Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

BACKGROUND: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. METHODS: The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. RESULTS: Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05-1.44]); preterm induced labor (aHR, 1.31 [1.03-1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants. CONCLUSIONS: In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

Gestational weight change in a diverse pregnancy cohort and mortality over 50 years: a prospective observational cohort study.

BACKGROUND: High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later. METHODS: The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality. FINDINGS: Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m2; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m2; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m2; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m2; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight. INTERPRETATION: This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality. FUNDING: National Institutes of Health.

Chemicals in menstrual products: A systematic review.

BACKGROUND: From menarche until menopause, the average menstruator will use over 11 000 tampons or sanitary pads. Vaginal and vulvar tissue is highly permeable, and chemicals are absorbed without undergoing first-pass metabolism. OBJECTIVES: To conduct a review of the literature to determine exposure to environmental chemicals in menstrual products. SEARCH STRATEGY: This review identified 15 papers over the past 10 years. SELECTION CRITERIA: Papers that measured chemicals in menstrual products and that measured human biomarkers of chemical exposure were included. Papers had to also be available in English. DATA COLLECTION AND ANALYSIS: Reviewers assessed the articles and data provided. Multiple chemical groups were found. MAIN RESULTS: Phthalates, volatile organic compounds, parabens, environmental phenols, fragrance chemicals, dioxins and dioxin-like compounds were detected in menstrual products. Research gaps were identified, including the lack of studies on newer products such as menstrual underwear and cups/discs. In addition to measuring chemicals in these products, future research should focus on clarifying the exposure per menstrual cycle to these chemicals to understand how menorrhagia and cycle length influence exposure from menstrual products. CONCLUSION: Menstrual products contained measurable levels of a range of endocrine disrupting chemicals including phthalates, phenols and parabens. This reflects a potentially important route of exposure to chemicals that can impact women's reproductive health.

Infant sex at birth and long-term maternal mortality.

BACKGROUND: Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain. OBJECTIVE: The objective of the study was to examine whether male infants increase the risk of maternal mortality. METHODS: This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity. RESULTS: Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups. CONCLUSIONS: Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women.

Long-Term Mortality in Women With Pregnancy Loss and Modification by Race/Ethnicity.

Pregnancy loss is a common reproductive complication, but its association with long-term mortality and whether this varies by maternal race/ethnicity is not well understood. Data from a racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959 to 1966 were used for this study. CPP records were linked to the National Death Index and the Social Security Death Master File to identify deaths and underlying cause (until 2016). Pregnancy loss comprised self-reported losses, including abortions, stillbirths, and ectopic pregnancies. Among 48,188 women (46.0% White, 45.8% Black, 8.2% other race/ethnicity), 25.6% reported at least 1 pregnancy loss and 39% died. Pregnancy loss was associated with a higher absolute risk of all-cause mortality (risk difference, 4.0 per 100 women, 95% confidence interval: 1.4, 6.5) and cardiovascular mortality (risk difference, 2.2 per 100 women, 95% confidence interval: 0.8, 3.5). Stratified by race/ethnicity, a higher risk of mortality persisted in White, but not Black, women. Women with recurrent losses are at increased risk of death, both overall and across all race/ethnicity groups. Pregnancy loss is associated with death; however, it does not confer an excess risk above the observed baseline risk in Black women. These findings support the need to assess reproductive history as part of routine screening in women.

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

BACKGROUND: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. OBJECTIVES: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. METHODS: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. RESULTS: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. CONCLUSIONS: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.

Disability and suicidal behaviors among women of reproductive age.

Limited research exists on suicidal behaviors among women with disabilities. This study examined disability, suicidal behaviors, and associated health determinants among non-pregnant women of reproductive age. Data from the 2015-2019 National Survey on Drug Use and Health (n = 76,750) were used to estimate associations between disability and suicidal behaviors and evaluate the effects of health determinants on suicidal behaviors among non-pregnant women of reproductive age with disabilities. Approximately 22% of non-pregnant women of reproductive age with disabilities reported suicidal behaviors compared to only 4.3% of women without disabilities. Women with disabilities had greater adjusted odds of past-year suicidal behaviors (AOR 1.73; 95% CI 1.60-1.87) than those without disabilities. Psychological distress (OR 3.66; 95% CI 2.98-4.49), major depressive episode (OR 3.22; 95% CI 2.82-3.67), unmet perceived mental health need (OR 2.29; 95% CI 1.98-2.65), age 18-25 years (OR 1.65; 95% CI 1.43-1.92), and illicit drug use (OR 1.40; 95% CI 1.20-1.64) were significantly associated with higher odds of suicidal behaviors, and specifically suicidal ideation, among women with disabilities. Non-pregnant women of reproductive age with disabilities are at increased risk for exhibiting suicidal behaviors. Better understanding of suicidal behaviors among women with disabilities can assist public health officials and medical professionals in developing meaningful prevention, detection, and intervention programs.

Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.

STUDY QUESTION: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses? SUMMARY ANSWER: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth. WHAT IS KNOWN ALREADY: As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case-control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking. STUDY DESIGN, SIZE, DURATION: Participants included 1228 women aged 18-40 years with a history of 1-2 prior pregnancy losses who were recruited at four university medical centers (2006-2012). PARTICIPANTS/MATERIALS, SETTING, METHODS: Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62). LIMITATIONS, REASONS FOR CAUTION: Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35 years, limiting our ability to evaluate associations among older women. Participants had a history of 1-2 prior pregnancy losses; therefore, our findings may not be widely generalizable. WIDER IMPLICATIONS OF THE FINDINGS: Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov, number NCT00467363.

Occupational Exposures to Phthalates among Black and Latina U.S. Hairdressers Serving an Ethnically Diverse Clientele: A Pilot Study.

Hairdressers may be differentially exposed to phthalates through hair salon services provided and products used, yet no U.S. studies have investigated these exposures in this population. We characterized concentrations and exposure determinants to nine phthalate metabolites in postshift urine samples among 23 hairdressers from three Black and three Dominican salons, as well as a comparison group of 17 female office workers from the Maryland/Washington D.C. metropolitan area. Overall, hairdressers had higher metabolite concentrations than office workers. The geometric mean (GM) for monoethyl phthalate (MEP) was 10 times higher in hairdressers (161.4 ng/mL) than office workers (15.3 ng/mL). Hairdressers providing select services and using certain products had higher GM MEP concentrations than those who did not: permanent waves/texturizing (200.2 vs 115.4 ng/mL), chemical straightening/relaxing (181.6 vs 92.1 ng/mL), bleaching (182.3 vs 71.6 ng/mL), permanent hair color (171.9 vs 83.2 ng/mL), and Brazilian blowout/keratin treatments (181.4 vs 134.6 ng/mL). Interestingly, hairdressers providing natural services had lower GM MEP concentrations than those who did not: twists (129.1 vs 215.8 ng/mL), sister locs/locs (86.0 vs 241.9 ng/mL), and afros (94.7 vs 203.9 ng/mL). Larger studies are warranted to confirm our findings and identify disparities in occupational phthalate exposures.

Adipose to serum ratio and mixtures of persistent organic pollutants in relation to endometriosis: Findings from the ENDO Study.

BACKGROUND: Endometriosis is an estrogen-dependent disease. Endocrine disrupting chemicals (EDCs) and their mixtures may play an etiologic role. OBJECTIVES: We evaluated an adipose-to-serum ratio (ASR) of lipophilic EDCs and their mixtures associated with incident endometriosis. METHODS: We quantified 13 polychlorinated biphenyl (PCB) congeners, 6 polybrominated diphenyl ether (PBDE) congeners, and 11 organochlorine pesticides (OCPs) in serum and omental fat among women from the ENDO Study (2007-2009) aged 18-44 years diagnosed with (n=190) or without (n=283) surgically-visualized incident endometriosis. Odds ratios (OR) and 95% confidence intervals (CI) between ASR and endometriosis were estimated using logistic regression models adjusted for age (years), body mass index (kg/m2), serum cotinine (ng/ml), and breastfeeding conditional on parity. Bayesian hierarchical models (BHM) compared estimated associations for adipose and ASR to serum. Bayesian kernel machine regression (BKMR) estimated change in latent health and 95% posterior intervals (PI) between chemical mixtures and endometriosis. RESULTS: Select ASR for estrogenic PCBs and OCPs were associated with an increased odds of an endometriosis diagnosis, but not for anti-estrogenic PCBs or PBDEs. Across all chemicals, BHMs generated ORs that were on average 14% (95% PI: 6%, 22%) higher for adipose and 20% (95% PI: 12%, 29%) higher for ASR in comparison to serum. ORs from BHMs were greater for estrogenic PCBs and OCPs, with no differences for PBDEs. BKMR models comparing the 75th to 25th percentile were moderately associated with endometriosis for estrogenic PCBs [adipose 0.27 (95% PI: 0.18, 0.72) and ASR 0.37 (95% PI: 0.06, 0.80)] and OCPs [adipose 0.17 (95% PI: 0.21, 0.56) and ASR 0.26 (95% PI: 0.05, 0.57)], but not for antiestrogenic PCBs and PBDEs. DISCUSSION: ASR added little insight beyond adipose for lipophilic chemicals. BKMR results supported associations between ASR and adipose estrogenic PCB and OCP mixtures and incident endometriosis. These findings underscore the importance of choice of biospecimen and considering mixtures when assessing exposure-disease relationships.

Commuter types identified using clustering and their associations with source-specific PM2.5.

Traffic-related fine particulate matter air pollution (tr-PM2.5) has been associated with adverse health outcomes such as cardiopulmonary morbidity and mortality, with in-vehicle tr-PM2.5 exposure contributing to total personal pollution exposure. Trip characteristics, including time of day, day of the week, and traffic congestion, are associated with in-vehicle PM2.5 exposures. We hypothesized that some commuter characteristics, such as whether commuters travel primarily during rush hour, would also be associated with increased tr-PM2.5 exposures. The commute data consisted of unscripted personal vehicle trips of 46 commuters in the Washington, D.C. metro area over 48-h, with a total of 320 trips. We identified commuter types using sparse K-means clustering, which identifies the hours throughout the day important for clustering commuters. Source-specific PM2.5 over 48 h was estimated using Positive Matrix Factorization. Linear regression was used to estimate differences in source-specific PM2.5 by commuter cluster. Two commuter clusters were identified using the clustering approach: rush hour commuters, who primarily travelled during rush hour, and sporadic commuters, who travelled throughout the day. The hours given the largest weights by sparse K-means were 7-8 a.m. and 6-7 p.m., corresponding to peak travel times. Integrated black carbon (BC) was higher for rush hour commuters (median = 3.1 µg/m3 (IQR = 1.5)) compared to sporadic commuters (2.0 µg/m3 (IQR = 1.9)). Mobile PM2.5, consisting primarily of tailpipe emissions and brake/tire wear, was also higher for rush hour commuters (2.9 µg/m3 (IQR = 1.6)) compared to sporadic commuters (2.1 µg/m3 (IQR = 2.4)), though this difference was not statistically significant in regression models. Estimated differences between commuter types for secondary/mixed PM2.5 and road salt PM2.5 were smaller. Further research may elucidate whether commuter characteristics are an efficient way to identify individuals with highest tr-PM2.5 exposures associated with commuting and to develop effective mitigation strategies.

Chronic exposure to air pollution and risk of mental health disorders complicating pregnancy.

BACKGROUND: Air pollution is associated with mental health in the general population, but its influence on maternal mental health during pregnancy has not been assessed. OBJECTIVE: We evaluated the relationship between unspecified mental disorders complicating pregnancy and depression with average air pollution exposure during 3-months preconception, first trimester and whole pregnancy. METHODS: Ambient air pollution was derived from a modified Community Multiscale Air Quality model and mental health diagnoses were based on electronic intrapartum medical records. Logistic regression models assessed the odds of unspecified mental disorder complicating pregnancy (n = 11,577) and depression (n = 9793) associated with an interquartile range increase in particulate matter (PM) less than 2.5 µm (PM2.5), PM10, carbon monoxide (CO), nitrogen dioxide (NO2), nitrogen oxide (NOx), sulfur dioxide (SO2), and ozone (O3). Pregnancies without mental health disorders were the reference group (n = 211,645). Models were adjusted for maternal characteristics and study site; analyses were repeated using cases with no additional mental health co-morbidity. RESULTS: Whole pregnancy exposure to PM10, PM2.5, NO2, and NOx was associated with a 29%-74% increased odds of unspecified mental disorders complicating pregnancy while CO was associated with 31% decreased odds. Results were similar for depression: whole pregnancy exposure to PM10, PM2.5, NO2, and NOx was associated with 11%-21% increased odds and CO and O3 were associated with 16%-20% decreased odds. SO2 results were inconsistent, with increased odds for unspecified mental disorders complicating pregnancy and decreased odds for depression. While most findings were similar or stronger among cases with no co-morbidity, PM2.5 and NOx were associated with reduced risk and SO2 with increased risk for depression only. DISCUSSION: Whole pregnancy exposure to PM10, PM2.5, NO2, and NOx were associated with unspecified mental disorder complicating pregnancy and depression, but some results varied for depression only. These risks merit further investigation.

Associations between blood cadmium and endocrine features related to PCOS-phenotypes in healthy women of reproductive age: a prospective cohort study.

BACKGROUND: Cadmium is an endocrine disrupting chemical that affects the hypothalamic-pituitary-gonadal axis. Though evidence suggests its potential role in altering androgen synthesis and metabolic pathways that are characteristic of polycystic ovary syndrome (PCOS), its relation in healthy women of reproductive age is largely unknown. As women with mild sub-clinical features of PCOS who do not meet the diagnostic criteria of PCOS may still experience reduced fecundability, investigating associations between cadmium and PCOS-phenotypes among healthy women may provide unique insight into the reproductive implications for many on the PCOS spectrum. Therefore, the objective of this study was to evaluate associations between cadmium and androgens, anti-Müllerian hormone (AMH), and metabolic markers in women of reproductive age. METHODS: This was a prospective cohort study of 251 healthy premenopausal women without self-reported PCOS (mean age 27.3 years and BMI 24.1 kg/m2). Cadmium was measured in blood collected at baseline. Reproductive hormones and metabolic markers were measured in fasting serum 8 times per menstrual cycle for 2 cycles. Linear mixed models and Poisson regression with a robust error variance were used to examine associations between cadmium and reproductive hormones and metabolic markers and anovulation, respectively. RESULTS: Median (interquartile range) blood cadmium concentrations at baseline were 0.30 (0.19-0.43) µg/L. Higher levels of testosterone (2.2 %, 95 % confidence interval [CI] 0.4, 4.1), sex hormone-binding globulin (2.9 %, 95 % CI 0.5, 5.5), and AMH (7.7 %, 95 % CI 1.1, 14.9) were observed per 0.1 µg/L increase in cadmium concentrations. An 18 % higher probability of a mild PCOS-phenotype (95 % CI 1.06, 1.31), defined by a menstrual cycle being in the highest quartile of cycle-averaged testosterone and AMH levels, was also found per 0.1 µg/L increase in cadmium levels. No associations were observed for insulin and glucose. These findings were consistent even after analyses were restricted to non-smokers or further adjusted for dietary factors to account for potential sources of exposure. CONCLUSIONS: Overall, among healthy reproductive-aged women, cadmium was associated with endocrine features central to PCOS, but not with metabolic markers. These suggest its potential role in the hormonal milieu associated with PCOS even at low levels of exposure.

Vital Status Ascertainment for a Historic Diverse Cohort of U.S. Women.

BACKGROUND: Studies linking large pregnancy cohorts with mortality data can address critical questions about long-term implications of gravid health, yet relevant US data are scant. We examined the feasibility of linking the Collaborative Perinatal Project, a large multiracial U.S. cohort study of pregnant women (n = 48,197; 1959-1966), to death records. METHODS: We abstracted essential National Death Index (NDI) (1979-2016) (n = 46,428). We performed a linkage to the Social Security Administration Death Master File through 2016 (n = 46,450). Genealogists manually searched vital status in 2016 for a random sample of women (n = 1,249). We conducted agreement analyses for women with abstracted data among the three sources. As proof of concept, we calculated adjusted associations between mortality and smoking and other sociodemographic factors using Cox proportional hazards regression. RESULTS: We successfully abstracted identifying information for most of the cohort (97%). National Death Index identified the greatest proportion of participants deceased (35%), followed by genealogists (31%) and Death Master File (23%). Estimates of agreement (κ [95% confidence interval]) between National Death Index and Death Master File were lower (0.52 [0.51, 0.53]) than for National Death Index and genealogist (0.66 [0.61, 0.70]). As expected, compared with nonsmokers, smoking ≥1 pack per day was associated with elevated mortality for all vital sources and was strongest for National Death Index. CONCLUSIONS: Linking this historic cohort with mortality records was feasible and agreed reasonably on vital status when compared with other data sources. Such linkage enables future examination of pregnancy conditions in relation to mortality in a diverse U.S. cohort.

Urinary levels of environmental phenols and parabens and antioxidant enzyme activity in the blood of women.

BACKGROUND: The balance between oxidative stress and antioxidant enzymes is one biological mechanism by which environmental and lifestyle exposures affect health outcomes. Yet, no studies have examined the relationship between environmental phenolic compounds and parabens or their mixtures in relation to antioxidant enzyme activity in women of reproductive age. METHODS: Sixteen environmental phenols and parabens were measured in urine 2-5 times across two months of follow-up in 143 women aged 18-44 years. Four antioxidant enzymes, erythrocyte and plasma glutathione peroxidase (eGPx, pGPx), glutathione reductase (GSHR), superoxide dismutase (SOD) were measured in plasma. Linear mixed models were adjusted for age, body mass index, race, and creatinine and were weighted with inverse probability of exposure weights. Multi-chemical exposures were estimated using hierarchical principal component analysis (PCA). RESULTS: In line with our hypothesis that environmental phenols and parabens would be associated with decreased antioxidant enzymes, butyl, benzyl, ethyl, and propyl parabens were associated with lower levels of eGPx. Methyl paraben, 2,4-dichlorophenol and 2,5-dichlorophenol were associated with reduced SOD. 2,4,6-trichlorophenol was associated with increased levels of pGPx and GSHR. Several parabens were associated with modest decreases in eGPx and SOD, biomarkers of antioxidant defense. Increases in pGPx and GSHR were noted in relation to butyl and ethyl parabens. Co-exposures to parabens were associated with decreased eGPx (ß = -1.08, 95% CI: -1.74, -0.43) in principal components mixed models, while co-exposure to benzophenones-3 and -1 were associated with increased eGPx (ß = 0.92, 95% CI: 0.20, 1.64). CONCLUSION: These findings indicate that nonpersistent chemicals altered antioxidant enzyme activity. Further human studies are necessary to delineate the relationship between environmental phenol and paraben exposures with erythrocyte and plasma activities of antioxidant enzymes.

Estimating exposure to traffic-related PM2.5 for women commuters using vehicle and personal monitoring.

Exposure to traffic-related fine particulate matter air pollution (tr-PM2.5) has been associated with adverse health outcomes including preterm birth and low birthweight. In-vehicle exposure to tr-PM2.5 can contribute substantially to total tr-PM2.5 exposure. Because average commuting habits of women differ from men, a research gap is estimating in-vehicle tr-PM2.5 exposures for women commuters. For 46 women commuters in the Washington, D.C. metro area, we measured personal exposure to PM2.5 during all vehicle trips taken in a 48-h sampling period. We also measured 48-h integrated PM2.5 chemical constituents including black carbon and zinc. We identified trip times using vehicle monitors, specifically on-board diagnostics data loggers and dashboard cameras. For 386 trips, we estimated associations between PM2.5 exposure and trip characteristics using linear mixed models accounting for participant, day, and time of day. Additionally, we estimated associations between rush hour trip PM2.5 and 48-h integrated PM2.5 chemical constituents using linear models. Exposure to PM2.5 during trips was 1.9 µg/m3 (95% confidence interval (CI): 0.9, 2.9) higher than non-trip exposures and rush hour trip exposures were 3.2 µg/m3 (95% CI: 1.8, 4.6) higher than non-trip exposures on average. We did not find differences in PM2.5 exposure by trip length. Although concentrations of tr-PM2.5 chemical constituents were generally positively associated with rush hour trip PM2.5, associations were weak indicating that other settings contribute to total tr-PM2.5 exposure. Our study demonstrates the utility of combining vehicle monitors and personal PM2.5 monitors for estimating personal exposure to tr-PM2.5. Future work will investigate whether additional data collected by vehicle monitors, such as traffic and speed, can be leveraged to better understand tr-PM2.5 exposure among commuters.

Combining Biomarker Calibration Data to Reduce Measurement Error.

Biomarker assay measurement often consists of a two-stage process where laboratory equipment yields a relative measure which is subsequently transformed to the unit of interest using a calibration curve. The calibration curve establishes the relation between the measured relative units and sample biomarker concentrations using stepped samples of known biomarker concentrations. Samples from epidemiologic studies are often measured in multiple batches or plates, each with independent calibration experiments. Collapsing calibration information across batches before statistical analysis has been shown to reduce measurement error and improves estimation. Additionally, collapsing in practice can also create an additional layer of quality control (QC) and optimization in a part of the laboratory measurement process that is often highly automated. Principled recalibration is demonstrated via. a three-step process of identifying batches where recalibration might be beneficial, forming a collapsed calibration curve and recalibrating identified batches, and using QC data to assess the appropriateness of recalibration. Here, we use inhibin B measured in biospecimens from the BioCycle study using 50 enzyme-linked immunosorbent assay (ELISA) batches (3875 samples) to motivate and display the benefits of collapsing calibration experiments, such as detecting and overcoming faulty calibration experiments, and thus improving assay coefficients of variation from reducing unwanted measurement error variability. Differences in the analysis of inhibin B by testosterone quartile are also demonstrated before and after recalibration. These simple and practical procedures are minor adjustments implemented by study personnel without altering laboratory protocols which could have positive estimation and cost-saving implications especially for population-based studies.

Tampon use, environmental chemicals and oxidative stress in the BioCycle study.

BACKGROUND: Tampons are used by up to 86% of US women and are a rarely considered potential source of pesticide and metal exposure. Tampons may be of particular concern given the likely higher absorption that occurs in the vagina. Our objective was to examine the potential associations between tampon use and metal concentrations, and biomarkers of inflammation and oxidative stress among healthy women. METHODS: We used information from a prospective cohort of 259 regularly menstruating women, aged 18-44, followed for two menstrual cycles. Tampon use was assessed using information provided in participant study diaries. Metal concentrations were measured from a blood sample collected at enrollment. Oxidative stress and inflammation biomarker concentrations were determined from blood samples collected at up to 8 clinic visits for each cycle. Linear regression models were used to estimate associations of tampon use with metal exposure, and linear mixed models to estimate associations of tampon use with inflammation and oxidative stress biomarkers at different times during the menstrual cycle. RESULTS: We observed non-significantly higher mean levels of mercury for tampon users compared to non-tampon users (exp(ß) = 1.25, 95% CI = 0.93, 1.68). We found no evidence of an association between tampon use and inflammation biomarkers. We observed consistently higher isoprostane levels, an oxidative stress biomarker, among tampon users compared to non-tampon users (e.g. exp.(ß) = 1.05, 95%CI = 0.96, 1.16, for the average isoprostane during the menstruating week); however, these results were not statistically significant. CONCLUSIONS: While our results are not statistically significant, we observed suggestive associations between tampon use and elevated levels of mercury and oxidative stress biomarkers. Although our finding should be interpreted in light of our limitations, they indicate that tampons may be a source of exposure to metals and chemicals that have been largely ignored, and any related health effects are an important public health concern.

Blood lead, cadmium and mercury in relation to homocysteine and C-reactive protein in women of reproductive age: a panel study.

BACKGROUND: To examine the relationship between cadmium, lead, and mercury concentrations with high-sensitivity C-reactive protein (hs-CRP) and homocysteine in women. METHODS: Metals were measured at enrollment in whole blood. Homocysteine and hs-CRP were measured in one (N = 9) or two (N = 250) menstrual cycles up to 3 and 8 times per cycle, respectively. Linear mixed models with inverse probability of exposure weights to account for time varying confounding were used and models were stratified by dietary and serum vitamin status (dietary: vitamin B6, B12, folate; serum: folate). RESULTS: Geometric mean (95% confidence interval (CI)) concentrations for cadmium, lead, and mercury were 0.29 (0.26-0.31) µg/L, 0.91 (0.86-0.96) µg/dL, and 1.05 (0.93-1.18) µg/L, respectively. Lead was associated with increased homocysteine (0.08; 95% CI: 0.01, 0.15) and this persisted among those in the lower three quartiles of consumption of vitamin B6, B12, folate, and serum folate but was not significant among those in the upper quartile. No associations were observed between metals and hs-CRP. CONCLUSIONS: Blood lead was associated with increased homocysteine in a cohort of healthy, premenopausal women but these associations did not persist among those consuming ≥75th percentile of essential micronutrients. Cadmium, lead, and mercury were not associated with hs-CRP concentrations.