Association between peri-conceptional bisphenol A exposure in women and men and time to pregnancy-The HOPE study

Definition of Infertility and Indications for Fertility Evaluation: Consensus Document

Minjeur M et al., 2026 · Journal of Restorative Reproductive Medicine · Free to read

Infertility is a clinical condition that is recognized by the symptom of an inability to conceive through sexual intercourse or to sustain a pregnancy, with that symptom indicating underlying male and/or female pathology. This definition of infertility was developed through a structured, consensus-informed process involving broad stakeholder engagement. Initially, multiple definitions currently used by various medical professional organizations were reviewed, and a definition document was drafted and submitted to the Board of Directors of the International Institute for Restorative Reproductive Medicine (IIRRM). All IIRRM members were invited to provide feedback on the draft. Approximately 2,500 individuals and 44 organizations from 92 countries were then invited to review the proposed document, representing clinical, scientific, patient, policy, and advocacy perspectives. Submitted comments were reviewed thematically, with suggested revisions evaluated for clarity, clinical relevance, inclusiveness, and consistency with contemporary restorative reproductive medicine. Following this review, 3 substantive changes, 18 minor changes, and 15 citation corrections were incorporated into the final draft which resulted in a revised definition intended to better reflect the medical, social, and practical realities of modern infertility evaluation and care. Final approval by the IIRRM Board of Directors was unanimous.

Subfecundity, Infertility Treatment, and Child Neurodevelopment

Kahn LG et al., 2026 · JAMA Network Open · Free full text on PubMed Central

Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment. To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity. DESIGN, SETTING, This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026. Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment. Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment. In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.

Potential increase of the U.S. total fertility rate resulting from restorative treatment of unresolved subfertility: a simulation study

Stanford JB et al., 2026 · Frontiers in Reproductive Health · Free full text on PubMed Central

Background The total fertility rate (TFR) in most developed countries has been declining for decades. In the United States (U.S.), the total fertility rate has remained below replacement level since 2007. Subfertility affects at least 15% of women or couples over their reproductive lifespan and contributes to reduced TFR. Restorative reproductive medicine (RRM) is a medically based approach to subfertility care that can be delivered in primary care settings to increase live birth rates. Objective To estimate the theoretical impact of use of RRM among subfertile couples in the United States. Methods We conducted a simulation study. Model inputs included the number of women of reproductive age in the United States by 5-year age groups; current age-specific and total fertility rates; the proportion of women in each age group with subfertility; estimated spontaneous live birth rates among women with subfertility; and age-specific crude live birth rates with RRM treatment. We evaluated fifteen scenarios including sensitivity analyses: two different varying assumptions for spontaneous conception (25% vs. 50%), two levels of RRM utilization among subfertile women (20% vs. 50%), three different estimates of the number of subfertile women who would be potentially eligible for RRM treatment, and 4 different levels of effectiveness (live birth) from RRM treatment. Results The baseline TFR in the United States was 1.77 during 2015-2019, and 13.5% of women ages 20-44 were estimated to have subfertility. In a conservative scenario (50% spontaneous births; 20% RRM utilization; married women trying to conceive for at least 12 months, 20.7% RRM live births), the TFR increased to 1.79, representing a 1.0% relative increase (absolute +0.02). In an optimistic scenario (25% spontaneous births; 50% RRM utilization; all subfertile women), the TFR increased to 2.02, a 14.5% relative increase (absolute +0.26), approaching replacement-level fertility. Conclusion Simulation results suggest that expanding access to RRM within primary care settings could meaningfully increase the U.S. TFR, by reducing unresolved subfertility. Realizing this potential would require policy and health system changes to address workforce capacity, insurance coverage, and equitable access. These findings underscore the potential contribution of non-IVF fertility care pathways in addressing population-level fertility decline.

Restorative Reproductive Medicine Restricting Access to Care

Minjeur M et al., 2026 · JAMA

Environmental Contaminants Affecting Fertility and Somatic Health

Chiang C et al., 2017 · Semin Reprod Med · Free full text on PubMed Central

This review article summarizes the epidemiological findings published between 2011 and 2016 concerning bisphenol A (BPA), phthalates, dioxins, pesticides, air pollution, fracking chemicals, triclosan, and parabens and fertility parameters in men (i.e., semen volume, sperm concentration, sperm motility, and sperm morphology) as well as fertility parameters in women (i.e., cyclicity, fertility treatment outcomes), pregnancy outcomes (i.e., preterm birth,miscarriage), and reproductive disorders (i.e., polycystic ovary syndrome, endometriosis, and uterine fibroids). Overall, this review indicates that several environmental toxicants are significantly associated with reduced fertility parameters in men and women as well as several reproductive disorders in women. Although many studies reported that the selected exposures are associated with adverse fertility outcomes, several studies reported null associations. Thus, future studies are still needed to better elucidate the associations and potential mechanisms between these environmental chemicals and fertility outcomes in men and women.

Developmental low-dose bisphenol A exposure leads to extensive transcriptome female masculinization and male feminization later in life

Lind T et al., 2025 · Communications Medicine · Free full text on PubMed Central

Bisphenol A (BPA) is an endocrine disruptor, and exposure to low doses in utero has been associated with the development of metabolic diseases. Previous studies have suggested that bone marrow (BM) may be particularly susceptible to BPA exposure. Here, we investigate how developmental exposure to low levels of BPA affects the BM transcriptome and the blood metabolic profile in Fischer 344 rats later in life. We compare these effects to those observed in human metabolic syndrome (MetS) using a population-based cohort. The results show an unexpectedly extensive sex-biased effect on the BM transcriptome from a BPA dose approximately eight times lower than the recent temporary European Food Safety Authority (EFSA) human tolerable daily intake (TDI) and a higher dose considered safe in 2015. BPA exposure induces sex-specific changes in gene expression, progressing toward a hypometabolic cancer-like state in females and a hypermetabolic autoimmunity-like state in males, with a blood metabolic profile that significantly overlaps with human MetS in a cross-sectional study. We conclude that developmental low-dose BPA exposure might induce metabolic syndrome specifically in males, possibly by affecting T cell activity in a sex-specific manner. Our study provides biologically plausible and convincing evidence for significant effects from low-dose BPA exposure, supporting the substantial lowering of the human BPA TDI by EFSA based on its critical effects on T cells.

Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study

Buck Louis GM et al., 2013 · Fertil Steril · Free full text on PubMed Central

To assess in utero exposures and the odds of an endometriosis diagnosis. Matched cohort design. Fourteen participating clinical centers in geographically defined areas in Utah and California. PATIENT(S): Operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and an ageand residence-matched population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007-2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Women completed standardized interviews before surgery or MRI regarding in utero exposures: mothers' lifestyle during the index pregnancy, and the index woman's gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site. RESULT(S): Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, adjust odds ratios (AORs) were elevated for maternal vitamin usage (1.27; 95% CI, 0.85-1.91), maternal cigarette smoking (1.16; 95% CI = 0.61-2.24), and low birth weight (1.1; 95% CI, 0.92-1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI, 0.64-1.54), alcohol (0.82; 95% CI, 0.35-1.94), paternal cigarette smoking (0.72; 95% CI, 0.43-1.19), and preterm delivery (0.98; 95% CI, 0.47-2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI, 0.18-0.94) when restricting to visualized and histologically confirmed endometriosis in the operative cohort. CONCLUSION(S): In utero exposures were not statistically significantly associated with the odds of an endometriosis diagnosis in either cohort.

Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort

Liew Z et al., 2020 · Environmental health perspectives · Free full text on PubMed Central

Per- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied. Using a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted. We observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women. Maternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history. https://doi.org/10.1289/EHP6202.