Hum. Reprod. [JOURNAL]
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200 papers
How big is the time window for cell-free fetal DNA testing after pregnancy loss and which factors are associated with a successful result?
El Sammaa-Aru YI, Hartwig TS, Bro-Jørgensen MH … +8 more , Münter EJ, Werge L, Banasik K, Stener Jørgensen F, COPL Consortium, Ambye L, Westergaard D, Nielsen HS
Hum Reprod · 2026 May · PMID 41875045 · Publisher ↗
STUDY QUESTION: How fast does cell-free fetal DNA (cffDNA) decline after early pregnancy loss and which factors affect the decline? SUMMARY ANSWER: After pregnancy loss cffDNA declines gradually with detectable levels pe...
STUDY QUESTION: How fast does cell-free fetal DNA (cffDNA) decline after early pregnancy loss and which factors affect the decline? SUMMARY ANSWER: After pregnancy loss cffDNA declines gradually with detectable levels persisting up to 3 days post-tissue passage correlating with β-hCG decline. WHAT IS KNOWN ALREADY: Postpartum clearance of cffDNA occurs within hours, but little is known about its decline following early pregnancy loss. Initial results from the Copenhagen Pregnancy Loss (COPL) study showed slower clearance in relation to pregnancy loss with detectable levels found up to 24 h after tissue passage. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 1463 women from the COPL cohort, enrolled between 12 November 2020 and 19 December 2022. Participants were divided into three groups based on sampling time: the standard group (samples collected before tissue passage), the delayed sample group (samples collected after tissue passage at maximum 24 h), and the repeated sample group (samples collected at multiple time points after medical and surgical treatment). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible women were 18 years old with a confirmed intrauterine pregnancy loss before 22 gestational weeks. Exclusion criteria included ectopic, molar, or unknown-location pregnancies and inability to consent. For the repeated sample group, additional exclusions were vaginal bleeding at diagnosis, anembryonic pregnancies, and opting for expectant management. Blood samples were analyzed for β-hCG and cffDNA, with fetal fraction measured using the sequencing-based fetal fraction (SeqFF) method. In the repeated sampling group, analyses were performed on Days 2 and 3 for surgically treated and Days 7 and 14 for medically treated. MAIN RESULTS AND THE ROLE OF CHANCE: After pregnancy tissue passage, both cffDNA and β-hCG levels declined consistently over time with a corresponding increase in no-call rates. The decline in SeqFF following pregnancy loss occurred more gradually than the immediate clearance previously reported after delivery, remaining measurable for up to 3 days after pregnancy loss, though 30% of samples became inconclusive at this timepoint. The fetal fraction of cffDNA was highest when tissue remained in utero and declined significantly beyond 12-h post-passage (median 4.7% <6 h vs 2.8% >12 h). The no call rate was 9.1% when the tissue was still in situ but increased to 27.1% in the 12- to 24-h post-passage group. Higher β-hCG levels correlated with increased odds of a conclusive cffDNA test (OR 1.30, 95% CI: 1.20-1.43, P < 0.001). β-hCG is accounting for 20% of the variability in fetal fraction measurements. Variability in the decline of cffDNA between groups reflects the differences in the timing of sampling and treatment approaches. LIMITATIONS, REASONS FOR CAUTION: The small size of the repeated sample group may limit the generalizability of the findings. Reliance on the SeqFF method introduces variability, as it may not perform consistently. Adjustment for key confounders including BMI, gestational age, type of pregnancy loss, and timing of sampling was performed, but residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: As a non-invasive method, cffDNA testing offers critical genetic insights for couples facing time-sensitive reproductive decisions or those with recurrent pregnancy loss. The correlation between β-hCG and fetal fraction suggests β-hCG screening could optimize sequencing decisions. These findings support refining cffDNA diagnostics to enhance pregnancy loss evaluation and reproductive care. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Ole Kirks Foundation, the BioInnovation Institute Foundation (BII21SG1020554, NNF20SA0066125, and NNF15OC0016662), the Novo Nordisk Foundation (NNF22OC0077221 and NNF23OC0087269), and the A.P. Møller Foundation. The authors have declared their COI. TRIAL REGISTRATION NUMBER: N/A.
The World Health Organization infertility guidelines: "Presumption of ovulation".
Kamath MS
Hum Reprod · 2026 Jun · PMID 41875022 · Publisher ↗
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Periconceptional ultra-processed food consumption in women and men, fertility, and early embryonic development.
Lin CHX, Gaillard R, Mulders AGMGJ … +2 more , Jaddoe VWV, Schipper MC
Hum Reprod · 2026 May · PMID 41871947 · Full text
STUDY QUESTION: Is periconceptional ultra-processed food (UPF) consumption in women and men associated with fertility, embryonic growth, and yolk sac development? SUMMARY ANSWER: Higher maternal UPF consumption was assoc...
STUDY QUESTION: Is periconceptional ultra-processed food (UPF) consumption in women and men associated with fertility, embryonic growth, and yolk sac development? SUMMARY ANSWER: Higher maternal UPF consumption was associated with smaller embryonic growth and yolk sac volume, and higher paternal UPF consumption was associated with reduced fertility. WHAT IS KNOWN ALREADY: The periconceptional period is critical for the probability of conception, pregnancy outcomes, and long-term offspring health, and maternal dietary patterns during this period may influence fertility as well as early embryonic development. No studies have examined the combined influence of maternal and paternal UPF consumption on fertility outcomes and early development. STUDY DESIGN, SIZE, DURATION: This study is embedded in a population-based prospective cohort study from preconception onwards, with follow-up into childhood. The present study included 831 women and 651 male partners. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed periconceptional dietary intake via a food frequency questionnaire at median 12+3 weeks of gestation (95% range 10+6, 18+3). Foods were categorized using NOVA classification, and UPF intake was expressed as a percentage of total food intake (grams per day). Information on time to pregnancy was obtained through questionnaires, with fecundability defined as the probability of conceiving within 1 month and subfertility as time to pregnancy ≥12 months or use of assisted reproductive technology. Crown-rump length (CRL) and yolk sac volume were measured by transvaginal ultrasound examinations at 7, 9, and 11 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Median UPF intake was 22.0% of total food intake for women and 25.1% for men. UPF intake was not associated with fertility outcomes in women. In fully adjusted continuous models, higher maternal UPF intake was associated with smaller CRL at 7 weeks gestation [difference: -0.13 standard deviation score (SDS), 95% CI: -0.25, -0.01, per SDS increase in UPF intake]. Higher maternal UPF intake was also associated with smaller yolk sac volume at 7 weeks gestation in fully adjusted continuous models [difference: -0.14 SDS, 95% CI: -0.26, -0.02, per SDS increase in UPF intake]. These associations attenuated at 9 and 11 weeks gestation. In men, higher UPF intake was associated with decreased fecundability and increased subfertility risk in the continuous models (fecundability ratio: 0.90, 95% CI: 0.83, 0.99, OR: 1.36, 95% CI: 1.11, 1.67, per SDS increase in UPF intake), but not with first trimester development, after adjusting for socio-demographic, lifestyle factors, and female partner's UPF consumption. LIMITATIONS, REASONS FOR CAUTION: The inclusion of a relatively healthy population may limit the generalizability of our findings to broader or higher-risk groups. WIDER IMPLICATIONS OF THE FINDINGS: These sex-specific findings underscore the importance of considering UPF intake in preconception and early pregnancy diets to optimize reproductive outcomes, embryonic development, and long-term offspring health. STUDY FUNDING/COMPETING INTEREST(S): The Generation R Study is financially supported by the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development. R.G. received funding from the Netherlands Organization for Health Research and Development (NWO, ZonMw VIDI 09150172110034, and NWO, ZonMW, grant number 05430052110007), from the Dutch Diabetes Foundation (grant no. 2024.28.001), and from the European Union (ERC, OBESE-EMBRYO, ERC-2024-STG-101161004). V.W.V.J received a grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw 05430052110007) and a European Research Council Consolidator Grant (ERC-2014-CoG-648916). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. This project has received funding from the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action (No. 727565), European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL), EndObesity, ZonMW Netherlands (No. 529051026). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Depression and anxiety among women going through medically assisted reproduction: a register-based cohort study.
Sonne H, Egsgaard S, Munk-Olsen T … +3 more , Cesta CE, Schmidt L, Bliddal M
Hum Reprod · 2026 May · PMID 41871457 · Publisher ↗
STUDY QUESTION: How do the incidence and prevalence of depression and anxiety change for women during the 3 years before and after initiation of medically assisted reproduction (MAR)? SUMMARY ANSWER: Women initiating MAR...
STUDY QUESTION: How do the incidence and prevalence of depression and anxiety change for women during the 3 years before and after initiation of medically assisted reproduction (MAR)? SUMMARY ANSWER: Women initiating MAR experienced a decline in depression and anxiety before treatment initiation, followed by an increase after initiation, returning to pre-treatment levels 3 years later. WHAT IS KNOWN ALREADY: Infertility and its treatment are associated with psychological distress, and previous research has examined mental health trajectories shortly before, during, and after treatment. Studies suggest that emotional adjustment varies across treatment phases and outcomes, but population-based evidence on clinical depression and anxiety patterns in a longer period before treatment initiation is lacking. STUDY DESIGN, SIZE, DURATION: Nationwide register-based cohort study including all women in Denmark initiating MAR from 2006 to 2018 (n = 64 611) and a matched comparison group of women without MAR (n = 64 611), matched on the date of the first MAR treatment. Depression and anxiety were examined from 3 years before to 3 years after MAR initiation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were identified from the Danish National Register of Assisted Reproductive Technology and matched on age, calendar year, parity, and psychiatric history. Depression and anxiety were defined as hospital diagnoses or filled prescriptions for antidepressants or anxiolytics. Incidence rates were defined as new registrations of depression or anxiety, requiring no registration in the preceding 12 months. Prevalence was defined as the proportion of person-time affected by depression or anxiety based on diagnoses or prescriptions within the preceding 12 months. MAIN RESULTS AND THE ROLE OF CHANCE: Among women undergoing MAR, the incidence rate of depression and anxiety declined from 19 to 11 per 1000 persons per half-year before treatment and rose to 17 three years after, forming a U-shaped pattern. In the comparison group, rates remained stable at about 25 per 1000 half-years. Results were consistent across subgroups defined by psychiatric history, age, and parity, and when restricting outcomes to hospital-based diagnoses. LIMITATIONS, REASONS FOR CAUTION: The study relied on registry data and did not capture untreated or subclinical cases. Information on partnership status, socioeconomic characteristics, and parenthood intentions was unavailable and may differ between groups, potentially influencing both MAR initiation and mental health outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that women undergoing MAR experience a temporary period of improved mental health before treatment, followed by an increased risk afterwards. These descriptive patterns suggest that mental health varies across phases of fertility treatment and may help identify periods of particular relevance for mental health support in women undergoing MAR. STUDY FUNDING/COMPETING INTEREST(S): H.S. is funded by The Novo Nordisk Foundation (grant number 3110412) and The Independent Research Fund Denmark (grant number 2110290). S.E., T.M.-O., and M.B. are funded by The Novo Nordisk Foundation (grant number NNF21OC0072397). S.E. is also funded by The Psychiatric Research Fund in the Region of Southern Denmark (grant number A5752) and The Region of Southern Denmark (grant number A1784). Funding sources had no role in designing, planning, analysing, interpreting, or reviewing the manuscript. TRIAL REGISTRATION NUMBER: Not applicable.
Endometriotic cystectomy as an unaccounted mediator of early menopause and adverse health outcomes in later life.
Younis JS, Taylor HS
Hum Reprod · 2026 May · PMID 41866667 · Publisher ↗
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Ovarian and reproductive hormone characteristics and risk of cycle cancellation in immediate versus postponed modified natural cycle frozen embryo transfer (mNC-FET) cycles.
Bergenheim S, Somuncu Johansen A, Colombo C … +13 more , Saupstad M, Dam TV, Bogstad JW, la Cour Freiesleben N, Prætorius L, Behrendt-Møller I, Oxlund-Mariegaard B, Nøhr B, Husth M, Sopa N, Løkkegaard E, Pinborg A, Løssl K
Hum Reprod · 2026 May · PMID 41866664 · Publisher ↗
STUDY QUESTION: Do ovarian and reproductive hormone characteristics and risk of cycle cancellation differ between immediate and postponed modified natural cycle (mNC) frozen embryo transfer (FET) cycles? SUMMARY ANSWER:...
STUDY QUESTION: Do ovarian and reproductive hormone characteristics and risk of cycle cancellation differ between immediate and postponed modified natural cycle (mNC) frozen embryo transfer (FET) cycles? SUMMARY ANSWER: Ovarian morphology, early follicular phase levels of progesterone and LH, and follicular phase length differed significantly between immediate and postponed mNC-FET. Cancellation rates differed numerically. WHAT IS KNOWN ALREADY: The optimal timing of mNC-FET following ovarian stimulation and oocyte retrieval is heavily debated. Concerns about suboptimal ovarian and hormonal conditions in the NC immediately following ovarian stimulation have led to the widespread practice of postponing FET for at least 1 month. However, emerging evidence suggests that reproductive outcomes in immediate programmed FET cycles are comparable, or even superior, to those achieved in postponed cycles. Studies of the NC immediately following ovarian stimulation and oocyte retrieval are lacking, leaving a limited understanding of its functionality, cycle characteristics, hormonal profiles, and ovarian morphology. STUDY DESIGN, SIZE, DURATION: This descriptive study is based on data from a recently completed Danish multicentre randomised controlled non-inferiority trial (RCT) evaluating the optimal timing of FET following ovarian stimulation and oocyte retrieval. Women were randomised 1:1 to mNC-FET in the cycle immediately following ovarian stimulation and oocyte retrieval, or after a 1-month delay. Data from 468 women, collected from March 2021 to May 2025, were included in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a regular menstrual cycle, aged 18-40 years, and undergoing autologous single blastocyst mNC-FET were eligible for inclusion. The presence of cystic intraovarian structures > 10 mm and plasma levels of FSH, LH, estradiol, and progesterone from cycle initiation to blastocyst transfer were assessed, as were the length of the follicular phase and cancellation rates between groups. MAIN RESULTS AND THE ROLE OF CHANCE: The number of cystic ovarian structures was significantly higher in the immediate group than in the postponed group on Days 2-5 of the treatment cycle (median, 3 [IQR, 1-6] vs 0 [IQR, 0-1]; P < 0.001) as well as on the day of ovulation trigger (median, 1 [IQR, 0-2] vs 0 [IQR, 0-1]; P < 0.001). In the early follicular phase, plasma progesterone levels were higher (median, 1.2 [IQR, 0.7-1.7] vs 0.8 [IQR, 0.6-1.5] nmol/L; P < 0.001) in the immediate compared to postponed cycles, and plasma LH levels were lower (median, 4.1 [IQR, 2.7-6.1] vs 5.9 [IQR, 4.7-7.5] IU/L; P < 0.001), as were FSH levels (median, 6.6 [IQR, 5.0-8.2] vs 6.9 [IQR, 5.9-7.9] IU/L; P = 0.047). The time to ovulation trigger was longer in the immediate than in the postponed group (mean, 15.0 [SD, 3.9] vs 13.0 [SD, 3.0] days; P < 0.001): an effect driven by freeze-all cycles. As a natural consequence of the increased time to ovulation trigger, more follicular scans were performed in the immediate group (median, 3 [IQR, 2-3] vs 2 [IQR, 1-3]; P < 0.001). Cycle cancellation was more frequent in immediate cycles, however, the difference was not statistically significant (10.3% vs 6.2%; P = 0.078). LIMITATIONS, REASONS FOR CAUTION: The main endpoints of this study were specified in the study protocol of the RCT, but some post hoc analyses were performed to explore unexpected findings. Due to variations in clinical practice, data were subjected to multiple subdivisions. No power calculations were performed for the reported endpoints. WIDER IMPLICATIONS OF THE FINDINGS: The follicular phase of immediate cycles seems to differ from postponed cycles in terms of ovarian morphology, follicular phase length, and early follicular phase levels of progesterone and LH. The rate of cycle cancellation raises concerns about the clinical feasibility of immediate FET treatment in NCs. STUDY FUNDING/COMPETING INTEREST(S): The RCT is 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. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. M.S. benefitted from a grant from Gedeon Richter and received support for meeting attendance from the same. M.S. received payment for lectures from IBSA and Gedeon Richter. J.W.B. received support from meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. N.C.F. received consulting fees and honoraria for a presentation from Merck A/S and Ferring Pharmaceuticals 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. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. B.O.-M. received support for meeting attendance from Gedeon Richter and Ferring Pharmaceuticals and participate on a board for Ferring Pharmaceuticals. B.N. benefitted from grants from Merck A/S and Gedeon Richter. B.N. received support for meeting attendance from Gedeon Richter and participate on a board for Ferring Pharmaceuticals. E.L. received honoraria from Pfizer and Gedeon Richter, and support for meeting attendance from Gedeon Richter, Merck A/S, and Astellas. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, and Merck A/S as payment to the institution. A.P. received consulting fees from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S, and honoraria from Ferring Pharmaceuticals, Gedeon Richter, Abbott, and Merck A/S. K.L. received a grant from Gedeon Richter as payment to the institution. K.L. received consulting fees and honoraria from Ferring Pharmaceuticals and support for attending meetings from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S. A.S.J., T.V.D., I.B.-M., M.H., and N.S. declare no conflicts of interest. TRIAL REGISTRATION NUMBER: The study is registered at ClinicalTrials.gov: NCT04748874.
Reply: Endometriotic cystectomy as an unaccounted mediator of early menopause and adverse health outcomes in later life.
Chung HF, Mishra GD
Hum Reprod · 2026 May · PMID 41866663 · Publisher ↗
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A clinical protocol for the detection of comorbidities associated with monogenic causes of male infertility.
van der Heijden GW, Westra D, van Olden MCS … +11 more , Hobo W, Oud MS, Smits RM, Baysal Ö, Bogers H, D'Hauwers K, Kempers MJE, Jacobs JFM, Veltman JA, Stokman MF, Ramos L
Hum Reprod · 2026 May · PMID 41863311 · Full text
STUDY QUESTION: How can comorbidities associated with monogenic forms of male infertility systematically be identified? SUMMARY ANSWER: Via a framework that consists of seven sequential steps, gene-specific phenotyping p...
STUDY QUESTION: How can comorbidities associated with monogenic forms of male infertility systematically be identified? SUMMARY ANSWER: Via a framework that consists of seven sequential steps, gene-specific phenotyping protocols can be generated for all monogenic causes of male infertility. WHAT IS KNOWN ALREADY: Infertility negatively impacts men's health. When loss of a single gene is causal for infertility (i.e. monogenic), the associated comorbidities are largely unknown. STUDY DESIGN, SIZE, DURATION: A framework was developed that allows the generation of gene-specific phenotyping protocols. The framework was applied to generate such protocols for two men, each with a different monogenic cause for their infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: A multidisciplinary medical team formulated seven sequential steps to develop gene-specific phenotyping protocols. Gene-specificity was obtained by using a gene's expression pattern in the human body to identify tissues/cell types that show high levels of expression, as well as a literature search on the gene of interest, for potential morbidities. With these insights, tailored questionaries and tests are designed. We applied this framework to generate gene-specific protocols for two men in whom infertility was caused by the respective disruption of the genes MEI1 and DNAH17. These genes respectively show very high levels of expression in various types of immune cells and retinal cells. With gene-specific phenotyping protocols, we assessed the functionality of these cells in these men. MAIN RESULTS AND THE ROLE OF CHANCE: Our framework facilitated the generation of two gene-specific phenotyping protocols that were used to systematically identify potential comorbidities associated with two forms of monogenic male infertility. Analyses of the gene expression in the human body identified immune cells (MEI1) and retinal cells and oligodendrocytes (DNAH17) as somatic cell types with high expression. Gene-specific phenotyping protocols contained targeted questions as well as clinical tests for these tissues/cell types. The questionnaires indicated no increased susceptibility to infections, allergies nor autoimmune disease (MEI1) or visual problems (DNAH17). The clinical tests comprised extensive immune profiling for the MEI1-participant and functional evaluation and imaging of the retinal cells of the DNAH17-participant. None of the test results indicated clinically relevant alterations at present. To identify true comorbidities, or lack thereof, more men with the same monogenic cause should be phenotyped. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The Human Protein Atlas database was used to assess the expression pattern of the causal gene. This database only contains expression data in adult tissues. Potential comorbidities due to a developmental function of a gene can therefore be missed. In addition, comorbidities might develop later in life and might not be present during the phenotyping. WIDER IMPLICATIONS OF THE FINDINGS: Knowledge on the presence or absence of infertility-associated comorbidities allows clinicians to counsel patients on possible additional health risks for themselves and potential future offspring. As a consequence, medical care for infertile people extends beyond reproductive needs to general health. STUDY FUNDING/COMPETING INTEREST(S): J.A.V. was funded by an Investigator Award in Science from the Wellcome Trust (209451) and by The Netherlands Organization for Scientific Research (918-15-667). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
From tablets to targeted therapy: the APHRODITE era in male infertility.
Esteves SC, Humaidan P
Hum Reprod · 2026 Jun · PMID 41863283 · Publisher ↗
Treatment of idiopathic male infertility has traditionally relied on the empirical use of oral agents such as clomiphene citrate and aromatase inhibitors, often prescribed without rigorous endocrine phenotyping. The newl...
Treatment of idiopathic male infertility has traditionally relied on the empirical use of oral agents such as clomiphene citrate and aromatase inhibitors, often prescribed without rigorous endocrine phenotyping. The newly proposed APHRODITE criteria (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) introduce a biologically rational framework for stratifying infertile men and tailoring hormonal therapy. This opinion article draws a conceptual parallel with the evolution of ovarian stimulation in IVF, in which exogenous gonadotropins supplanted oral agents due to their superior physiological control and better outcomes. Similarly, the APHRODITE system may catalyze a paradigm shift in male infertility treatment-from empirical, tablet-based regimens to biology-driven gonadotropin therapy. Here, we revisit the hormonal regulation of spermatogenesis, critically appraise the limited efficacy of selective estrogen receptor modulators and aromatase inhibitors, and summarize evidence supporting gonadotropin therapy. We further highlight the potential impact of FSH and LH/hCG genetic polymorphisms on treatment responsiveness. While clomiphene citrate and aromatase inhibitors retain a role in specific endocrine profiles, the new positioning of exogenous gonadotropins-LH/hCG and FSH-as targeted, earlier-line interventions holds promise to improve outcomes and efficacy in male fertility care. Future progress will depend on prospective trials that apply the APHRODITE criteria and on comparative analyses of oral agents versus injectable gonadotropin regimens in well-defined patient phenotypes.
CD138 expression in the endometrium associates with endometrial timing and inflammatory status but not microbiota composition.
Odendaal J, Fishwick K, Correia GDS … +19 more , Lee YS, Makwana K, Black N, Southcombe J, Thornton J, Larsen K, Hussain Q, Hawkes A, Kandiyil A, Muter J, Brighton PJ, Vrljicak P, Lucas E, Granne I, Bouliotis G, Bennett PR, Brosens J, MacIntyre DA, Quenby S
Hum Reprod · 2026 May · PMID 41858134 · Full text
STUDY QUESTION: What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? SUMMARY ANSWER: The presence of CD138+ cells in endometrial stroma is c...
STUDY QUESTION: What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? SUMMARY ANSWER: The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. WHAT IS KNOWN ALREADY: CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. STUDY DESIGN, SIZE, DURATION: Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. MAIN RESULTS AND THE ROLE OF CHANCE: IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). LARGE SCALE DATA: Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). LIMITATIONS, REASONS FOR CAUTION: This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. WIDER IMPLICATIONS OF THE FINDINGS: This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. TRIAL REGISTRATION NUMBER: ISRCTN23947730.
Preconception health and fertility health: overlapping, yet distinct domains.
Grace B, Hammarberg K, Schoenaker D … +1 more , Stephenson J
Hum Reprod · 2026 May · PMID 41849221 · Publisher ↗
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Reply: Preconception health and fertility health: overlapping, yet distinct domains.
Cheong Y, Delbaere I, Sermon K … +1 more , Tassot J
Hum Reprod · 2026 May · PMID 41849214 · Publisher ↗
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From disease prevention to fertility treatment: rethinking the use of mitochondrial donation for oocyte-related infertility in the light of safety and efficacy.
Pasturino F, De Wert GMWR, Herbrand C … +1 more , Smeets HJM
Hum Reprod · 2026 Apr · PMID 41821298 · Publisher ↗
Maternal spindle transfer (MST) and pronuclear transfer (PNT) raise a number of important ethical and regulatory issues. These IVF procedures that transfer nuclear DNA to enucleated oocytes or zygotes aim to prevent tran...
Maternal spindle transfer (MST) and pronuclear transfer (PNT) raise a number of important ethical and regulatory issues. These IVF procedures that transfer nuclear DNA to enucleated oocytes or zygotes aim to prevent transmitting mitochondrial disease by female carriers of mitochondrial DNA (mtDNA) mutations and enable them to have healthy genetically related children. MST/PNT might also prove effective in treating oocyte-related infertility, but are not permitted in the UK and Australia, unlike MST/PNT for mtDNA disorders. The paper discusses the regulation of MST/PNT for both applications in relation to their risks and efficacy, highlighting the scarcity of clinical data. Based on risk reduction, it has even been proposed to treat oocyte-related infertility first before moving to mtDNA disorders. We argue that a prohibition of MST/PNT for infertility is not justified, neither should it initially be applied only for infertility because of the little evidence yet available regarding its efficacy and potential risks. We propose a staged approach to identify MST/PNT-treatable causes of oocyte-related infertility first, followed by a preclinical study and clinical trial and, if positive, wider application. Importantly, we call for transparency in publishing regular trial results, deeper ethical reflection, and more consistent policies that consider comparable uncertainties in mtDNA disorders and oocyte-related infertility.
Endometriosis lesion distribution by age at presentation: an international multicentre database study.
Lewin J, Vashisht A, Langan D … +4 more , Vincent K, Saridogan E, Becker CM, Hirsch M
Hum Reprod · 2026 May · PMID 41818725 · Publisher ↗
STUDY QUESTION: How does the frequency and location of endometriosis lesions observed at laparoscopy vary with patient age? SUMMARY ANSWER: We find that older patients have more deep lesions and ovarian endometriomas at...
STUDY QUESTION: How does the frequency and location of endometriosis lesions observed at laparoscopy vary with patient age? SUMMARY ANSWER: We find that older patients have more deep lesions and ovarian endometriomas at laparoscopy, although this plateaus around 30 years of age. WHAT IS KNOWN ALREADY: The natural history and aetiology of endometriosis remain uncertain, with evidence of progression, spontaneous regression, and stable disease in various studies. STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of a prospectively collected surgical registry, including data from 104 accredited endometriosis centres across 7 countries, with 14 670 cases in total. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed data from the British Society for Gynaecological Endoscopy (BSGE) endometriosis centres database, a multicentre international prospective cohort of patients undergoing surgery for deep endometriosis. We included all patients aged 10-55 years from 2009 to 2021. The change in lesion prevalence with age was modelled using three different logistic regression models-non-quadratic, quadratic, and segmented, adjusted for whether they had undergone endometriosis excision in the past. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 14 670 cases from 104 centres across 7 countries. The mean age at the time of surgery was 35.9 years (SD 7.4). The odds of superficial endometriosis decreased linearly with age by 3% per year (adjusted odds ratio (aOR) 0.97, 95% CI 0.96-0.97, P < 0.001). The following increased before plateauing: bowel endometriosis increased by 7% per year (aOR 1.07, 95% CI 1.05-1.09, P < 0.001) until 32.9 years of age (95% CI 30.5-35.3); deep sidewall disease increased by 7% per year (aOR 1.07, 95% CI 1.05-1.09, P < 0.001) until 31.3 years (95% CI 29.2-33.5); and uterosacral disease increased by 4% per year (aOR 1.04, 95% CI 1.02-1.06, P < 0.001) until 33 years (95% CI 29.3-36.6). Deep bladder disease increased by 12% per year (aOR 1.12, 95% CI 1.04-1.22, P = 0.005) until 28.2 (95% CI 25.8-30.6) years, after which the odds decreased by 2% per year (aOR 0.98, 95% CI 0.97-1.00, P = 0.007). Ovarian endometrioma was best described by a quadratic model, with a starting increase in odds of endometrioma of 20% per year at 10 years (aOR 1.20, 95% CI 1.16-1.23, P < 0.001), and a peak prevalence at 40.9 years of age (95% CI 34.1-47.7, P < 0.001). The total number of sites affected by endometriosis increased by 0.12 sites per year (95% CI 0.10-0.14, P < 0.001) until 32.8 years of age, with no correlation with age after this point. LIMITATIONS, REASONS FOR CAUTION: This cross-sectional study only includes patients undergoing excision with pararectal dissection for the treatment of pain, so does not capture patients who do not undergo such surgery, including asymptomatic patients, and cannot provide data on potential disease progression on an individual level. WIDER IMPLICATIONS OF THE FINDINGS: This study supports existing evidence suggesting that older patients with endometriosis have more deep nodules and endometriomas and less superficial disease. STUDY FUNDING/COMPETING INTEREST(S): No funding was provided for this study. K.V. reports consulting fees from Eli Lilly, Gedeon Richter, Gesynta, and Rickett (all paid to institution); speakers' fees from Gedeon Richter and Reckitt (both paid to institution); membership of the Medical Advisory Panel of Endometriosis UK (unpaid); past presidency of the International Association for the Study of Pain (IASP) Special Interest Group (SIG) on Abdominal and Pelvic Pain (unpaid). TRIAL REGISTRATION NUMBER: N/A.
Experiences of infertility-related traumatic events and their association with symptoms of Post-Traumatic Stress Disorder (PTSD) and Complex PTSD: results from a mixed-methods online survey.
Gameiro S, Dummer A, Copeland L … +5 more , McCluskey G, Ross R, McLaughlin D, McGowan I, Knight H
Hum Reprod · 2026 May · PMID 41818724 · Full text
STUDY QUESTION: What are experiences of infertility-related traumatic events and are these associated with symptoms of Post-Traumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD)? SUMMARY ANSWER: Infertility-related t...
STUDY QUESTION: What are experiences of infertility-related traumatic events and are these associated with symptoms of Post-Traumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD)? SUMMARY ANSWER: Infertility-related trauma results from the interplay between a strong unfulfilled desire for children, negative reproductive events and (lack of) associated care, with 9% and 32% of those reporting a traumatic event meeting criteria for PTSD and CPTSD, respectively. WHAT IS KNOWN ALREADY: There is worldwide recognition that fertility treatment is highly stressful, but limited understanding of its potential to trigger traumatic responses like PTSD and CPTSD. PTSD is a mental health disorder characterized by reexperiencing the traumatic event, avoidance of traumatic reminders, and a sense of ongoing threat. CPTSD is diagnosed when trauma also leads to difficulty managing emotions, negative self-concept, and disturbances in relationships. We aimed to document infertility-related traumatic events and how these are associated with symptoms of PTSD and CPTSD. STUDY DESIGN, SIZE, DURATION: Mixed-methods online survey co-produced with and disseminated by the charity Fertility Network UK. Inclusion criteria were being an adult, having suffered from infertility or attended a fertility clinic within the last 5 years, and the ability to read/write English. Eight hundred and sixty-five consented, and 590 (68%, final sample) reported on their most troubling infertility experience. PARTICIPANTS/MATERIALS, SETTING, METHODS: Most participants were highly educated white heterosexual women in a relationship. The average age was 37.54% had children, 65% were trying to have (more) children, and 30% were undergoing treatment. Infertility-related trauma experiences and symptoms were assessed with the International Trauma Questionnaire (ITQ, Cloitre et al, 2018, 2021), a validated questionnaire that asks people to describe the experience that troubles them the most and to rate how much 18 trauma-related symptoms bothered them in the past month (Likert scale, from 1-none at all to 5-extremely). The ITQ is used to identify participants meeting criteria for PTSD, CPTSD, or both. We replaced 'experience' with 'infertility experience'. Participants also reported on other traumatic experiences, on 12 negative reproductive events (e.g. failed cycle, treatment, [recurrent] miscarriage, stillbirth, and experiences of care). MAIN RESULTS AND THE ROLE OF CHANCE: Descriptions of infertility troubling experiences yielded 31 categories, 7 themes and 3 meta-themes. Themes showed that suffering and distress are omnipresent in fertility care due to the stressful nature of fertility treatment journeys (e.g. emotional burden, invasive procedures), reproductive loss (e.g. cycle failures, miscarriages), and lack of control (e.g. over access to treatment and its outcomes). This repeated accumulation of distress was compounded by care perceived as dismissive (e.g. insensitive and unsupportive care) and medical trauma (e.g. complications, errors) and had a functional impact at the individual and social level. Fifty-three (9%) participants met criteria for PTSD, 189 (32%) for CPTSD, with 242 (41%) meeting criteria for PTSD or CPTSD. Three-hundred and twenty-eight (56%) participants reported other traumatic events, the 3 most frequent referring to achievement (45%, health and parenthood goals, for example, adoption disruption, recurrent miscarriage), survival (27%, e.g. accidents, traumatic birth) and autonomy (17%, e.g. rape, domestic abuse). The most reported negative reproductive events were unsuccessful cycle (79%), miscarriage (57%), and unsuccessful treatment (52%). Ninety (16%) participants reported that staff discussed trauma with them, 154 (28%) that staff put in place support, and 334 (61%) that the care received made their distress worse. Logistic regression (χ2 = 78.600, df = 11, P < .001) explained 21.7% of variance in meeting criteria for CPTSD. Participants who met criteria for CPTSD were less likely to have children (OR = 0.461 [0.280, 0.759]), more likely to report a strong child desire (OR = 1.202 [1.036, 1.395]), to have experienced their troublesome infertility experience within the last year (ref category within last year, 1 to 5 years OR = 0.557[0.339, 0.917]), having ended treatment without children (OR = 1.630 [1.051, 2.529], having experienced recurrent miscarriage (OR = 2.2028 [1.109, 3.709]), and reporting that care received made trauma worse (OR = 1.788 [1.124, 2.845]). Background factors (e.g. ethnicity, sexual orientation) were not associated with CPTSD and none of the factors measured were associated with PTSD. LIMITATIONS, REASONS FOR CAUTION: The survey may have attracted people self-identifying as having experienced traumatic events, but the sample is overall representative of the typical fertility care population and at risk-groups (e.g. ethnicity, sexual orientation, asylum seekers) were unrepresented. Participants meeting criteria for PTSD and CPTSD diagnoses were identified using a self-reporting questionnaire, but which is validated, sound and internationally used. WIDER IMPLICATIONS OF THE FINDINGS: Many fertility patients have experienced or will experience traumatic events prior to and/or during treatment, and trauma responses can be compounded by poor care and psychosocial contexts. Traumatic events and symptoms must be recognised in clinical practice to prevent (re)traumatising patients, as many will return for treatment and risk re-exposure. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable.
Ovulatory Recovery following weight loss in women with polycystic ovary syndrome and obesity: a post hoc analysis of the BAMBINI randomised controlled trial.
Samarasinghe SNS, Abbara A, Ortega PM … +6 more , Ahmed AR, Tsironis C, Purkayastha S, Menon V, Randeva H, Miras AD
Hum Reprod · 2026 May · PMID 41808368 · Full text
STUDY QUESTION: What is the frequency of ovulatory recovery (OvR) after different degrees of total weight loss (TWL) in women with polycystic ovary syndrome (PCOS) and obesity, and can an excessive degree of TWL be ident...
STUDY QUESTION: What is the frequency of ovulatory recovery (OvR) after different degrees of total weight loss (TWL) in women with polycystic ovary syndrome (PCOS) and obesity, and can an excessive degree of TWL be identified that is harmful to the chance of OvR? SUMMARY ANSWER: Any degree of TWL was associated with a higher likelihood of OvR, and no upper threshold of TWL associated with reduced OvR was identified. WHAT IS KNOWN ALREADY: Modest weight loss (5-10%) improves reproductive function in women with PCOS. However, the relationship between greater degrees of TWL and OvR remains uncertain. STUDY DESIGN, SIZE, DURATION: Secondary post hoc analysis of a multicentre, open-label, randomised controlled trial (BAMBINI) conducted in the UK between February 2020 and April 2023. Eighty women were randomised (1:1) to standard medical care or vertical sleeve gastrectomy. Seventy-five were included in this analysis and followed up for 52 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants had PCOS, a BMI of 35 kg/m2 or higher, and oligomenorrhea/amenorrhoea. OvR was defined as two consecutive biochemically confirmed ovulatory events (serum progesterone 16.0 nmol/l or higher), occurring 3-5 weeks apart within the 52 week follow up period. Associations between TWL, reproductive hormones, and OvR were analysed using logistic regression. Analyses were exploratory and not prespecified. MAIN RESULTS AND THE ROLE OF CHANCE: At 52 weeks, 50.8% (38/75) achieved OvR. OvR occurred in 19% of participants without weight loss and in >50% of those who lost weight. Each 1% reduction in body weight was associated with a 5.6% increase in the odds of OvR (OR 0.944, 95% CI 0.900-0.990). Higher baseline serum anti-Müllerian hormone (OR 0.963, 95% CI [0.938-0.988]; P = 0.004) and higher plasma total testosterone (OR 0.324, 95% CI [0.142-0.742]; P = 0.008) were associated with lower odds of OvR. Greater TWL following bariatric surgery was associated with increased sex hormone-binding globulin and reduced free androgen index. LIMITATIONS, REASONS FOR CAUTION: This was an exploratory post hoc analysis not designed to define optimal or upper TWL thresholds. The study was not powered to detect potential adverse reproductive effects at higher degrees of TWL. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that OvR in women with PCOS and obesity improves progressively with increasing TWL, supporting weight loss strategies including bariatric surgery in appropriately selected women not seeking imminent pregnancy. STUDY FUNDING/COMPETING INTEREST(S): The Jon Moulton Charity Trust funded the BAMBINI trial. This work was supported by grants from the National Institute of Health Research (NIHR), the NIHR/Wellcome Trust Imperial Clinical Research Facility, and the NIHR Imperial Biomedical Research Centre. The Section of Endocrinology and Investigative Medicine was funded by grants from the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), and the NIHR, and was supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the author(s) and not necessarily those of the MRC, the NHS, the NIHR, or the Department of Health. S.N.S.S. was supported by an Imperial post-doctoral post-CCT Fellowship. A.A. was supported by an NIHR Clinician Scientist Award CS-2018-18-ST2-002. All authors acknowledge infrastructure support for this research from the NIHR Imperial Biomedical Research Centre (BRC).A.D.M. has received research funding from the Medical Research Council (MRC), National Institute for Health and Care Research (NIHR), Jon Moulton Charitable Foundation, PEACEPLUS programme (EU and UK government), Anabio, Fractyl, Boehringer Ingelheim, Eli Lilly, Gila, Randox, and Novo Nordisk. A.D.M. has received honoraria for lectures and presentations from Novo Nordisk, AstraZeneca, Currax Pharmaceuticals, Boehringer Ingelheim, Screen Health, GI Dynamics, Algorithm, Eli Lilly, Ethicon, and Medtronic. A.D.M. is a shareholder in the Beyond BMI clinic, which provides clinical obesity care. H.R. is on the advisory board for Novo Nordisk and is the national lead for the REDEFINE 3 trial. TRIAL REGISTRATION NUMBER: N/A.
Revisiting the promise and pitfalls of mitochondrial replacement therapies.
Costa-Borges N, Wells D
Hum Reprod · 2026 Apr · PMID 41795216 · Publisher ↗
Mitochondrial replacement therapies (MRTs) have been proposed as a means of avoiding the transmission of pathogenic mitochondrial DNA (mtDNA) mutations from mother to child. While clinical cases using this groundbreaking...
Mitochondrial replacement therapies (MRTs) have been proposed as a means of avoiding the transmission of pathogenic mitochondrial DNA (mtDNA) mutations from mother to child. While clinical cases using this groundbreaking strategy have now been reported for the two principal MRT methods-pronuclear transfer and maternal spindle transfer-recent data continues to raise questions about the reliability of these approaches for disease prevention.
Navigating uncertainty in PGT-A: aligning analytical, biological, and clinical evidence.
Popovic M, Miguel-Escalada I, Mounts E … +2 more , Scott R, Jalas C
Hum Reprod · 2026 May · PMID 41795215 · Publisher ↗
Preimplantation genetic testing for aneuploidy (PGT-A) is widely used to guide embryo selection, yet its analytical performance, interpretive consistency, and clinical value remain active areas of debate. Advances in seq...
Preimplantation genetic testing for aneuploidy (PGT-A) is widely used to guide embryo selection, yet its analytical performance, interpretive consistency, and clinical value remain active areas of debate. Advances in sequencing and haplotype-based methods have improved resolution and enabled classification of aneuploidies by their mechanistic origin, however they have also revealed substantial variability between platforms, laboratory thresholds, and reporting practices. As a result, the same embryo may receive different classifications depending on the analytical framework, with direct implications for transfer decisions and cumulative live birth potential. This mini-review examines how analytical, biological, and clinical layers of validation intersect in PGT-A, with emphasis on predictive values and the limits of current technologies in resolving biological uncertainty. Across the available evidence, whole-chromosome meiotic aneuploidies show consistent patterns that support their clinical relevance. In contrast, diagnoses of chromosomal mosaicism and segmental abnormalities remain variable and less consistently predictive. Taken together, these observations underscore the need for validation frameworks that integrate analytical precision, biological plausibility, and outcome-anchored clinical data. Without such measures, increasing technological complexity risks widening, rather than narrowing, the gap between PGT-A results and real-world clinical decision-making.
Why does surgery for endometriosis-associated infertility often fail to improve pregnancy outcome?
Pirtea P, Vigano P, Salmeri N … +2 more , Vercellini P, Somigliana E
Hum Reprod · 2026 May · PMID 41785416 · Publisher ↗
Endometriosis can impair natural reproduction through multiple mechanisms, including distortion of pelvic anatomy and chronic peritoneal inflammation. On this basis, surgical treatment might be reasonably expected to ben...
Endometriosis can impair natural reproduction through multiple mechanisms, including distortion of pelvic anatomy and chronic peritoneal inflammation. On this basis, surgical treatment might be reasonably expected to benefit. However, clinical evidence challenges this belief. Surgery can indeed improve natural reproduction, but real benefits are modest. The reasons for the disappointing efficacy of surgery are discussed in this review. They include the presence of 'microscopic' endometriosis, the co-occurrence of other undetected causes of infertility, the rapid reoccurrence of adhesions, the inability of surgery to interfere with underlying pathogenetic mechanisms, the frequent recurrence of endometriotic lesions, and the association with other gynecological conditions that cannot be effectively treated with surgery (such as adenomyosis). On the other hand, the frequently discussed ovarian reserve injury may not be a determining factor (even if of utmost relevance for ART), and the strength of the evidence linking superficial peritoneal disease, ovarian endometriomas, and deep endometriosis to infertility is rather debatable. In conclusion, surgery for infertile women with endometriosis remains an option, but it cannot intrinsically ensure high rates of reproductive success. Realistic and comprehensive information on safety, effectiveness, and alternatives must be given for valid shared decision-making.
Clinical outcomes of dichorionic diamniotic twin pregnancies following single versus double embryo transfer in human medically assisted reproduction.
Hattori H, Goto Y, Kasahara Y … +1 more , Kyono K
Hum Reprod · 2026 May · PMID 41782376 · Full text
STUDY QUESTION: Do clinical and perinatal outcomes of dichorionic diamniotic (DCDA) twin pregnancies differ between single embryo transfer (SET) and double embryo transfer (DET) in human medically assisted reproduction (...
STUDY QUESTION: Do clinical and perinatal outcomes of dichorionic diamniotic (DCDA) twin pregnancies differ between single embryo transfer (SET) and double embryo transfer (DET) in human medically assisted reproduction (MAR)? SUMMARY ANSWER: In DCDA twin pregnancies, SET was associated with a significantly higher incidence of complete miscarriage and a lower rate of twin live births than DET. WHAT IS KNOWN ALREADY: While DET has historically been the major contributor to dizygotic DCDA twins, the global adoption of SET has markedly reduced such cases. However, monozygotic twinning (MZT) occurs more frequently after MAR, especially in blastocyst transfer cycles, and the prognosis of monozygotic DCDA twins remains poorly understood. STUDY DESIGN, SIZE, DURATION: This single-center retrospective cohort study analyzed 206 clinical multiple pregnancies achieved between January 2014 and December 2024, following 4658 fresh and 15 872 frozen-warmed embryo transfer cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only cycles using autologous oocytes were included. Clinical and perinatal outcomes of DCDA twin pregnancies derived from SET and DET were compared. To account for baseline differences between SET and DET groups, an exploratory multivariable logistic regression analysis was performed for clinical outcomes. Statistical analyses were performed using the Mann-Whitney U-test and Fisher's exact test, with P < 0.05 considered significant. MAIN RESULTS AND THE ROLE OF CHANCE: When comparing the clinical course of DCDA twin pregnancies, the incidence of two gestational sacs and two fetal heartbeats was significantly higher in the DET group than in the SET group (98.0% vs 47.2%, P < 0.0001; 63.5% vs 25.5%, P < 0.0001) (two fetal heartbeats: adjusted odds ratios [aOR], 0.276; 95% CI, 0.108-0.706; P < 0.007). Twin live birth occurred in 53.1% of DET-derived DCDA twins and 17.6% of SET-derived DCDA twins (P < 0.0001) (aOR, 0.324; 95% CI, 0.121-0.867; P = 0.025), whereas complete miscarriage was more frequent after SET (49.0% vs 17.7%, P < 0.0001) (aOR, 9.140; 95% CI, 3.030-27.600; P < 0.0001). Perinatal outcomes, including gestational age, birth weight, and congenital anomaly rates, did not differ significantly between groups. LIMITATIONS, REASONS FOR CAUTION: The number of monozygotic cases was limited, and zygosity could not be genetically confirmed. Some same-sex DCDA twins may have been dizygotic in origin. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight that DCDA twin pregnancies should not be regarded as a uniform clinical entity in MAR. Even within the same chorionicity category, early outcomes differ significantly between monozygotic twins after SET and dizygotic twins after DET. Although SET remains the optimal strategy to prevent multiple pregnancies, further studies should aim to identify embryos at higher risk of post-transfer splitting and to refine preventive criteria for MZT. STUDY FUNDING/COMPETING INTEREST(S): There is no funding for this study. TRIAL REGISTRATION NUMBER: N/A.
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