Epigenetic age acceleration in follicular fluid and markers of ovarian response among women undergoing IVF.

STUDY QUESTION: Are markers of epigenetic age acceleration in follicular fluid associated with outcomes of ovarian stimulation? SUMMARY ANSWER: Increased epigenetic age acceleration of follicular fluid using the Horvath clock, but not other epigenetic clocks (GrimAge and Granulosa Cell), was associated with lower peak estradiol levels and decreased number of total and mature oocytes. WHAT IS KNOWN ALREADY: In granulosa cells, there are inconsistent findings between epigenetic age acceleration and ovarian response outcomes. STUDY DESIGN, SIZE, DURATION: Our study included 61 women undergoing IVF at an academic fertility clinic in the New England area who were part of the Environment and Reproductive Health Study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants provided a follicular fluid sample during oocyte retrieval. DNA methylation of follicular fluid was assessed using a genome-wide methylation screening tool. Three established epigenetic clocks (Horvath, GrimAge, and Granulosa Cell) were used to predict DNA-methylation-based epigenetic age. To calculate the age acceleration, we regressed epigenetic age on chronological age and extracted the residuals. The association between epigenetic age acceleration and ovarian response outcomes (peak estradiol levels, follicle stimulation hormone, number of total, and mature oocytes) was assessed using linear and Poisson regression adjusted for chronological age, three surrogate variables (to account for cellular heterogeneity), race, smoking status, initial infertility diagnosis, and stimulation protocol. MAIN RESULTS AND ROLE OF CHANCE: Compared to the median chronological age of our participants (34 years), the Horvath clock predicted, on an average, a younger epigenetic age (median: 24.2 years) while the GrimAge (median: 38.6 years) and Granulosa Cell (median: 39.0 years) clocks predicted, on an average, an older epigenetic age. Age acceleration based on the Horvath clock was associated with lower peak estradiol levels (-819.4 unit decrease in peak estradiol levels per standard deviation increase; 95% CI: -1265.7, -373.1) and fewer total (% change in total oocytes retrieved per standard deviation increase: -21.8%; 95% CI: -37.1%, -2.8%) and mature oocytes retrieved (% change in mature oocytes retrieved per standard deviation increase: -23.8%; 95% CI: -39.9%, -3.4%). The age acceleration based on the two other epigenetic clocks was not associated with markers of ovarian response. LIMITATIONS, REASONS FOR CAUTION: Our sample size was small and we did not specifically isolate granulosa cells from follicular fluid samples so our samples could have included mixed cell types. WIDER IMPLICATIONS OF THE FINDINGS: Our results highlight that certain epigenetic clocks may be predictive of ovarian stimulation outcomes when applied to follicular fluid; however, the inconsistent findings for specific clocks across studies indicate a need for further research to better understand the clinical utility of epigenetic clocks to improve IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants ES009718, ES022955, ES000002, and ES026648 from the National Institute of Environmental Health Sciences (NIEHS) and a pilot grant from the NIEHS-funded HERCULES Center at Emory University (P30 ES019776). RBH was supported by the Emory University NIH Training Grant (T32-ES012870). TRIAL REGISTRATION NUMBER: N/A.

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.

Associations between exposure to extreme ambient heat and neural tube defects in Georgia, USA: A population-based case-control study.

INTRODUCTION: The association between extreme ambient heat exposures during pregnancy and neural tube defects (NTDs) in offspring remains unclear. This study sought to estimate the association between exposure to extreme ambient heat during periconception and NTDs. METHODS: This population-based case-control study in Georgia, USA (1994-2017) included 825 isolated NTD cases (473 anencephaly, 352 spina bifida) and 3,300 controls matched 1:4 on county of residence and time period of delivery. Daily ambient temperature data were linked to fetal death and birth records by county of residence. Extreme ambient heat exposure was defined as the number of consecutive days the daily apparent temperature exceeded the county-specific 95th percentile (derived over 1980-2010) during an eight-week periconception period. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CI) using conditional logistic regression models adjusted for maternal age, education, and ethnicity and month and year of last menstrual period. RESULTS: The aORs for NTDs were 1.09 (95% CI 1.01, 1.17), 1.18 (95% CI 1.03, 1.36), and 1.29 (95% CI 1.04, 1.58) for exposure to 1-2, 3-5, and 6 or more consecutive days with apparent ambient temperatures exceeding the county-specific 95th percentile during periconception, respectively, compared to no days of extreme ambient heat exposure. Weekly analysis of extreme heat exposure indicated consistently elevated odds of offspring NTDs during periconception. These results were largely driven by spina bifida cases. CONCLUSIONS: Our results highlight potential health threats posed by increasing global average temperatures for pregnant people with implications for increased risk of neural tube defects in their offspring.

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.

History of infertility and risk of breast cancer: a prospective cohort study.

PURPOSE: Research on infertility and risk of breast cancer has been conflicting, potentially because many well-established breast cancer risk factors, such as pregnancy history, are strongly correlated with infertility. METHODS: We followed participants in the Nurses' Health Study II from 1989 to 2015 (n = 103,080) for the development of invasive breast cancer and calculated Hazard Ratios (HR) and 95% confidence intervals (CI) using Cox regression. Participants with a self-reported history of infertility (12 months of trying without conception) were compared to gravid women with no history of infertility. We classified breast cancer by menopausal status and investigated mediation by reproductive factors. RESULTS: Over 26 years of follow-up, 26,208 (25.4%) women reported a history of infertility, and 3,201 women were newly diagnosed with invasive breast cancer. We observed no association between infertility history and risk of overall breast cancer (HR: 1.05, 95% CI: 0.97-1.14) or premenopausal breast cancer (RR: 0.93, 95% CI: 0.83-1.03). However, we observed a modest association between history of infertility and risk of postmenopausal breast cancer (HR: 1.13, 95% CI: 1.00-1.28), approximately 50% of which could be attributed to lower total parity and later age at first birth (95% CI: 8.2%-91.0%). CONCLUSIONS: Women with a history of infertility were at increased risk of postmenopausal breast cancer. Older age at first birth and lower total parity explained approximately half of the association between infertility and risk of postmenopausal breast cancer.

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.

Dietary Iron Intake in Relation to Age at Menarche: A Prospective Cohort Study in Chilean Girls.

BACKGROUND: Early onset of menarche is considered an important risk factor for a number of diseases in adulthood. Iron intake may be related to pubertal timing because of its role in childhood growth and reproductive function. OBJECTIVE: We investigated the relation between dietary iron intake and age at menarche in a prospective cohort of Chilean girls. METHODS: Overall, 602 Chilean girls were included in the Growth and Obesity Cohort Study, a longitudinal study that began in 2006 when the girls were 3-4 y old. Starting in 2013, diet was assessed every 6 mo through 24-h recall. The date of menarche was reported every 6 mo. Our analysis included 435 girls with prospective data on diet and age at menarche. We used a multivariable Cox proportional hazards regression model with restricted cubic splines to estimate HRs and 95% CIs for the association between cumulative mean iron intake and age at menarche. RESULTS: Most girls (99.5%) attained menarche with a mean (standard deviation) age at menarche of 12.2 (0.9) y. The mean dietary iron intake was 13.5 (range: 4.0-30.6) mg/d. Only 3.7% of girls consumed below 8 mg/d, the RDA. After multivariable adjustment, cumulative mean iron intake had a nonlinear association with menarche (P-for-nonlinearity: 0.02). Iron intakes above the RDA, between 8 and 15 mg/d, were associated with progressively lower probability of earlier menarche. Above 15 mg/d, the HRs were imprecise but tended to approach the null as iron intake increased. This association was attenuated after adjusting for girls' BMI and height before menarche (P-for-nonlinearity: 0.11). CONCLUSION: In Chilean girls, iron intake during late childhood, independent of body weight, was not an important determinant of menarche timing.

Predicted probabilities of live birth following assisted reproductive technology using United States national surveillance data from 2016 to 2018.

BACKGROUND: As the use of in vitro fertilization continues to increase in the United States, up-to-date models that estimate cumulative live birth rates after multiple oocyte retrievals and embryo transfers (fresh and frozen) are valuable for patients and clinicians weighing treatment options. OBJECTIVE: This study aimed to develop models that generate predicted probabilities of live birth in individuals considering in vitro fertilization based on demographic and reproductive characteristics. STUDY DESIGN: Our population-based cohort study used data from the National Assisted Reproductive Technology Surveillance System 2016 to 2018, including 196,916 women who underwent 207,766 autologous embryo transfer cycles and 25,831 women who underwent 36,909 donor oocyte transfer cycles. We used data on autologous in vitro fertilization cycles to develop models that estimate a patient's cumulative live birth rate after all embryo transfers (fresh and frozen) within 12 months after 1, 2, and 3 oocyte retrievals in new and returning patients. Among patients using donor oocytes, we estimated the cumulative live birth rate after their first, second, and third embryo transfers. Multinomial logistic regression models adjusted for age, prepregnancy body mass index (imputed for 18% of missing values), parity, gravidity, and infertility diagnoses were used to estimate the cumulative live birth rate. RESULTS: Among new and returning patients undergoing autologous in vitro fertilization, female age had the strongest association with cumulative live birth rate. Other factors associated with higher cumulative live birth rates were lower body mass index and parity or gravidity ≥1, although results were inconsistent. Infertility diagnoses of diminished ovarian reserve, uterine factor, and other reasons were associated with a lower cumulative live birth rate, whereas male factor, tubal factor, ovulatory disorders, and unexplained infertility were associated with a higher cumulative live birth rate. Based on our models, a new patient who is 35 years old, with a body mass index of 25 kg/m2, no previous pregnancy, and unexplained infertility diagnoses, has a 48%, 69%, and 80% cumulative live birth rate after the first, second, and third oocyte retrieval, respectively. Cumulative live birth rates are 29%, 48%, and 62%, respectively, if the patient had diminished ovarian reserve, and 25%, 41%, and 52%, respectively, if the patient was 40 years old (with unexplained infertility). Very few recipient characteristics were associated with cumulative live birth rate in donor oocyte patients. CONCLUSION: Our models provided estimates of cumulative live birth rate based on demographic and reproductive characteristics to help inform patients and providers of a woman's probability of success after in vitro fertilization.

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.

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.

Pregnancy loss and risk of cardiovascular disease: the Nurses' Health Study II.

AIMS: The aim of this study was to explore the association of pregnancy loss (PL) with the incidence of cardiovascular disease (CVD) and examine the extent to which this relation is mediated by subsequent metabolic disorders. METHODS AND RESULTS: We followed 95 465 ever-gravid women participating in the Nurses' Health Study II between 1993 and 2017. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of CVD, including coronary heart disease (CHD), and stroke, according to the occurrence of PL. A mediation analysis was conducted to explore the intermediating effect of subsequent type 2 diabetes, hypertension, or hypercholesterolaemia. During 2 205 392 person-years of follow-up (mean 23.10 years), 2225 (2.3%) incident CVD cases were documented. After adjusting for confounding factors, PL was associated with an HR of 1.21 [95% confidence interval (CI) 1.10-1.33] for CVD during follow-up. A similar association was observed for CHD (HR 1.20; 95% CI 1.07-1.35) and stroke (HR 1.23; 95% CI 1.04-1.44). The risk of CVD increased with the number of PLs [HR 1.18 (95% CI 1.06-1.31) for 1 and 1.34 (95% CI 1.13-1.59) for ≥2 times] and was greater for PL occurring early in reproductive lifespan [HR 1.40 (95% CI 1.21-1.62) for age ≤23 years, 1.25 (95% CI 1.09-1.43) for age 24-29 years, and 1.03 (95% CI 0.88-1.19) for age ≥30 years]. Hypertension, hypercholesterolaemia, and type 2 diabetes all explained <1.80% of the association between PL and CVD. CONCLUSION: PL was associated with a greater CVD risk, independently of subsequent development of metabolic disorders.

A prospective study of the association between SARS-CoV-2 infection and COVID-19 vaccination with changes in usual menstrual cycle characteristics.

BACKGROUND: Despite anecdotal reports, the impacts of SARS-CoV-2 infection or COVID-19 vaccination on menstrual health have not been systemically investigated. OBJECTIVE: This study aimed to examine the associations of SARS-CoV-2 infection and COVID-19 vaccination with menstrual cycle characteristics. STUDY DESIGN: This study prospectively observed 3858 premenopausal women in the Nurses' Health Study 3 living in the United States or Canada who received biannual follow-up questionnaires between January 2011 and December 2021 and completed additional monthly and quarterly surveys related to the COVID-19 pandemic between April 2020 and November 2021. History of positive SARS-CoV-2 test, COVID-19 vaccination status, and vaccine type were self-reported in surveys conducted in 2020 and 2021. Current menstrual cycle length and regularity "before COVID-19" were reported at baseline between 2011 and 2016, and current menstrual cycle length and regularity "after COVID-19" were reported in late 2021. Pre- to post-COVID change in menstrual cycle length and regularity was calculated between reports. Logistic or multinomial logistic regression models were used to assess the associations between SARS-CoV-2 infection and COVID-19 vaccination and change in menstrual cycle characteristics. RESULTS: The median age at baseline and the median age at end of follow-up were 33 years (range, 21-51) and 42 years (range, 27-56), respectively, with a median follow-up time of 9.2 years. This study documented 421 SARS-CoV-2 infections (10.9%) and 3527 vaccinations (91.4%) during follow-up. Vaccinated women had a higher risk of increased cycle length than unvaccinated women (odds ratio, 1.48; 95% confidence interval, 1.00-2.19), after adjusting for sociodemographic and behavioral factors. These associations were similar after in addition accounting for pandemic-related stress. COVID-19 vaccination was only associated with change to longer cycles in the first 6 months after vaccination (0-6 months: odds ratio, 1.67 [95% confidence interval, 1.05-2.64]; 7-9 months: odds ratio, 1.43 [95% confidence interval, 0.96-2.14]; >9 months: odds ratio, 1.41 [95% confidence interval, 0.91-2.18]) and among women whose cycles were short, long, or irregular before vaccination (odds ratio, 2.82 [95% confidence interval, 1.51-5.27]; odds ratio, 1.10 [95% confidence interval, 0.68-1.77] for women with normal length, regular cycles before vaccination). Messenger RNA and adenovirus-vectored vaccines were both associated with this change. SARS-CoV-2 infection was not associated with changes in usual menstrual cycle characteristics. CONCLUSION: COVID-19 vaccination may be associated with short-term changes in usual menstrual cycle length, particularly among women whose cycles were short, long, or irregular before vaccination. The results underscored the importance of monitoring menstrual health in vaccine clinical trials. Future work should examine the potential biological mechanisms.

Erectile Dysfunction in a Sample of Sexually Active Young Adult Men from a U.S. Cohort: Demographic, Metabolic and Mental Health Correlates.

PURPOSE: Little is understood about physiological and psychological correlates of erectile dysfunction among younger men. We examined prevalence and correlates of erectile dysfunction in a large U.S. sample of 18 to 31-year-old men. MATERIALS AND METHODS: Erectile dysfunction prevalence and severity (defined using the International Index of Erectile Function-5 scale) were examined in cross-sectional survey data from 2,660 sexually active men, age 18 to 31 years, from the 2013 Growing Up Today Study. Erectile dysfunction medication and supplement use were self-reported. Multivariable models estimated associations of moderate-to-severe erectile dysfunction with demographic (age, marital status), metabolic (body mass index, waist circumference, history of diabetes, hypertension, hypercholesterolemia) and mental health (depression, anxiety, antidepressant use, tranquilizer use) variables. RESULTS: Among sexually active men 11.3% reported mild erectile dysfunction and 2.9% reported moderate-to-severe erectile dysfunction. Married/partnered men had 65% lower odds of erectile dysfunction compared to single men. Adjusting for history of depression, antidepressant use was associated with more than 3 times the odds of moderate-to-severe erectile dysfunction. Anxiety was associated with greater odds of moderate-to-severe erectile dysfunction, as was tranquilizer use. Few men (2%) reported using erectile dysfunction medication or supplements. However, among them, 29.7% misused prescription erectile dysfunction medication. Limitations include reliance upon cross-sectional data and the sample's limited racial/ethnic and socioeconomic diversity. CONCLUSIONS: Erectile dysfunction was common in a large sample of sexually active young adult men from a U.S. cohort and was associated with relationship status and mental health. Health providers should screen for erectile dysfunction in young men, and monitor use of prescription erectile dysfunction medications and supplements for sexual functioning.

Substantial Weight Gain in Adulthood Is Associated with Lower Probability of Live Birth Following Assisted Reproduction.

BACKGROUND: Overweight and obesity among women have been associated with lower success of assisted reproduction technologies (ARTs). However, the relation of adolescent body weight and adult weight change to ART outcomes is not well understood. OBJECTIVE: Our objective was to evaluate the associations of female BMI (in kg/m2) at 18 y and weight change from 18 y to current age with ART outcomes. METHODS: We included 486 women in a prospective cohort at the Massachusetts General Hospital Fertility Center (2004-2018) who underwent 863 ART cycles. At study entry, height and weight were measured by research personnel. Women recalled their weight at 18 y. Restricted cubic splines were used to evaluate the associations between BMI at 18 y and weight change since 18 y and ART outcomes adjusting for age, race, education, smoking, and height and accounting for the correlated cycles within women. RESULTS: Women had a median (range) BMI of 20.6 (14.8 to 36.4) at 18 y and 23.3 (16.1 to 45.8) at study entry. The median (range) weight change since 18 y was 7.4 kg (-12.1 to 60.1 kg). There was no association between BMI at 18 y and clinical ART outcomes. Long-term weight change had a nonlinear association with live birth such that higher weight gain since 18 y (particularly ≥15 kg) and weight loss were both associated with lower odds of live birth. The negative association between weight change and live birth was stronger in women ≥22.5 kg/m2 at 18 y such that each 10-kg increase was associated with a 30% (6%, 48%) lower odds of live birth. CONCLUSIONS: Weight gain in adulthood is negatively associated with ART success, particularly among women who were heavier at 18 y. These results add to the growing literature supporting the benefits of preventing weight gain in adulthood on female fertility.

The effect of donor and recipient race on outcomes of assisted reproduction.

BACKGROUND: A growing literature suggests that minority races, particularly Black women, have a lower probability of live birth and higher risk of perinatal complications after autologous assisted reproductive technology. However, questions still remain as to whether these racial disparities have arisen because of associations between race and oocyte/embryo quality, the uterine environment, or a combination of the two. Oocyte donation assisted reproductive technology represents a unique approach to examine this question. OBJECTIVE: This study aimed to evaluate the associations between the race of female oocyte donors and recipients and live birth rates following vitrified donor oocyte assisted reproductive technologies. STUDY DESIGN: This was a retrospective study conducted at a single, private fertility clinic that included 327 oocyte donors and 899 recipients who underwent 1601 embryo transfer cycles (2008-2015). Self-reported race of the donor and recipient were abstracted from medical records. Live birth was defined as the delivery of at least 1 live-born neonate. We used multivariable cluster weighted generalized estimating equations with binomial distribution and log link function to estimate the adjusted risk ratios of live birth, adjusting for donor age and body mass index, recipient age and body mass index, tubal and uterine factor infertility, and year of oocyte retrieval. RESULTS: The racial profile of our donors and recipients were similar: 73% white, 13% Black, 4% Hispanic, 8% Asian, and 2% other. Women who received oocytes from Hispanic donors had a significantly higher probability of live birth (adjusted risk ratio, 1.20; 95% confidence interval, 1.05-1.36) than women who received oocytes from white donors. Among Hispanic recipients, however, there was no significant difference in probability of live birth compared with white recipients (adjusted risk ratio, 1.07; 95% confidence interval, 0.90-1.26). Embryo transfer cycles using oocytes from Black donors (adjusted risk ratio, 0.86; 95% confidence interval, 0.72-1.03) and Black recipients (adjusted risk ratio, 0.84; 95% confidence interval, 0.71-0.99) had a lower probability of live birth than white donors and white recipients, respectively. There were no significant differences in the probability of live birth among Hispanic, Asian, and other race recipients compared with white recipients. CONCLUSION: Black female recipients had a lower probability of live birth following assisted reproductive technology, even when using vitrified oocytes from healthy donors. Female recipients who used vitrified oocytes from Hispanic donors had a higher probability of live birth regardless of their own race.

Occupational use of high-level disinfectants and asthma incidence in early- to mid-career female nurses: a prospective cohort study.

OBJECTIVES: Occupational use of disinfectants among healthcare workers has been associated with asthma. However, most studies are cross-sectional, and longitudinal studies are not entirely consistent. To limit the healthy worker effect, it is important to conduct studies among early- to mid-career workers. We investigated the prospective association between use of disinfectants and asthma incidence in a large cohort of early- to mid-career female nurses. METHODS: The Nurses' Health Study 3 is an ongoing, prospective, internet-based cohort of female nurses in the USA and Canada (2010-present). Analyses included 17 280 participants without a history of asthma at study entry (mean age: 34 years) and who had completed ≥1 follow-up questionnaire (sent every 6 months). Occupational use of high-level disinfectants (HLDs) was evaluated by questionnaire. We examined the association between HLD use and asthma development, adjusted for age, race, ethnicity, smoking status and body mass index. RESULTS: During 67 392 person-years of follow-up, 391 nurses reported incident clinician-diagnosed asthma. Compared with nurses who reported ≤5 years of HLD use (89%), those with >5 years of HLD use (11%) had increased risk of incident asthma (adjusted HR (95% CI), 1.39 (1.04 to 1.86)). The risk of incident asthma was elevated but not statistically significant in those reporting >5 years of HLD use and current use of ≥2 products (1.72 (0.88 to 3.34)); asthma risk was significantly elevated in women with >5 years of HLD use but no current use (1.46 (1.00 to 2.12)). CONCLUSIONS: Occupational use of HLDs was prospectively associated with increased asthma incidence in early- to mid-career nurses.

The influence of fine particulate matter on the association between residential greenness and ovarian reserve.

BACKGROUND: Natural vegetation, or greenness, is thought to improve health through its ability to buffer and reduce harmful environmental exposures as well as relieve stress, promote physical activity, restore attention, and increase social cohesion. In concert, these effects could help mitigate the detrimental effects of air pollution on reproductive aging in women. METHODS: Our analysis included 565 women attending the Massachusetts General Hospital Fertility Center (2004-2014) who had a measured antral follicle count (AFC), a marker of ovarian reserve. We calculated peak residential greenness in the year prior to AFC using 250 m2 normalized difference vegetation index (NDVI) from the Terra and Aqua satellites operated by the United States National Aeronautics and Space Administration. Validated spatiotemporal models estimated daily residential exposure to particulate matter <2.5 µm (PM2.5) for the 3 months prior to AFC. Poisson regression models with robust standard errors were used to estimate the association between peak greenness, average PM2.5 exposure, and AFC adjusted for age, BMI, smoking status, education, year, and season. RESULTS: Women in our study had a mean age of 35.2 years with a standard deviation (SD) of 4.3 years (min: 20 years, max: 45 years). The peak residential NDVI ranged from 0.07 to 0.92 with a SD of 0.18. There was no statistically significant association between peak residential greenness and AFC; however, higher exposure to PM2.5 was associated with lower AFC (-6.2% per 2 µg/m3 [1 SD increase] 95% CI -11.8, -0.3). There was a significant interaction between exposure to PM2.5 and peak greenness on AFC (P-interaction: 0.03). Among women with an average PM2.5 exposure of 7 µg/m3, a SD increase in residential peak greenness was associated with a 5.6% (95% CI -0.4, 12.0) higher AFC. Conversely, among women with a PM2.5 exposure of 12 µg/m3, a SD increase in residential peak greenness was associated with a 5.8% (95% CI -13.1, 2.1) lower AFC. CONCLUSIONS: Residing in an area with high levels of greenness may slow reproductive aging in women only when exposure to PM2.5 is low.

When using donor oocytes, does embryo stage matter? An analysis of blastocyst versus cleavage stage embryo transfers using a cryopreserved donor oocyte bank.

PURPOSE: Oocyte donor in vitro fertilization (IVF) represents an ideal model to study the effects of embryo stage on reproductive success, as embryos come from young women with high-quality oocytes. Our study aimed to determine if embryo transfer stage affected outcomes in oocyte donor IVF, including the common scenario where only a limited number of quality embryos are available after culture. METHODS: This retrospective cohort analyzed anonymous vitrified donor oocyte cycles at a single clinic between 2008 and 2015. Overall, 983 recipients underwent 1178 warming cycles resulting in fresh transfer of one-to-two embryos. Our primary outcome was live birth; secondary outcomes included multiple birth, birthweight, and gestational age. Log binomial regression with cluster-weighted generalized estimating equations were used to calculate adjusted risk ratios (aRR) accounting for recipient age, race, and transfer year. RESULTS: Among 132 cleavage and 1046 blastocyst transfer cycles, cleavage transfers were associated with lower probability of live birth (aRR 0.72, 95% CI 0.59-0.88). Subgroup analysis focused on cycles with a limited number of quality embryos 3 days post-fertilization (≤2), as clinically these women were most likely to be considered for cleavage transfers. Among these cycles (120 cleavage, 371 blastocyst), cleavage transfers were still associated with lower live birth rates compared to blastocyst (aRR 0.66, 95% CI 0.51-0.87) CONCLUSIONS: Even in a donor oocyte model with high-quality oocytes, there was a benefit to extended culture and blastocyst transfer, including when only one-to-two quality embryos were available after early culture. This is possibly owed to improved uterine synchronicity or decreased contractility.

Sodium Intake during Pregnancy, but Not Other Diet Recommendations Aimed at Preventing Cardiovascular Disease, Is Positively Related to Risk of Hypertensive Disorders of Pregnancy.

BACKGROUND: The role of diet on hypertensive disorders of pregnancy (HDPs), including preeclampsia and gestational hypertension (GHTN), remains unclear. OBJECTIVES: We evaluated whether adherence during pregnancy to dietary recommendations that reduce cardiovascular disease (CVD) in the general population is related to the risk of HDPs. METHODS: We followed 66,651 singleton pregnancies from 62,774 women participating in the Danish National Birth Cohort. Diet was assessed during week of gestation 25 with an FFQ from which we created 2 dietary pattern scores: 1) AHA, based on the diet recommendations from the AHA 2020 Strategic Impact Goals; and 2) the Dietary Approaches to Stop Hypertension (DASH) diet. Cases of HDPs were identified through linkage with the Danish National Patient Registry. RRs and 95% CIs of HDPs were estimated by increasing quintiles of adherence to the AHA and DASH scores using log-Poisson regression models with generalized estimating equations-to account for repeated pregnancies per woman-while adjusting for potential confounders. RESULTS: We identified 1809 cases of HDPs: n = 1310 preeclampsia (n = 300 severe preeclampsia) and n = 499 cases of GHTN. Greater adherence to AHA or DASH scores was not related to the risk of HDPs. However, when each component of the scores was separately evaluated, there were positive linear relations of sodium intake with HDPs (P-linearity < 0.01). Women with the highest sodium intake [median 3.70 g/d (range: 3.52, 7.52 g/d)] had 54% (95% CI:16%, 104%) higher risk of GHTN and 20% (95% CI:1%, 42%) higher risk of preeclampsia than women with the lowest intake [median 2.60 g/d (range: 0.83, 2.79 g/d)]. In addition, intake of whole grains was positively related to the risk of GHTN but not to preeclampsia ( P-heterogeneity = 0.002). CONCLUSION: Sodium intake during pregnancy, but no other diet recommendations to prevent CVD among nonpregnant adults, is positively related to the occurrence of HDPs among pregnant Danish women.

The use of personal and indoor air pollution monitors in reproductive epidemiology studies.

BACKGROUND: Personal and indoor air pollution monitors represent two ways to assess acute air pollution exposures; however, few reproductive epidemiology studies have incorporated these tools. OBJECTIVE: To provide an overview of the unique challenges and opportunities that arise when measuring acute exposure to air pollution in two ongoing reproductive epidemiology studies. METHODS: The Air Pollution, In Vitro Fertilization (IVF), and Reproductive Outcomes (AIR) Study recruits women undergoing IVF to wear a personal particulate matter (PM) air pollution monitor (AirBeam2©) for the 72-hour period following the start of controlled ovarian stimulation. The Reproductive Effects of Chemicals and Air Pollutants (RECAP) Study recruits men across the United States to place an air pollution monitor (emmET) in their home for 3 months, use a smartphone application, and provide a semen sample. We highlight the key issues identified in implementing exposure assessment for both studies. RESULTS: The main advantages of using the AirBeam2© personal monitor are as follows: (a) the low cost, (b) the ability to collect multiple size fractions of PM data every second, (c) the portability, (d) its capability to track GPS location, and (e) the ability for the participant to observe their real-time exposure information. The limited battery life, incompatibility with iOS-based smartphones, and frequent connection issues that arise between the AirBeam2© and smartphone are the main disadvantages. The main advantages of the emmET are the ability to measure multiple air pollutants at a high level of accuracy, collect data for a long period of time without burdening the participant, and ship monitors to participants around the country without the need for in-person set-up by trained technicians; however, the monitor only measures the indoor home environment. CONCLUSIONS: Novel methods can be utilised to characterise short-term air pollution exposure in reproductive epidemiology studies and represent an exciting area for future research.