Irregular Cycles, Ovulatory Disorders, and Cardiometabolic Conditions in a US-Based Digital Cohort.

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions. Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions. Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys. Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles. Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated. Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity. Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

Vitamin D status and supplementation, calcium supplementation, and timing of natural menopause.

Vitamin D status has been inconsistently associated with ovarian reserve and menopause. We used data from the Sister Study cohort to examine the associations of vitamin D supplement use, total 25-hydroxyvitamin D (25OHD) level, and calcium supplement use with the timing of natural menopause. Vitamin D and calcium supplement use were assessed on a questionnaire at baseline (mean age: 46) and two follow-up time points, and characterized in multiple ways based on type, dose, and duration of use. Serum samples from a random subset of participants were analyzed for total 25OHD (25OHD3 + 25OHD2 + epi-25OHD3) using liquid chromatography-mass spectrometry. Menopause was assessed at each yearly follow-up with the question "Have you had a menstrual period in the past 12 months?"; if the response was "no", age at last menstrual period was recorded. We censored women at time of hysterectomy or medically induced menopause, death, loss to follow-up or October 2020. We used multivariable Cox proportional hazard models with age as the time scale to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs), adjusting for race/ethnicity, education, body mass index, alcohol use, smoking status, and physical activity. Among the 13,102 eligible premenopausal participants, 8897 experienced natural menopause during follow-up. Concomitant use of a multivitamin and a vitamin D supplement was associated with slightly earlier menopause (HR(CI): 1.10 (0.98, 1.24)). None of the remaining vitamin D or calcium supplement variables (alone or in combination) were meaningfully associated with timing of natural menopause. In a subsample with 25OHD measurements (n = 906), neither total 25OHD nor 25OHD3 was associated with timing of menopause. Our study includes, on average, 6 years of follow-up from an average age of 46 years and did not find associations between vitamin D or calcium supplement use and timing of menopause. Future studies should focus on a life course approach to this question and include 25OHD measures from early mid-life when examining menopause timing.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Association between serum 25-hydroxyvitamin D and antimüllerian hormone levels in a cohort of African-American women.

OBJECTIVE: To examine the association between serum 25-hydroxyvitamin D [25(OH)D] levels and ovarian reserve as measured using antimüllerian hormone (AMH) levels. DESIGN: Cross-sectional study. SETTING: Detroit, Michigan area. PATIENTS: Data were obtained from a prospective cohort of self-identified Black or African American women aged 23-35 years at the time of enrollment (N = 1,593), who had no prior diagnosis of polycystic ovary syndrome, were not currently pregnant, and were not missing AMH or 25(OH)D level measures. INTERVENTION: Serum 25(OH)D. MAIN OUTCOME MEASURE(S): The serum AMH level was the main outcome. Linear regression was used to examine the associations between categorical 25(OH)D levels (<12, 12-<20, 20-<30, and ≥30 ng/mL) and continuous natural log-transformed AMH levels. Associations between 25(OH)D and high (upper 10th percentile: >7.8 ng/mL) or low AMH (<0.7 ng/mL) levels were estimated with logistic regression. Models were adjusted for age, age-squared, body mass index (kg/m2), hormonal contraceptive use, smoking, and exercise. RESULTS: The 25(OH)D levels were low; 70% of participants were below 20 ng/mL. In fully adjusted models, compared with 25(OH)D levels <12 ng/mL, those with 25(OH)D levels of 12-<20, 20-<30, and ≥30 ng/mL had an AMH level that was 7% (95% confidence interval [CI]: -4, 20), 7% {95% CI: -6, 22}, or 11% {95% CI: -7, 34} higher, respectively. Moreover, these groups had lower odds of having low AMH levels (odds ratio [95% CI]: 0.63 {0.40, 0.99}, 0.60 {0.34, 1.07}, and 0.76 {0.35, 1.65}, respectively), and the highest category of 25(OH)D levels had higher odds of having high AMH levels (odds ratio [95% CI]: 1.42 {0.74, 2.72}). Exclusion of participants with either irregular cycles or very high AMH (>25 ng/mL) levels did not alter the associations. CONCLUSION: Taken together, these results indicate that higher levels of 25(OH)D are associated with slightly higher AMH levels, lower odds of low AMH levels, and higher odds of high AMH levels. This evidence is weak, however, because only a small percentage of participants had high 25(OH)D levels. Future studies should examine populations with a wide distribution of 25(OH)D levels (both high and low), with a clinical trial design, or with longitudinal measures of both 25(OH)D and AMH levels.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Toxic metal mixtures in private well water and increased risk for preterm birth in North Carolina.

BACKGROUND: Prenatal exposure to metals in private well water may increase the risk of preterm birth (PTB) (delivery < 37 weeks' gestation). In this study, we estimated associations between arsenic, manganese, lead, cadmium, chromium, copper, and zinc concentrations in private well water and PTB incidence in North Carolina (NC). METHODS: Birth certificates from 2003-2015 (n = 1,329,071) were obtained and pregnancies were assigned exposure using the mean concentration and the percentage of tests above the maximum contaminant level (MCL) for the census tract of each individuals' residence at the time of delivery using the NCWELL database (117,960 well water tests from 1998-2019). We evaluated associations between single metals and PTB using adjusted logistic regression models. Metals mixtures were assessed using quantile-based g-computation. RESULTS: Compared with those in other census tracts, individuals residing in tracts where > 25% of tests exceeded the MCL for lead (aOR 1.10, 95%CI 1.02,1.18) or cadmium (aOR 1.11, 95% CI 1.00,1.23) had an increased odds of PTB. Conversely, those residing in areas with > 25% MCL for zinc (aOR 0.77 (95% CI: 0.56,1.02) and copper (aOR 0.53 (95% CI: 0.13,1.34)) had a reduced odds of PTB. A quartile increase in the concentrations of a mixture of lead, cadmium, and chromium was associated with a small increased odds for PTB (aOR 1.02, 95% CI 1.01, 1.03). This metal mixture effect was most pronounced among American Indian individuals (aOR per quartile increase in all metals: 1.19 (95% CI 1.06,1.34)). CONCLUSIONS: In a large study population of over one million births, lead and cadmium were found to increase the risk of PTB individually and in a mixture, with additional mixtures-related impacts estimated from co-exposure with chromium. This study highlights critical racial and ethnic health disparities in relation to private well water thereby emphasizing the urgent need for improved private well water quality to protect vulnerable populations.

Seminar: Extracellular Vesicles as Mediators of Environmental Stress in Human Disease.

BACKGROUND: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress. OBJECTIVES: This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27-28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on "Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress." The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field. DISCUSSION: The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and in vitro approaches and how these have the potential to extend findings in population-based studies of EVs in exposure-related diseases. Given the complex challenges of identifying cell-specific EVs related to environmental exposures, as well as the general heterogeneity and variability in EVs in blood and other accessible biological samples, there is a critical need for rigorous reporting of experimental methods and validation studies. The authors note that these efforts, combined with cross-disciplinary approaches, would ensure that future research efforts in environmental health studies on EV biomarkers are rigorous and reproducible. https://doi.org/10.1289/EHP12980.

Urinary Paraben Concentrations and Associations with the Periconceptional Urinary Metabolome: Untargeted and Targeted Metabolomics Analyses of Participants from the Early Pregnancy Study.

BACKGROUND: Parabens, found in everyday items from personal care products to foods, are chemicals with endocrine-disrupting activity, which has been shown to influence reproductive function. OBJECTIVES: This study investigated whether urinary concentrations of methylparaben, propylparaben, or butylparaben were associated with the urinary metabolome during the periconceptional period, a critical window for female reproductive function. Changes to the periconceptional urinary metabolome could provide insights into the mechanisms by which parabens could impact fertility. METHODS: Urinary paraben concentrations were measured in paired pre- and postconception urine samples from 42 participants in the Early Pregnancy Study, a prospective cohort of 221 women attempting to conceive. We performed untargeted and targeted metabolomics analyses using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry. We used principal component analysis, orthogonal partial least-squares discriminant analysis, and permutation testing, coupled with univariate statistical analyses, to find metabolites associated with paraben concentration at the two time points. Potential confounders were identified with a directed acyclic graph and used to adjust results with multivariable linear regression. Metabolites were identified using fragmentation data. RESULTS: Seven metabolites were associated with paraben concentration (variable importance to projection score >1, false discovery rate-corrected q-value<0.1). We identified four diet-related metabolites to the Metabolomics Standards Initiative (MSI) certainty of identification level 2, including metabolites from smoke flavoring, grapes, and olive oil. One metabolite was identified to the class level only (MSI level 3). Two metabolites were unidentified (MSI level 4). After adjustment, three metabolites remained associated with methylparaben and propylparaben, two of which were diet-related. No metabolomic markers of endocrine disruption were associated with paraben concentrations. DISCUSSION: This study identified novel relationships between urinary paraben concentrations and diet-related metabolites but not with metabolites on endocrine-disrupting pathways, as hypothesized. It demonstrates the feasibility of integrating untargeted metabolomics data with environmental exposure information and epidemiological adjustment for confounders. The findings underscore a potentially important connection between diet and paraben exposure, with applications to nutritional epidemiology and dietary exposure assessment. https://doi.org/10.1289/EHP12125.

Large-Scale Data Harmonization Across Prospective Studies.

The Preconception Period Analysis of Risks and Exposures Influencing Health and Development (PrePARED) Consortium creates a novel resource for addressing preconception health by merging data from numerous cohort studies. In this paper, we describe our data harmonization methods and results. Individual-level data from 12 prospective studies were pooled. The crosswalk-cataloging-harmonization procedure was used. The index pregnancy was defined as the first postbaseline pregnancy lasting more than 20 weeks. We assessed heterogeneity across studies by comparing preconception characteristics in different types of studies. The pooled data set included 114,762 women, and 25,531 (22%) reported at least 1 pregnancy of more than 20 weeks' gestation during the study period. Babies from the index pregnancies were delivered between 1976 and 2021 (median, 2008), at a mean maternal age of 29.7 (standard deviation, 4.6) years. Before the index pregnancy, 60% of women were nulligravid, 58% had a college degree or more, and 37% were overweight or obese. Other harmonized variables included race/ethnicity, household income, substance use, chronic conditions, and perinatal outcomes. Participants from pregnancy-planning studies had more education and were healthier. The prevalence of preexisting medical conditions did not vary substantially based on whether studies relied on self-reported data. Use of harmonized data presents opportunities to study uncommon preconception risk factors and pregnancy-related events. This harmonization effort laid the groundwork for future analyses and additional data harmonization.

Menstrual cycle length variation by demographic characteristics from the Apple Women's Health Study.

Menstrual characteristics are important signs of women's health. Here we examine the variation of menstrual cycle length by age, ethnicity, and body weight using 165,668 cycles from 12,608 participants in the US using mobile menstrual tracking apps. After adjusting for all covariates, mean menstrual cycle length is shorter with older age across all age groups until age 50 and then became longer for those age 50 and older. Menstrual cycles are on average 1.6 (95%CI: 1.2, 2.0) days longer for Asian and 0.7 (95%CI: 0.4, 1.0) days longer for Hispanic participants compared to white non-Hispanic participants. Participants with BMI ≥ 40 kg/m2 have 1.5 (95%CI: 1.2, 1.8) days longer cycles compared to those with BMI between 18.5 and 25 kg/m2. Cycle variability is the lowest among participants aged 35-39 but are considerably higher by 46% (95%CI: 43%, 48%) and 45% (95%CI: 41%, 49%) among those aged under 20 and between 45-49. Cycle variability increase by 200% (95%CI: 191%, 210%) among those aged above 50 compared to those in the 35-39 age group. Compared to white participants, those who are Asian and Hispanic have larger cycle variability. Participants with obesity also have higher cycle variability. Here we confirm previous observations of changes in menstrual cycle pattern with age across reproductive life span and report new evidence on the differences of menstrual variation by ethnicity and obesity status. Future studies should explore the underlying determinants of the variation in menstrual characteristics.

Circulating miRNAs in the first trimester and pregnancy complications: a systematic review.

Most pregnancy complications originate with early placentation. MicroRNAs (miRNAs) may play an important role in placentation and function as biomarkers of future pregnancy complications. We summarized from the literature all first trimester circulating miRNAs associated with pregnancy complications of placental origin and further identified the miRNAs which have the most evidence as potential early biomarkers for pregnancy complications. We conducted a systematic review following PRISMA reporting guidelines (PROSPERO CRD42020183421). We identified all first trimester serum or plasma miRNAs associated with a pregnancy complication of placental origin (preeclampsia, intrauterine growth restriction (IUGR), gestational hypertension, preterm delivery) and the number of times those miRNAs were identified, as a measure of replication. Twenty-one studies examined 118 unique miRNAs, and 87 were associated with at least one pregnancy complication; preeclampsia was the most common. Seven miRNAs were significantly associated with a pregnancy complication in at least two studies: miR-125b, miR-518b, miR-628-3p, miR-365a-3p, miR-520h, miR-374a-5p, miR-191-5p. Few miRNAs were associated with more than one pregnancy complication: miR-518b and miR-520h with preeclampsia and gestational hypertension, miR-374a-5p and miR-191-5p with preterm birth and preeclampsia. Our systematic review suggests seven miRNAs as potential biomarkers of pregnancy complications. These complications are thought to originate with early placental defects and these miRNAs may also be biomarkers of placental pathology. First-trimester biomarkers of pregnancy complications can facilitate early detection and interventions.

Abnormal uterine bleeding patterns determined through menstrual tracking among participants in the Apple Women's Health Study.

BACKGROUND: Use of menstrual tracking data to understand abnormal bleeding patterns has been limited because of lack of incorporation of key demographic and health characteristics and confirmation of menstrual tracking accuracy. OBJECTIVE: This study aimed to identify abnormal uterine bleeding patterns and their prevalence and confirm existing and expected associations between abnormal uterine bleeding patterns, demographics, and medical conditions. STUDY DESIGN: Apple Women's Health Study participants from November 2019 through July 2021 who contributed menstrual tracking data and did not report pregnancy, lactation, use of hormones, or menopause were included in the analysis. Four abnormal uterine bleeding patterns were evaluated: irregular menses, infrequent menses, prolonged menses, and irregular intermenstrual bleeding (spotting). Monthly tracking confirmation using survey responses was used to exclude inaccurate or incomplete digital records. We investigated the prevalence of abnormal uterine bleeding stratified by demographic characteristics and used logistic regression to evaluate the relationship of abnormal uterine bleeding to a number of self-reported medical conditions. RESULTS: There were 18,875 participants who met inclusion criteria, with a mean age of 33 (standard deviation, 8.2) years, mean body mass index of 29.3 (standard deviation, 8.0), and with 68.9% (95% confidence interval, 68.2-69.5) identifying as White, non-Hispanic. Abnormal uterine bleeding was found in 16.4% of participants (n=3103; 95% confidence interval, 15.9-17.0) after accurate tracking was confirmed; 2.9% had irregular menses (95% confidence interval, 2.7-3.1), 8.4% had infrequent menses (95% confidence interval, 8.0-8.8), 2.3% had prolonged menses (95% confidence interval, 2.1-2.5), and 6.1% had spotting (95% confidence interval, 5.7-6.4). Black participants had 33% higher prevalence (prevalence ratio, 1.33; 95% confidence interval, 1.09-1.61) of infrequent menses compared with White, non-Hispanic participants after controlling for age and body mass index. The prevalence of infrequent menses was increased in class 1, 2, and 3 obesity (class 1: body mass index, 30-34.9; prevalence ratio, 1.31; 95% confidence interval, 1.13-1.52; class 2: body mass index, 35-39.9; prevalence ratio, 1.25; 95% confidence interval, 1.05-1.49; class 3: body mass index, >40; prevalence ratio, 1.51; 95% confidence interval, 1.21-1.88) after controlling for age and race/ethnicity. Those with class 3 obesity had 18% higher prevalence of abnormal uterine bleeding compared with healthy-weight participants (prevalence ratio, 1.18; 95% confidence interval, 1.02-1.38). Participants with polycystic ovary syndrome had 19% higher prevalence of abnormal uterine bleeding compared with participants without this condition (prevalence ratio, 1.19; 95% confidence interval, 1.08-1.31). Participants with hyperthyroidism (prevalence ratio, 1.34; 95% confidence interval, 1.13-1.59) and hypothyroidism (prevalence ratio, 1.17; 95% confidence interval, 1.05-1.31) had a higher prevalence of abnormal uterine bleeding, as did those reporting endometriosis (prevalence ratio, 1.28; 95% confidence interval, 1.12-1.45), cervical dysplasia (prevalence ratio, 1.20; 95% confidence interval, 1.03-1.39), and fibroids (prevalence ratio, 1.14; 95% confidence interval, 1.00-1.30). CONCLUSION: In this cohort, abnormal uterine bleeding was present in 16.4% of those with confirmed menstrual tracking. Black or obese participants had increased prevalence of abnormal uterine bleeding. Participants reporting conditions such as polycystic ovary syndrome, thyroid disease, endometriosis, and cervical dysplasia had a higher prevalence of abnormal uterine bleeding.

Systemic inflammation and menstrual cycle length in a prospective cohort study.

BACKGROUND: Local inflammation plays an important role in normal folliculogenesis and ovulation, and conditions of chronic systemic inflammation, such as obesity and polycystic ovarian syndrome, can disrupt normal follicular dynamics. OBJECTIVE: This study aimed to determine the association between systemic inflammation, as measured by C-reactive protein levels, and menstrual cycle length. STUDY DESIGN: This study was a secondary analysis using data from Time to Conceive, a prospective time-to-pregnancy cohort study. The association between cycle length and C-reactive protein was analyzed using multivariable linear mixed and marginal models adjusted for age, race, education, body mass index, time since oral contraceptive use, alcohol, smoking, caffeine consumption, and exercise. Time to Conceive enrolled women aged 30 to 44 years with no history of infertility who were attempting to conceive for <3 months. Serum C-reactive protein levels were measured on cycle day 2, 3, or 4. Participants recorded daily menstrual cycle data for ≤4 months. RESULTS: Main outcome measures included menstrual cycle length and follicular and luteal phase lengths. Multivariable analysis included 1409 cycles from 414 women. There was no linear association between C-reactive protein levels and menstrual cycle length. However, compared with <1 mg/L, a C-reactive protein level >10 mg/L was associated with >3 times the odds (adjusted odds ratio, 3.7; 95% confidence interval, 1.67-8.11) of long cycles (defined as ≥35 days). When evaluating follicular phase length, a C-reactive protein level of >10 mg/L was associated both with follicular phases that were 1.7 (95% confidence interval, 0.23-3.09) days longer and with >2 times the odds of a long follicular phase (adjusted odds ratio, 2.2; 95% confidence interval, 1.05-4.74). CONCLUSION: There is a potential pathophysiological association between systemic inflammation and menstrual cycle changes. Further studies are needed to determine if systemic inflammation alters the menstrual cycle or if long menstrual cycles are a marker for elevated systemic inflammation.

Urinary phenol concentrations and fecundability and early pregnancy loss.

STUDY QUESTION: Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss? SUMMARY ANSWER: 2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability. WHAT IS KNOWN ALREADY: Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations. STUDY DESIGN, SIZE, DURATION: Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE. MAIN RESULTS AND THE ROLE OF CHANCE: ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined. LIMITATIONS, REASONS FOR CAUTION: Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Markers of ovarian reserve as predictors of future fertility.

OBJECTIVE: To determine the association between ovarian reserve biomarkers and future fertility among late reproductive-age women. DESIGN: Cohort study of participants enrolled in Time to Conceive (TTC), a time-to-pregnancy cohort study of the ovarian reserve biomarkers. SETTING: Community. PATIENT(S): Women aged 30-44 years without a history of infertility who provided a blood sample at enrollment in TTC and who agreed to future follow-up. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The primary outcomes were probability of achieving a live birth >3 years after enrollment in TTC, diagnosis of infertility at any time, and time-to-pregnancy in future pregnancy attempts. RESULT(S): Women with diminished ovarian reserve, defined as those with an antimüllerian hormone (AMH) level <0.7 ng/mL or follicle-stimulating hormone (FSH) level ≥10 mIU/mL, did not have low risk of future live birth (relative risk [RR], 1.32; 95% confidence interval [CI], 0.95-1.83 and RR, 1.28; 95% CI, 0.97-1.70, respectively) compared with women with normal ovarian reserve after adjusting for age at blood draw, race, obesity, use of hormonal contraception, and year of enrollment in original study. Among women in the cohort that attempted to conceive, there was not a significant association between diminished ovarian reserve, as measured by AMH or FSH, and risk of future infertility (RR, 0.65; 95% CI, 0.21-2.07 and RR,1.69; 95% CI, 0.86-3.31, respectively). Similarly, there was no association between AMH and FSH levels and future fecundability (fecundability ratio, 0.97; 95% CI, 0.59, 1.60; and fecundability ration, 0.86; 95% CI, 0.55-1.36, respectively). CONCLUSION: Diminished ovarian reserve is not associated with reduced future reproductive capacity. Given the lack of association, women should be cautioned regarding use biomarkers of ovarian reserve as predictors of their future reproductive capacity.

Covid-19 vaccination and menstrual cycle length in the Apple Women's Health Study.

COVID-19 vaccination may be associated with change in menstrual cycle length following vaccination. We estimated covariate-adjusted differences in mean cycle length (MCL), measured in days, between pre-vaccination cycles, vaccination cycles, and post-vaccination cycles within vaccinated participants who met eligibility criteria in the Apple Women's Health Study, a longitudinal mobile-application-based cohort of people in the U.S. with manually logged menstrual cycles. A total of 9652 participants (8486 vaccinated; 1166 unvaccinated) contributed 128,094 cycles (median = 10 cycles per participant; inter-quartile range: 4-22). Fifty-five percent of vaccinated participants received Pfizer-BioNTech's mRNA vaccine, 37% received Moderna's mRNA vaccine, and 8% received the Johnson & Johnson/Janssen (J&J) vaccine. COVID-19 vaccination was associated with a small increase in MCL for cycles in which participants received the first dose (0.50 days, 95% CI: 0.22, 0.78) and cycles in which participants received the second dose (0.39 days, 95% CI: 0.11, 0.67) of mRNA vaccines compared with pre-vaccination cycles. Cycles in which the single dose of J&J was administered were, on average, 1.26 days longer (95% CI: 0.45, 2.07) than pre-vaccination cycles. Post-vaccination cycles returned to average pre-vaccination length. Estimated follicular phase vaccination was associated with increased MCL in cycles in which participants received the first dose (0.97 days, 95% CI: 0.53, 1.42) or the second dose (1.43 days, 95% CI: 1.06, 1.80) of mRNA vaccines or the J&J dose (2.27 days, 95% CI: 1.04, 3.50), compared with pre-vaccination cycles. Menstrual cycle change following COVID-19 vaccination appears small and temporary and should not discourage individuals from becoming vaccinated.

Feasibility of leveraging menstrual cycle tracking apps for preconception research recruitment.

Background: Mobile applications (apps) present a new opportunity to study menstrual cycles and time to pregnancy. Understanding the characteristics of cycle tracking app users is important to evaluate the feasibility of recruiting participants for preconception research. Methods: Users of a cycle tracking smartphone app, Ovia Fertility, aged 18 or older in the U.S. were randomly invited via email to complete a "fertility research" questionnaire that included demographic and reproductive characteristics. Among those attempting pregnancy without medical assistance, attempt duration, factors influencing pregnancy planning, health history and behaviors while attempting to conceive were queried. Respondents could choose to enter a raffle for a $50 gift card. Results: Initially, 639 people responded to the demographics portion of the survey representing 49 states and Washington DC. Of these, 344 (54%) were trying to conceive and of those, 297 (86%) were not using medical treatments. Of those not trying to conceive, 12% reported that they planned to start in the next 3 months. Most participants were ages 26-35 (63%), of White race (70%), reported non-Hispanic ethnicity (87%), had at least a bachelor's degree (56%) and an income between $50,000 and $200,000 (58%). One-third were of recommended BMI (35%), 24% overweight, and 41% obese. Most participants reported no fertility-related health conditions (58%). Forty-eight participants (17%) had been trying to conceive for 1 month or less, 88 (31%) had been trying for 2 months or less, and 122 (43%) for 3 months or less. Interruptions in pregnancy attempts were common, 31% reported periods without intercourse. Of those attempting pregnancy, 47% of partners completed their own questionnaire. Conclusion: This first-of its-kind analysis describes users of a cycle-tracking smartphone app who could be eligible for recruitment to a prospective time-to-pregnancy study. Survey respondents were diverse with respect to geographic location, BMI, and income. However, special recruitment efforts will be needed to recruit participants and partners who identify as other than non-Hispanic White. Participants with fertility-related conditions are not overly represented among app users who are trying to conceive. Targeting and pre-enrolling app users who are planning to begin a pregnancy attempt in the next 3 months may be an advantage of app-based recruitment.

Serum Vitamin D Concentrations, Time to Pregnancy, and Pregnancy Outcomes among Preconception Couples: A Cohort Study in Shanghai, China.

BACKGROUND: The role of vitamin D in reproductive health is still unclear. This study aimed to assess the effect of serum 25-hydroxyvitamin D (25(OH)D), among preconception couples, on fecundity, and the associations between 25(OH)D concentrations before and during pregnancy, and pregnancy outcomes. METHODS: 200 preconception couples attempting to conceive were recruited and were followed-up until childbirth. Time to pregnancy was collected via telephone every two months or obtained via a questionnaire during pregnancy. Blood samples were collected to measure serum 25(OH)D levels from both partners at enrollment and from women during the second and third trimester of pregnancy. RESULTS: Couples had higher conception rates within six months (adjusted odds ratio (aOR): 3.72, 95% CI: 1.16, 11.9) and reduced time to pregnancy (adjusted fecundability ratio (aFR): 1.50, 95% CI: 1.01, 2.23) if male partners had sufficient 25(OH)D compared with insufficient 25(OH)D. Compared to pregnant women with insufficient 25(OH)D in the third trimester of pregnancy, sufficient 25(OH)D was associated with reduced odds of anemia (OR: 0.22, 95% CI: 0.06, 0.82), longer gestational age (ß: 0.53, 95% CI: 0.04, 1.01) and newborns' higher ponderal index (ß: 0.10, 95% CI: 0.01, 0.19). CONCLUSIONS: Sufficient serum 25(OH)D levels among preconception men or during pregnancy were associated with better reproductive health.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts.

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.