Assisted reproductive technology (ART) patient information-seeking behavior: a qualitative study.

BACKGROUND: Approximately 13% of women in the United States of reproductive age seek infertility services. Assisted reproductive technology (ART), including in vitro fertilization, is used to help patients achieve pregnancy. Many people are not familiar with these treatments prior to becoming patients and possess knowledge gaps about care. METHODS: This study employed qualitative methods to investigate how patients interact with information sources during care. Patients who underwent ART including embryo transfer between January 2017 and April 2022 at a large urban healthcare center were eligible. Semi-structured, in-depth interviews were conducted between August and October 2022. Fifteen females with an average age of 39 years participated. Reflexive thematic analysis was performed. RESULTS: Two main themes emerged. Participants (1) utilized clinic-provided information and then turned to outside sources to fill knowledge gaps; (2) struggled to learn about costs, insurance, and mental health resources to support care. Participants preferred clinic-provided resources and then utilized academic sources, the internet, and social media when they had unfulfilled information needs. Knowledge gaps related to cost, insurance, and mental health support were reported. CONCLUSION: ART clinics can consider providing more information about cost, insurance, and mental health support to patients. TRIAL REGISTRATION: The Massachusetts General Hospital Institutional Review Board approved this study (#2022P000474) and informed consent was obtained from each participant.

Environmental Exposures and Anti-Müllerian Hormone: A Mixture Analysis in the Nurses' Health Study II.

BACKGROUND: Previous studies have linked environmental exposures with anti-Müllerian hormone (AMH), a marker of ovarian reserve. However, associations with multiple environment factors has to our knowledge not been addressed. METHODS: We included a total of 2,447 premenopausal women in the Nurses' Health Study II (NHSII) who provided blood samples during 1996-1999. We selected environmental exposures linked previously with reproductive outcomes that had measurement data available in NHSII, including greenness, particulate matter, noise, outdoor light at night, ultraviolet radiation, and six hazardous air pollutants (1,3-butadiene, benzene, diesel particulate matter, formaldehyde, methylene chloride, and tetrachloroethylene). For these, we calculated cumulative averages from enrollment (1989) to blood draw and estimated associations with AMH in adjusted single-exposure models, principal component analysis (PCA), and hierarchical Bayesian kernel machine regression (BKMR). RESULTS: Single-exposure models showed negative associations of AMH with benzene (percentage reduction in AMH per interquartile range [IQR] increase = 5.5%, 95% confidence interval [CI] = 1.0, 9.8) and formaldehyde (6.1%, 95% CI = 1.6, 10). PCA identified four major exposure patterns but only one with high exposure to air pollutants and light at night was associated with lower AMH. Hierarchical BKMR pointed to benzene, formaldehyde, and greenness and suggested an inverse joint association with AMH (percentage reduction comparing all exposures at the 75th percentile to median = 8.2%, 95% CI = 0.7, 15.1). Observed associations were mainly among women above age 40. CONCLUSIONS: We found exposure to benzene and formaldehyde to be consistently associated with lower AMH levels. The associations among older women are consistent with the hypothesis that environmental exposures accelerate reproductive aging.

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.

Use of personal care products during pregnancy and birth outcomes - A pilot study.

Prenatal exposure to endocrine disrupting chemicals (EDCs) from personal care products may be associated with birth outcomes including preterm birth and low birth weight. There is limited research examining the role of personal care product use during pregnancy on birth outcomes. Our pilot study consisted of 164 participants in the Environmental Reproductive and Glucose Outcomes (ERGO) study (Boston, MA), with data on self-reported personal care product use at four study visits throughout pregnancy (product use in the 48 h before a study visit and hair product use in the month before a study visit). We used covariate-adjusted linear regression models to estimate differences in mean gestational age at delivery, birth length, and sex-specific birth weight-for-gestational age (BW-for-GA) Z-score based on personal care product use. Hair product use in the past month prior to certain study visits was associated with decreased mean sex-specific BW-for-GA Z-scores. Notably, hair oil use in the month prior to study visit 1 was associated with a lower mean BW-for-GA Z-score (V1: -0.71, 95% confidence interval: -1.12, -0.29) compared to non-use. Across all study visits (V1-V4), increased mean birth length was observed among nail polish users vs. non-users. In comparison, decreased mean birth length was observed among shave cream users vs. non-users. Liquid soap, shampoo, and conditioner use at certain study visits were significantly associated with higher mean birth length. Suggestive associations were observed across study visits for other products including hair gel/spray with BW-for-GA Z-score and liquid/bar soap with gestational age. Overall, use of a variety of personal care products throughout pregnancy was observed to be associated with our birth outcomes of interest, notably hair oil use during early pregnancy. These findings may help inform future interventions/clinical recommendations to reduce exposures linked to adverse pregnancy outcomes.

Evaluation of Menstrual Cycle Tracking Behaviors in the Ovulation and Menstruation Health Pilot Study: Cross-Sectional Study.

BACKGROUND: Menstrual cycle tracking apps (MCTAs) have potential in epidemiological studies of women's health, facilitating real-time tracking of bleeding days and menstrual-associated signs and symptoms. However, information regarding the characteristics of MCTA users versus cycle nontrackers is limited, which may inform generalizability. OBJECTIVE: We compared characteristics among individuals using MCTAs (app users), individuals who do not track their cycles (nontrackers), and those who used other forms of menstrual tracking (other trackers). METHODS: The Ovulation and Menstruation Health Pilot Study tested the feasibility of a digitally enabled evaluation of menstrual health. Recruitment occurred between September 2017 and March 2018. Menstrual cycle tracking behavior, demographic, and general and reproductive health history data were collected from eligible individuals (females aged 18-45 years, comfortable communicating in English). Menstrual cycle tracking behavior was categorized in 3 ways: menstrual cycle tracking via app usage, that via other methods, and nontracking. Demographic factors, health conditions, and menstrual cycle characteristics were compared across the menstrual tracking method (app users vs nontrackers, app users vs other trackers, and other trackers vs nontrackers) were assessed using chi-square or Fisher exact tests. RESULTS: In total, 263 participants met the eligibility criteria and completed the digital survey. Most of the cohort (n=191, 72.6%) was 18-29 years old, predominantly White (n=170, 64.6%), had attained 4 years of college education or higher (n= 209, 79.5%), and had a household income below US $50,000 (n=123, 46.8%). Among all participants, 103 (39%) were MCTA users (app users), 97 (37%) did not engage in any tracking (nontrackers), and 63 (24%) used other forms of tracking (other trackers). Across all groups, no meaningful differences existed in race and ethnicity, household income, and education level. The proportion of ever-use of hormonal contraceptives was lower (n=74, 71.8% vs n=87, 90%, P=.001), lifetime smoking status was lower (n=6, 6% vs n=15, 17%, P=.04), and diagnosis rate of gastrointestinal reflux disease (GERD) was higher (n=25, 24.3% vs n=12, 12.4%, P=.04) in app users than in nontrackers. The proportions of hormonal contraceptives ever used and lifetime smoking status were both lower (n=74, 71.8% vs n=56, 88.9%, P=.01; n=6, 6% vs n=11, 17.5%, P=.02) in app users than in other trackers. Other trackers had lower proportions of ever-use of hormonal contraceptives (n=130, 78.3% vs n=87, 89.7%, P=.02) and higher diagnostic rates of heartburn or GERD (n=39, 23.5% vs n=12, 12.4%, P.03) and anxiety or panic disorder (n=64, 38.6% vs n=25, 25.8%, P=.04) than nontrackers. Menstrual cycle characteristics did not differ across all groups. CONCLUSIONS: Our results suggest that app users, other trackers, and nontrackers are largely comparable in demographic and menstrual cycle characteristics. Future studies should determine reasons for tracking and tracking-related behaviors to further understand whether individuals who use MCTAs are comparable to nontrackers.

Exploring the causes of semen quality changes post-bariatric surgery: a focus on endocrine-disrupting chemicals.

Rapid weight loss promoted by bariatric surgery (BS) can release accumulated lipophilic endocrine-disrupting chemicals (EDCs), making these chemicals systemically available. Men typically have a higher EDC body burden and lose more weight post-BS than women, which may put male BS patients at high risk for testicular toxicity. In this review, we analyze the impacts of BS on semen parameters with a particular focus on the potential effects of EDCs. After BS, serum EDC concentrations progressively increase; and there is evidence that semen parameters deteriorate after BS. Although elevated serum EDC concentrations are associated with inferior sperm parameters, links between semen parameters and EDCs post-BS have not been studied. Understanding these potential associations requires adequately powered studies, particularly within prospective longitudinal cohorts with long-term follow-up for sperm parameters, nutritional status, sex-hormones levels and serum EDC concentrations. Studying BS patients prospectively provides the important opportunity to evaluate dose-response effects of EDC serum concentrations on sperm quality and function. Research is also needed to identify critical chemical exposure periods post-BS to inform reproductive decisions, including consideration of sperm preservation before surgery.

Attempts to conceive and the COVID-19 pandemic: data from the Apple Women's Health Study.

BACKGROUND: Previous studies have suggested that emergent events may affect pregnancy planning decisions. However, few have investigated the effect of factors related to the COVID-19 pandemic on pregnancy planning, measured by attempting conception, and how attempting conception status may differ by individual-level factors, such as social status or educational level. OBJECTIVE: This study aimed to examine the effects of factors related to the COVID-19 pandemic, until March 2021, on attempting conception status and to assess the effect measure modification by educational level and subjective social status. STUDY DESIGN: We conducted a longitudinal analysis within a subgroup of 21,616 participants in the Apple Women's Health Study who enrolled from November 2019 to March 2021, who met the inclusion criteria, and who responded to the monthly status menstrual update question on attempting conception status (yes or no). Participants reporting hysterectomy, pregnancy, lactation, or menopause were excluded. We used generalized estimating equation methodology to fit logistic regression models that estimate odds ratios and 95% confidence intervals for the association between the proportion of participants attempting conception and the month of response (compared with a prepandemic reference month of February 2020) while accounting for longitudinal correlation and adjusting for age, race and ethnicity, and marital status. We stratified the analysis by social status and educational level. RESULTS: We observed a trend of reduced odds of attempting conception, with an 18% reduction in the odds of attempting conception in August 2020 and October 2020 compared with the prepandemic month of February 2020 (August odds ratio: 0.82 [95% confidence interval, 0.70-0.97]; October odds ratio: 0.82 [95% confidence interval, 0.69-0.97). The participants with lower educational level (no college education) experienced a sustained reduction in the odds of attempting to conceive from June 2020 to March 2021 compared with February 2020, with up to a 24% reduction in the odds of attempting to conceive in October 2020 (odds ratio, 0.76; 95% confidence interval, 0.59-0.96). Among participants that were college educated, we observed an initial reduction in the odds of attempting to conceive starting in July 2020 (odds ratio 0.73; 95% confidence interval, 0.54-0.99) that returned near prepandemic odds. Moreover, we observed a reduction in the odds of attempting to conceive among those with low subjective social status, with a decline in the odds of attempting to conceive beginning in July 2020 (odds ratio, 0.83; 95% confidence interval, 0.63-1.10) and continuing until March 2021 (odds ratio, 0.79; 95% confidence interval, 0.59-1.06), with the greatest reduction in odds in October 2020 (odds ratio, 0.67; 95% confidence interval, 0.50-0.91). CONCLUSION: Among women in the Apple Women's Health Study cohort, our findings suggested a reduction in the odds of attempting to conceive during the COVID-19 pandemic, until March 2021, particularly among women of lower educational level and lower perceived social status.

Design and methods of the Apple Women's Health Study: a digital longitudinal cohort study.

BACKGROUND: Prospective longitudinal cohorts assessing women's health and gynecologic conditions have historically been limited. OBJECTIVE: The Apple Women's Health Study was designed to gain a deeper understanding of the relationship among menstrual cycles, health, and behavior. This paper describes the design and methods of the ongoing Apple Women's Health Study and provides the demographic characteristics of the first 10,000 participants. STUDY DESIGN: This was a mobile-application-based longitudinal cohort study involving survey and sensor-based data. We collected the data from 10,000 participants who responded to the demographics survey on enrollment between November 14, 2019 and May 20, 2020. The participants were asked to complete a monthly follow-up through November 2020. The eligibility included installed Apple Research app on their iPhone with iOS version 13.2 or later, were living in the United States, being of age greater than 18 years (19 in Alabama and Nebraska, 21 years old in Puerto Rico), were comfortable in communicating in written and spoken English, were the sole user of an iCloud account or iPhone, and were willing to provide consent to participate in the study. RESULTS: The mean age at enrollment was 33.6 years old (±standard deviation, 10.3). The race and ethnicity was representative of the US population (69% White and Non-Hispanic [6910/10,000]), whereas 51% (5089/10,000) had a college education or above. The participant geographic distribution included all the US states and Puerto Rico. Seventy-two percent (7223/10,000) reported the use of an Apple Watch, and 24.4% (2438/10,000) consented to sensor-based data collection. For this cohort, 38% (3490/9238) did not respond to the Monthly Survey: Menstrual Update after enrollment. At the 6-month follow-up, there was a 35% (3099/8972) response rate to the Monthly Survey: Menstrual Update. 82.7% (8266/10,000) of the initial cohort and 95.1% (2948/3099) of the participants who responded to month 6 of the Monthly Survey: Menstrual Update tracked at least 1 menstrual cycle via HealthKit. The participants tracked their menstrual bleeding days for an average of 4.44 (25%-75%; range, 3-6) calendar months during the study period. Non-White participants were slightly more likely to drop out than White participants; those remaining at 6 months were otherwise similar in demographic characteristics to the original enrollment group. CONCLUSION: The first 10,000 participants of the Apple Women's Health Study were recruited via the Research app and were diverse in race and ethnicity, educational attainment, and economic status, despite all using an Apple iPhone. Future studies within this cohort incorporating this high-dimensional data may facilitate discovery in women's health in exposure outcome relationships and population-level trends among iPhone users. Retention efforts centered around education, communication, and engagement will be utilized to improve the survey response rates, such as the study update feature.

Ultraviolet radiation and age at natural menopause in a nationwide, prospective US cohort.

BACKGROUND: Solar ultraviolet radiation (UV) is a critical environmental factor for dermal conversion of vitamin D, which is suggested to support reproductive health. However, current epidemiological studies have reported conflicting results on the associations between vitamin D levels and ovarian reserve. Further, few studies have considered UV exposure and reproductive aging, which is closely related to declined ovarian reserve. OBJECTIVES: We sought to examine the associations of long-term UV exposure and age at natural menopause in a large, nationwide, prospective cohort. METHODS: Participants in the Nurses' Health Study II (NHS II) who were premenopausal at age 40 were included and followed through 2015. Erythemal UV radiation from a high-resolution geospatial model was linked to the participants' residential histories. Early-life UV was estimated using the reported state of residence at birth, age 15, and age 30. We used time-varying Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for natural menopause, adjusting for potential confounders and predictors of menopause. RESULTS: A total of 63,801 women reported natural menopause across the 1,051,185 person-years of follow-up among 105,631 eligible participants. We found very modest associations with delayed menopause for long-term UV exposure (adjusted HR comparing highest to lowest quartile of cumulative average UV: 0.96, 95% CI: 0.94, 0.99). There was a suggestive inverse association between UV at age 30 with menopause (adjusted HR comparing highest to lowest quartile: 0.97, 95% CI: 0.95, 1.00) but not with UV at birth and age 15. CONCLUSIONS: Solar UV exposure in adulthood was modestly associated with later onset of menopause. Although consistent with previous findings on vitamin D intake and menopause in the same population, these weak associations found in this study may not be of clinical relevance.

Fine particulate matter and polycystic ovarian morphology.

BACKGROUND: Polycystic ovary morphology (PCOM) is an ultrasonographic finding that can be present in women with ovulatory disorder and oligomenorrhea due to hypothalamic, pituitary, and ovarian dysfunction. While air pollution has emerged as a possible disrupter of hormone homeostasis, limited research has been conducted on the association between air pollution and PCOM. METHODS: We conducted a longitudinal cohort study using electronic medical records data of 5,492 women with normal ovaries at the first ultrasound that underwent a repeated pelvic ultrasound examination during the study period (2004-2016) at Boston Medical Center. Machine learning text algorithms classified PCOM by ultrasound. We used geocoded home address to determine the ambient annual average PM2.5 exposures and categorized into tertiles of exposure. We used Cox Proportional Hazards models on complete data (n = 3,994), adjusting for covariates, and additionally stratified by race/ethnicity and body mass index (BMI). RESULTS: Cumulative exposure to PM2.5 during the study ranged from 4.9 to 17.5 µg/m3 (mean = 10.0 µg/m3). On average, women were 31 years old and 58% were Black/African American. Hazard ratios and 95% confidence intervals (CI) comparing the second and third PM2.5 exposure tertile vs. the reference tertile were 1.12 (0.88, 1.43) and 0.89 (0.62, 1.28), respectively. No appreciable differences were observed across race/ethnicity. Among women with BMI ≥ 30 kg/m2, we observed weak inverse associations with PCOM for the second (HR: 0.93, 95% CI: 0.66, 1.33) and third tertiles (HR: 0.89, 95% CI: 0.50, 1.57). CONCLUSIONS: In this study of reproductive-aged women, we observed little association between PM2.5 concentrations and PCOM incidence. No dose response relationships were observed nor were estimates appreciably different across race/ethnicity within this clinically sourced cohort.

Endocrine disrupting chemical-associated hair product use during pregnancy and gestational age at delivery: a pilot study.

BACKGROUND: Prenatal endocrine disrupting chemical (EDC) exposure has been associated with increased risk of preterm birth. Non-Hispanic Black women have higher incidence of preterm birth compared to other racial/ethnic groups and may be disproportionately exposed to EDCs through EDC-containing hair products. However, research on the use of EDC-associated hair products during pregnancy and risk of preterm birth is lacking. Therefore, the objective of this pilot study was to estimate associations of prenatal hair product use with gestational age at delivery in a Boston, Massachusetts area pregnancy cohort. METHODS: The study population consisted of a subset of participants enrolled in the Environmental Reproductive and Glucose Outcomes (ERGO) Study between 2018 and 2020. We collected self-reported data on demographics and hair product use using a previously validated questionnaire at four prenatal visits (median: 12, 19, 26, 36 weeks' gestation) and abstracted gestational age at delivery from medical records. We compared gestational age and hair product use by race/ethnicity and used linear regression to estimate covariate-adjusted associations of product use and frequency of use at each study visit with gestational age at delivery. Primary models were adjusted for maternal age at enrollment and delivery method. RESULTS: Of the 154 study participants, 7% delivered preterm. Non-Hispanic Black participants had lower mean gestational age at delivery compared to non-Hispanic White participants (38.2 vs. 39.2 weeks) and were more likely to report ever and more frequent use of hair products. In regression models, participants reporting daily use of hair oils at visit 4 had lower mean gestational age at delivery compared to non-users (ß: -8.3 days; 95% confidence interval: -14.9, -1.6). We did not find evidence of associations at earlier visits or with other products. CONCLUSIONS: Frequent use of hair oils during late pregnancy may be associated with shorter gestational duration. As hair oils are more commonly used by non-Hispanic Black women and represent potentially modifiable EDC exposure sources, this may have important implications for the known racial disparity in preterm birth.

Multimodal Recruitment to Study Ovulation and Menstruation Health: Internet-Based Survey Pilot Study.

BACKGROUND: Multimodal recruitment strategies are a novel way to increase diversity in research populations. However, these methods have not been previously applied to understanding the prevalence of menstrual disorders such as polycystic ovary syndrome. OBJECTIVE: The purpose of this study was to test the feasibility of recruiting a diverse cohort to complete a web-based survey on ovulation and menstruation health. METHODS: We conducted the Ovulation and Menstruation Health Pilot Study using a REDCap web-based survey platform. We recruited 200 women from a clinical population, a community fair, and the internet. RESULTS: We recruited 438 women over 29 weeks between September 2017 and March 2018. After consent and eligibility determination, 345 enrolled, 278 started (clinic: n=43; community fair: n=61; internet: n=174), and 247 completed (clinic: n=28; community fair: n=60; internet: n=159) the survey. Among all participants, the median age was 25.0 (SD 6.0) years, mean BMI was 26.1 kg/m2 (SD 6.6), 79.7% (216/271) had a college degree or higher, and 14.6% (37/254) reported a physician diagnosis of polycystic ovary syndrome. Race and ethnicity distributions were 64.7% (176/272) White, 11.8% (32/272) Black/African American, 7.7% (21/272) Latina/Hispanic, and 5.9% (16/272) Asian individuals; 9.9% (27/272) reported more than one race or ethnicity. The highest enrollment of Black/African American individuals was in clinic (17/42, 40.5%) compared to 1.6% (1/61) in the community fair and 8.3% (14/169) using the internet. Survey completion rates were highest among those who were recruited from the internet (159/174, 91.4%) and community fairs (60/61, 98.4%) compared to those recruited in clinic (28/43, 65.1%). CONCLUSIONS: Multimodal recruitment achieved target recruitment in a short time period and established a racially diverse cohort to study ovulation and menstruation health. There were greater enrollment and completion rates among those recruited via the internet and community fair.

Air pollution exposure and risk of spontaneous abortion in the Nurses' Health Study II.

STUDY QUESTION: Is there an association between air pollution exposures and the risk of spontaneous abortion (SAB)? SUMMARY ANSWER: Higher exposure to particulate matter (PM) air pollution above and beyond a woman's average exposure may be associated with greater risk of SAB, particularly among women experiencing at least one SAB during follow-up. WHAT IS KNOWN ALREADY: There is sufficient biologic plausibility to suggest that air pollution adversely affects early pregnancy outcomes, particularly pregnancy loss; however, the evidence is limited. STUDY DESIGN, SIZE, DURATION: Our prospective cohort study included 19 309 women in the Nurses' Health Study II who contributed a total of 35 025 pregnancies between 1990 and 2008. We also conducted a case-crossover analysis among 3585 women (11 212 pregnancies) with at least one SAB and one live birth during follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Proximity to major roadways and exposure to PM <10 microns (PM10), 2.5-10 microns (PM2.5-10) and <2.5 microns (PM2.5) were determined for residential addresses between 1989 and 2007. Pregnancy outcomes were self-reported biannually throughout follow-up and comprehensively in 2009. Multivariable log-binomial regression models with generalized estimating equations were used to estimate the risk ratios and 95% CIs of SAB. Conditional logistic regression was used for the case-crossover analysis. MAIN RESULTS AND THE ROLE OF CHANCE: During the 19 years of follow-up, 6599 SABs (18.8% of pregnancies) were reported. In the main analysis, living closer to a major roadway and average exposure to PM10, PM10-2.5 or PM2.5 in the 1 or 2 years prior to pregnancy were not associated with an increased risk of SAB. However, small positive associations between PM exposures and SAB were observed when restricting the analysis to women experiencing at least one SAB during follow-up. In the case-crossover analysis, an increase in PM10 (per 3.9 µg/m3), PM2.5-10 (per 2.3 µg/m3) and PM2.5 (per 2.0 µg/m3) in the year prior to pregnancy was associated with 1.12 (95% CI 1.06, 1.19), 1.09 (95% CI 1.03, 1.14) and 1.10 (95% CI 1.04, 1.17) higher odds of SAB, respectively. LIMITATIONS, REASONS FOR CAUTION: We did not have information on the month or day of SAB, which precluded our ability to examine specific windows of susceptibility or acute exposures. We also used ambient air pollution exposures as a proxy for personal exposure, potentially leading to exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS: In our case-crossover analysis (but not in the entire cohort) we observed positive associations between exposure to all size fractions of PM exposure and risk of SAB. This may suggest that changes in PM exposure confer greater risk of SAB or that women with a history of SAB are a particularly vulnerable subgroup. STUDY FUNDING/COMPETING INTEREST(S): The authors are supported by the following NIH grants UM1CA176726, R00ES026648 and P30ES000002. The authors have no actual or potential competing financial interests to disclose.

Do prenatal exposures pose a real threat to ovarian function? Bisphenol A as a case study.

Fetal development represents a time of potential vulnerability due to rapid cell division, organ development and limited fetal kidney/liver activity for detoxification and metabolism of exposures. Health effects of prenatal toxicant exposure have previously been described, but there is little cohesive evidence surrounding effects on ovarian function. Using bisphenol A (BPA) as a case study, we seek to examine whether a prominent prenatal environmental exposure can pose a real threat to human ovarian function. To do so, we broadly review human oogenesis and menstrual cycle biology. We then present available literature addressing prenatal bisphenol A and diverse outcomes at the level of the ovary. We highlight relevant human cohorts and mammalian models to review the existing data on prenatal exposures and ovarian disruption. Doing so suggests that while current exposures to BPA have not shown marked or consistent results, there is data sufficient to raise concerns regarding ovarian function. Challenges in the examination of this question suggest the need for additional models and pathways by which to expand these examinations in humans.

Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses' Health Study II.

Previous studies evaluating the association of prenatal exposure to diethylstilbestrol (DES), a potent endocrine disruptor, with incidence of uterine leiomyomata (UL) have had conflicting results. We evaluated the association between prenatal DES exposure and incident UL in women in the Nurses' Health Study II from 1989 to 2009. Women were aged 25-42 years at enrollment and had a prenatal exposure window corresponding to DES use. The analytical sample was larger than previous studies and included 102,164 premenopausal women with intact uteri, no prior history of UL or cancer, and prenatal DES exposure. Multivariable-adjusted Cox proportional hazard models were used to estimate the relationship between DES exposure and UL risk. During 1,273,342 person-years of follow-up, there were 11,831 incident cases of UL. Women with prenatal exposure to DES had a higher incidence of UL compared with unexposed women, with an adjusted hazard ratio of 1.12 (95% confidence interval: 0.98, 1.27). Risk was strongest for women exposed to DES in the first trimester, when exposure corresponds to early stages of fetal Müllerian development (adjusted hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). These results suggest that first-trimester DES exposure may be associated with an increased risk of UL, but they must be interpreted with concern for detection and recall biases.

Air pollution and risk of uterine leiomyomata.

BACKGROUND: Air pollution, particularly from vehicle exhaust, has been shown to influence hormonal activity. However, it is unknown whether air pollution exposure is associated with the occurrence of uterine leiomyomata, a hormonally sensitive tumor of the uterus. METHODS: For 85,251 women 25-42 years of age at enrollment in the Nurses' Health Study II, we examined proximity to major roadways and outdoor levels of particulate matter less than 10 microns (PM10) or 2.5 microns (PM2.5) or between 10 and 2.5 microns (PM10-2.5) in diameter for all residential addresses from September 1989 to May 2007. To be eligible for this analysis, a woman had to be alive and respond to questionnaires, premenopausal with an intact uterus, and without diagnoses of cancer or prevalent uterine leiomyomata. Incidence of ultrasound- or hysterectomy-confirmed uterine leiomyomata and covariates were reported on biennial questionnaires sent through May 2007. Multivariable time-varying Cox proportional hazard models were used to estimate the relationship between distance to road or PM exposures and uterine leiomyomata risk. RESULTS: During 837,573 person-years of follow-up, there were 7760 incident cases of uterine leiomyomata. Living close to a major road and exposures to PM10 or PM10-2.5 were not associated with an increased risk of uterine leiomyomata. However, each 10 µg/m increase in 2-year average, 4-year average, or cumulative average PM2.5 was associated with an adjusted hazard ratio of 1.08 (95% confidence interval = 1.00-1.17), 1.09 (0.99-1.19), and 1.11 (1.03-1.19), respectively. CONCLUSIONS: Chronic exposure to PM2.5 may be associated with a modest increased risk of uterine leiomyomata.

Prenatal drinking-water exposure to tetrachloroethylene and ischemic placental disease: a retrospective cohort study.

BACKGROUND: Prenatal drinking water exposure to tetrachloroethylene (PCE) has been previously related to intrauterine growth restriction and stillbirth. Pathophysiologic and epidemiologic evidence linking these outcomes to certain other pregnancy complications, including placental abruption, preeclampsia, and small-for-gestational-age (SGA) (i.e., ischemic placental diseases), suggests that PCE exposure may also be associated with these events. We examined whether prenatal exposure to PCE-contaminated drinking water was associated with overall or individual ischemic placental diseases. METHODS: Using a retrospective cohort design, we compared 1,091 PCE-exposed and 1,019 unexposed pregnancies from 1,766 Cape Cod, Massachusetts women. Exposure between 1969 and 1990 was estimated using water distribution system modeling software. Data on birth weight and gestational age were obtained from birth certificates; mothers self-reported pregnancy complications. RESULTS: Of 2,110 eligible pregnancies, 9% (N = 196) were complicated by ≥1 ischemic placental disease. PCE exposure was not associated with overall ischemic placental disease (for PCE ≥ sample median vs. no exposure, risk ratio (RR): 0.90; 95% confidence interval (CI): 0.65, 1.24), preeclampsia (RR: 0.36; 95% CI: 0.12-1.07), or SGA (RR: 0.98; 95% CI: 0.66-1.45). However, pregnancies with PCE exposure ≥ the sample median had 2.38-times the risk of stillbirth ≥27 weeks gestation (95% CI: 1.01, 5.59), and 1.35-times of the risk of placental abruption (95% CI: 0.68, 2.67) relative to unexposed pregnancies. CONCLUSIONS: Prenatal PCE exposure was not associated with overall ischemic placental disease, but may increase risk of stillbirth.

Urinary benzophenone-3 concentrations and ovarian reserve in a cohort of subfertile women.

OBJECTIVE: To evaluate the association between the urinary benzophenone-3 concentrations and measures of ovarian reserve (OR) among women in the Environment and Reproductive Health study seeking fertility treatment at Massachusetts General Hospital (MGH) in Boston, Massachusetts. DESIGN: Prospective cohort study. SETTING: MGH infertility clinic in Boston, Massachusetts. PATIENT(S): Women in the Environment and Reproductive Health cohort seeking fertility treatment. INTERVENTION(S): Women contributed spot urine samples prior to assessment of OR outcomes that were analyzed for benzophenone-3 concentrations. MAIN OUTCOME MEASURE(S): Antral follicle count (AFC) and day 3 follicle-stimulating hormone (FSH) levels were evaluated as part of standard infertility workups during unstimulated menstrual cycles. Quasi-Poisson and linear regression models were used to evaluate the association of the specific gravity-adjusted urinary benzophenone-3 concentrations with AFC and FSH, with adjustment for age and physical activity. In the secondary analyses, models were stratified by age. RESULT(S): This study included 142 women (mean age ± standard deviation, 36.1 ± 4.6 years; range, 22-45 years) enrolled between 2009 and 2017 with both urinary benzophenone-3 and AFC measurements and 57 women with benzophenone-3 and FSH measurements. Most women were White (78%) and highly educated (49% with a graduate degree). Women contributed a mean of 2.7 urine samples (range, 1-10), with 37% contributing ≥2 samples. Benzophenone-3 was detected in 98% of samples. The geometric mean specific gravity-corrected urinary benzophenone-3 concentration was 85.9 µg/L (geometric standard deviation, 6.2). There were no associations of benzophenone-3 with AFC and day 3 FSH in the full cohort. In stratified models, a 1-unit increase in the log geometric mean benzophenone-3 concentration was associated with a 0.91 (95% confidence interval, 0.86-0.97) times lower AFC among women aged ≤35 years and an increase in the FSH concentration of 0.73 (95% confidence interval, 0.12-1.34) IU/L among women aged >35 years. CONCLUSION(S): In the main models, urinary benzophenone-3 was not associated with OR. However, younger patients may be vulnerable to the potential effects of benzophenone-3 on AFC. Further research is warranted.

Predicting polycystic ovary syndrome with machine learning algorithms from electronic health records.

Introduction: Predictive models have been used to aid early diagnosis of PCOS, though existing models are based on small sample sizes and limited to fertility clinic populations. We built a predictive model using machine learning algorithms based on an outpatient population at risk for PCOS to predict risk and facilitate earlier diagnosis, particularly among those who meet diagnostic criteria but have not received a diagnosis. Methods: This is a retrospective cohort study from a SafetyNet hospital's electronic health records (EHR) from 2003-2016. The study population included 30,601 women aged 18-45 years without concurrent endocrinopathy who had any visit to Boston Medical Center for primary care, obstetrics and gynecology, endocrinology, family medicine, or general internal medicine. Four prediction outcomes were assessed for PCOS. The first outcome was PCOS ICD-9 diagnosis with additional model outcomes of algorithm-defined PCOS. The latter was based on Rotterdam criteria and merging laboratory values, radiographic imaging, and ICD data from the EHR to define irregular menstruation, hyperandrogenism, and polycystic ovarian morphology on ultrasound. Results: We developed predictive models using four machine learning methods: logistic regression, supported vector machine, gradient boosted trees, and random forests. Hormone values (follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone binding globulin) were combined to create a multilayer perceptron score using a neural network classifier. Prediction of PCOS prior to clinical diagnosis in an out-of-sample test set of patients achieved an average AUC of 85%, 81%, 80%, and 82%, respectively in Models I, II, III and IV. Significant positive predictors of PCOS diagnosis across models included hormone levels and obesity; negative predictors included gravidity and positive bHCG. Conclusion: Machine learning algorithms were used to predict PCOS based on a large at-risk population. This approach may guide early detection of PCOS within EHR-interfaced populations to facilitate counseling and interventions that may reduce long-term health consequences. Our model illustrates the potential benefits of an artificial intelligence-enabled provider assistance tool that can be integrated into the EHR to reduce delays in diagnosis. However, model validation in other hospital-based populations is necessary.

First trimester plasma PER- AND Polyfluoroalkyl Substances (PFAS) and blood pressure trajectories across the second and third trimesters of pregnancy

BACKGROUND: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. OBJECTIVES: To estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. METHODS: In 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters - adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. RESULTS: We collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity - compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. CONCLUSION: Early pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.