BACKGROUND:Oil and gas development-a highly prevalent industry in North America-is often located near residential communities. This industry produces a complex mixture of pollutants that may impact human health. Despite well-documented associations between residential proximity to oil and gas development and adverse birth outcomes, no study has examined gestational diabetes mellitus (hereafter, gestational diabetes)-a condition with long-term consequences for maternal-infant health. METHODS:We examined associations between residential proximity to active oil and gas development during pregnancy and gestational diabetes risk by using data from Pregnancy Study Online (PRESTO)-an internet-based preconception cohort study in the USA and Canada. We developed residential proximity measures for active oil and gas development at the estimated date of conception, including distance to the nearest site. For participants whose pregnancy progressed for ≥28 weeks of gestation, we evaluated diagnoses of gestational diabetes via self-administered questionnaires and birth records. We implemented log-binomial regression to estimate risk ratios (RRs) and 95% confidence intervals (CIs), adjusting for covariates, including stratification by pre-pregnancy body mass index (BMI) (<25.0, 25.0-29.9, ≥30.0 kg/m2) and parity (nulliparous, parous). RESULTS:Among 6285 participants, 8.6% of participants reported gestational diabetes. Residence within 5 km of active oil and gas development was not appreciably associated with gestational diabetes (RR: 1.07, 95% CI: 0.81, 1.40) compared with residence ≥20 km away. Associations did not vary by pre-pregnancy BMI or parity. CONCLUSION:We found no consistent evidence of an association between residential proximity to active oil and gas development at conception and the risk of gestational diabetes.

STUDY QUESTION:To what extent is perceived stress during preconception and pregnancy associated with miscarriage incidence? SUMMARY ANSWER:Perceived stress during early pregnancy, but not preconception, was associated with higher miscarriage incidence. WHAT IS KNOWN ALREADY:Some studies have found that higher stress levels are associated with miscarriage risk. However, many of these studies were retrospective, focused on occupational stress only, and/or suffered from under-ascertainment of miscarriage. STUDY DESIGN, SIZE, DURATION:Pregnancy Study Online (PRESTO) is an ongoing prospective preconception cohort study that recruited participants during 2013-2025. Eligible participants were females aged 21-45 years, who resided in the USA or Canada and were trying to conceive without fertility treatments. Eligible partners were males aged ≥21 years. PARTICIPANTS/MATERIALS, SETTING, METHODS:We collected data on perceived stress using the 10-item version of the Perceived Stress Scale (PSS-10) during preconception (every 8 weeks) and early pregnancy for female participants and during preconception only for male participants. We identified pregnancies and miscarriages on bimonthly follow-up questionnaires during preconception and additional questionnaires during early and late pregnancy and postpartum. We fit Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% CIs for the effect of preconception PSS-10 scores (n = 11 189 female and 2656 male participants) and early pregnancy PSS-10 scores (n = 8319 female participants) on miscarriage incidence, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE:About 20% of the pregnancies ended in miscarriage, with the loss occurring at a median of six gestational weeks. Preconception PSS-10 scores in the female or male partner were not appreciably associated with miscarriage incidence. Female PSS-10 scores during gestational weeks 5-8 were strongly associated with higher miscarriage incidence: adjusted HRs for PSS-10 scores of 10-14, 15-19, 20-24, and ≥25 vs <10 in gestational weeks 5-8 were 1.38 (95% CI: 1.07, 1.77), 1.17 (95% CI: 0.89, 1.52), 1.35 (95% CI: 1.00, 1.83), and 2.05 (95% CI: 1.40, 2.99), respectively. In week-specific analyses, an association existed during weeks 4-8 and peaked at week 7. LIMITATIONS, REASONS FOR CAUTION:Our results may be susceptible to reverse causation, unmeasured confounding by nausea and vomiting in pregnancy, and exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS:Interventions aimed at decreasing stress during early pregnancy may be effective at reducing miscarriage incidence, but confirmation of our results in randomized studies is warranted. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD086742, R01-HD105863). Lauren Wise has received in-kind donations for primary data collection in PRESTO from ChartNeo.com. The other authors have no conflicts to report. TRIAL REGISTRATION NUMBER:N/A.

In the United States (U.S.), 15% of couples attempting pregnancy experience infertility, and 20% of pregnancies end in miscarriage. Environmental chemical exposures, particularly endocrine-disrupting chemicals (EDCs) from consumer products, may contribute to reproductive health challenges. We mailed wearable passive samplers (Fresh Air wristbands) to 132 female participants across 39 U.S. states and 24 of their male partners in the Pregnancy Study Online (PRESTO) to characterize exposure among couples trying to conceive between January and October 2021. Wristbands were analyzed using thermal desorption gas chromatography-high-resolution mass spectrometry with targeted and nontargeted approaches. Nontargeted analysis revealed exposure to 491 chemicals, predominantly benzenoids (36.9%) and organoheterocyclic compounds (18.3%). Health hazard assessment identified 107 high-risk EDCs and 47 compounds predicted to have medium-to-high impacts on reproductive outcomes, including galaxolide, salicylates, and phthalates. Targeted analysis quantified 43 chemicals, revealing universal exposure to polycyclic aromatic hydrocarbons and phthalates. Lifestyle factors influenced exposures: frequent sunscreen users had up to 3.1 times higher ultraviolet filter exposures, while dog owners had 1.2-2.6 times higher exposure to fragrance compounds. Among cohabitating couples, few similarities were observed, despite shared environments. The findings demonstrate that consumer products contribute to complex exposure mixtures with reproductive health implications during preconception.

STUDY QUESTION:To what extent are self-reported sleep health measures associated with semen quality? SUMMARY ANSWER:Poor sleep health-including short and long sleep durations, increased frequency of sleep trouble, and poor sleep quality-was associated with reduced sperm concentration, total sperm count, and total motile sperm count, and, in the case of short sleep duration and increased frequency of sleep trouble, reduced semen volume. WHAT IS KNOWN ALREADY:Semen quality has declined over the past several decades. Sleep health may affect semen quality through multiple pathways, including endocrine dysfunction, and population-based prospective studies of the association are scarce. STUDY DESIGN, SIZE, DURATION:We analyzed cross-sectional data from 690 male participants (1247 semen samples) aged ≥21 years at enrollment (2015-2023) in Pregnancy Study Online, a North American preconception cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS:At baseline, participants provided self-reported data on sleep duration in the past month and frequency of sleep trouble in the previous 2 weeks. A subset of participants completed the Pittsburgh Sleep Quality Index. We used generalized estimating equations (GEE) models to estimate mean percentage differences (%D) and 95% CIs for the associations of sleep health with semen parameters (semen volume, sperm concentration, percent motility), ascertained using a validated at-home semen testing kit. We also used GEE models to estimate prevalence ratios for poor semen quality (low vs normal) based on World Health Organization (WHO) standards. MAIN RESULTS AND THE ROLE OF CHANCE:Comparing sleep durations of <6 vs 7-8.9 h/day, %Ds (95% CIs) were -11.3% (-23.6%, 1.1%), -16.4% (-45.0%, 26.9%), -27.1% (-53.1%, 13.2%), and -20.0% (-50.3%, 28.8%) for semen volume, sperm concentration, total sperm count, and total motile sperm count, respectively. We observed similar associations for ≥9 vs 7-8.9 h/day and sperm concentration (-14.4% [-44.9%, 33.0%]), total sperm count (-13.9% [-44.1%, 32.7%]), and total motile sperm count (-6.8% [-42.1%, 49.9%]). Comparing sleep trouble >50% of the time vs never, %Ds (95% CIs) were -3.3% (-12.0%, 5.4%), -11.9% (-29.9%, 10.8%), -16.2% (-34.3%, 7.0%), and -16.9% (-37.3%, 9.9%) for semen volume, sperm concentration, total sperm count, and total motile sperm count, respectively. Comparing global Pittsburgh Sleep Quality Index scores of >5 (poor sleep quality) vs ≤5 (good sleep quality), %Ds (95% CIs) were -18.1% (-33.5%, 0.9%), -19.2% (-34.6%, -0.1%), and -16.3% (-33.5%, 5.4%) for sperm concentration, total sperm count, and total motile sperm count, respectively. Analyses based on WHO semen quality standards showed consistent results. LIMITATIONS, REASONS FOR CAUTION:Non-differential misclassification of sleep health was possible due to our reliance on self-reported data collected at a single point in time. Non-differential misclassification of semen quality was also possible, as participants used an at-home semen testing kit to measure semen parameters. We cannot rule out bias due to residual or unmeasured confounding. Given that the study population was restricted to pregnancy planners who enrolled via the Internet, our findings may not be generalizable to other populations. WIDER IMPLICATIONS OF THE FINDINGS:Our findings are generally consistent with previous research, supporting a relationship between poor sleep health and worse semen quality. We analyzed data from a population-based sample of pregnancy planners, which overcomes limitations from most prior studies that relied on convenience samples of infertile couples or sperm donors. These findings may inform sleep interventions to improve reproductive health outcomes. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the following grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA: R01HD086742, R01HD105863, R21HD094322. J.J.Y. is an employee of Optum and owns stock in UnitedHealth Group. G.J.S. is an employee of and holds stock in Labcorp, which manufactures the male fertility testing kits used in this study. He is also a co-inventor on multiple patents related to the male fertility testing kits reported in this manuscript: US #10 376 877, US #11 471 881, and US #11 714 034. M.L.E. is an advisor for Doveras, Hannah, Next, Illumicell, Legacy, and HisTurn, which includes a small equity grant of options. S.M.B. has received consulting fees from Idorsia Pharmaceuticals and Apnimed in the past 12 months, participated in a Data Safety Monitoring Board or Advisory Board for PCORI and AHRQ, and served in a leadership role for the Sleep Research Society and American Academy of Sleep Medicine. All other authors have no disclosures to report. TRIAL REGISTRATION NUMBER:N/A.

BACKGROUND:Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting chemicals associated with adverse reproductive health outcomes (e.g., reduced fecundability). Identifying correlates of PFAS exposure in females is therefore an important public health objective, but less research has been conducted in the preconception period. METHODS:We evaluated correlates of PFAS exposure using cross-sectional data from 449 participants enrolled in Pregnancy Study Online, a preconception cohort study, during 2014-2023. We measured concentrations of four PFAS in serum (n = 293) or capillary whole blood (n = 156) at baseline (preconception). Participants reported sociodemographic and reproductive history correlates at baseline. We used multivariable linear regression models to assess associations between correlates and PFAS concentrations, adjusting for all correlates, sampling year, and biospecimen sample type. We estimated percent differences in PFAS concentrations with 95% confidence intervals (CIs). RESULTS:Demographic correlates (higher education, non-Hispanic White race and ethnicity, being married) were associated with higher PFAS concentrations. We observed geographical differences in PFAS concentrations, but limited association with tap water consumption. Typical menstrual characteristics, especially flow intensity and cycle length, were associated with lower PFAS concentrations, notably, perfluorooctanesulfonic acid (moderate versus light flow: β = -31.4%, 95% CI = -53.6%, 1.5%; 27-29 days versus <27 days of cycle length: β = -28.4%, 95% CI = -43.3%, -9.5%). Longer breastfeeding duration and later sampling year were consistently associated with lower PFAS concentrations. CONCLUSION:Several demographic and reproductive correlates were associated with PFAS concentrations among pregnancy planners. These findings can help to identify females at increased risk for PFAS exposure in the sensitive preconception period.

Research question: Is preconception maternal or paternal alcohol intake associated with risk of miscarriage? Design: Pregnancy Study Online (PRESTO) is an ongoing web-based prospective cohort study of couples trying to conceive. All primary data collection occurred via self-administered questionnaires. Baseline questionnaires in both partners collected data on sociodemographics, medical history, anthropometrics and lifestyle factors, including preconception alcohol consumption. Female participants reported data on pregnancy outcomes on follow-up questionnaires. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals (95% CI) for the association between preconception alcohol consumption in both partners and miscarriage rate. Results: The study included 9414 female (mean age 30 years) and 2613 male (mean age 32 years) participants. About 27% of the female participants reported no preconception alcohol use, compared with 20% of males. Approximately 20% of pregnancies ended in miscarriage. After adjustment for demographic, lifestyle and reproductive variables, no appreciable association was observed between preconception alcohol intake and miscarriage. In the couples-based analysis of the association of miscarriage with preconception alcohol use, compared with female participants who reported no alcohol intake, the hazard ratios for those reporting 0.1-6.9, 7-13.9 and >= 14 drinks per week were 0.91 (95% CI 0.74-1.13), 1.06 (95% CI 0.77-1.46) and 0.80 (95% CI 0.43-1.52), respectively; for male the hazard ratios were 0.94 (95% CI 0.74-1.19), 0.93 (95% CI 0.70-1.25) and 0.84 (95% CI 0.59-1.19), respectively. Results were consistent across alcohol types (wine, liquor, beer) and within strata of age, history of miscarriage and gestational age. Conclusions: Preconception alcohol use in either partner was not associated with higher miscarriage risk.

ABSTRACT Background Epidemiologic studies have demonstrated that ambient concentrations of particulate matter < 2.5 μm (PM 2.5 ) are associated with reduced fecundability, the per cycle probability of conception. The specific constituents driving this association are unknown. Objectives We examined the association between ambient concentrations of PM 2.5 constituents and fecundability in a Danish preconception cohort study. Methods During 2007–2018, we enrolled female pregnancy planners in an Internet‐based preconception cohort study. We included the 5905 participants who had been trying to conceive for < 3 cycles at study enrollment. Participants completed a baseline questionnaire and follow‐up questionnaires every 8 weeks to update pregnancy status. We geocoded time‐varying residential addresses to estimate ambient concentrations of total PM 2.5 and the following PM 2.5 constituents: elemental carbon (EC), primary organic aerosol (POA), secondary organic aerosols (SOA), sulfate (SO 4 2− ), ammonium (NH 4 + ), nitrate (NO 3 − ), and sea salt. We averaged concentrations of each pollutant across each menstrual cycle at risk. We fit proportional probabilities regression models to estimate fecundability ratios (FR) and 95% confidence intervals (CI), adjusting for potential confounders and co‐pollutants. Results Total PM 2.5 concentrations were associated with reduced fecundability (the FR for an IQR increase, corresponding to 3.2 μg/m 3 , was 0.93 [95% CI 0.87, 0.99]). The association was strongest for POA: the FR for an IQR increase, corresponding to 1.3 μg/m 3 , was 0.92 (95% CI 0.84, 1.01). The corresponding FRs for the remaining PM 2.5 constituents were 0.96 (95% CI 0.87, 1.05) for EC (IQR = 0.5 μg/m 3 ), 0.98 (95% CI 0.91, 1.06) for SOA (IQR = 0.5), 0.97 (95% CI 0.92, 1.02) for SO 2 4− (IQR = 0.4), 0.95 (95% CI 0.91, 1.01) for NH 4 + (IQR = 0.5), 0.97 (95% CI 0.93, 1.01) for NO 3 − (IQR = 1.0), and 1.00 (95% CI 0.95, 1.06) for sea salt (IQR = 0.4). Conclusions In this Danish preconception cohort study, PM 2.5 constituents derived from biomass and transportation‐related combustion may drive the association between PM 2.5 concentrations and fecundability.

BACKGROUND:Recreational and medicinal use of cannabis is increasing among North American reproductive-aged couples. Studies of cannabis use and semen quality are limited and have produced inconsistent findings. OBJECTIVES:We examined the association between male cannabis use and semen parameters. MATERIALS AND METHODS:We analyzed data from 1654 semen samples contributed by 921 male participants in Pregnancy Study Online (PRESTO), a North American preconception cohort study. Participants aged ≥21 years completed a baseline questionnaire on which they reported their cannabis use within the past 2 months. After enrollment, we invited participants to perform at-home semen testing. We used linear regression to estimate percent differences in mean semen parameter values (%D) and 95% confidence intervals (CI) for associations between cannabis use and semen volume (mL), total sperm count (TSC, million), sperm concentration (million/mL), motility (%), and total motile sperm count (TMSC, million), controlling for potential confounders. We used log-binomial regression to estimate risk ratios (RRs) for low semen quality based on 2021 World Health Organization cut-points. RESULTS:Overall, 22.6% of participants reported current cannabis use and 3.3% reported daily use. Nearly 6% of participants had low semen volume (≤1.5 mL), 13% low sperm concentration (≤15 million/L), 8% low TSC (≤39 million), 25% low sperm motility (≤40%), and 11% low TMSC (≤16 million). Adjusted %Ds (95% CIs) comparing current cannabis use versus non-use were -3.2 (-9.1, 2.7) for semen volume, 3.5 (-10.3, 19.5) for sperm concentration, -0.6 (-14.3, 15.3) for TSC, 2.5 (-2.9, 8.0) for motility, and 3.0 (-13.4, 22.4) for TMSC. Cannabis use ≥1 times/week (vs. non-use) was associated with low semen volume (RR = 2.16, 95% CI = 0.93-5.04). Associations were imprecise and showed no monotonic association between frequency of cannabis use and the semen parameters evaluated. CONCLUSION:In this North American preconception cohort study, current cannabis use was not appreciably associated with semen quality.

STUDY QUESTION:To what extent is male physical activity (PA) associated with fecundability (per-cycle probability of conception)? SUMMARY ANSWER:Preconception levels of vigorous, moderate, or total PA were not consistently associated with fecundability across Danish and North American cohorts, but there was suggestive evidence that bicycling with a 'soft, comfort seat' was associated with reduced fecundability in both cohorts, especially among males with greater BMI. WHAT IS KNOWN ALREADY:Among males, some studies indicate that moderate PA might improve fertility, whereas vigorous PA, especially bicycling, might be detrimental. STUDY DESIGN, SIZE, DURATION:We assessed the association between male PA and fecundability among couples participating in two preconception cohort studies: SnartForaeldre.dk (SF) in Denmark (2011-2023) and Pregnancy Study Online (PRESTO) in North America (2013-2024). We restricted analyses to 4921 males (1088 in SF and 3833 in PRESTO) who had been trying to conceive with their partners for ≤6 cycles at enrollment. PARTICIPANTS/MATERIALS, SETTING, METHODS:At baseline, male partners reported data on medical history, lifestyle, behavioral, anthropometric factors, and their PA levels using different instruments [SF: International Physical Activity Questionnaire (IPAQ); PRESTO: average annual hours/week and type]. Both cohorts included additional questions on bicycling (frequency, bike seat type). After linking couple data at baseline, the female partner completed follow-up questionnaires to update their pregnancy status every 8 weeks for 12 months or until conception, whichever occurred first. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, controlling for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE:Average hours/week of vigorous PA, moderate PA, and total metabolic equivalents of task were generally inversely associated with fecundability in SF, but not PRESTO. While there was little association with bicycling overall in either cohort, we observed an inverse association for bicycling using a 'soft, comfort seat' (≥3 vs 0 h/week: SF: FR = 0.75, 95% CI: 0.53-1.05; PRESTO: FR = 0.81, 95% CI: 0.62-1.07) but not a 'hard, racing-style seat' (≥3 vs 0 h/week: SF: FR = 1.16, 95% CI: 0.95-1.41; PRESTO: FR = 1.06, 95% CI: 0.89-1.28). Among males with BMI ≥25 kg/m2, associations with bicycling using a 'soft, comfort seat' were similar or stronger (≥3 vs 0 h/week: SF: FR = 0.75, 95% CI: 0.45-1.24; PRESTO: FR = 0.73, 95% CI: 0.52-1.03). LIMITATIONS, REASONS FOR CAUTION:Misclassification of PA was likely the most important study limitation because we ascertained PA only once at enrollment using different instruments in each cohort. We would expect misclassification of PA to be non-differential given the prospective study design. Additional weaknesses include the narrow range of PA levels evaluated, reduced precision when stratifying the data by selected covariates, and limited generalizability due to the large percentage of non-Hispanic White participants and restriction of the cohort to pregnancy planners. WIDER IMPLICATIONS OF THE FINDINGS:Further evaluation of the potential deleterious effects of bicycling on male fertility, with additional consideration of the influence of bike seat type and BMI, may be warranted. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by NICHD Grants R21-HD072326, R01-HD086742, R01 HD105863, and R03-HD094117. These funding bodies had no involvement in the: study design; collection, analysis, and interpretation of data; writing of the report; or decision to submit the article for publication. L.A.W. serves as a paid consultant for AbbVie, Inc. and the Bill and Melinda Gates Foundation. She also receives in-kind donations for primary data collection in Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility apps). All of these relationships are for work unrelated to this manuscript. M.L.E. is an advisor for and holds stock in Legacy, Doveras, VSeat, Hannah, Illumicell, HisTurn, & Next. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER:N/A.

Hormone exposure in utero affects male- and female-typical behavior in animals, and these effects may persist in the next generation. Prenatal exposure to diethylstilbestrol (DES), a potent estrogen and endocrine disruptor, has been associated with a tendency toward greater heterosexual behavior in women, but the association in the next generation has not been studied. We evaluated the associations of maternal prenatal DES exposure with sexual behavior, sexual identity, and gender identity in 982 female offspring participating in the National Cancer Institute's DES Third Generation Study, a cohort born to mothers who were prenatally exposed and unexposed to DES. Odds ratio (OR) and 95% confidence intervals (CIs) were estimated from logistic regression models that included birth year. The ORs were 0.71 (CI 0.46-1.1) for DES in relation to non-heterosexual compared with heterosexual behavior, and 0.99 (CI 0.55-1.8) for non-heterosexual identity, compared with heterosexual identity. Results were similar after additional adjustment for education. Only three individuals reported a gender identity distinct from what was reported by the mother at cohort inception, preventing meaningful quantitative analysis of DES and gender identity. These data do not provide evidence of differences in sexual behavior and sexual identity in female offspring of mothers with and without prenatal exposure to DES.

BACKGROUND:Few studies have prospectively evaluated semen quality (using the most up-to-date clinically relevant definitions) and fecundability (the per-cycle probability of conception). OBJECTIVE:To study semen quality in relation to fecundability. MATERIALS AND METHODS:We analyzed prospectively collected data from 763 male participants aged ≥21 years from Pregnancy Study Online (PRESTO), a North American preconception cohort study (2015-2024). Eligible participants for the semen testing substudy resided in the contiguous United States, had been attempting conception for ≤6 cycles at cohort entry, and had a female partner aged 21-45 years with regular menses. Participants used an at-home semen testing device to measure semen volume, sperm concentration, and motile sperm concentration. Participants contributed up to two semen tests during the preconception period (1376 total semen samples). We calculated sperm motility, total sperm count, and total motile sperm count. We evaluated results according to 2021 World Health Organization (WHO)-defined thresholds for low semen quality. Female participants reported their pregnancy status on bimonthly follow-up questionnaires for up to 12 cycles or until conception, whichever came first. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS:After accounting for censoring using life-table methods, 80.7% of couples conceived within 12 cycles. FRs were 1.48 (95% CI, 1.05-2.08) for low semen volume (≤1.5 vs. >1.5 mL), 0.74 (95% CI, 0.56-0.97) for low sperm concentration (≤16 vs. >16 million/mL), 0.98 (95% CI, 0.81-1.19) for low sperm motility (≤42 vs. >42%), 0.58 (95% CI, 0.38-0.88) for low total sperm count (≤39 vs. >39 million), and 0.73 (95% CI, 0.52-1.04) for low total motile sperm count (≤21 vs. >21 million). Associations between low total motile sperm count and fecundability were stronger among couples with <3 cycles of attempt time at cohort entry. DISCUSSION:In this prospective preconception cohort study of North American couples, most suboptimal semen parameters based on WHO criteria were associated with reduced fecundability, with the exception of low semen volume. CONCLUSION:Semen quality at suboptimal levels may adversely affect fecundability.

STUDY QUESTION:To what extent are self-reported diagnoses of food allergies associated with fecundability, the per-cycle probability of conception? SUMMARY ANSWER:Fecundability was not appreciably associated with self-reported food allergy diagnoses, number of food allergies, age at first diagnosis, or time since last allergic reaction. WHAT IS KNOWN ALREADY:Food allergies are atopic diseases that are characterized by an inappropriate immune response to a normally harmless dietary substance. While some studies have observed associations between atopic disorders and infertility, no study has examined the association between food allergies and fecundability, the per-cycle probability of conception. STUDY DESIGN, SIZE, DURATION:A prospective cohort study including 7711 females trying to conceive without fertility treatment at enrollment (2018-2022) and followed for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS:We analyzed data from an internet-based prospective cohort of pregnancy planners in North America. At baseline, female participants completed an online questionnaire on demographic, medical, and lifestyle factors that included questions on food allergy diagnoses, age at diagnosis, and time since last reaction. Participants completed bimonthly follow-up questionnaires for up to 12 months to ascertain pregnancy status. The analysis included 7711 PRESTO participants with ≤6 menstrual cycles of pregnancy attempt time at enrollment (2018-2022). We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusted for demographic, lifestyle, and behavioral characteristics. MAIN RESULTS AND THE ROLE OF CHANCE:A total of 1028 (13%) participants reported a history of diagnosed food allergy, with the most commonly reported allergy being dairy or shellfish. A history of diagnosed food allergy (vs none) was not appreciably associated with fecundability (FR = 0.93, 95% CI: 0.86-1.02), though specific allergens were associated with fecundability in opposing directions (e.g. inverse association with egg and positive association with soy). We observed non-monotonic associations between fecundability and number of food allergies, age at first allergy diagnosis, and time since last allergic reaction. Inverse associations between self-reported diagnosed food allergens (all types combined) and reduced fecundability were slightly stronger among those with BMI ≥25 (FR = 0.90, 95% CI: 0.80-1.01) than those with BMI <25 (FR = 0.97, 95% CI: 0.86-1.10) and among those born ≥1990 (FR = 0.91, 95% CI: 0.80-1.03) compared with those born <1990 (FR = 0.96, 95% CI: 0.86-1.08). LIMITATIONS, REASONS FOR CAUTION:Non-differential misclassification of food allergies was likely given that we relied on self-reported diagnoses. Confounding by unmeasured dietary factors may have influenced associations between specific food allergens and fecundability, if participants were deficient in specific nutrients because they excluded or substituted selected foods due to the allergy. Generalizability may be reduced given our study population was restricted to North American pregnancy planners. WIDER IMPLICATIONS OF THE FINDINGS:Diagnoses of food allergies have substantially increased over the past several decades. Our findings indicate that self-reported diagnoses of food allergies were not meaningfully associated with subfertility. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by NIH/NICHD grant R01-HD086742. S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a paid consultant for AbbVie, Inc. and the Gates Foundation. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER:N/A.

Background: Female sexual function is important for sexual well-being, general health, fertility, and relationship satisfaction. Distressing impairments in sexual function, clinically recognized as female sexual dysfunction (FSD), can manifest as issues with interest/desire, arousal, orgasm, and pain during vaginal penetration. Some evidence suggests that exposure to endocrine-disrupting chemicals may adversely affect female sexual function, but associations for per- and polyfluoroalkyl substances (PFAS) have not been previously evaluated. Objective: We investigated associations between serum PFAS concentrations and female sexual function among U. S. pregnancy planners. Methods: We used cross-sectional data from participants from Pregnancy Study Online (PRESTO), a prospective preconception cohort study. Participants reported sexual function and distress at baseline on two validated measures: a modified version of the Female Sexual Function Index-6 (FSFI-6) and the Female Sexual Distress Scale (FSDS). We quantified PFAS serum concentrations in samples collected in the preconception period (i.e., at baseline) using solid phase extraction-high performance liquid chromatography-isotope-dilution-mass spectrometry. Participants reported sociodemographic information on structured baseline questionnaires. We included 78 participants with complete PFAS and sexual function data and fit multivariable linear regression models to estimate mean differences in FSFI-6 scores (beta) or percent differences (%) in FSDS scores per interquartile range (IQR) increase in PFAS concentrations, adjusting for age, annual household income, years of education, parity, and body mass index. We further investigated effect measure modification by parity (parous vs. nulliparous) in stratified models. Results: An IQR increase in perfluorohexanesulfonic acid was associated with a 1.0-point decrease (95% CI = -1.8, -0.1) in reported FSFI-6 scores, reflecting poorer sexual function. PFAS were consistently associated with lower FSFI-6 scores among parous participants. PFAS were also associated, though imprecisely, with greater sexual distress. Conclusion: Some PFAS were associated with poorer sexual function among U.S. pregnancy planners, but future studies are needed to clarify the extent to which PFAS influences female sexual health.

Introduction/Background: Diethylstilbestrol (DES), a synthetic estrogen and potent endocrine disruptor, was prescribed between the 1940s and 1970s to reduce risk of pregnancy complications and loss. DES was later found to be associated with increased risk of vaginal and other cancers among those who were prenatally exposed and is thus no longer prescribed during pregnancy. Whether in utero DES exposure is also associated with subsequent risk of developing benign breast disease (BBD), a risk factor for breast cancer, is unknown, and evaluating the impact of DES may serve as a model of potential intergenerational chemical toxicity. We assessed the risk of developing BBD, overall and by histologic BBD subtype, associated with prenatal DES exposure. Methods: From the National Cancer Institute Combined DES Cohorts Follow-Up Study, we examined associations of prenatal DES exposure with BBD risk among 4208 DES-exposed and 1830 unexposed women born between 1933 and 1976. Prenatal DES exposure status was abstracted from medical records or physician notes, and cumulative high or low DES dose was assigned in cohorts with recorded regional prescribing patterns. BBD diagnoses were self-reported on questionnaires from 1990 to 2017. Pathology-confirmation of BBD was available for 600 out of 1086 self-reported BBD cases. Cox proportional hazards models with age as the time scale were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the association of DES exposure (DES unexposed, exposed) with BBD risk. Follow-up started at birth and ended at the earliest of a diagnosis of BBD or breast cancer, death, or loss to follow up; the baseline hazard was stratified by year of birth (1933-1951, 1952-1953, 1954-1957, 1958-1976) and cohort, and further adjusted for baseline questionnaire year (1994, 1997 or 2001) and number of questionnaires a woman had answered in a time-varying fashion. We estimated cumulative incidence of BBD by DES exposure status. In additional analyses, we censored women with a BBD diagnosis only obtained by self-report at the age of BBD, and considered risk by histologic BBD subtype (nonproliferative, proliferative without atypia, proliferative with atypia) separately. To test for heterogeneity of associations of DES exposure by histologic BBD subtype, we used case-only polytomous logistic regression models adjusted for follow-up time and year of reported BBD. Results: 6038 women contributed a total of 333,455 person-years with a median follow-up of 43.0 (range: 13.8-74.0) years for cases (n=1086) and 59.9 (range: 19.7-80.3) years for non-cases (n=4952). BBD diagnoses were confirmed by pathology among 225/350 (64%) unexposed women and 375/736 (51%) DES-exposed women. For the 600 BBD cases with pathologic confirmation, histology did not vary meaningfully by DES exposure: 54.7% nonproliferative, 32.1% proliferative without atypia, and 9.5% proliferative with atypia. Comparing women who were prenatally exposed to DES to unexposed women, we found no evidence of an association between DES exposure and risk of BBD (aHR: 0.98; 95%CI: 0.85, 1.12). There was no evidence of a dose-response relationship or difference in cumulative incidence by exposure status. The aHRs for nonproliferative BBD, proliferative BBD without atypia, and proliferative BBD with atypia were 0.83 (95%CI: 0.64, 1.07), 0.94 (95%CI: 0.67, 1.32), and 0.60 (95%CI: 0.33, 1.09), respectively, with no evidence of statistical heterogeneity by BBD subtype (p-heterogeneity: 0.86). Conclusions: The risk of BBD was not elevated among women who were exposed to DES in utero, suggesting that previously observed increases in breast cancer risk associated with DES are not likely meditated through this pathological mechanism. Citation Format: Paloma R. Mitra, Kimberly A. Bertrand, Ruth M. Pfeiffer, Julie R. Palmer, Soumya Ramireddy, Marianne Hyer, William C. Strohsnitter, Kjersti Aagaard, Dezheng Huo, Elizabeth E. Hatch, Linda Titus, Rebecca Troisi, Gretchen L. Gierach. Prenatal diethylstilbestrol (DES) exposure and risk of benign breast disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-06-02.

[This corrects the article DOI: 10.3389/frph.2022.1052231.].

INTRODUCTION:We evaluated association of preconception nicotine vaping among female and male partners with spontaneous abortion (SAB) incidence, and the extent to which associations vary by cigarette smoking. METHODS:In a prospective cohort study, 6136 participants assigned female-at-birth and 1688 of their partners assigned male-at-birth reported preconception nicotine vaping and cigarette smoking via online questionnaire. Female partners reported incident pregnancies and outcomes (e.g., SAB) on follow-up questionnaires completed every 8 weeks and in early and late pregnancy. We used multivariable Cox proportional hazards regression models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for association between vaping and SAB incidence, overall and by smoking history. RESULTS:Mean age was 30 and 32 for females and males respectively. Among females, 13% reported ever-vaping and 14% reported ever-smoking, while 19% of males reported ever-vaping and 24% reported ever-smoking. Relative to female never-vapers, aHRs were 1.03 for former vaping (95% CI 0.86-1.24) and 0.91 for current vaping (95% CI 0.61-1.36). Former and current vaping were also not appreciably associated with SAB rate among ever-smokers. In the couple-based cohort, relative to male never-vapers, aHRs were 1.00 for male former-vapers (95% CI: 0.74-1.35) and 0.67 for male current-vapers (95% CI: 0.35-1.25). Additional analysis of female participants after stratifying by finer categories of smoking status did not identify any meaningful association with SAB incidence. CONCLUSION:The current study found that vaping in either partner during the preconception period was not associated with SAB incidence. Cigarette smoking also did not modify this association. IMPLICATIONS:The rising prevalence of vaping invokes greater scrutiny on its possible adverse reproductive effects. Studies have linked vaping to adverse birth events, and clear guidance is made to avoid vaping in pregnant people. However, guidance about vaping during preconception is less clear despite research showing how preconception behaviors are linked to adverse pregnancies and birth outcomes. Our cohort study finds little association between preconception vaping and spontaneous abortion. In context of established risks of vaping on fetal outcomes, this study highlights the need for additional evidence-based information about preconception vaping to help couples make lifestyle decisions for optimal reproductive outcomes.

Food frequency questionnaires require updating over time due to population changes in diet, posing analytical challenges in consistently measuring diet in prospective studies. We compared reliability and agreement between nutrients in versions of the National Cancer Institute's web-based Diet History Questionnaire (DHQ, III vs II) in an ongoing North American preconception study. We invited 51 consecutively enrolled US female participants aged 21-45 years to complete both DHQ versions within a 2-week period in a randomized order. We compared 30 nutrients from both DHQ versions and calculated within-person reliability using intraclass correlation coefficients (ICCs). Bland-Altman plots and 95% limits of agreement (LOA) were generated to assess nutrient agreement between DHQ versions. We observed highest reliability in percent energy from carbohydrates and cholesterol (ICCs, 0.88; 95% IC, 0.80-0.93) and lowest for percent energy from protein and vitamin D (ICCs, 0.56; 95% IC, 0.34-0.72). At the group level, all nutrients had most observations within the LOA. Bland-Altman plots showed assessment differences between DHQs for protein, fat, monounsaturated fat, and vitamin D. The remaining nutrients showed good agreement and good to moderate reliability. Some nutrients may require adjustment and calibration analysis before using them interchangeably across DHQ versions.

STUDY QUESTION: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle? SUMMARY ANSWER: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis. WHAT IS KNOWN ALREADY: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group. LIMITATIONS, REASONS FOR CAUTION: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1. WIDER IMPLICATIONS OF THE FINDINGS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis.