY: Increasing numbers of children conceived with identity-release gamete donation are approaching the age when they can obtain donor information, but there is very little knowledge about their perspectives regarding this possibility, particularly among those conceived with donor oocytes. STUDY DESIGN, SIZE, DURATION: The present cross-sectional survey study was conducted 2022-2023 as part of a longitudinal follow-up of lesbian- and heterosexual-couple families following identity-release sperm donation (SD-L, SD-H) or oocyte donation (OD-H). We approached parents in a total of 216 families with a survey and also requested their consent to contact their donor-conceived child, provided he/she was aware of the donor conception. Parents in 165 families participated in this follow-up and, among these, parents in 123 families (75%) also provided contact information to their child(ren). Out of 128 approached adolescents, 100 completed the survey (78% response rate). Following exclusion of four adolescents with known/directed donors, the study sample consisted of 96 donor-conceived children aged 13-16 years (47 SD-L, 27 SD-H, and 22 OD-H), most of whom had been aware of their donor conception from an early age. PARTICIPANTS/MATERIALS, SETTING, METHOD: The present study was based on the fifth wave of data collection of the Swedish Study on Gamete Donation, which used consecutive recruitment of recipient couples starting donation treatment 2005-2008. In Sweden, recipients of donor gametes receive no information about the donor. Only the donor-conceived person has the legal right, when sufficiently mature, to request information about the donor, including his/her identity. Study-specific items were used to assess adolescents' experiences and perceptions of disclosure issues, interest in requesting any donor information (identifying and/or non-identifying) as well as interest in contact with the donor and same-donor peers. Family relationships were assessed with the FAD GF6+ and study-specific items measuring perceived parent-child closeness and resemblance. Comparisons between the three donation groups (SD-L, SD-H, OD-H) were performed with χ2 test and Fisher exact test. Multinomial logistic regression analysis was performed in two separate models to investigate if the intention to request donor information was associated with family type (lesbian/heterosexual-couple) and with donation type in heterosexual-couple families (SD-H/OD-H). MAIN RESULTS AND THE ROLE OF CHANCE: More than half (58%) of adolescents intended to request information about the donor (as soon as possible or sometime in the future), while 1 in 10 had no such intention, and a third of adolescents were uncertain. Regression analysis showed no significant effect of family form (lesbian/heterosexual-couple) on the intention to request donor information, but better family functioning (FAD GF6+) was associated with being uncertain about making such requests (P = 0.036) (OR 0.19, 95% CI 0.04-0.90). The second regression analysis, restricted to adolescents from heterosexual-couple families, showed that those from SD-H families were more likely than OD-H adolescents to be uncertain about requesting donor information (P = 0.028) (OR 0.17, 95% CI 0.04-0.82), when controlling for gender, family functioning, and closeness with the non-genetic parent. The most common motivations for intending to request donor information were to look for resemblance to the donor and to learn about one's heritage, and one in five was motivated by a desire to contact the donor. The adolescents wanted to receive information about the donor's background (78%), identity (61%), and openness to being contacted (52%), with no significant differences between donation groups. In addition, a third of the adolescents were interested in contact with same-donor peers, irrespective of donation group or existence of siblings in the family. LIMITATIONS, REASONS FOR CAUTION: Participants were recruited from a multicenter longitudinal cohort study of families following donor conception and achieved a high response rate among adolescents, but we cannot exclude the possibility of attrition bias with less well-functioning families opting out of the longitudinal study over time. Also, despite a relatively large study sample, small subgroups limit statistical power, and results should therefore be regarded with caution. Finally, the study was conducted in Sweden with mandatory identity-release donation, limiting generalizability to other contexts. WIDER IMPLICATIONS OF FINDINGS: Among young people who are aware of their conception with identity-release donation from an early age, a majority intend to obtain information about the donor. Type of donation and quality of family relationships seem to have relevance for adolescents' interest in seeking donor information, but more research is necessary. There appears to be a considerable variation regarding interest in different types of information, ranging from non-identifying characteristics to the donor's identity and openness to contact. These findings suggest that release of donor information should be adapted to the individual wishes of the donor-conceived person. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Swedish Research Council (grant number 2021-03174) and Umeå University. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Obstetric outcomes after IVF/ICSI treatment in women with endometriosis and/or adenomyosis diagnosed by ultrasonography: a prospective cohort study.
Alson S, Mattsson K, Sladkevicius P
Hum Reprod · 2026 May · PMID 42204604 · Publisher ↗
STUDY QUESTION: Among women pregnant after IVF/ICSI, do obstetric outcomes differ for women diagnosed with endometriosis and/or adenomyosis according to definitions by International Deep Endometriosis (IDEA) and the revi...
STUDY QUESTION: Among women pregnant after IVF/ICSI, do obstetric outcomes differ for women diagnosed with endometriosis and/or adenomyosis according to definitions by International Deep Endometriosis (IDEA) and the revised Morphological Uterus Sonographic Assessment (MUSA) groups, compared to women without the disease? SUMMARY ANSWER: Women with endometriosis and/or adenomyosis have a higher risk of preterm birth, hypertensive disorders of pregnancy, placenta previa, antepartum hemorrhage, and pelvic pain, compared to women without. WHAT IS KNOWN ALREADY: Evidence regarding the impact of endometriosis and adenomyosis on obstetric outcomes remains inconsistent, largely due to heterogeneity in study design, diagnostic methods, disease criteria, and mode of conception. Therefore, clinical guidance on antenatal management for affected women remains limited. STUDY DESIGN, SIZE, DURATION: This was a prospective, observational cohort study of 1035 women who underwent up to three consecutive IVF/ICSI treatments at a university hospital. Published data suggest a preterm birth risk of 8-10% after IVF/ICSI without endometriosis, with higher rates in endometriosis and adenomyosis. Assuming 10% versus 20% preterm birth, 492 women were needed for 80% power. In total, 666 women gave birth to a child between January 2019 and April 2024. Of these, 607 (91.1%) women, for which the obstetric outcomes were known, were included in the study, while the remaining 59 (8.9%) were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible for publicly funded IVF/ICSI treatments are non-smoking women aged 25 to ≤39 years, with a BMI of 18 to <30 kg/m2 and no previous children with the present partner. Women are entitled to up to three consecutive, publicly subsidized IVF/ICSI treatments, until the birth of the first child is achieved. All women underwent pretreatment ultrasound examination by an expert examiner, using the IDEA and revised MUSA definitions. Out of 607 included women, in total 144/607 (23.7%) women had endometriosis and/or adenomyosis. The primary outcome was preterm birth (delivery before completed 37 weeks gestation). Secondary outcomes included placenta previa, antepartum or postpartum hemorrhage, hypertensive disorders of pregnancy, gestational diabetes mellitus, caesarean section delivery, placental abruption, oligohydramnios, pelvic pain, and neonate small for gestational age, as well as outcomes stratified for women with different disease phenotypes. The adjusted relative risk for the different outcomes was calculated using modified Poisson regression analyses with robust error variances. MAIN RESULTS AND THE ROLE OF CHANCE: Preterm birth occurred in 27/144 (18.9%) women with endometriosis and/or adenomyosis compared to 53/463 (11.4%) in disease-free women, corresponding to an aRR 1.63 (95% CI, 1.06-2.49), P = 0.025. However, this was only significant for late preterm birth between gestational week 34 + 0-36 + 6 [21 (16%) vs 37 (8.0%), aRR 2.56 (95% CI, 1.26-5.21)] and not for earlier preterm birth. In addition, women with endometriosis and/or adenomyosis had an increased risk for placenta previa [13 (9.0%) vs 7 (1.5%), aRR 5.82 (95% CI, 2.32-14.6), P < 0.001], antepartum hemorrhage [17 (11.8%) vs 30 (6.5%), aRR 2.02 (95% CI, 1.19-3.41), P = 0.009], hypertensive disorders of pregnancy [19 (13.2%) vs 31 (6.7%), aRR 2.26 (95% CI, 1.29-3.97), P = 0.004] and pelvic pain [24 (16.7%) vs 40 (8.6), aRR 1.91 (95% CI, 1.21-3.01), P = 0.005] compared to disease-free women. There was a statistically non-significant tendency for an increased risk for developing oligohydramnios [10 (6.9%) vs 15 (3.3%), aRR 2.10, 95% CI, 0.98-4.48, P = 0.055] as well as delivering an SGA infant, [22 (15.3%) vs 45 (9.7%), aRR 1.58, 95% CI, 0.98-2.53, P = 0.059]. However, the risk for caesarean delivery, gestational diabetes mellitus, placental abruption, and postpartum hemorrhage was not increased. LIMITATIONS, REASONS FOR CAUTION: Excluding women aged ≥40 years or with a BMI ≥ 30 kg/m2 may limit the generalizability to other populations. The presence of superficial, peritoneal endometriosis was not accounted for. The study was powered for the primary outcome preterm birth in the total cohort and may have lacked sufficient power for the secondary outcomes. The composite endometriosis and/or adenomyosis group is dominated by isolated endometriosis, with relatively few women with combined disease. Women with adenomyosis only may represent a biologically and clinically distinct subgroup. Pooling them with endometriosis could potentially dilute or mask disease-specific associations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that women with endometriosis and/or adenomyosis are at increased risk of common adverse pregnancy outcomes. Clinicians should recognize these risks when counseling affected women and consider tailored antenatal care. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by regional research grants from Region Skåne, Sweden. There was no competing interest. TRIAL REGISTRATION NUMBER: Not applicable.
Fertility treatment and risk of cerebral palsy: has the association changed in Australia?
Hansen M, Kemp-Casey A, McIntyre S … +6 more , Badawi N, Kiss NM, Hart RJ, Milne E, Bower C, Goldsmith S
Hum Reprod · 2026 May · PMID 42177772 · Publisher ↗
STUDY QUESTION: What is the association between treated (ART, ovulation induction (OI)) and untreated subfertility and risk of cerebral palsy (CP)? SUMMARY ANSWER: There is no increased risk of CP in births to subfertile...
STUDY QUESTION: What is the association between treated (ART, ovulation induction (OI)) and untreated subfertility and risk of cerebral palsy (CP)? SUMMARY ANSWER: There is no increased risk of CP in births to subfertile untreated women; the risk of CP has declined in ART conceptions (IVF, ICSI) and is greatest in births conceived using OI medications as a sole therapy. WHAT IS KNOWN ALREADY: Nordic data suggest a decline in risk of CP for ART births over time with the shift to single embryo transfer (SET), but there are no recent data from other countries and no Australian data for births after 2002. Few studies have examined the risk of CP in births conceived after OI or untreated subfertility; these comparison groups may assist in separating ART treatment effects from potential effects of subfertility itself. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study using linked population-based data for women with a live birth (LB) in Western Australia from 2003 to 2014, corresponding to 10 126 ART births (3.1%), 4102 births after OI (1.2%), 11 554 births to subfertile untreated women (3.5%), and 305 508 (92.2%) births to fertile women conceiving naturally. PARTICIPANTS/MATERIALS, SETTING, METHODS: Statutory ART, birth, hospital, CP, and pharmacy data were linked to identify four 'conception groups' (ART, OI, subfertile untreated, and fertile natural conceptions), outcome data, and potential confounders. CP descriptions were verified at 5 years of age. Birth prevalence of CP was calculated for each conception group per 1000 LB. Poisson regression with robust standard errors was used to estimate adjusted risk ratios (aRR) for CP with adjustment for maternal demographic characteristics, pre-existing conditions, and adverse obstetric history (with 95% CI). Births to fertile women were the reference group. Analyses included all children and singletons and twins separately. Weinberg's differential rule was used to estimate the rate of monozygotic twinning across our four conception groups and, for ART births, by length of embryo culture. MAIN RESULTS AND THE ROLE OF CHANCE: CP was diagnosed in 29 ART children (2.9/1000 LB; 95% CI 1.92-4.11), 16 children born after OI (3.9/1000 LB; 95% CI 2.23-6.33), 23 children in the subfertile untreated group (2.0/1000 LB; 95% CI 1.26-2.99), and 610 in the fertile group (2.0/1000 LB; 95% CI 1.84-2.16). When stratified by plurality and prematurity, risk was increased only for ART twins (aRR 2.8, 95% CI 1.42-5.39) born preterm (<37 weeks) and OI singletons (aRR 2.9, 95% CI 1.41-5.84) born preterm. Twins after SET comprised an increasing proportion of all ART twins over time, and of all ART twins with CP. Most twins after SET were same-sex twins (90.7%) and we estimated that 81% were monozygous, with the majority conceived after the transfer of a single blastocyst. The monozygotic twinning rate was higher after blastocyst-SET compared with cleavage-SET (prevalence ratio 1.7 (95% CI 1.07-2.73)). LIMITATIONS, REASONS FOR CAUTION: Small numbers of children with CP in subfertile groups prevented more detailed analyses of pregnancy complications and ART cycle characteristics. More recent data from larger populations are required to confirm whether risk of CP is increased following blastocyst transfer, in twins after SET, and following OI as a sole therapy. As zygosity data were not available, Weinberg's differential rule was used to estimate the rate of monozygotic twinning and may have led to some misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Prevalence of CP following ART has declined in Western Australia, as in the Nordic countries. Avoiding multiple embryo transfer remains important. Monozygotic twinning after SET may increase the risk of CP for ART twins and is more common after blastocyst compared with cleavage-stage transfer. Embryo culture, manipulation, and freezing strategies to reduce monozygotic twinning should be explored. Data about OI (as a sole therapy) are not routinely collected in most countries, but OI-conceived births had the highest risk of CP and may warrant closer scrutiny. Pre-treatment counselling should continue to promote SET while incorporating the small risk of embryo splitting; risk of multiple birth should be discussed with those planning to use OI. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Australian National Health and Medical Research Council, grant number 1086530 (to M.H.) and The Research Foundation of Cerebral Palsy Alliance, grant number 06221 (to M.H.). The sponsors had no role in the design or conduct of the study, or the decision to submit for publication.Professor Hart is the Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Fertility Clinic, a shareholder in CHA SMG; he has received accommodation support from Merck to attend ESHRE and has received travel and accommodation support, as well as educational sponsorship from MSD, Merck-Serono, Origio, Igenomix, and Ferring Pharmaceuticals. He has also received personal fees for presenting a Merck webinar. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Does intracytoplasmic sperm injection outperform conventional in vitro fertilization in couples without severe male factor infertility? A systematic review and meta-analysis of randomized controlled trials.
Kayimu K, Berntsen S, Fu Y … +19 more , Yuan Y, Vomstein K, Tian T, Liu F, Gao J, Vuong LN, Ho TM, Huynh BG, Pham TD, Dang VQ, Skipper DF, Zedeler A, Pinborg A, Westergaard D, Mol BW, Nielsen HS, la Cour Freiesleben N, Qiao J, Wang Y
Hum Reprod · 2026 May · PMID 42172285 · Publisher ↗
STUDY QUESTION: Does ICSI improve the live birth rate in couples without severe male factor infertility compared to conventional IVF (cIVF)? SUMMARY ANSWER: High-quality evidence showed no benefit of ICSI over cIVF in im...
STUDY QUESTION: Does ICSI improve the live birth rate in couples without severe male factor infertility compared to conventional IVF (cIVF)? SUMMARY ANSWER: High-quality evidence showed no benefit of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. WHAT IS KNOWN ALREADY: Although ICSI is an effective method within ART for severe male factor infertility, it is frequently used for other infertility etiologies despite insufficient evidence. The effectiveness of ICSI compared with cIVF in couples with mild male or without severe male factor infertility remains uncertain. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis. PubMed, EMBASE, MEDLINE, Web of Science, Cochrane Library, ProQuest Dissertations & Theses Global, Scopus, CINAHL Plus, Chinese Wan Fang, and CNKI databases were searched from inception to 31 May 2025 without language restrictions. The search strategy encompassed three key domains: ICSI, cIVF, and ART treatment outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included randomized controlled trials (RCTs) comparing outcomes of ICSI versus cIVF per couple. Exclusion criteria were duplicate studies, conference abstracts or proceedings, trial registry records, editorials, letters, non-randomized designs, RCTs that did not randomize participants to ICSI or cIVF, studies comparing effects per oocyte rather than per couple, studies lacking complete outcome data, and those not meeting predefined criteria for trustworthiness. Study characteristics and ART outcomes were extracted. The risk of bias and study trustworthiness were independently evaluated by two investigators using the Cochrane Collaboration's Risk of Bias 2 Tool and TRACT checklist, respectively. GRADE decision-making was used to evaluate the quality of evidence. MAIN RESULTS AND THE ROLE OF CHANCE: Six RCTs reporting on couples without severe male factor infertility were included. The meta-analysis showed no benefit from ICSI over cIVF in live birth rate (four studies, N = 1438, 32.8% vs 34.5%, pooled risk ratio (RR) = 0.96, 95% CI: 0.85-1.09, I2 = 37%, high-quality evidence) or cumulative live birth rate (three studies, N = 1911, 43.2% vs 47.4%, pooled RR = 0.92, 95% CI: 0.84-1.01, I2 = 41%, high-quality evidence). ICSI was associated with a lower preterm birth rate (three studies, N = 222, 4.6% vs 6.0%, pooled RR = 0.77, 95% CI: 0.59-1.00, P = 0.0447, I2 = 0, high-quality evidence). No significant differences were observed for other fertility or pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION: The findings should be interpreted with caution due to the limited number of high-quality studies reporting live birth data, limited subgroup-specific evidence, and some heterogeneity in outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: Evidence from this meta-analysis shows no advantage of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. Based on current evidence, ICSI should not be routinely recommended for indications other than severe male infertility. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Natural Science Foundation of China (No. 82204052), the National Key Research and Development Program of China (No. 2022YFC2703102), and Peking University Third Hospital (No. BYSYDL2022001, BYSYDL2024003) with salaries for J.Q., Y.W., K.K., Y.F., Y.Y., T.T., F.L., and J.G. The funders of the study played no role in study design, data collection, data analysis, data interpretation, or writing of the report. S.B. has received scientific grants from Gedeon Richter and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Fond. K.V. has received speakers' fees from Gedeon Richter, Merck, and IBSA. L.N.V. has received grants, speakers' fees, and conference fees (including travel support) from Merck Sharp & Dohme, and Ferring, and scientific board fees from Ferring. T.M.H. has received speakers' fees from Merck, Merck Sharp & Dohme, and Ferring. A.P. has received speakers' fees (including those classified as honoraria) from Ferring Pharmaceuticals, Merck, Gedeon Richter, IBSA, Abbott and Consulting fees from Gedeon Richter and Ferring and travel support from Gedeon Richter. H.S.N. received speakers' fees from Ferring Pharmaceuticals, Merck, Astra Zeneca, Cook Medical, Gedeon Richter, Ibsa Nordic, Novo Nordisk, and Bessins. B.W.M. reports consulting fees, travel support, and research funding from Merck and consulting fees from Ferring, Organon, Repronovo, UNILAB, Vitra, and Norgine. N.l.C.F. has received speakers' fees from Merck and Ferring Pharmaceuticals, consulting fees from Merck, and meeting support/registration fees from Merck, Ferring Pharmaceuticals, IBSA, and Gedeon Richter (paid to institution). She is also an unpaid chair in the steering committee for the guideline groups of The Danish Fertility Society. All other authors declare no competing interests. REGISTRATION NUMBER: CRD42023479967.
From revolution to indication creep: ICSI in the absence of severe male factor infertility.
Li W, Kirkegaard K, Barratt C
Hum Reprod · 2026 May · PMID 42172281 · Publisher ↗
Abstract loading — click title to view on PubMed.
Prenatal maternal stress is associated with alterations in the structural integrity of the hypothalamic-pituitary-gonadal axis 20 years later: Project Ice Storm.
Jones SL, Anastassiadis C, Dupuis M … +8 more , Elgbeili G, Marcoux FP, Gazetas J, Devenyi GA, Near J, Laplante DP, Pruessner JC, King S
Hum Reprod · 2026 May · PMID 42166041 · Publisher ↗
STUDY QUESTION: Is prenatal maternal stress (PNMS) in humans associated with alterations in the sexually differentiated reproductive axis structures in the offspring? SUMMARY ANSWER: PNMS, experienced by pregnant mothers...
STUDY QUESTION: Is prenatal maternal stress (PNMS) in humans associated with alterations in the sexually differentiated reproductive axis structures in the offspring? SUMMARY ANSWER: PNMS, experienced by pregnant mothers exposed to a natural disaster in 1998, was associated with structural changes in hypothalamic-pituitary-axis (HPG) structures of 18.5-year-old offspring. WHAT IS KNOWN ALREADY: In a human prospective study, PNMS was associated with higher childhood BMI, which in turn predicted earlier menarche. Epidemiological studies have shown that maternal life event stress is associated with changes in gonadal morphology and function. STUDY DESIGN, SIZE, DURATION: A prospective study of mothers exposed to a severe ice storm in 1998 (N = 224) collected measures of PNMS (objective hardship and subjective distress). Offspring reproductive structures were assessed in early adulthood. PARTICIPANTS/MATERIALS, SETTING, METHODS: PNMS-exposed offspring (ICE; n = 39, 21 F, 18 M) and a control group (n = 31, 14 F, 17 M; born in 1997) were assessed at age 18.5 years. Participants underwent MRI. Using a novel approach, the structural integrity of the entire HPG axis was assessed using gold-standard manual delineation from their MRI scans. Ovarian antral follicles (2-10 mm) were also counted from MRI images. Salivary estradiol and testosterone were measured with ELISA. Data were analyzed with ANOVA and multiple regression. MAIN RESULTS AND THE ROLE OF CHANCE: The expected sex difference in hypothalamic volume (M > F) was detected in controls. Within ICE, the sex difference was observed at low, but not at high, levels of PNMS (objective and subjective). Greater objective hardship was associated with smaller hypothalamic volume in men. Similarly, pituitary volume was smaller in ICE men compared to control men. Within ICE, greater objective hardship was associated with smaller left testicular volume. Finally, compared to controls, the left ovary had more antral follicles and tended to be larger in ICE women. The group differences and associations between PNMS and HPG morphology were generally medium to large. LIMITATIONS, REASONS FOR CAUTION: The relatively small sample size may have limited our ability to detect small differences and to test interactions with gestational timing of prenatal stress exposure. In addition, the majority of women were taking oral contraceptives, and thus results must be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: PNMS from a natural disaster may lead to functional changes in the human reproductive axis in adulthood. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by a grant from the Canadian Institutes of Health Research (CIHR, FRN 125892; to S.K., D.P.L., and J.C.P., and CIHR MOP 125892 to co-investigators S.K. S.L.J. was funded by a postdoctoral fellowship provided by the Fonds de Québec-Santé (FRQ-S). The funding sources were not involved in the collection, analyses, or interpretation of the data, or writing of the report. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.
Hypertension and dyslipidemia in women with PCOS: a population-based multiregister study in Sweden.
Persson S, Turkmen S, Hirschberg AL … +2 more , Sundström Poromaa I, Elenis E
Hum Reprod · 2026 May · PMID 42120012 · Publisher ↗
STUDY QUESTION: What is the impact of PCOS and the hyperandrogenic (HA) PCOS phenotype on the risk of developing hypertension and dyslipidemia? SUMMARY ANSWER: PCOS is an independent risk factor for the development of hy...
STUDY QUESTION: What is the impact of PCOS and the hyperandrogenic (HA) PCOS phenotype on the risk of developing hypertension and dyslipidemia? SUMMARY ANSWER: PCOS is an independent risk factor for the development of hypertension and dyslipidemia, with the risk being higher among women with the HA PCOS phenotype. WHAT IS KNOWN ALREADY: PCOS is an established risk factor for insulin resistance and the metabolic syndrome. However, prospective data regarding the risk of hypertension and dyslipidemia in population-based cohorts of women with PCOS are limited. STUDY DESIGN, SIZE, DURATION: This nationwide multiregister-based cohort study included a total of 297 215 women with PCOS and matched controls followed for up to 20 years. Data were retrieved from the Swedish Patient Register, the Prescribed Drug Register, the Medical Birth Register, the Cause of Death Register, the Total Population Register, and the Education Register. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants resided in Sweden and were born between 1950 and 1999. The median age at study entry was 28 years. Women with a diagnosis of PCOS, androgen excess, or anovulatory infertility recorded in the Swedish Patient Register between 1 January 1997 and 31 December 2016 constituted the study population (n = 50 969). For each woman with PCOS, five controls matched by birth year and municipality were randomly selected from the Total Population Register (n = 246 246). The primary outcomes were incident hypertension and dyslipidemia after PCOS diagnosis, defined by International Classification of Diseases-10 codes and/or filled prescriptions for antihypertensive or lipid-lowering medications, respectively. Women with PCOS were further classified as hyperandrogenic (HA) if they had been diagnosed with androgen excess or had a filled prescription for anti-androgenic drugs in the Prescribed Drug Register; otherwise, they were classified as normoandrogenic (NA). Cox regression analyses were performed, adjusted for birth period, country of birth, and education. Overweight and obesity were accounted for in separate models using either BMI or an obesity ICD-10 diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had a higher risk of developing hypertension compared with non-PCOS women [adjusted Hazard Ratio (aHR) 2.25 (95% CI: 2.13-2.39), adjusted for obesity]. Those with the HA-PCOS phenotype had more than 5-fold increased risk [aHR 5.51 (95% CI: 4.97-6.10)]. Similarly, PCOS was associated with a higher risk of dyslipidemia [aHR 3.05 (95% CI: 2.69-3.46), adjusted for obesity], and women with the HA phenotype exhibited a more than 7-fold increased risk [aHR 7.82 (95% CI: 6.34-9.64)]. LIMITATIONS, REASONS FOR CAUTION: Inclusion of the most severe cases of PCOS could have led to an overestimation of risk estimates. Information on BMI was only available among parous women. The study comprised mainly women with Nordic origin and should be replicated in cohorts with other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS, especially those with the HA phenotype, face a substantially increased long-term risk of hypertension and dyslipidemia, highlighting the need for early cardiovascular risk assessment and preventive strategies in this population. The findings underscore that PCOS is not only a reproductive disorder but also a significant cardiovascular risk factor, warranting tailored prevention and management strategies. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Family Planning Fund, Uppsala, and the Selanders Fund, Uppsala University (grant number 464251850). Furthermore, E.E. has a part-time research position funded by Uppsala University Hospital (grant number ALF 937815). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. E.E. has received lecture fees from Merck AB, none in any way related to this manuscript. The rest of the authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: n/a.
Microplastics and reproductive health: implications for human health and areas for future research.
Hyman S, Kahn LG, Cowell W
Hum Reprod · 2026 May · PMID 42114971 · Publisher ↗
Microplastics (MPs), conventionally defined as plastic particles 1 μm-5 mm in size, are ubiquitous contaminants, infiltrating both our environment and our bodies. These particles, either manufactured at this scale or for...
Microplastics (MPs), conventionally defined as plastic particles 1 μm-5 mm in size, are ubiquitous contaminants, infiltrating both our environment and our bodies. These particles, either manufactured at this scale or formed from the breakdown of larger plastics, possess diverse characteristics that allow them to absorb and release toxic substances, form biofilms, and abrade and inflame tissues. In humans, MPs have been detected in testes, semen, ovarian follicular fluid, placental tissue, and other locations in the reproductive system. Recent studies suggest that MPs may disrupt male and female reproduction through mechanisms involving oxidative stress, inflammation, DNA damage, and endocrine disruption. Over the past 5 years, there has been increasing excitement about MPs research and a burgeoning literature in this area. Despite this growing body of evidence, the full spectrum of MP-associated reproductive toxicity in humans remains poorly understood, with limited research on effects at environmentally relevant exposure levels and in the general population, and a poor understanding of the specific toxicity of different polymer types, sizes, and shapes. As the literature rapidly expands, it is important to take note of current constraints and how research in this field may be optimized for quality. This review summarizes current knowledge about MPs and their reproductive toxicity, highlights emerging research areas, and identifies key challenges and needs for future research on this class of contaminant.
Bi-allelic mutations of CAMSAP1 result in teratozoospermia with sperm head and flagella defects in humans.
Zheng R, Yan J, Zhi W … +8 more , Huang G, Du X, Zhang H, Shaiq PA, Tan Y, Tu C, Shi Q, Xu W
Hum Reprod · 2026 May · PMID 42114970 · Publisher ↗
STUDY QUESTION: What is the role of calmodulin-regulated spectrin-associated protein 1 (CAMSAP1) in human spermatogenesis? SUMMARY ANSWER: Biallelic CAMSAP1 variants cause human male infertility with multiple sperm head...
STUDY QUESTION: What is the role of calmodulin-regulated spectrin-associated protein 1 (CAMSAP1) in human spermatogenesis? SUMMARY ANSWER: Biallelic CAMSAP1 variants cause human male infertility with multiple sperm head deformities and MMAF-like phenotypes by disrupting manchette microtubule dynamics and the microtubule-spectrin-actin scaffold essential for sperm head shaping. WHAT IS KNOWN ALREADY: Sperm head shaping requires coordinated acrosome formation, chromatin condensation, and manchette-driven nuclear remodeling. Although several genes have been implicated in globozoospermia, macrozoospermia, and multiple morphological abnormalities of the sperm flagella (MMAF), the genetic causes of other forms of abnormal sperm head morphology remain largely unknown. Camsap1-deficient mice exhibit severe spermatogenic defects, including abnormal sperm head shaping and flagellar malformations resulting from disruption of the acrosome-acroplaxome-manchette complex, ultimately leading to male infertility. However, whether CAMSAP1 plays a conserved role in human sperm development has not been established. STUDY DESIGN, SIZE, DURATION: The CAMSAP1 variants were identified by whole-exome sequencing in a cohort of 3757 male infertility patients, and all participants were recruited from 2015 to 2025. In vitro functional assays, immunoprecipitation-mass spectrometry, and sperm morphological analyses were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three infertile men with severely impaired sperm morphology and motility were recruited. Bioinformatic assessment, cell-based expression assays, immunostaining, and co-immunoprecipitation (Co-IP) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) using human testicular extracts were used to characterize the functional impact of the variants. MAIN RESULTS AND THE ROLE OF CHANCE: Homozygous CAMSAP1 variants were identified in two individuals from consanguineous families (Chinese and Pakistani), and compound heterozygous missense variants in a third individual from a non-consanguineous Chinese family through whole-exome sequencing and further confirmed by Sanger sequencing. Sperm from affected individuals displayed MMAF phenotypes and diverse head abnormalities, including pyriform, amorphous, small, and globozoospermic forms. All four CAMSAP1 variants were predicted to be damaging and exhibited markedly reduced protein stability in vitro. Proteomic analysis revealed that CAMSAP1 interacts with proteins involved in actin cytoskeleton organization, acrosomal vesicle trafficking, microtubule bundle assembly, and calmodulin regulation. Mechanistically, CAMSAP1 associates with CALM1 and SPTBN1 to couple manchette microtubules with the perinuclear spectrin-actin network, ensuring proper force transmission for nuclear shaping. Mutations disrupted these interactions, leading to defective manchette architecture, abnormal acrosome assembly, and nuclear deformation. LIMITATIONS, REASONS FOR CAUTION: Although CRISPR-Cas9 knock-in cell lines carrying patient-derived CAMSAP1 variants were generated, this in vitro model could not reproduce the highly dynamic processes of manchette assembly and nuclear remodeling that occur uniquely during spermiogenesis, and therefore cannot fully capture the mechanistic sequence leading to sperm head deformation. Additionally, the number of affected individuals remains limited, and larger multi-center, multi-ethnic cohorts will be required to validate the pathogenicity of CAMSAP1 variants and further delineate the associated clinical spectrum. WIDER IMPLICATIONS OF THE FINDINGS: This work identifies CAMSAP1 as a previously unrecognized cause of human asthenoteratozoospermia and expands the genetic landscape of sperm head deformities. The findings underscore the essential role of CAMSAP1 in manchette-mediated nuclear remodeling and provide new insights for genetic diagnosis, counseling, and management of male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (grant no. 82301815), the National Key R&D Program of China (grant no. 2022YFC2702603), the Sichuan Province Science and Technology Innovation Talent Project (grant no. 2024JDRC0006), the 2024 Key Open Project of Sichuan Provincial Key Laboratory for Human Disease Gene Research (grant no. 2024kflx002), and the China Postdoctoral Science Foundation (grant nos. 2023M732468 and GZC20231835). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Ethnic disparity in the use of ART treatment: a national register-based cross-sectional study among women in Denmark.
Petersen AA, Østergaard SS, Kyhl FN … +4 more , Passet-Wittig J, Milewski N, Schmidt L, Vassard D
Hum Reprod · 2026 May · PMID 42114839 · Publisher ↗
STUDY QUESTION: Is ethnic background among 18- to 45-year-old women associated with initiating ART treatment in Denmark? SUMMARY ANSWER: Results indicate ethnic disparity in the use of ART treatment, with immigrants and...
STUDY QUESTION: Is ethnic background among 18- to 45-year-old women associated with initiating ART treatment in Denmark? SUMMARY ANSWER: Results indicate ethnic disparity in the use of ART treatment, with immigrants and their descendants having lower odds of initiating ART treatment compared to women with Danish origin. WHAT IS KNOWN ALREADY: The use of fertility treatment has increased over the past decades. Ethnic disparity exists in the use of health care, but there is limited knowledge about the association between migrant origin and use of fertility treatment. Previous studies have shown that women with lower socioeconomic position (SEP) have lower odds of initiating ART treatment compared to women with higher SEP. Immigrants and their descendants often have lower SEP compared to the general population (i.e. non-migrants or natives), but specific mechanisms might be at play when residing and navigating in a new country and healthcare system. STUDY DESIGN, SIZE, DURATION: This is a national, register-based study based on a sample of the Danish National ART-Couple (DANAC II) cohort, a full population cohort encompassing men and women registered with a Danish residence and with birth year between 1948 and 2006. Women initiating ART treatment (IVF or ICSI) aged 18-45 years were identified in the Danish IVF Register from 1994 to 2017. According to the time of ART treatment women were included in the study and randomly age-matched with 10 untreated women in the untreated background population. The study population consisted of 676 355 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The probability of initiating ART treatment was compared across ethnic groups and examined in logistic regression analyses. Migration status and country of origin were used as proxies for ethnic groups in separate analysis. Age was accounted for by matching, and additional factors of interest such as SEP measures were classified as potential mediators and thus not included in the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The study population consisted of 526 507 (78%) women of Danish origin, 142 656 (21%) immigrants, and 7192 (1%) descendants of immigrants. Among women of Danish origin 11% had initiated ART treatment compared to 5% of immigrants and 9% of descendants. Immigrants had 56% lower odds of receiving first ART treatment compared to women of Danish origin (odds ratio (OR) 0.44, CI 95% 0.43-0.45), while descendants had 22% lower odds compared to women of Danish origin (OR 0.78, CI 95% 0.72-0.84). Regarding the analysis examining country of origin, results showed that 3-4% of women originating from western countries had received first ART treatment compared to 6-8% of women originating from non-western countries. Women originating from western countries had between 65% and 78% lower odds for receiving first ART treatment compared to women of Danish origin. Odds of receiving ART treatment among women of non-western origin were between 34% and 47% lower compared to women of Danish origin. LIMITATIONS, REASONS FOR CAUTION: Information on the reason for infertility and desire to have children could have provided more insight into existing disparities. Data about the basis for residence could have provided information on reasons for immigration and duration of residence. WIDER IMPLICATIONS OF THE FINDINGS: Infertility and childlessness can have severe consequences for individuals and society, and equal access to fertility treatment is important, particularly in a universal welfare society. The results of this study indicate ethnic disparity in the use of ART treatment, and we encourage further research into the possible causes and barriers to initiate treatment. STUDY FUNDING/COMPETING INTEREST(S): The funding for the establishment of the Danish National ART-Couple II Cohort (DANAC II Cohort) was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Correction to: Spatial transcriptomics in the human adult ovary: insights into key signalling pathways during follicular atresia.
Hum Reprod · 2026 May · PMID 42112982 · Publisher ↗
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The International Glossary on Infertility and Fertility Care, 2025†.
Zegers-Hochschild F, Dyer S, Adamson GD … +30 more , Baker V, Barnhart K, Bhattacharya S, Boothroyd C, Chambers G, De Mouzon J, Elgindy E, Fauser B, Hammarberg K, Horton M, Ishihara O, Jwa SC, Khrouf M, Kupka M, Lamb DJ, Luna M, Martinez AG, Monseur B, Nagy P, Pinborg A, Racowsky C, Rienzi L, Schlegel P, Schmidt L, Vuong LN, Turner T, Vázquez-Levin MH, Wada I, Wells D, Wyns C
Hum Reprod · 2026 Jun · PMID 42100799 · Full text
STUDY QUESTION: What updates of the International Glossary on Infertility and Fertility Care are required, to reflect contemporary scientific knowledge, social needs, and inclusive definitions, while harmonizing internat...
STUDY QUESTION: What updates of the International Glossary on Infertility and Fertility Care are required, to reflect contemporary scientific knowledge, social needs, and inclusive definitions, while harmonizing international communication across clinical, research, policy, and public domains? SUMMARY ANSWER: This 4th edition presents 348 consensus-based terms and definitions, including numerous revisions from the previous edition and 79 newly introduced definitions reflecting advances in reproductive science, technology, and evolving social contexts. WHAT IS KNOWN ALREADY: Previous glossary editions (2006, 2009, 2017) established internationally recognized definitions related to clinical practice, research, and policy. The 2017 edition comprised 283 terms and, among many others, expanded the concept of infertility to include not only its recognition as a disease, but also as an impairment of function generating disability. The glossary has been extensively used worldwide and has contributed to international standardization of data collection, appropriate comparison of outcome measures, and provided a reference for all stakeholders including policy makers. STUDY DESIGN, SIZE, DURATION: Under guidance of the organizing committee, 21 professionals from across the world, and representing expertise in different sub-specialties, formed five working groups: clinical definitions; outcome measures; embryology laboratory; clinical and laboratory andrology; and epidemiology, public health and gender related definitions. The definitions from the previous glossary were evaluated and new terms identified. All definitions were then reviewed by an international advisory panel of nine experts that evaluated the glossary from scientific, ethical, cultural, and policy perspectives. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between November 2024 and October 2025, periodical virtual meetings were held within and between working groups and the organizing committee. Following circulation of the first consensually agreed draft, a one-day in-person meeting with representatives of all working groups and members of the international advisory panel was held at ESHRE, June 2025. Most terms and definitions were discussed and agreed. In the absence of agreement, further discussions were held between the organizing committee, working group chairs and members of the advisory panel. It had been determined at the outset that final disagreement would be resolved via a two-third majority vote. All terms and definitions were, however, reached by consensus and adopted following a final round of review and approval by all authors. MAIN RESULTS AND THE ROLE OF CHANCE: The glossary now includes 348 terms. Compared to the previous edition, 14 terms were deleted, numerous terms modified and 79 new terms were added. Modifications reflect current scientific knowledge, technological advancements, and inclusivity related to gender and family structures. Chance does not play a role, as all definitions are consensus-based. LIMITATIONS, REASONS FOR CAUTION: Some terms may require future refinement as scientific knowledge evolves and societal contexts change. The glossary reflects consensus rather than empirical testing of all definitions. WIDER IMPLICATIONS OF THE FINDINGS: This glossary provides a global reference for standardized terminology, supporting clinical care, research, international comparisons, policy making, patient communication, and reproductive health literacy. STUDY FUNDING/COMPETING INTEREST(S): Neither ICMART, responsible for conducting this project, nor any of the participants received specific financial support for their activities in this project. Ferring provided ICMART with a fixed amount to cover venue costs and a one-day hotel accommodation for participants attending the in-person meeting held prior to the ESHRE Congress in June 2025. Disclosures were provided by all authors, and none reported any conflict of interest related to this manuscript. TRIAL REGISTRATION NUMBER: N/A.
'The more, the better' a decade later. Still true?
Polyzos NP, Donno V
Hum Reprod · 2026 May · PMID 42083378 · Publisher ↗
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Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissues: impact and legacy two decades latter.
Andersen CY, Dolmans MM, Ernst E
Hum Reprod · 2026 May · PMID 42083377 · Publisher ↗
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The impact of endometrial preparation on pregnancy loss in vitrified-warmed euploid blastocyst transfer cycles: a randomized controlled trial.
Roelens C, Santos-Ribeiro S, Mackens S … +7 more , De Vos A, Keymolen K, Verdyck P, De Vos M, Tournaye H, Verpoest W, Blockeel C
Hum Reprod · 2026 Jun · PMID 42081915 · Publisher ↗
STUDY QUESTION: Does artificial cycle (AC) endometrial preparation result in increased pregnancy loss rates in patients undergoing vitrified-warmed euploid blastocyst transfer (frozen embryo transfer (FET))? SUMMARY ANSW...
STUDY QUESTION: Does artificial cycle (AC) endometrial preparation result in increased pregnancy loss rates in patients undergoing vitrified-warmed euploid blastocyst transfer (frozen embryo transfer (FET))? SUMMARY ANSWER: The randomized controlled trial (RCT) demonstrates that artificial endometrial preparation is associated with significantly higher early pregnancy loss (EPL) compared to natural cycles when transferring euploid embryos. WHAT IS KNOWN ALREADY: The increased use of FET cycles has fueled discussion regarding the optimal endometrial preparation method. While earlier reviews found no significant differences in pregnancy outcomes between preparation strategies, recent studies suggest that artificial preparation may be associated with higher pregnancy loss rates and, more recently, with hypertensive disorders of pregnancy. However, these findings were not confirmed in a recent RCT using genetically untested embryos. Since up to 70% of EPLs are attributed to genetic anomalies in the embryo, analyzing FET of euploid embryos provides a more accurate evaluation of the impact of endometrial preparation on pregnancy loss. STUDY DESIGN, SIZE, DURATION: An RCT was conducted in a university hospital (May 2019-May 2024) investigating the impact of endometrial preparation on pregnancy loss in FET. A power calculation based on internal data determined that 261 patients per arm were needed to detect an increase in pregnancy loss from 9.9% in tNC-FET to 18.4% in AC-FET (80% power, 5% significance). Due to safety concerns regarding hypertensive disorders following AC-FET, the trial was discontinued after enrolling 354 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-42 years undergoing FET after preimplantation genetic testing for aneuploidy (PGT-A) with or without testing for a monogenic disorder (PGT-M) or a structural chromosomal rearrangement (PGT-SR) were randomized (1:1) to either true NC-FET (spontaneous ovulation without luteal phase support (LPS)) or AC-FET (using estradiol and single-route LPS). Only the first FET per patient using a euploid blastocyst was included. The primary outcome was EPL (before 8 weeks of gestation). Secondary outcomes included clinical pregnancy rate (CPR), ongoing pregnancy, live birth rate (LBR), and obstetric outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2019 and May 2024, 354 patients were randomized (NC-FET: 178, AC-FET: 176). In the intention-to-treat analysis, EPL per started FET cycle occurred in 6.7% of patients in the NC-FET group and 14.2% in the AC-FET group (P = 0.022). Additionally, EPL per positive hCG was 9.0% in the NC-FET group and 21.6% in the AC-FET group (P = 0.006). CPRs were significantly higher in the NC-FET group (72.5% versus 52.3%, P < 0.001), as were LBRs (67.4% versus 47.2%, P < 0.001). The study was prematurely terminated after obstetrical safety concerns of AC-FET emerged from other studies. While obstetric and neonatal outcomes did not differ significantly between groups in our study, the trial was not powered for these endpoints. Despite the premature halt, the observed difference in EPL was in line with the anticipated effect size. LIMITATIONS, REASONS FOR CAUTION: Although this randomized study achieved the estimated difference in the primary outcome, the premature cessation necessitates cautious interpretation. Additionally, the absence of luteal phase progesterone measurements in both groups represents a limitation. Nevertheless, these findings offer valuable insights for counseling patients on the optimal FET preparation method. WIDER IMPLICATIONS OF THE FINDINGS: The results of this RCT reinforce concerns regarding AC-FET cycles. In addition to previously reported higher obstetrical complications, an increased risk of pregnancy loss was associated with AC-FET cycles. This protocol should therefore preferentially be used in patients with (premature) ovarian insufficiency or those resistant to ovulation induction agents. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. C.R. declares speaker's fees from Organon, Ferring, Abbott, IBSA; travel support from Gedeon Richter, Ferring, Organon, Abbott, IBSA. S.S.-R. declares employment and stock ownership in IVIRMA Lisboa; grants/contracts (paid to institution) from Theramex, Organon, Gedeon-Richter, Roche Pharmaceuticals; consulting fees from Organon, IBSA, Besins; travel support (paid to institution) and speaker's fees from Organon, Ferring, Theramex, IBSA, Gedeon-Richter, Abbott, and Besins; being a member of the Executive Committee, Past-Senior Deputy of Safety and Quality SIG for ESHRE. S.M. declares grants/contracts (to institution) from Merck, Gedeon Richter, Ferring; advisory board for Oxolife; speakers' fees and travel support from Merck, Gedeon Richter, Ferring, and IBSA. W.V. declares research grants (to institution) from Merck B.V. and IBSA; consulting fees (to institution) from CooperSurgical and Cook Medical; advisory board (payment to institution) for Goodlife; speaker fees (to institution) from CooperSurgical, Merck B.V., Organon Pharma B.V., Ferring B.V., and Gedeon Richter. C.B. declares speaker's fees from Abbott, Ferring Pharmaceuticals, IBSA, Organon, Gedeon Richter, and Merck. The other authors declare no conflict of interest related to this manuscript. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT03976544. TRIAL REGISTRATION DATE: 6 April 2019. DATE OF FIRST PATIENT’S ENROLMENT: 25 May 2019.
Single-cell proteomics reveals cytoplasmic defects in Patl2-deficient oocytes rescued by spindle transfer.
Cardona Barberán A, Araftpoor E, Christodoulaki A … +11 more , Fakhar-I-Adil M, Goethals J, Rybouchkin A, Arnoult C, Boel A, Bühler M, Pavani KC, Stoop D, Gevaert K, Vanden Meerschaut F, Heindryckx B
Hum Reprod · 2026 May · PMID 42062216 · Publisher ↗
STUDY QUESTION: Can single-cell, mass spectrometry-based proteomics identify proteins associated with reduced developmental competence of Patl2-/- Metaphase II (MII) mouse oocytes and reveal therapeutic targets for Patl2...
STUDY QUESTION: Can single-cell, mass spectrometry-based proteomics identify proteins associated with reduced developmental competence of Patl2-/- Metaphase II (MII) mouse oocytes and reveal therapeutic targets for Patl2-related infertility? SUMMARY ANSWER: Abnormal protein content is detected in Patl2-/- MII oocytes, which can be rescued by spindle transfer (ST). WHAT IS KNOWN ALREADY: PATL2 is an RNA-binding protein that represses maternal mRNA translation during oocyte maturation. PATL2 mutations in humans often cause germinal vesicle (GV) arrest, although some affected patients produce MII oocytes with reduced fertilization and embryo developmental potential. Consequently, oocyte donation is required. The Patl2-/- knockout mouse model offers a unique opportunity to study Patl2-related infertility and evaluate potential treatments. STUDY DESIGN, SIZE, DURATION: Patl2 -/- mice (C57BL/6NTac-Patl2tm1a), with deletion of exon 7, were bred from April 2021 to October 2023, yielding 36 homozygous females from 271 pups. To investigate the role of Patl2 at the MII stage, in vivo MII oocytes from Patl2-/- and Patl2+/+ females were collected for analysis of key quality markers and single-cell proteomics. Based on these results, maternal ST was tested to rescue abnormal embryo development. At least three replicates were conducted per experiment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Four- to 12-week-old mice underwent superovulation and oocyte collection to assess in vitro and in vivo maturation. In vivo-matured MII oocytes were used to evaluate activation (AR) and blastocyst rates (BR) after PIEZO-ICSI, spindle configuration, and calcium oscillatory patterns following SrCl2 exposure. Vitrified-warmed oocytes were used for single-cell proteomics using a timsTOF ultra mass spectrometer operated in diaPASEF mode. ST involved transferring the Patl2-/- spindle to Patl2+/+ enucleated cytoplasm, followed by parthenogenetic activation (PA) via SrCl2 exposure. MAIN RESULTS AND THE ROLE OF CHANCE: Patl2 -/- females exhibit lower in vivo MII rates (79.63%) than Patl2+/+ females (89.39%, P = 0.0123) but similar in vitro maturation rates (GV-MII = 48.74%) compared to Patl2+/+ females (52.85%, P = 0.5230). After PIEZO-ICSI with wild-type sperm, reduced AR (Patl2-/- = 31.71%, Patl2+/+ = 76.74%, P < 0.0001) and BR (Patl2-/- = 7.69%, Patl2+/+ = 42.42%, P = 0.0237) were observed in knockout oocytes. However, Patl2-/- oocytes exhibited normal spindle rates (78.57%) as seen in Patl2+/+ oocytes (86.00%, P = 0.3491), as well as a similar capacity to sustain long-lasting calcium oscillations (A×F = 6.15 ± 4.80) compared to Patl2+/+ oocytes (A×F = 4.59 ± 2.96, P = 0.1453). Single-cell proteomics identified 4882 proteins and confirmed the absence of Patl2 in knockout oocytes, from analyzing 25 Patl2+/+ and 27 Patl2-/- MII oocytes. After filtering, 3747 proteins were used for statistical analysis, revealing 1508 differentially expressed proteins (q-value < 0.05; 992 downregulated, 516 upregulated in Patl2-/- oocytes). The levels of multiple RNA-binding proteins, some of which are proposed Patl2 interactors (Cpeb1, Eif4e1b), were found to be significantly reduced in Patl2-/- oocytes. Additionally, the protein products of several maternal effect genes (MEGs) implicated in mRNA regulation (Zar1, Igf2bp2) and cell cycle division (Tcl1a, Cdk1, Mos) were downregulated, while MEGs participating in epigenetic modifications (Zfp57, Trim28) were upregulated in the knockout group. Consistent with these observations, ST-PA treatment significantly increased AR (100%) and BR (75%) in the Patl2-/- oocytes in comparison to PA alone (AR = 75.95%, P = 0.0078; BR = 45.00%, P = 0.0128), effectively rescuing development to wild-type levels. Lastly, ST-PA treatment did not alter embryonic development in Patl2+/+ oocytes and produced outcomes comparable to PA alone, supporting the technical safety and applicability of the technique. LARGE SCALE DATA: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE massIVE partner repository with the dataset identifier MSV000100606. LIMITATIONS, REASONS FOR CAUTION: Patl2 -/- mice exhibit a less severe phenotype compared to patients carrying PATL2 variants. Patl2-/- female mice display a high MII rate without significant spindle abnormalities, which contrasts with a previously published report. Additionally, ST treatment was conducted using parthenogenetically activated oocytes, rather than biparental embryos. WIDER IMPLICATIONS OF THE FINDINGS: ST represents a promising treatment for PATL2-related female infertility in patients with MII oocytes, as it appears to restore cytoplasmic defects linked to abnormal RNA-binding proteins and MEGs identified by single-cell proteomics. In contrast, other proposed treatments for poor embryo development, such as assisted oocyte activation, is unlikely to be effective since Patl2-/- oocytes show a normal calcium response. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Special Research Fund (BOF) (starting grant BOF.STG.2021.0042.01 awarded to B.H.) and the Research Foundation-Flanders (FWO) (fellowship 1177425 N awarded to E.A.). B.H. has been receiving unrestricted educational funding from Ferring Pharmaceuticals (Aalst, Belgium). A.C.B., E.A., A.C., M.F-I-A., J.G., A.R., M.B., A.B., C.A., K.C.P., D.S., K.G., and F.V.M. have nothing to disclose. B.H. reports being board member of the Belgian Ethical Committee on embryo research.
Reply: Concerns regarding the WHO guideline on infertility: implications for contemporary reproductive medicine.
Mburu G, Ombelet W, Kucuk T … +11 more , Rebar RW, Giudice LC, Boivin J, Esteves SC, Balen AH, Vuong LN, Santesso N, Brignardello-Petersen R, Kennedy R, Kiarie J, WHO Guideline Development Group
Hum Reprod · 2026 Jun · PMID 42049210 · Full text
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