Reproductive Risk Research Articles

Problems of reproductive risk management in occupational medicine and issues of causation

In the Russian Federation, 2024 has been declared the year of the family, which, in the context of the growth of domestic industrial production, determines the importance of preserving the reproductive health of women working in harmful and unfavorable working conditions, preventing the adverse effects of factors in the working environment and the labor process on women’s health indicators. The review examines publications presented in the RSCI, PubMed, Scopus, and Google Scholar databases, which cover mainly the last 10 years (2013–2023)

Reproductive Factors and Thyroid Cancer Risk: The Multiethnic Cohort Study.

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice.

Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study

Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.

Intergenerational Occurrence of Premature Birth and Reproductive Health in Prematurely-Born Women in the Women’s Health Initiative

ObjectiveTo compare reproductive history and postmenopausal health by birth status (preterm vs. full term) in a U.S. longitudinal study of postmenopausal women. Birth status was examined according to region of residence, household, and neighborhood socioeconomic status (SES).MethodsIn the Women’s Health Initiative Observational Study, 2271 women were born prematurely (< 37 weeks). ANOVA and Chi-square determined birth status differences of reproductive history, pregnancy, and postmenopausal health. Odds ratios were calculated using either binary logistic or multinomial logistic regression. SES and U.S. region of residence were examined as potential effect modifiers.ResultsPreterm-born women compared to term-born women had higher risk of delivering a premature infant (aOR 1.68, 95% CI [1.46, 1.93]), higher odds of later-age first pregnancy (aOR 1.27 95% CI [1.02, 1.58]), longer duration to become pregnant (> 1 year to pregnancy) (aOR 1.10 95% CI [1.01, 1.21]), more miscarriages (aOR 1.23 95% CI [1.11, 1.37]), and more pregnancy complications including hypertension (aOR 1.58 95% CI (1.13, 2.21)], preeclampsia (aOR 1.64 95% CI [1.24, 2.16]), and gestational diabetes (aOR 1.68 95% CI [1.11, 2.53]). Preterm-born women had higher odds of menopause before age 50 (aOR 1.09 95% CI [1.05, 1.14]). Post-menopause, they had higher rates of diabetes (p = .01), hypertension (p = .01), hysterectomy (p = .045), and higher Charlson Comorbidity Index scores (p = .01).ConclusionsPreterm-born women had higher reproductive and pregnancy risks which when coupled with early menopause, may indicate a shorter childbearing period than term-born women. Guidelines for integration of preterm history in women’s health care across the life course are needed to identify and manage their higher risk.

Long-term effect of fine particulate matter constituents on reproductive hormones homeostasis in women attending assisted reproductive technologies: A population-based longitudinal study

Fine particulate matter (PM2.5) may disrupt women's reproductive hormones, posing potential reproductive risks. However, the exact compositions of PM2.5 responsible for these effects remain unclear. Our investigation explored the long-term impacts of PM2.5 constituents on reproductive hormones, based on a large longitudinal assisted reproductive cohort study in Anhui, China. We included 24,396 reproductive hormone samples from 19,845 women attending assisted reproductive technologies (ART) between 2014 and 2020. Using high-resolution gridded data (1-km resolution), we calculated the residence-specified PM2.5 constituents during the year before the month of hormone testing. Relationships between PM2.5 constituents [organic matter (OM), chloride (Cl-), sulfate (SO42-), ammonium (NH4+), black carbon, and nitrate] and reproductive hormones were investigated using the linear mixed model with subject-specific intercepts. The constituent-proportion model and the constituent-residual model were also constructed. Additionally, cubic spline analysis was used to examine the potential non-linear exposure-response relationship. We found that per interquartile range (IQR) increment in OM was associated with a 5.31 % (3.74 %, 6.89 %) increase in estradiol, and per IQR increment in Cl- and NH4+ were associated with 13.56 % (7.63 %, 19.82 %) and 9.07 % (4.35 %, 14.01 %) increases in luteinizing hormone. Conversely, per IQR increment in OM and Cl- were associated with −7.27 % (-9.34 %, −5.16 %) and −8.52 % (-10.99 %, −5.98 %) decreases in progesterone, and per IQR increment in SO42- was associated with a −9.15 % (-10.31 %, −7.98 %) decrease in testosterone. These associations were held in both proportional and residual models. Moreover, exposure-response curves for estradiol and progesterone with PM2.5 constituents exhibited approximately U-shaped. These results suggested that specific PM2.5 constituents might disrupt reproductive hormone homeostasis in women attending ART, providing new evidence for formulating PM2.5 pollution reduction strategies that could benefit women's reproductive health.

Preconception carrier screening and preimplantation genetic testing in the infertility management.

Genetic testing serves as a valuable element of reproductive care, applicable at various stages of the reproductive journey: (i) before pregnancy, when a couple's genetic reproductive risk can be evaluated; (ii) before embryo implantation, as part of in vitro fertilization (IVF) treatment, to ascertain several inherited or de novo genetic/chromosomal diseases ofthe embryo before transfer; (iii) during the prenatal period, to assess the genetic costitution of the fetus. Preconception carrier screening (CS) is a genetic test typically performed on couples planning a pregnancy. The primary purpose of CS is to identify couples at-risk of conceiving a child affected by a severe genetic disorder with autosomal recessive or X-linked inheritance. Detection of high reproductive risk through CS allows prospective parents to be informed of their predisposition and improve reproductive decision-making. These include undergoing IVF with preimplantation genetic testing (PGT) or donor gametes, prenatal diagnosis, adoption, remaining childless, taking no actions. Both the presence of the affected gene (PGT-M) and chromosomal status (PGT-A) of the embryo can be comprehensively assessed through modern approaches. We provide a review of CS and PGT applications to equip healthcare providers with up-to-date information regarding their opportunities and complexities. The use of CS and PGT is currently considered the most effective intervention for avoiding both an affected pregnancy whilst using autologous gametes in couples with known increased risk, and chromosomal abnormalities. As our understanding in the genetic component in pathological conditions increases, the number of tested disorders will expand, offering a more thorough assessment of one's genetic inheritance. Nevertheless, implementation and development in this field must be accompanied by scientific and ethical considerations to ensure this approach serves the best long-term interests of individuals and society, promoting justice and autonomy and preserving parenthood and the healthcare system. The combination of CS and PGT aligns with principles of personalized medicine by offering reproductive care tailored to the individual's genetic makeup.

Perfluoroalkyl and Polyfluoroalkyl Substances in Relation to the Participant-Reported Total Pregnancy and Live Birth Numbers among Reproductive-Aged Women in the United States.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), widely utilized in various industries, may pose potential reproductive well-being risks. However, the research on the impact of PFAS exposures on pregnancy and live birth rates remains scarce. To address this gap, we conducted a cross-sectional study using the data from the United States National Health and Nutrition Examination Survey (NHANES) collected between 2013 and 2018. We focused on six PFAS compounds measured in the serum of women aged 20 to 50 years, employing the Poisson regression, Quantile G-composition (Qgcomp), and Weighted Quantile Sum (WQS) regression models. Adjusting for age, racial/ethnic origin, educational level, marital status, family income, body mass index (BMI), menarche age, birth control pill use, and other female hormone consumption, the Poisson regression identified significant negative associations between the individual PFAS exposures and pregnancy and live birth numbers (p < 0.05 for all 24 null hypotheses for which the slope of the trend line is zero). The Qgcomp analysis indicated that a one-quartile increase in the mixed PFAS exposures was associated with reductions of 0.09 (95% CI: -0.15, -0.03) in the pregnancy numbers and 0.12 (95% CI: -0.19, -0.05) in the live birth numbers. Similarly, the WQS analysis revealed that a unit increase in the WQS index corresponded to decreases of 0.14 (95% CI: -0.20, -0.07) in the pregnancy numbers and 0.14 (95% CI: -0.21, -0.06) in the live birth numbers. Among the six specific PFAS compounds we studied, perfluorononanoic acid (PFNA) had the most negative association with the pregnancy and live birth numbers. In conclusion, our findings suggest that PFAS exposures are associated with lower pregnancy and live birth numbers among women of reproductive age.

Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology

PurposeThe objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS).MethodsThe study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses.ResultsA total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97).ConclusionsThe findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

Reproductive factors and risk of cardiovascular outcomes in women with ST-elevation myocardial infarction

BackgroundThere are many sex-specific factors affecting myocardial infarction (MI) outcomes in males and females. This study aimed to evaluate the relationship between reproductive factors and cardiovascular outcomes in women after ST-elevation MI.MethodThis retrospective cohort study was initiated in 2016–2017 at Chamran Hospital, Isfahan, Iran. One hundred eighty women with a diagnosis of ST-elevation MI were followed up for 3 years, and any occurrence of cardiovascular events (CVs) was recorded. All information regarding reproductive factors was recorded via questionnaire. This information was compared between women with cardiovascular events and women without adverse events using a sample t test, chi-square test, and multiple backward logistic regression analysis. SPSS version 24 was used to conduct all analyses.ResultSixty-four women with a mean age of 65.81 ± 13.14 years experienced CV events, and 116 women with a mean age of 65.51 ± 10.88 years did not experience CV events. A history of ischemic heart disease and diabetes mellitus were more prevalent in women with CV events (P = 0.024 and P = 0.019). After adjusting for ischemic heart disease and diabetes mellitus, oral contraceptive pill (OCP) usage was more prevalent in women with CV events than in women without CV events (60.9% vs. 40.4%, P = 0.008). There was a greater chance of CV events in women with OCP usage (OR = 3.546, P = 0.038) and a lower chance of CV events in women with greater age at menarche (OR = 0.630, P = 0.009) and longer breastfeeding duration (OR = 0.798, P = 0.041) according to multiple backward logistic regression models.ConclusionBased on this study, OCP consumption is a risk factor, while older age at menarche and longer duration of breastfeeding are protective factors for cardiovascular outcomes in women after STEMI.

Polystyrene microplastics and di-2-ethylhexyl phthalate co-exposure: Implications for female reproductive health

Microplastics and phthalates are prevalent and emerging pollutants that pose a potential impact on human health. Previous studies suggest that both microplastics and phthalates can adversely affect the reproductive systems of humans and mammals. However, the combined impact of these pollutants on the female reproductive system remains unclear. Here we show the impacts of exposure to polystyrene microplastics (PS-MPs) and di-2-ethylhexyl phthalate (DEHP) on female Sprague-Dawley rats’ reproductive systems. We find that co-exposure to PS-MPs and DEHP results in a marked increase in cystic and atretic follicles, oxidative stress, fibrosis, and dysregulation of serum sex hormone homeostasis in the ovaries of the rats. Proteomic analysis identified differentially expressed proteins that were predominantly enriched in signaling pathways related to fatty acid metabolism and tight junctions, regulated by transforming growth factor β1 (TGF-β1). We further confirm that co-exposure to DEHP and PS-MPs activates the TGF-β1/Smad3 signaling pathway, and inhibiting this pathway alleviates oxidative stress, hormonal dysregulation, and ovarian fibrosis. These results indicate that exposure to the combination of microplastics and phthalates leads to a significant increase in atretic follicles and may increase the risk of polycystic ovary syndrome (PCOS). Our study provides new insights into the reproductive toxicity effects of microplastics and DEHP exposure on female mammals, highlighting the potential link between environmental pollutants and the occurrence of PCOS. These findings highlight the need for comprehensive assessments of the reproductive health risks posed by microplastic pollution to women and contribute to the scientific basis for evaluating such risks.

A comprehensive review of current practices, challenges, and future perspectives in Koi fish (Cyprinus carpio var. koi) cultivation.

The Koi fish (Cyprinus carpio var. koi) is an ornamental fish with a high selling value because of its attractive colors, color patterns, body shape, and swimming motion. Koi fish is extensively traded in the international fish market because of their popularity among hobbyists from numerous countries worldwide. This review discusses various aspects of Koi fish cultivation, including genetic involvement, selective breeding strategies, and management systems. By examining crucial factors such as water parameters, technological innovations, and evolving cultivation methods, this review explored their influence on the quality of Koi fish. Breakthrough technologies, such as ornamental fish warehousing and recirculation aquaculture systems, enhance breeding efficiency and profitability. Molecular sexing, feed optimization, and color enhancement strategies are central to pursuing superior Koi fish. Reproduction management, disease prevention, and risk reduction during transport underscore ongoing efforts to ensure their survival. Despite notable progress, several challenges remain, including limited genetic studies, gaps in disease research, and unexplored herbal alternatives. The active involvement of hobbyists and breeders in research initiatives is a pivotal force in unlocking the untapped potential. The holistic approaches to enhance production efficiency and improve care standards require further exploration, paving the way for a sustainable future in the evolving management of Koi fish cultivation.

Female Mice Exposed to Pyriproxyfen Since Prepuberty Showed Reproductive Impairment During Sexual Maturity and Increased Fetal Death in Their Offspring.

Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre-puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre-pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound.

Perspectives on progression of transboundary disease, one health and ecosystem health management in the Greater Mekong Subregion and beyond

Livestock production in the Greater Mekong Subregion (GMS) reflects the inefficient smallholder ‘keeper’ system that has been slow to adapt to the rapidly expanding demand for animal protein-sourced foods in the region as urban economies have flourished and food preferences altered. The prolonged surge in demand, with only modest increases in local production, has increased the movement of animals and products into and from the GMS, accompanied by surging risks of transboundary animal disease (TAD) incursions, including the one health (OH) threats of zoonoses and antimicrobial resistance. As a consequence, the region has been subjected to epidemics of highly pathogenic avian influenza (HPAI), new strains of foot-and-mouth disease (FMD) virus, with recent incursions of African swine fever (ASF), lumpy skin disease (LSD), porcine reproductive and respiratory syndrome (PRRS) and risks of peste petits ruminants (OPR) occurring in Southeast Asia (SEA) and beyond. These incidents reflect inadequate biosecurity, a sustainability issue that was clearly of relevance in the covid-19 pandemic, reflecting ecosystem health (EH) deficits, including land-use issues and unregulated trading in wildlife-sourced and poorly processed foods through the predominant ‘wet markets’. These challenges are increasingly confounded by slow adaption to the impacts of the climate crisis, including flooding, drought, crop failures and hypothermia episodes. The increase in animal and product movements enhances disease transmission risk, yet coincides with emerging concerns of greenhouse-gas emissions (GHGe) from livestock production, especially from large ruminants, as the world attempts to find pathways in managing the climate crisis. Despite the prolonged collaborative efforts of the SEA China FMD program from 1997 to 2023, a recent review confirmed persistent deficits in biosecurity, vaccine resourcing, disease surveillance, engagement of farmers, and national emergency disease-response capacities. A major project is about to fund major improvements in livestock value chains in Cambodia, including more effective biosecurity, surveillance and emergency disease-response capacities for TADs, antimicrobial resistance (AMR) and zoonoses. Similarly, a private-sector investment in Laos has developed a more climate-resilient livestock-feeding system that decreases GHGe impacts from ruminant production. These developments are likely to extend beyond both countries and be potentially transformational for the livelihoods of many of the poorest citizens in the region.

Systematic Review and Meta-Analysis of Lifestyle and Reproductive Factors Associated with Risk of Breast Cancer in Asian Women.

Assessing breast cancer risks from lifestyle and reproductive factors is critical for developing population-specific risk prediction tools. However, limited studies have evaluated these risks in recent Asian birth cohorts. We systematically reviewed articles published from January 2010 to December 2023, examining breast cancer risk factors in Asian women. Data were described narratively, estimates pooled, and prevalence and attributable proportions compared across Asian populations. Of the 128 studies reviewed, 103 reported adjusted effect sizes for meta-analysis. Lifestyle and reproductive factors were predictive of breast cancer risk in Asian women, with varying impacts on premenopausal and postmenopausal women. Relative risks were similar within Asian populations and in comparison to European populations, except for menarche, menopause, and hormone receptor therapy. However, risk factor distributions differed across populations. While alcohol intake (21%) and oral contraceptive use (20%) emerged as the most attributable modifiable risk factors in Europeans, passive smoking (24%) and higher BMI (17%, ≥24 kg/m2 among postmenopausal women) were predominant in Asians. Our study shows that while the effects of lifestyle and reproductive breast cancer risk factors are largely similar across different populations, their distributions vary. Our analysis underscores the importance of considering population-specific risk factor distributions when developing risk prediction tools for Asian populations.

Epidemiology of Gestational Diabetes Mellitus: Newer Evidence to curtail

Gestational diabetes mellitus (GDM) is a state metabolic disorder caused by carbohydrate intolerance during pregnancy for the first time. This disease is very important as it affects the mother and fetus. It is said that GDM disrupts the pregnancy process and causes many diseases, such as recurrent miscarriage, congenital anomalies, preeclampsia, stillbirth, macrosomia, preterm birth, and emergency delivery after pregnancy, pregnancy, and delivery. It also causes long-term complications by inducing type 2 diabetes mellitus in mothers and children. GDM is generally considered a lifestyle disorder, and therefore, its burden varies by race, geographic boundaries, genetics, and reproductive risk. Consequently, it is necessary to investigate the prevalence and risk of GDM to evaluate prevention strategies. Ist Trimester early management of Dysglycemia with Medical Nutrition Treatment (MNT) and Metformin is promising. It might be advocated in the future for curtailing the epidemic of GDM and Type 2 Diabetes. Recently, the TOBOGM study and our ongoing trial with early dysglycemia in 8-10 weeks of gestation resulted in better maternal-fetal outcomes and reduced GDM conversion during pregnancy. This publication is important as the final results of our trial will be published soon

P-508 Management of incidental findings after preconception expanded carrier screening: identifying genetic predispositions to cancer and metabolic conditions in 8010 screened ART patients

Abstract Study question How do individuals and fertility clinics navigate incidental findings from Expanded Carrier Screening (ECS) in reproductive decision-making? Summary answer Incidental ECS findings prompted varied responses from patients and gamete donors, influencing diverse reproductive choices and underscoring the pivotal role of pre-test genetic counseling. What is known already ECS aims to assess reproductive risk in the general population for specific autosomal recessive and X-linked conditions. These manifest in infancy or early childhood and impact life expectancy or the quality of life. ECS results may guide interventions to avoid affected pregnancies, such as the implementation of preimplantation genetic testing of embryos (PGT-M). Additionally, ECS has the potential to uncover incidental findings with significant health implications, such as an elevated cancer risk or diagnosis. However, the lack of comprehensive reporting guidelines necessitates meticulous analysis to ensure effective clinical guidance for these individual findings. Study design, size, duration This retrospective descriptive study assessed the results of ECS tests performed in 5475 patients and 2535 oocyte and semen donors from four different fertility clinics between July 2017 and December 2023. ECS reports with incidental findings in the ATM, FH or LDLR genes were identified and further examined. We calculated individual and reproductive risks for affected individuals and recorded the subsequent clinical management pertaining to each case. Participants/materials, setting, methods Pre-test counselling was offered to both patients and gamete donors before consenting to ECS. Testing was outsourced to an external genetics laboratory using a panel of 309 genes analyzed through next generation sequencing and complementary molecular techniques. The laboratory reported pathogenic and likely pathogenic variants that were subsequently manually reviewed by an internal genetics committee. Personal and reproductive risks were assessed for each case and genetic counseling was provided in a subsequent meeting. Main results and the role of chance Genetic variants in ATM, FH, or LDLR genes were reported in 134 out of 8010 individuals undergoing ECS (1.67%). Among these, 108 variants were identified in patients: 53.7% (n = 58) in ATM, 19.4% in FH (n = 21), and 26.8% (n = 29) in LDLR. Out of the variants identified as incidental findings, 20/108 were actionable and eligible for PGT-M: 19 were associated with an increased risk for breast cancer and 1 for renal cancer. After being informed of the findings and their implications, 7/20 couples opted to revoke treatment as, according to internal policies, PGT-M was mandatory in such cases; 6/20 couples chose to undergo double gamete donation; 6/20 couples opted for PGT-M. Patients with pathogenic variants in LDLR linked to autosomal dominant inheritance for familial hypercholesterolemia (20/108, 18.5%), received follow-up guidelines and family genetic counseling. Pathogenic variants in ATM, FH, and LDLR were also identified in 26 gamete donors (24 oocyte donors and 2 sperm donors). Following internal review, 14 of these variants were considered incidental findings with an increased risk for breast cancer (13/14) or familial hypercholesterolemia (1/14), leading to the exclusion of these potential donors from the donation program. Limitations, reasons for caution The reproductive handling of incidental findings in our population relies on subjective decisions by the internal genetics committee, which may evolve with scientific advancements and recommendations from professional societies. Follow-up data on long-term reproductive outcomes are lacking. Wider implications of the findings This study reveals the diverse reproductive decisions made in response to incidental findings, underscoring the importance of pre-test genetic counseling. Our findings also highlight the subsequent impact on fertility programs, which may lead to the exclusion of gamete donors or patients choosing to revoke treatment. Trial registration number Not Applicable

P-497 Increasing use of pan-ethnic carrier screening for donor gametes creates new challenges for clinics and recipient counselling

Abstract Study question How can clinics support recipients to understand a positive or negative carrier status following pan-ethnic carrier screening. Summary answer A combination of recipient testing and genetic counselling enables the use of donor sperm irrespective of pan-ethnic screening results. What is known already Data reported by the HFEA, UK reveals that in 2020, more than half of new donor registrations were from donor imports - 48% were American or Danish in origin, where the level of genetic screening for recessive conditions can vary from 3 to 502 genes. Donor banks generally state that donors are screened to professional guidelines for the countries they supply. Variations in the practice for carrier screening of gamete donors and how this information is shared and charged can be opaque to clinics and complex for recipients to navigate without specialist support to understand relevance and reproductive risk. Study design, size, duration This study reports on the number of genetic counselling requests from several IVF clinic referrals in the UK for the period Jan 2020 - Dec 2023. A total of 412 recipients interested in purchasing samples from donors identified as a positive carrier of one or more recessive condition(s) after undergoing extended carrier screening. Referrals for ECS negative donors were not received. Participants/materials, setting, methods Recipients were provided with the opportunity of genetic counselling to include the meaning of the carrier status, risk estimates, and options. Recipients were then given the opportunity to review the consultation report and were supported through their subsequent decision-making. The recipient’s choice to accept the risk for using the donor or proceed to counter-screening was evaluated to give insight into the recipient decision-making for accepting risk or wishing to undertake carrier screening. Main results and the role of chance UK screening recommendations cumulatively account for only 9.3% of identified mutations within a sperm donor applicant population at a single commercial US sperm bank screened using ECS, highlighting international inconsistencies in donor recruitment and acceptance criteria. 15.3 % (n = 63) of recipients elected to be screened for the conditions their donor was a carrier for, with most opting to be screened on a matched gene panel to provide information for a child and allow future matching with an alternative donor. 84.7% (n = 359) proceeded with treatment without counter screening appreciating their relatively low reproductive risk. Patients who undertake consultation with a genetic professional can understand their reproductive risk for autonomous decision-making, indicating ECS positive results are not a barrier to donor gamete selection for treatment. Limitations, reasons for caution ECS panels are variable by commercial provider, donor banks may vary their carrier screening policy or commercial ECS options over time, limiting the findings to the time frame in which the abstract was written Wider implications of the findings Review and implementation of carrier screening guidelines are required to ensure consistency and transparency with access to suitably qualified genetics professionals to provide information counselling and genetic testing options. This allows recipients to maintain a level of autonomy for donor selection and may ultimately widen the available donor pool. Trial registration number not applicable

P-569 Reciprocal expanded carrier screening for intended parents and gamete donors: experience of a global surrogacy support network

Abstract Study question Is expanded carrier screening an effective tool to identify carriers of clinically relevant genes and determine the reproductive risk between a donor and recipient pair? Summary answer This study has determined that there is a strong rationale for performing matching according to expanded carrier screening results, especially for gamete donor programs. What is known already Carrier screening (CS) identifies carriers of autosomal recessive (AR) and/or X-linked (XL) genetic conditions to establish reproductive risk. If both partners (egg and sperm providers) carry a pathogenic variant in the same gene (co-carriage), there is 25% risk that offspring will be affected. The same risk is present for egg providers who carry an XL disorder. In expanded carrier screening (ECS), many clinically relevant conditions are screened simultaneously using a single-panel approach. The implementation of ECS is becoming commonplace across gamete donor banks. Providing recipients with a matching panel is key in determining reproductive risk and suitable treatment options. Study design, size, duration In this retrospective review, data was collected for 104 gamete recipients and 31 gamete donors who underwent ECS between March 2021-January 2024. ECS was provided through a single genetic testing laboratory, using a whole exome sequencing (WES) platform. The panel used for the gamete donors/recipients consisted of approximately 500 AR genes; optional analysis of 66 X-Linked genes was available for biologically female donors/recipients. Participants/materials, setting, methods In total, 104 gamete recipients were screened against one or more donor(s) using the same ECS panel. All donors/recipients underwent testing in a clinical setting and received pre/post-test genetic counselling, where required. The testing laboratory provided the referring clinician with the results for each individual. Matching was overseen by My Surrogacy Journey and the relevant donor bank. Donor-recipient match reports were requested from the testing laboratory. Individual and matched reports were used for this review. Main results and the role of chance In total, 76.9% (80/104) of gamete recipients presented with a positive result in at least one clinically relevant gene that could have an impact on reproductive planning. Between the 80 positive gamete recipients, 177 gene variants were carried; variant classification was available for 132 variants (74.6%). The majority of gene variants carried were classified as pathogenic (59.9%), meaning that these variants are associated with causing disease. Most frequently, recipients were carriers of a variant in 1-3 genes (1 gene: 36.3%; 2 genes: 27.5%; 3 genes: 22.5%). In addition to this, 77.4% (24/31) of gamete donors were identified to carry a variant in at least one clinically relevant gene, which includes one egg donor (3.2%; 1/24) who was a carrier of an XL condition. This meant that despite the lack of co-carriage in the AR gene(s) of interest, the recipient could not proceed with this donor due to the associated risk (25%). Of the 43 recipients matched with a donor, 9.3% (4/43) showed a high reproductive risk (25%) due to their reciprocal matching results. This expanded carrier screening strategy demonstrates significant utility in identifying positive carrier status and supporting donor-recipient matching programmes by determining high risk reproductive pairs. Limitations, reasons for caution This study was retrospective in nature. The majority of recipients were Caucasian (∼80% of cases). Ethnic groups are not homogenous; there can be significant genetic, cultural, and environmental diversity between/within ethnic groups. Decision outcome data should be collected to improve this work. Wider implications of the findings The findings from this analysis suggest that there is a strong rationale for performing donor-recipient matching using an ECS approach. Increasing awareness and accessibility of ECS in this setting should be a global initiative, with the ultimate aim of reducing the burden of genetic disease in donor-conceived offspring. Trial registration number N/A

O-233 The current landscape for carrier screening in donor conception; a game of chance for donors and recipients?

Abstract Study question How do international regulatory and commercial factors influence donor carrier screening and pose dilemmas for donors, clinics, and recipients. Summary answer Inconsistencies in international carrier screening guidelines and practice for donor conception create a two-tier system for donors and recipients. What is known already Carrier screening is used to identify those who are at risk to have a child with an autosomal recessive or X-linked genetic disorder. Donor banks adopt a commercially viable approach for carrier screening for their market and export, which creates inequalities in donor recruitment and reproductive risk for recipients. For example, UK guidelines require donors to be screened only for cystic fibrosis, with non-European donors screened for conditions known to be more common by ancestry. Real-world pan-ethnic approaches, however, are taken in varying degrees in other countries via extended carrier screening, posing dilemmas for donors, recipients, and clinics. Study design, size, duration Using current available public information, 14 UK, European, and US donor banks were surveyed to understand the screening level for recessive conditions and how this was conveyed to the patient or clinic client. Separately, expanded carrier screening (ECS) results (283 - 502 genes) from 1742 prospective donors from a &amp;gt; 6 year period at a US sperm bank were analysed to calculate acceptance rates if minimal screening and exclusion criteria were applied. Participants/materials, setting, methods UK, European, and US donor gamete banks were identified and surveyed using public information (2023). Separately, internal data from a US sperm bank related to ECS results from 2017 – 2023 was extracted, collated, and evaluated against the UK donor sperm genetic screening guidelines. Main results and the role of chance All donor banks surveyed state donors are genetically screened. For recessive conditions, UK and European banks screened for a small panel of between 3-20 genes, published on a general screening page on the donor bank website, and exclude donors that are carriers. Some offer an additional paid ECS genetic matching service without revealing what the donor or recipient may be carriers for. US banks who perform ECS include these results with a donor profile; some banks exclude carriers of more common recessive disease, while others accept all donors regardless of carrier status. Results from the US sperm bank indicated that of 1742 prospective donors who had ECS, only 117 (6.7%) of carriers would have been reported if screening under minimal guidelines. 665 of the 782 US positive carrier donors would not have been identified as carriers if tested according to UK guidelines. This, together with the observed varying regulation and commercial ECS panels used by donor banks internationally, demonstrate a tiered system of information availability and sharing for reproductive risk knowledge for donors and recipients; recipients are not consistently informed of the limitations of screening of a selected donor, and acceptance of donors to programs is inconsistent. Limitations, reasons for caution The panel composition and number of genes are variable by commercial ECS provider and donor banks may vary their carrier screening policy or commercial ECS options over time. Additionally, other European countries may have differing recommendations in regards to carrier screening practices. Wider implications of the findings As donor sperm imports from within and outside Europe increase, registered donors within countries will present differing genetic risk. Review and implementation of current carrier screening guidelines are required to ensure consistency of methodology and availability of transparent information for donors, recipients, and clinics to consider the wider implications. Trial registration number not applicable

P-509 Unveiling reproductive risks: a retrospective analysis of carrier screening in 873 non-consanguineous couples

Abstract Study question What is the prevalence of at-risk couples for recessive genetic diseases, and can preconception carrier testing effectively identify these potential couples at risk? Summary answer High-risk couples, comprising mostly carriers of the ABCA4 and HBB genes, accounted for 3.7% of the analyzed cases, while another 3.2% categorized as moderate risk. What is known already It is widely recognized that approximately 2-3% of couples may be at risk of having an affected child with a genetic recessive disease. Expanded carrier screening tests (ECS) are currently employed to identify carrier status in healthy individuals for various severe recessive and X-linked diseases that manifest early in life, and often lack treatment options. ECS facilitates the detection of couples sharing mutated genes, allowing for risk calculation and further interventions to avoid affected pregnancies. Study design, size, duration In this retrospective descriptive study, we evaluated couples in which both partners elected to complete ECS before undergoing medically assisted reproduction across our Spanish and Italian clinics between August 2018 and January 2024. A total of 873 non-consanguineous couples were identified during the study period. Participants/materials, setting, methods All couples received pre-test genetic counseling alongside the informed consent for ECS. Saliva or blood samples were sent to an external genetics lab for the analysis of 309 genes (recessive and X linked), using NGS and complementary molecular techniques to detect pathogenic and likely pathogenic variants. Each couple’s risk was subsequently calculated. Post-test genetic counselling was offered to all of couples. Main results and the role of chance A total of 55 couples were identified as having reproductive risk, carrying pathogenic or likely pathogenic variants in genes exhibiting recessive or recessive digenic inheritance. These couples were categorized into high and moderate-risk groups based on the severity, actionability, and probability of causing classical gene-linked diseases. Ultimately, 3.5% (n = 31/873) of couples were deemed high-risk, with ABCA4 and HBB being the most frequently mutated genes, observed in 6 and 5 couples respectively (0.7% and 0.6%). Additionally, 24 couples (2.74%) were classified as moderate risk, primarily carrying a classical pathogenic variant and a non-classical pathogenic variant in the CFTR gene. This allele combination could result in a child presenting a mild cystic fibrosis phenotype, predominantly observed in males, and characterized by the absence of a vas deferens. Limitations, reasons for caution The main limitation of the study rests in interpreting the variants in healthy patients. The study does not delve into exploring the genetic heterogeneity within the identified risk groups, which may influence the severity and manifestation of diseases. Wider implications of the findings The cumulative risk observed in close to 6% of the cohort underscores the critical importance of carrier testing in guiding preconception interventions and the role and importance of having a well-trained, multidisciplinary genetics team to support these couples in reproductive decision-making with minimal anxiety and maximum knowledge. Trial registration number Not Applicable