BMI status and weight trajectories across females' reproductive years and risk of adverse pregnancy outcomes: a prospective cohort study.

BACKGROUND: Prepregnancy body mass index (BMI) is a well-established risk factor of adverse pregnancy outcomes (APOs). The associations of long-term and short-term weight trajectories with APOs are less clear. OBJECTIVES: This study aimed to determine the associations of weight trajectories during females' reproductive years, before and between pregnancies, with risk of APOs. METHODS: We followed 16,241 females (25,386 singleton pregnancies) participating in a prospective cohort, the Nurses' Health Study II. Weight at age 18 y, current weight, and height were assessed at baseline (1989), and weight was updated biennially. Pregnancy history was self-reported in 2009. The primary outcome was a composite of hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM), preterm birth, and stillbirth. Secondary outcomes were individual APOs. The associations of weight change with APOs were estimated using log-binomial regression, adjusting for demographic, lifestyle, reproductive factors, and baseline BMI (in kg/m2). RESULTS: The mean (standard deviation [SD]) age at first in-study pregnancy was 33.7 (4.1) y. The mean (SD) time from age 18 y to pregnancy, baseline to pregnancy, and between pregnancies was 16.3 (4.0), 6.1 (3.0), and 2.9 (1.6) y, with a corresponding weight change of 6.4 (9.1), 3.1 (5.8), and 2.3 (4.8) kg, respectively. Of the pregnancies, 4628 (18.2%) were complicated by ≥1 APOs. Absolute weight change since age 18 y was most strongly associated with APOs. Compared with females whose weight remained stable (0-2 kg) since age 18, females who gained >2 kg had higher risk of APO (2.1-9.9 kg, relative risk [RR]: 1.12; 95% confidence interval [CI]: 1.02, 1.23; 10.0-14.9 kg, RR: 1.43; 95% CI: 1.29, 1.60; ≥15 kg, RR: 1.87; 95% CI: 1.69, 2.08), primarily driven by HDP and GDM. The associations of per 1 kg weight gain before and between pregnancies with HDP were nearly identical. CONCLUSIONS: Weight trajectories prior to and between pregnancies were associated with the risk of APOs, particularly HDP. Longer periods of weight gain, corresponding to greater absolute weight gain, were most strongly associated with higher risk of APOs.

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction.

BACKGROUND: Phthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. METHODS: Participants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. RESULTS: Metabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. CONCLUSION: Our study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Neighborhood deprivation in relation to ovarian reserve and outcomes of ovarian stimulation among oocyte donors.

OBJECTIVE: To study the relationship between neighborhood deprivation index (NDI) and markers of ovarian reserve and outcomes of controlled ovarian stimulation among young, healthy oocyte donors. DESIGN: Retrospective cohort study. PATIENTS: A total of 547 oocyte donors who underwent 905 oocyte retrieval cycles (2008-2020) at a private fertility center in Sandy Springs, Georgia, United States. INTERVENTIONS: Neighborhood deprivation index was calculated using principal component analysis applied to census-level measures of poverty, employment, household composition, and public assistance, which was then standardized and linked to donor information on the basis of donor residence. MAIN OUTCOME MEASURES: Markers of ovarian reserve, including antral follicle count (AFC) and antimüllerian hormone (AMH) levels, and outcomes of controlled ovarian stimulation including number of total and mature oocytes retrieved and ovarian sensitivity index (OSI) (defined as the number of oocytes retrieved/total gonadotropin dose × 1,000). Multivariable generalized estimating equations with Poisson and normal distribution were used to model the relationship between NDI and outcome measures adjusting for age, body mass index, and year of retrieval. RESULTS: The mean (SD) age of donors was 25.0 (2.8) years and 29% of the donors were racial or ethnic minorities. There were no associations between donor NDI and ovarian reserve markers. For every interquartile range increase in NDI, there was a reduction of -1.5% (95% confidence interval: -5.3% to 2.4%) in total oocytes retrieved although the effect estimate was imprecise. Associations of NDI with a number of mature oocytes retrieved and OSI were in a similar direction. We observed evidence for effect modification of the NDI and OSI association by donor race. There was a suggestive positive association between NDI and OSI in Black donors but no association in White donors. CONCLUSION: In this cohort of young, healthy, racially diverse oocyte donors, we found little evidence of associations between NDI and markers of ovarian reserve or outcomes of ovarian stimulation.

Former smoking associated with epigenetic modifications in human granulosa cells among women undergoing assisted reproduction.

Smoking exposure during adulthood can disrupt oocyte development in women, contributing to infertility and possibly adverse birth outcomes. Some of these effects may be reflected in epigenome profiles in granulosa cells (GCs) in human follicular fluid. We compared the epigenetic modifications throughout the genome in GCs from women who were former (N = 15) versus never smokers (N = 44) undergoing assisted reproductive technologies (ART). This study included 59 women undergoing ART. Smoking history including time since quitting was determined by questionnaire. GCs were collected during oocyte retrieval and DNA methylation (DNAm) levels were profiled using the Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study with robust linear models, regressing DNAm level at individual loci on smoking status, adjusting for age, ovarian stimulation protocol, and three surrogate variables. We performed differentially methylated regions (DMRs) analysis and over-representation analysis of the identified CpGs and corresponding gene set. 81 CpGs were differentially methylated among former smokers compared to never smokers (FDR < 0.05). We identified 2 significant DMRs (KCNQ1 and RHBDD2). The former smoking-associated genes were enriched in oxytocin signaling, adrenergic signaling in cardiomyocytes, platelet activation, axon guidance, and chemokine signaling pathway. These epigenetic variations have been associated with inflammatory responses, reproductive outcomes, cancer development, neurodevelopmental disorder, and cardiometabolic health. Secondarily, we examined the relationships between time since quitting and DNAm at significant CpGs. We observed three CpGs in negative associations with the length of quitting smoking (p < 0.05), which were cg04254052 (KCNIP1), cg22875371 (OGDHL), and cg27289628 (LOC148145), while one in positive association, which was cg13487862 (PLXNB1). As a pilot study, we demonstrated epigenetic modifications associated with former smoking in GCs. The study is informative to potential biological pathways underlying the documented association between smoking and female infertility and biomarker discovery for smoking-associated reproductive outcomes.

Neighborhood deprivation and racial differences in in vitro fertilization outcomes.

BACKGROUND: There are significant racial disparities in in vitro fertilization outcomes, which are poorly explained by individual-level characteristics. Environmental factors such as neighborhood-level socioeconomic factors may contribute to these disparities. However, few studies have directly addressed this research question in a large, racially diverse cohort. OBJECTIVE: This study aimed to investigate whether neighborhood deprivation is associated with differences in in vitro fertilization outcomes. STUDY DESIGN: Our retrospective cohort study included 1110 patients who underwent 2254 autologous in vitro fertilization cycles between 2014 and 2019 at an academic fertility center in the Southeastern United States. Neighborhood deprivation was estimated using the Neighborhood Deprivation Index, a composite variable measuring community levels of material capital based on poverty, occupation, housing, and education domains. Using multivariable log-binomial generalized estimating equations with cluster weighting, risk ratios and 95% confidence intervals were estimated for cycle cancellation, miscarriage (defined as spontaneous pregnancy loss before 20 weeks after a confirmed intrauterine gestation), and live birth according to patient Neighborhood Deprivation Index. RESULTS: There were positive associations between increasing Neighborhood Deprivation Index (indicating worsening neighborhood deprivation) and body mass index, as well as increasing prevalence of tubal and uterine factor infertility diagnoses. The crude probability of live birth per cycle was lower among Black (24%) than among White patients (32%), and the crude probability of miscarriage per clinical pregnancy was higher among Black (22%) than among White patients (12%). After adjustment, the Neighborhood Deprivation Index was not significantly associated with risk of cycle cancellation or live birth. Results were consistent when analyses were stratified by race. CONCLUSION: Our research demonstrates racial disparities between Black and White women in the incidence of miscarriage and live birth following in vitro fertilization. Although the level of neighborhood deprivation was closely related to race, it did not have strong associations with in vitro fertilization outcomes in our population as a whole or within strata of race.

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood.

BACKGROUND: There is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. METHODS: For this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004-2014). A total of 41 women who were born after the PBB contamination incident (1973-1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). RESULTS: Women in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0-3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) µg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. CONCLUSION: Higher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Ambient traffic related air pollution in relation to ovarian reserve and oocyte quality in young, healthy oocyte donors.

Studies in mice and older, subfertile women have found that air pollution exposure may compromise female reproduction. Our objective was to evaluate the effects of air pollution on ovarian reserve and outcomes of ovarian stimulation among young, healthy females. We included 472 oocyte donors who underwent 781 ovarian stimulation cycles at a fertility clinic in Atlanta, Georgia, USA (2008-2019). Antral follicle count (AFC) was assessed with transvaginal ultrasonography and total and mature oocyte count was assessed following oocyte retrieval. Ovarian sensitivity index (OSI) was calculated as the total number of oocytes divided by total gonadotrophin dose × 1000. Daily ambient exposure to nitric oxide (NOx), carbon monoxide (CO), and particulate matter ≤ 2.5 (PM2.5) was estimated using a fused regional + line-source model for near-surface releases at a 250 m resolution based on residential address. Generalized estimating equations were used to evaluate the associations of an interquartile range (IQR) increase in pollutant exposure with outcomes adjusted for donor characteristics, census-level poverty, and meteorological factors. The median (IQR) age among oocyte donors was 25.0 (5.0) years, and 31% of the donors were racial/ethnic minorities. The median (IQR) exposure to NOx, CO, and PM2.5 in the 3 months prior to stimulation was 37.7 (32.0) ppb, 612 (317) ppb, and 9.8 (2.9) µg/m3, respectively. Ambient air pollution exposure in the 3 months before AFC was not associated with AFC. An IQR increase in PM2.5 in the 3 months before AFC and during stimulation was associated with -7.5% (95% CI -14.1, -0.4) and -6.4% (95% CI -11.0, -1.6) fewer mature oocytes, and a -1.9 (95% CI -3.2, -0.5) and -1.0 (95% CI -1.8, -0.2) lower OSI, respectively. Our results suggest that lowering the current 24-h PM2.5 standard in the US to 25 µg/m3 may still not adequately protect against the reprotoxic effects of short-term PM2.5 exposure.

Food, nutrition, and fertility: from soil to fork.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

Deafening Silence of Male Infertility.

Think about 6 loved ones of reproductive age in your life. Now imagine that 1 of these 6 individuals is suffering from infertility. Perhaps they feel alone and isolated, unable to discuss their heartbreak with their closest friends, family, and support network. Suffering in silence. In this editorial, we discuss the infertility journey through the lens of the patients, the providers, and the scientists who struggle with infertility each and every day. Our goal is to open a dialogue surrounding infertility, with an emphasis on dismantling the longstanding societal barriers to acknowledging male infertility as a disease. Through education, communication, compassion, and advocacy, together we can all begin to break the deafening silence of male infertility.

Diet and recreational drug use in relation to male reproductive health.

Diet and lifestyle interventions present promising avenues for the improvement of male fertility. Our objective was to review and synthesize the existing observational and experimental studies among humans on the associations of diet and recreational drug use with semen quality and fertility outcomes. The available data on this topic are limited and, at times, conflicting. Nevertheless, on the basis of this review, dietary patterns that are composed of higher intakes of fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lower intakes of red and processed meats, sweets, and sugar-sweetened beverages were identified as having the strongest evidence for associations with better sperm quality. However, whether these dietary patterns translate into positive associations with clinical fertility endpoints such as assisted reproductive technology success rates or time-to-pregnancy among couples trying to conceive without medical assistance remains unclear. Male caffeine and alcohol intake, within low-to-moderate ranges of intake, do not appear to be detrimental to semen quality. Yet high-quality research on this topic, focused on clinical fertility endpoints, should continue given the conflicting evidence, particularly in populations undergoing infertility treatment with assisted reproductive technology. Recreational drug use, including marijuana, electronic cigarettes, and other illicit drugs, does not appear to be beneficial for male reproductive health and should be avoided or ceased. In conclusion, men should be encouraged to consume a healthy diet rich in fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lacking in red and processed meats, sweets, and sugar-sweetened beverages, and to avoid recreational drug use for improved male reproductive health.

Endocrine-disrupting chemicals and male reproductive health.

Modifiable factors, such as environmental exposures, can impact human fertility. The objective of this review is to summarize the potential effects of exposure to important endocrine-disrupting chemicals on male reproductive health. Most experimental and animal data demonstrate strong evidence for the negative effects of exposure to phenols, phthalates, pesticides, and perfluoroalkyl and polyfluoroalkyl substances on male reproductive health. Although evidence of negative associations in humans was overall strong for phthalates and pesticides, limited and inconclusive relationships were found for the other examined chemical biomarkers. Reasons for the discrepancies in results include but are not limited to, differences in study populations, exposure concentrations, number of samples collected, sample sizes, study design, and residual confounding. Additional studies are needed, particularly for newer phenols and perfluoroalkyl and polyfluoroalkyl substances, given the scarce literature on the topic and increasing exposures over time.

Exposure to Particulate Matter Air Pollution and Age of Menarche in a Nationwide Cohort of U.S. Girls.

BACKGROUND: It remains unclear whether in utero and childhood exposure to air pollution affects pubertal development, particularly age of menarche in girls. OBJECTIVE: The aim of this study was to determine whether residential ambient particulate matter (PM) exposure in utero and during childhood is associated with age of menarche. METHODS: We studied 5,201 girls in the Growing Up Today Study 2 (2004-present) who were 10-17 y of age at enrollment (47.7% premenarchal; 52.3% postmenarchal). Exposure to three size fractions of PM [fine PM with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameters between 2.5µm and 10µm (PM2.5-10), and PM with aerodynamic diameter 10µm (PM10)] was assigned based on maternal residential address, updated every 2 y, using nationwide spatiotemporal models. We estimated average PM exposure in utero, and time-varying windows: annual average exposure in the prior 1 and 2 y and cumulative average from birth. Age of menarche was self-reported on three surveys administered in 2004, 2006, and 2008. We calculated hazard ratios (HR) for menarche for an interquartile range (IQR) increase in PM exposure using Cox proportional hazard models adjusting for potential confounders. RESULTS: Girls attained menarche at 12.3 y of age on average. In the adjusted model, higher residential exposure to ambient PM2.5 during all time windows was associated with earlier age of menarche. The HRs of menarche for each IQR (4 µg/m3) increase in exposure to PM2.5 during the in utero period, 1 y prior to menarche, and throughout childhood were 1.03 [95% confidence interval (CI): 1.00, 1.06], 1.06 (95% CI: 1.02, 1.10) and 1.06 (95% CI: 1.02, 1.10), respectively. Effect estimates for PM10 exposure were similar, albeit attenuated, for all time windows. PM2.5-10 exposure was not associated with age of menarche. DISCUSSION: Among a large, nationwide, prospective cohort of U.S. girls, higher exposure to PM2.5 and PM10 in utero and throughout childhood was associated with an earlier age of menarche. Our results suggest that PM2.5 and PM10 may have endocrine-disrupting properties that could lead to altered timing of menarche. https://doi.org/10.1289/EHP12110.

Serum and follicular fluid metabolome and markers of ovarian stimulation.

STUDY QUESTION: What metabolic pathways and metabolites in the serum and follicular fluid are associated with peak estradiol levels and the number of mature oocytes? SUMMARY ANSWER: In the serum metabolome, mostly fatty acid and amino acid pathways were associated with estradiol levels and mature oocytes while in the follicular fluid metabolome, mostly lipid, vitamin, and hormone pathways were associated with peak estradiol levels and mature oocytes. WHAT IS KNOWN ALREADY: Metabolomics has identified several metabolic pathways and metabolites associated with infertility but limited data are available for ovarian stimulation outcomes. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of women undergoing IVF from 2009 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 125 women undergoing a fresh IVF cycle at a fertility clinic in the Northeast United States who provided a serum and follicular fluid sample. Untargeted metabolomics profiling was conducted using liquid chromatography with high-resolution mass spectrometry in two chromatography columns (C18 and hydrophilic interaction chromatography (HILIC)). The main ovarian stimulation outcomes were peak serum estradiol levels and number of mature oocytes. We utilized adjusted generalized linear regression models to identify significant metabolic features. Models were adjusted for age,BMI, initial infertility diagnosis, and ovarian stimulation protocol. We then conducted pathway analysis using mummichog and metabolite annotation using level-1 evidence. MAIN RESULTS AND ROLE OF CHANCE: In the serum metabolome, 480 and 850 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively. Additionally, 437 and 538 features were associated with mature oocytes in the C18 and HILIC columns, respectively. In the follicular fluid metabolome, 752 and 929 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively, Additionally, 993 and 986 features were associated with mature oocytes in the C18 and HILIC columns, respectively. The most common pathways associated with peak estradiol included fatty acids (serum and follicular fluid), hormone (follicular fluid), and lipid pathways (follicular fluid). The most common pathways associated with the number of mature oocytes retrieved included amino acids (serum), fatty acids (serum and follicular fluid), hormone (follicular fluid), and vitamin pathways(follicular fluid). The vitamin D3 pathway had the strongest association with both ovarian stimulation outcomes in the follicularfluid. Four and nine metabolites were identified using level-1 evidence (validated identification) in the serum and follicular fluid metabolomes, respectively. LIMITATIONS, REASONS FOR CAUTION: Our sample was majority White and highly educated and may not be generalizable to thewider population. Additionally, residual confounding is possible and the flushing medium used in the follicular fluid could have diluted our results. WIDER IMPLICATIONS OF THE FINDINGS: The pathways and metabolites identified by our study provide novel insights into the biologicalmechanisms in the serum and follicular fluid that may underlie follicular and oocyte development, which could potentially be used to improve ovarian stimulation outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the following grants from the National Institute of Environmental Health Sciences (P30-ES019776, R01-ES009718, R01-ES022955, P30-ES000002, R00-ES026648, and T32-ES012870), and National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Association of Gestational Diabetes With Subsequent Long-Term Risk of Mortality.

Importance: Gestational diabetes has been associated with numerous chronic diseases. However, few studies have examined the association of gestational diabetes with long-term mortality risk. Objective: To investigate the associations between gestational diabetes and long-term risks of total and cause-specific mortality. Design, Setting, and Participants: This cohort study analyzed participants of the Nurses' Health Study II who were followed for 30 years (1989-2019). Participants included US female nurses aged 25 to 42 years who reported at least 1 pregnancy (≥6 months) at 18 years or older across their reproductive life span. Data were analyzed from May 1, 2022, to May 25, 2023. Exposure: Gestational diabetes across the reproductive life span. Main Outcomes and Measures: Hazard ratios (HRs with 95% CIs) for total and cause-specific mortality were estimated by Cox proportional hazards regression models. Results: A total of 91 426 parous participants were included, with a mean (SD) age of 34.9 (4.7) years and a body mass index of 24.1 (4.7) at baseline. During a follow-up period of 2 609 753 person-years, 3937 deaths were documented, including 255 deaths from cardiovascular disease and 1397 from cancer. Participants with a history of gestational diabetes had a higher crude mortality rate than those without a history of gestational diabetes (1.74 vs 1.49 per 1000 person-years; absolute difference = 0.25 per 1000 person-years). The corresponding HR for total mortality was 1.28 (95% CI, 1.13-1.44), which did not materially change after additional adjustment for potential confounders and lifestyle factors during the reproductive life span (HR, 1.25; 95% CI, 1.11-1.41). The association persisted regardless of the subsequent development of type 2 diabetes and was more robust among participants who adopted less healthy lifestyles; experienced gestational diabetes in 2 or more pregnancies (HR, 1.48; 95% CI, 0.99-2.19); had gestational diabetes both in the initial and subsequent pregnancies (HR, 1.71; 95% CI, 1.11-2.63); and concurrently reported hypertensive disorders in pregnancy (HR, 1.80; 95% CI, 1.21-2.67), preterm birth (HR, 2.46; 95% CI, 1.66-3.64), or low birth weight (HR, 2.11; 95% CI, 1.21-3.68). Cause-specific mortality analyses revealed that gestational diabetes was directly associated with the risk of mortality due to cardiovascular disease (HR, 1.59; 95% CI, 1.03-2.47). Additionally, gestational diabetes was inversely associated with cancer mortality (HR, 0.76; 95% CI, 0.59-0.98); however, it was only evident among participants who later developed type 2 diabetes. Conclusions and Relevance: Results of this cohort study suggest that participants who reported a history of gestational diabetes exhibited a small but elevated risk of subsequent mortality over 30 years. The findings emphasize the importance of considering gestational diabetes as a critical factor in later-life mortality risk.

Mediterranean diet and female reproductive health over lifespan: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis of the effects of Mediterranean diet on female reproductive health outcomes over the life-course. DATA SOURCES: We searched PubMed, Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to identify eligible studies published till February 2022. Eligible references from identified studies and review articles were also considered. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective cohort studies, or nested case-control studies examining Mediterranean diet and major female reproductive outcomes over the lifespan, including clinical outcomes from childhood to adulthood (menarche, polycystic ovary syndrome, endometriosis, and outcomes related to fertility, pregnancy, and menopause), were included for review. METHODS: Two independent reviewers screened and performed data extraction and risk-of-bias assessment. We performed random-effects meta-analysis to obtain summary relative risks and 95% confidence intervals for major female reproductive outcomes. Subgroup analyses were performed for several pregnancy outcomes according to timing of the interventions for randomized controlled trials and timing of the dietary assessment for observational studies. RESULTS: Thirty-two studies (9 randomized controlled trials, 22 prospective cohort studies, and 1 nested case-control study) involving 103,204 predominantly White women (>95%) were included. The pooled relative risk (95% confidence interval) comparing randomization to Mediterranean diet vs a control diet based on 7 randomized controlled trials was 0.74 (0.55-0.99) for gestational diabetes mellitus, 0.45 (0.26-0.76) for preterm birth, 0.71 (0.51-1.00) for gestational hypertension, and 0.82 (0.54-1.22) for preeclampsia; the effect sizes for preterm birth were greater in randomized controlled trials that initiated the interventions in first trimester vs after first trimester (P heterogeneity=.02). We observed inverse associations for all the above-mentioned pregnancy outcomes based on 9 cohort studies. There was suggestive evidence of favorable associations between Mediterranean diet adherence with fertility and gestational weight management. Limited studies suggested associations between higher Mediterranean diet adherence and later time to menarche and fewer vasomotor menopausal symptoms, null associations for polycystic ovary syndrome-like phenotype and pregnancy loss, and positive associations for luteal phase deficiency. CONCLUSION: Adherence to Mediterranean diet may lower risks of adverse pregnancy outcomes among predominantly White populations. For fertility-related outcomes, available evidence supporting potential beneficial effects is suggestive yet limited. For other reproductive outcomes across the lifespan, data remains sparse.

Pregnancy Intention, Changes in Pregnancy Intention, and Pregnancy Incidence Among Female Nurses in North America.

Importance: Pregnancy intention assessment is a key element of preconception and contraceptive care. The association between a single screening question and the incidence of pregnancy is unknown. Objective: To prospectively evaluate the dynamics of pregnancy intention and pregnancy incidence. Design, Setting, and Participants: This prospective cohort study (the Nurses' Health Study 3) was conducted from June 1, 2010, to April 1, 2022, in 18 376 premenopausal, nonpregnant female nurses aged 19 to 44 years. Main Outcomes and Measures: Pregnancy intention and pregnancy status were assessed at baseline and approximately every 3 to 6 months thereafter. Cox proportional hazards regression models were used to estimate the association between pregnancy intention and pregnancy incidence. Results: A total of 18 376 premenopausal, nonpregnant women (mean [SD] age, 32.4 [6.5] years) participated in the study. At baseline, 1008 women (5.5%) were trying to conceive, 2452 (13.3%) were contemplating pregnancy within 1 year, and the remaining 14 916 (81.2%) were neither trying to conceive nor thought they would be pregnant within 1 year. A total of 1314 pregnancies were documented within 12 months of pregnancy intention assessment. The cumulative incidence of pregnancy was 38.8% in women actively trying to conceive (median [IQR] time to pregnancy, 3.3 [1.5-6.7] months), 27.6% in women contemplating pregnancy (median [IQR] time to pregnancy, 6.7 [4.2-9.3] months), and 1.7% in women neither trying to conceive nor contemplating pregnancy (median [IQR] time to pregnancy, 7.8 [5.2-10.5] months) among those who became pregnant. Women who were actively trying to conceive were 23.1 times (95% CI, 19.5-27.4 times) and women who were contemplating pregnancy were 13.0 times (95% CI, 11.1-15.2 times) more likely to conceive within 12 months than women who were neither attempting nor contemplating pregnancy. Among women contemplating pregnancy at baseline who did not get pregnant during follow up, 18.8% were actively trying and 27.6% were not trying by 12 months. Conversely, only 4.9% of women neither trying to conceive nor contemplating pregnancy within 1 year at baseline changed pregnancy intention during follow up. Conclusions and Relevance: In this cohort study of reproductive-aged nurses in North America, pregnancy intention was highly fluid among women who were contemplating pregnancy but relatively stable among women trying to conceive and women who were neither trying to conceive nor contemplating pregnancy. Pregnancy intention was strongly associated with pregnancy incidence, but the median time to pregnancy points to a relatively short time window to initiate preconception care.

Traffic-related air pollution and supplemental folic acid intake in relation to DNA methylation in granulosa cells.

BACKGROUND: Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1. RESULTS: There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies. CONCLUSIONS: We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Association of laparoscopically-confirmed endometriosis with long COVID-19: a prospective cohort study.

BACKGROUND: Women are at greater risk than men of developing chronic inflammatory conditions and "long COVID." However, few gynecologic health risk factors for long COVID-19 have been identified. Endometriosis is a common gynecologic disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiological mechanisms proposed for long COVID-19. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID-19. OBJECTIVE: This study aimed to investigate the association between history of endometriosis before SARS-CoV-2 infection and risk of long COVID-19. STUDY DESIGN: We followed 46,579 women from 2 ongoing prospective cohort studies-the Nurses' Health Study II and the Nurses' Health Study 3-who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires before the pandemic (1993-2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, polymerase chain reaction, or antibody test) and long-term COVID-19 symptoms (≥4 weeks) defined by the Centers for Disease Control and Prevention were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases). RESULTS: Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation, and 1598 (43.8%) reported experiencing long COVID-19 symptoms. Most women were non-Hispanic White (95.4%), with a median age of 59 years (interquartile range, 44-65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID-19 (adjusted risk ratio, 1.22; 95% confidence interval, 1.05-1.42) compared with those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID-19 as having symptoms for ≥8 weeks (risk ratio, 1.28; 95% confidence interval, 1.09-1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID-19 by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend indicating that the association may be stronger in women aged <50 years (<50 years: risk ratio, 1.37; 95% confidence interval, 1.00-1.88; ≥50 years: risk ratio, 1.19; 95% confidence interval, 1.01-1.41). Among persons who developed long COVID-19, women with endometriosis reported on average 1 additional long-term symptom compared with women without endometriosis. CONCLUSION: Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID-19. Healthcare providers should be aware of endometriosis history when treating patients for signs of persisting symptoms after SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.