Exposure to acute ambient temperature extremes and neonatal intensive care unit admissions: A case-crossover study.

BACKGROUND: Extreme in utero temperatures have been associated with adverse birth outcomes, including preterm birth and low birthweight. However, there is limited evidence on associations with neonatal intensive care unit (NICU) admissions, which reflect a range of poor neonatal health outcomes. METHODS: This case-crossover study assesses the associations between ambient temperature changes during the week of delivery and risk of NICU admission. Data from the Consortium on Safe Labor (2002-2008) were linked to ambient temperature at hospital referral regions. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) estimated NICU admission risk with a 1 °C increase on each day of the week of delivery and of the average weekly temperature, adjusted for particulate matter ≤2.5 µm (PM2.5) and relative humidity. We also estimated associations with 1 °C increases and 1 °C decreases in temperatures during weeks of site-specific extreme heat (>90th and 95th percentiles) and cold (<5th and 10th percentiles), respectively. RESULTS: There were 27,188 NICU admissions with median (25th, 75th) temperature of 16.4 °C (5.8, 23.0) during the week before delivery. A 1 °C increase in temperature during the week of delivery was not associated with risk of NICU admission. However, analyses of extreme temperatures found that a 1 °C decrease in weekly average temperatures below the 10th and 5th percentiles was associated with 30 % (aHR = 1.30, 95 % CI 1.28, 1.31) and 47 % (aHR = 1.47, 95 % CI 1.45, 1.50) increased risk of NICU admissions, while a 1 °C increase in weekly average temperatures above the 90th and 95th percentiles was associated with more than two- (aHR = 2.29, 95 % CI 2.17, 2.42) and four-fold (aHR = 4.30, 95 % CI 3.68, 5.03) higher risk of NICU admission, respectively. CONCLUSIONS: Our study found temperature extremes in the week before delivery increased NICU admission risk, particularly during extreme heat, which may translate to more adverse neonatal outcomes as extreme temperatures persist.

Cesarean delivery, labor duration and mothers' mortality risk over 50 years of follow-up: Cesarean delivery and maternal mortality.

BACKGROUND: Pregnancy complications have been recognized as a window to future health. Though cesarean delivery is common, it is unknown whether labor duration and mode of delivery are associated with maternal long-term mortality. OBJECTIVES: To examine whether labor duration and mode of delivery were associated with all-cause and cause-specific mortality. STUDY DESIGN: Participants were mothers from the multisite Collaborative Perinatal Project cohort (1959-1966; n=43646, limited to last Collaborative Perinatal Project delivery). We ascertained all-cause and specific causes of death as of 2016 via linkage to the National Death Index and Social Security Death Master File. Hazard ratios testing mode of delivery and labor duration were estimated using Cox proportional hazards models adjusted for demographic and clinical characteristics. We further stratified analyses by parity. RESULTS: Among participants with a recorded delivery mode, 5.9% (2486/42335) had a cesarean delivery. Participants who had a cesarean were older (26.9 versus 24.3 years), with higher BMI (24.0 versus 22.7 kg/m2), were less likely to be nulliparous (21% versus 30%), and more likely to have a household income of at least $6000 (22% versus 17%), to smoke ≥1 pack/day (18% versus 15%), to have diabetes mellitus (12% versus 1%) and to have a prior medical condition (47% versus 34%), compared to participants with a vaginal delivery. Delivery mode was similar by race/ethnicity, marital status, and education. Median labor duration was 395 minutes among participants who had an intrapartum cesarean delivery and 350 minutes among participants delivered vaginally. By 2016, 52.2% of participants with a cesarean delivery and 38.5% of participants with a vaginal delivery had died. Cesarean versus vaginal delivery was significantly associated with increased risk for all-cause mortality (hazard ratio = 1.16 (95% confidence interval: 1.09, 1.23); in nulliparas, hazard ratio = 1.27 (95% confidence interval: 1.09, 1.47); in multiparas, hazard ratio = 1.13 (95% confidence interval: 1.06, 1.21)) as well as increased risk of death from cardiovascular disease, diabetes, respiratory disease, infection, and kidney disease. Associations with death from cardiovascular disease, infection and kidney disease were stronger for multiparas than nulliparas, though the association with death from diabetes was stronger among nulliparas. Labor duration was not significantly related to overall mortality. CONCLUSIONS: In a historic United States cohort with a low cesarean delivery rate, cesarean delivery was an indicator for subsequent increased mortality risk, particularly related to cardiovascular disease and diabetes. Future studies with long-term follow-up are warranted given the current high prevalence of cesarean delivery.

Gestational exposure to wildfire PM2.5 and its specific components and the risk of gestational hypertension and eclampsia in the southwestern United States.

In the southwestern United States, the frequency of summer wildfires has elevated ambient PM2.5 concentrations and rates of adverse birth outcomes. Notably, hypertensive disorders in pregnancy (HDP) constitute a significant determinant associated with maternal mortality and adverse birth outcomes. Despite the accumulating body of evidence, scant research has delved into the correlation between chemical components of wildfire PM2.5 and the risk of HDP. Derived from data provided by the National Center for Health Statistics, singleton births from >2.68 million pregnant women were selected across 8 states (Arizona, AZ; California, CA, Idaho, ID, Montana, MT; Nevada, NV; Oregon, OR; Utah, UT, and Wyoming, WY) in the southwestern US from 2001 to 2004. A spatiotemporal model and a Goddard Earth Observing System chemical transport model were employed to forecast daily concentrations of total and wildfire PM2.5-derived exposure. Various modeling techniques including unadjusted analyses, covariate-adjusted models, propensity-score matching, and double robust typical logit models were applied to assess the relationship between wildfire PM2.5 exposure and gestational hypertension and eclampsia. Exposure to fire PM2.5, fire-sourced black carbon (BC) and organic carbon (OC) were associated with an augmented risk of gestational hypertension (ORPM2.5 = 1.125, 95 % CI: 1.109,1.141; ORBC = 1.247, 95 % CI: 1.214,1.281; OROC = 1.153, 95 % CI: 1.132, 1.174) and eclampsia (ORPM2.5 = 1.217, 95 % CI: 1.145,1.293; ORBC = 1.458, 95 % CI: 1.291,1.646; OROC = 1.309, 95 % CI: 1.208,1.418) during the pregnancy exposure window with the strongest effect. The associations were stronger that the observed effects of ambient PM2.5 in which the sources primarily came from urban emissions. Social vulnerability index (SVI), education years, pre-pregnancy diabetes, and hypertension acted as effect modifiers. Gestational exposure to wildfire PM2.5 and specific chemical components (BC and OC) increased gestational hypertension and eclampsia risk in the southwestern United States.

Target trial emulation of preconception serum vitamin D status on fertility outcomes: a couples-based approach.

OBJECTIVE: To evaluate associations between preconception 25-hydroxyvitamin D (25(OH)D) levels and biomarkers in female and male partners on live birth (LB), pregnancy loss, and semen quality. DESIGN: Secondary analysis using the folic acid and zinc supplementation trial of couples seeking infertility treatment at four US centers (2013-2017). A target trial emulation framework was applied to estimate associations. Couples were observed for 9 months or through pregnancy. SETTING: Clinics that provide reproductive endocrinology and infertility care in the US. PATIENT(S): Couples seeking infertility treatment. INTERVENTION(S): Preconception concentrations of 25(OH)D (primary) and associated biomarkers: vitamin D binding protein, calcium, free vitamin D, bioavailable vitamin D. MAIN OUTCOME MEASURE(S): Live birth and pregnancy loss were ascertained via self-report and medical records. Semen quality was ascertained 6 months after enrollment. Log-binomial regression estimated risk ratios and 95% confidence intervals (CIs). Individual and joint models and effect measure modification by preconception body mass index were considered. RESULT(S): Among 2,370 couples, 19.5% of females and 29.9% of males were 25(OH)D deficient. Females with sufficient status had a 28%-higher likelihood of LB than deficient females (95% CI, 1.05-1.56). Female and male 25(OH)D status were associated with LB among those with normal body mass index (sufficient vs. deficient: female adjusted risk ratio [aRR], 1.39; 95% CI, 1.00-1.99; male aRR, 1.51; 95% CI, 1.01-2.25) and among obese female partners (sufficient vs. deficient: aRR, 1.33; 95% CI, 0.95-1.85). Couples whose both partners had higher 25(OH)D status had increased likelihood of LB (both not deficient vs. both deficient aRR, 1.26; 95% CI, 1.00-1.58). No associations were observed with pregnancy loss or semen quality. Similar results were found for all biomarkers except calcium. CONCLUSION(S): Preconception vitamin D status and bioavailability impact fertility among couples seeking infertility therapy, likely unrelated to semen quality. Body mass index stratified analyses demonstrated heterogeneous associations. CLINICAL TRIAL REGISTRATION NUMBER: NCT01857310.

The Association of Female and Male Preconception Dyslipidemia with Live Birth in Couples Seeking Fertility Treatment.

CONTEXT: Dyslipidemia is common, and resultant endothelial dysfunction may impact reproductive outcomes. No prospective study has examined the effect of preconception lipid parameters in both female and male partners or their interaction on live birth. OBJECTIVE: To determine whether live birth is associated with preconception lipids in both partners by planned fertility treatment. DESIGN: Secondary analysis of the Folic Acid and Zinc Supplementation Trial, conducted between June 2013-December 2017. Couples were followed for nine months after randomization and until delivery. SETTING: Multicenter study. PARTICIPANTS: Couples seeking fertility treatment (n = 2370; females 18-45 years, males ≥18 years). EXPOSURES: Female, male, and couple abnormal versus normal preconception lipid concentrations (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides [TG]). MAIN OUTCOME MEASURES: Live birth. RESULTS: Among 2370 couples, most males (84%) and females (76%) had at least one abnormal lipid parameter. Males planning in vitro fertilization (IVF, n = 373) with elevated LDL had lower probability of live birth than those with normal levels (47.4% vs. 59.7%, aRR 0.79, 95% CI 0.65-0.98). In couples planning IVF where both partners had elevated TC or LDL, live birth was lower than those with normal levels (TC: 32.4% vs. 58.0%, aRR 0.53, 95% CI 0.36-0.79; and LDL: 41.9% vs. 63.8%, aRR 0.69, 95% CI 0.55-0.85). Lipid parameters were not associated with live birth for couples planning non-IVF treatments. CONCLUSIONS: Couples planning IVF where both partners had elevated TC or LDL and males planning IVF with elevated LDL had decreased probability of live birth. These findings may support lipid screening in patients seeking fertility treatment for prognostic information for reproductive outcomes.

Association between maternal cigarette smoking cessation and risk of preterm birth in Western New York.

BACKGROUND: Although many studies suggested the benefit of smoking cessation among pregnant women in reducing the risk of preterm birth (PTB), the timing of the effect of the cessation remains inconclusive. OBJECTIVES: To examine the association of trimester-specific smoking cessation behaviours with PTB risk. METHODS: We included 199,453 live births in Western New York between 2004 and 2018. Based on self-reported cigarette smoking during preconception and in each trimester, we created six mutually exclusive groups: non-smokers, quitters in each trimester, those who smoked throughout pregnancy, and inconsistent smokers. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using Poisson regression to examine the association between smoking cessation and PTB. Effect modification by illegal drug use, maternal age, race and ethnicity and pre-pregnancy body mass index (BMI) was investigated multiplicatively by ratio of relative risk and additively by relative excess risk due to interaction (RERI). RESULTS: Overall, 6.7% of women had a PTB; 14.1% smoked throughout pregnancy and 3.4%, 1.8% and 0.8% reported quitting smoking during the first, second and third trimesters, respectively. Compared to non-smokers, third-trimester cessation (RR 1.20, 95% CI 1.01, 1.43) and smoking throughout pregnancy (RR 1.27, 95% CI 1.21, 1.33) were associated with a higher PTB risk, while quitting smoking during the first or second trimester, or inconsistent smoking was not associated with PTB. A positive additive interaction was identified for maternal age and late smoking cessation or smoking throughout pregnancy on PTB risk (RERI 0.17, 95% CI 0.00, 0.36), and a negative interaction was observed for pre-pregnancy BMI ≥30 kg/m2 (ratio of relative risk 0.70, 95% CI 0.63, 0.78; RERI -0.42, 95% CI -0.56, -0.30). CONCLUSION: Compared to non-smokers, smoking throughout pregnancy and third-trimester smoking cessation are associated with an increased risk of PTB, while quitting before the third trimester may not increase PTB risk.

Prenatal exposure to air pollutant mixtures and birthweight in the upstate KIDS cohort.

BACKGROUND: Single-pollutant models have linked prenatal PM2.5 exposure to lower birthweight. However, analyzing air pollutant mixtures better captures pollutant interactions and total effects. Unfortunately, strong correlations between pollutants restrict traditional methods. OBJECTIVES: We explored the association between exposure to a mixture of air pollutants during different gestational age windows of pregnancy and birthweight. METHODS: We included 4,635 mother-infant dyads from a New York State birth cohort born 2008-2010. Air pollution data were sourced from the EPA's Community Multiscale Air Quality model and matched to the census tract centroid of each maternal home address. Birthweight and gestational age were extracted from vital records. We applied linear regression to study the association between prenatal exposure to PM2.5, PM10, NOX, SO2, and CO and birthweight during six sensitive windows. We then utilized Bayesian kernel machine regression to examine the non-linear effects and interactions within this five-pollutant mixture. Final models adjusted for maternal socio-demographics, infant characteristics, and seasonality. RESULTS: Single-pollutant linear regression models indicated that most pollutants were associated with a decrement in birthweight, specifically during the two-week window before birth. An interquartile range increase in PM2.5 exposure (IQR: 3.3 µg/m3) from the median during this window correlated with a 34 g decrement in birthweight (95 % CI: -54, -14), followed by SO2 (IQR: 2.0 ppb; ß: -31), PM10 (IQR: 4.6 µg/m3; ß: -29), CO (IQR: 60.8 ppb; ß: -27), and NOX (IQR: 7.9 ppb; ß: -26). Multi-pollutant BKMR models revealed that PM2.5, NOX, and CO exposure were negatively and non-linearly linked with birthweight. As the five-pollutant mixture increased, birthweight decreased until the median level of exposure. DISCUSSION: Prenatal exposure to air pollutants, notably PM2.5, during the final two weeks of pregnancy may negatively impact birthweight. The non-linear relationships between air pollution and birthweight highlight the importance of studying pollutant mixtures and their interactions.

Place-Based Child Opportunity at Birth and Child Development from Infancy to Age 4.

OBJECTIVE: The objective of this study was to evaluate whether the children's neighborhood quality, as a measure of place-based social determinants of health, is associated with the odds of developmental delay and developmental performance up to the age of 4 years. STUDY DESIGN: Mothers of 5702 children from the Upstate KIDS Study, a longitudinal population-based cohort of children born from 2008 through 2010, provided questionnaire data and a subset of 573 children participated in a clinic visit. The Child Opportunity Index 2.0 was linked to home census tract at birth. Probable developmental delays were assessed by the Ages and Stages Questionnaire up to 7 times between 4 and 36 months, and developmental performance was assessed via the Battelle Developmental Inventory at the age of 4 years. RESULTS: In unadjusted models, higher neighborhood opportunity was protective against developmental delays and was associated with slightly higher development scores at age 4. After adjusting for family-level confounding variables, 10-point higher Child Opportunity Index (on a 100-point scale) remained associated with a lower odds of any developmental delay (OR = .966, 95% CI = .940-.992), and specifically delays in the personal-social domain (OR = .921, 95% CI = .886-.958), as well as better development performance in motor (B = 0.79, 95% CI = 0.11-1.48), personal-social (B = 0.64, 95% CI = 0.003-1.28), and adaptive (B = 0.69, 95% CI = 0.04-1.34) domains at age 4. CONCLUSIONS: Community-level opportunities are associated with some aspects of child development prior to school entry. Pediatric providers may find it helpful to use neighborhood quality as an indicator to inform targeted developmental screening.

Impact of cash transfers on the association between prenatal exposures to high temperatures and low birthweight: Retrospective analysis from the LEAP 1000 study.

OBJECTIVE: To explore the associations between prenatal temperature exposures and low birthweight (LBW) and modification by cash transfer (CT) receipt. DESIGN: Retrospective cohort study. SETTING: Five rural districts in Northern Ghana. POPULATION OR SAMPLE: A total of 3016 infants born to women interviewed as part of the Livelihood Empowerment Against Poverty (LEAP 1000) impact evaluation between 2015 and 2017. METHODS: Birthweight was collected using household surveys administered to LEAP 1000 eligible women. We used a UNICEF-developed multiple imputation approach to address missingness of birthweight and applied an empirical heaping correction to the multiply imputed birthweight data. Survey data were linked to the European Centre for Medium-Range Weather Forecasts Reanalysis 5-hourly temperature averaged to weeks for 2011-2017 using community centroids. Using distributed-lag nonlinear models, we explored the lag-specific associations between weekly average temperatures greater than 30°C and LBW, and stratified by LEAP 1000 treatment. MAIN OUTCOME MEASURES: Low birthweight (<2.5 kg). RESULTS: Twelve percent (n = 365) of infants were LBW; the mean ± SD birthweight was 3.02 ± 0.37 kg. Overall, increasing temperatures were associated with increased odds of LBW, with the greatest odds observed in the 3 weeks before birth (odds ratio 1.005-1.025). These positive associations were even larger among comparison infants and null among treatment infants. CONCLUSIONS: Our study found increased odds of LBW with high weekly average temperatures throughout pregnancy and the preconception period and demonstrate mitigated effects by the LEAP 1000 CT program. More evidence on the potential of CTs to serve as adaptation interventions in low- and middle-income countries is needed to protect pregnant persons and their infants from the impacts of climate change.

Adverse pregnancy outcomes and risk of type 2 diabetes in postmenopausal women.

BACKGROUND: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established. OBJECTIVE: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women. STUDY DESIGN: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth. RESULTS: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes. CONCLUSION: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus.

History of multifetal gestation and long-term maternal mortality.

BACKGROUND: Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. OBJECTIVES: We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S. METHODS: We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality). RESULTS: Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96). CONCLUSIONS: In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality.

Association of prenatal exposure to PM2.5 and NO2 with gestational diabetes in Western New York.

BACKGROUND: Although many studies have examined the association between prenatal air pollution exposure and gestational diabetes (GDM), the relevant exposure windows remain inconclusive. We aim to examine the association between preconception and trimester-specific exposure to PM2.5 and NO2 and GDM risk and explore modifying effects of maternal age, pre-pregnancy body mass index (BMI), smoking, exercise during pregnancy, race and ethnicity, and neighborhood disadvantage. METHODS: Analyses included 192,508 birth records of singletons born to women without pre-existing diabetes in Western New York, 2004-2016. Daily PM2.5 and NO2 at 1-km2 grids were estimated from ensemble-based models. We assigned each birth with exposures averaged in preconception and each trimester based on residential zip-codes. We used logistic regression to examine the associations and distributed lag models (DLMs) to explore the sensitive windows by month. Relative excess risk due to interaction (RERI) and multiplicative interaction terms were calculated. RESULTS: GDM was associated with PM2.5 averaged in the first two trimesters (per 2.5 µg/m3: OR = 1.08, 95% CI: 1.01, 1.14) or from preconception to the second trimester (per 2.5 µg/m3: OR = 1.10, 95% CI: 1.03, 1.18). NO2 exposure during each averaging period was associated with GDM risk (per 10 ppb, preconception: OR = 1.10, 95% CI: 1.06, 1.14; first trimester: OR = 1.12, 95% CI: 1.08, 1.16; second trimester: OR = 1.10, 95% CI: 1.06, 1.14). In DLMs, sensitive windows were identified in the 5th and 6th gestational months for PM2.5 and one month before and three months after conception for NO2. Evidence of interaction was identified for pre-pregnancy BMI with PM2.5 (P-for-interaction = 0.023; RERI = 0.21, 95% CI: 0.10, 0.33) and with NO2 (P-for-interaction = 0.164; RERI = 0.16, 95% CI: 0.04, 0.27). CONCLUSION: PM2.5 and NO2 exposure may increase GDM risk, and sensitive windows may be the late second trimester for PM2.5 and periconception for NO2. Women with higher pre-pregnancy BMI may be more susceptible to exposure effects.

Preconception Phthalate Exposure and Women's Reproductive Health: Pregnancy, Pregnancy Loss, and Underlying Mechanisms.

BACKGROUND: Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive. OBJECTIVES: We aimed to determine the relationship of preconception phthalate metabolite exposure with a) fecundability and pregnancy loss and b) markers of potential biological mechanisms, including reproductive hormones, inflammation, and oxidative stress. METHODS: Data were collected from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a preconception study following 1,228 women who were attempting pregnancy, for up to six menstrual cycles and throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a consecutive 3-d pooled urine sample at enrollment. Pregnancy was determined through urinary human chorionic gonadotropin (hCG) at the expected date of menses during each cycle and pregnancy loss as an observed loss following positive hCG. Highly sensitive C-reactive protein (hsCRP) and isoprostanes were measured at enrollment, and reproductive hormones were measured during the follicular phase, ovulation, and luteal phase. Discrete-time Cox proportional hazards models evaluated the relationship of phthalate metabolites with fecundability and weighted Poisson models with robust variance evaluated the risk of pregnancy loss. RESULTS: An interquartile range (IQR) higher mono-(2-ethylhexyl) phthalate [fecundability odds ratio (FOR)=0.88; 95% confidence interval (CI): 0.78, 1.00], mono-butyl phthalate (FOR=0.82; 95% CI: 0.70, 0.96), and mono-benzyl phthalate (FOR=0.85; 95% CI: 0.74, 0.98) was associated with lower fecundability. No consistent associations were observed with pregnancy loss. Preconception phthalates were consistently associated with higher hsCRP and isoprostanes, as well as lower estradiol and higher follicle-stimulating hormone across the menstrual cycle. DISCUSSION: Women's preconception exposure to phthalates was associated with lower fecundability, changes in reproductive hormones, and increased inflammation and oxidative stress. The pre- and periconception periods may represent sensitive windows for intervening to limit the reproductive toxicity of phthalate exposure. https://doi.org/10.1289/EHP12287.

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.

Longitudinal Child Growth Patterns in Twins and Singletons in the Upstate KIDS Cohort.

OBJECTIVES: To investigate childhood growth patterns in twins and to determine whether they show the same signs of excess growth as singletons born small-for-gestational age (SGA), which may confer future cardiometabolic risk. STUDY DESIGN: In the Upstate KIDS cohort of infants delivered from 2008 through 2010, we compared height, weight, and body mass index (BMI) z-scores at 0-3 and 7-9 years of age, as well as risk of rapid weight gain (RWG) in infancy and overweight/obesity beginning at 2 years, among appropriate-for-gestational age (AGA) twins (n = 1121), AGA singletons (n = 2684), and two groups of SGA twins: uncertain SGA twins (<10th percentile for birthweight by a singleton reference but >10th% by a population-based twin birthweight reference; n = 319) and true SGA twins (<10th% by a population-based twin reference; n = 144). RESULTS: Compared with AGA twins, both SGA twin groups had lower weight and BMI z-scores at both time points. By 7-9 years, both groups caught up in height with AGA twins. Compared with AGA singletons, z-score differences decreased between 0-3 and 7-9 years for uncertain SGA and true SGA twins, though true SGA twins had the lowest z-scores for all measures. During infancy, twins were more likely to display RWG compared with AGA singletons (RR = 2.06 to 2.67), which may reflect normal catch-up growth, as no twin group had higher prevalence of overweight/obesity at either time point. CONCLUSIONS: Though twins had lower height, weight, and BMI z-scores at birth and into toddlerhood, differences were reduced by 7-9 years, with no evidence of pathological growth and no group of twins showing elevated risk of overweight/obesity.

Indoor air pollution exposure and early childhood development in the Upstate KIDS Study.

BACKGROUND: Limited human studies have investigated the impact of indoor air pollution on early childhood neurodevelopment among the US population. We aimed to examine the associations between prenatal and postnatal indoor air pollution exposure and early childhood development in a population-based birth cohort. METHODS: This analysis included 4735 mother-child pairs enrolled between 2008 and 2010 in the Upstate KIDS Study. Indoor air pollution exposure from cooking fuels, heating fuels, and passive smoke during pregnancy, and at 12 and 36 months after birth were assessed by questionnaires. Five domains of child development were assessed by the Ages and Stages Questionnaire at 4, 8, 12, 18, 24, 30, and 36 months. Generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Exposure to unclean cooking fuels (natural gas, propane, or wood) throughout the study period was associated with increased odds of failing any development domain (OR = 1.28, 95% CI 1.07, 1.53), the gross motor domain (OR = 1.52, 95% CI: 1.09, 2.13), and the personal-social domain (OR = 1.36, 95% CI: 1.00, 1.85), respectively. Passive smoke exposure throughout the study period increased the odds of failing the problem-solving domain by 71% (OR = 1.71, 95% CI 1.01, 2.91) among children of non-smoking mothers. No association was found between heating fuel use and failing any or specific domains. CONCLUSION: Unclean cooking fuel use and passive smoke exposure during pregnancy and early life were associated with developmental delays in this large prospective birth cohort.

Maternal asthma in relation to infant size and body composition.

Background: Asthma affects 10% of pregnancies and may influence offspring health, including infant size and body composition, through hypoxic and inflammatory pathways. Objective: We sought to determine associations between maternal asthma and asthma phenotypes during pregnancy and infant size and body composition. Methods: The B-WELL-Mom study (2015-19) is a prospective cohort of 418 pregnant persons with and without asthma recruited in the first trimester of pregnancy from 2 US obstetric clinics. Exposures were maternal self-reported active asthma (n = 311) or no asthma (n = 107), and asthma phenotypes were classified on the bases of atopy, onset, exercise induced, control, severity, symptomology, and exacerbations. Outcomes were infant weight, length, head circumference, and skinfold measurements at birth and postnatal follow-up, as well as fat and lean mass assessed by air displacement plethysmography at birth. Adjusted multivariable linear regression examined associations of maternal asthma and asthma phenotypes with infant outcomes. Results: Offspring were born at a mean ± SD of 38 ± 2.3 weeks' gestation and were 18 ± 2.2 weeks of age at postnatal follow-up. Infants of participants with asthma had a mean ± SD fat mass of 11.0 ± 4.2%, birth weight of 3045.8 ± 604.3 g, and postnatal follow-up weight of 6696.4 ± 964.2 g, which were not different from infants of participants without asthma (respectively, ß [95% confidence interval]: -0.1 [-1.4, 1.3], -26.7 [-156.9, 103.4], and 107.5 [-117.3, 332.3]). Few associations were observed between asthma or asthma phenotypes and infant size or body composition. Conclusions: In a current obstetric cohort, maternal asthma during pregnancy was not associated with differential infant size or body composition.

Prenatal exposure to perceived stress, maternal asthma, and placental size.

INTRODUCTION: Prenatal exposure to stress has been associated with poor pregnancy outcomes, yet evidence linking stress and placental size is limited. Asthma is associated with worse pregnancy outcomes and women with asthma may be more susceptible to stress. Using the asthma-enriched B-WELL-Mom cohort, we examined the association between perceived stress and placental size. METHODS: Placental measures of weight, length, width, and thickness were available for 345 women (262 with asthma) via placental pathology report. Perceived Stress Scale (PSS) scores were obtained in each trimester of pregnancy and categorized into quartiles (low quartile as reference). For associations between PSS and placental size, generalized estimating equations adjusted for maternal and infant factors were used to estimate regression coefficients (ß) and 95% confidence intervals (95% CI). Full models and models stratified by asthma status were run. RESULTS: Compared to Quartile 1, high levels of stress (Quartile 4) were associated with smaller placental weight (-20.63 95% CI: -37.01,-4.26) and length (-0.55 95% CI: -0.96,-0.15), but not width or thickness. Results by asthma status show a stronger association between perceived stress and shorter placental length in those with asthma and a stronger association between perceived stress and smaller placental thickness in those without asthma. Findings were robust to sensitivity analyses DISCUSSION: Higher levels of perceived stress were associated with smaller placental size. Additional research is warranted to understand the relationship between stress and placental size.

The Association of Periconception Asthma Medication Discontinuation with Adverse Obstetric Outcomes.

OBJECTIVE: This study aimed to investigate asthma medication reduction in the periconceptional period as it relates to asthma status and adverse outcomes in pregnancy. STUDY DESIGN: In a prospective cohort study, self-reported current and past asthma medications were collected and analyzes compared measures of asthma status in women who discontinued asthma medication in the 6 months prior to enrollment ("step-down") versus those who did not ("no change"). Evaluation of asthma was done at three study visits (one per trimester) and by daily diaries, including measures of lung function (percent predicted forced expiratory volume in 1 and 6 s [%FEV1, %FEV6], peak expiratory flow [%PEF], forced vital capacity [%FVC], FEV1 to FVC ratio [FEV1/FVC]), lung inflammation (fractional exhaled nitric oxide [FeNO], ppb), rate of asthma symptoms (activity limitation, night symptoms, rescue inhaler use, wheeze, shortness of breath, cough, chest tightness, chest pain), and rate of asthma exacerbations. Adverse pregnancy outcomes were also evaluated. Adjusted regression analyses examined whether adverse outcomes differed by periconceptional asthma medication changes. RESULTS: Of 279 participants included in analyses, 135 (48.4%) did not change asthma medication in the periconceptional period, whereas 144 (51.6%) reported a step down in medication. Those in the step-down group were more likely to have milder disease (88 [61.1%] in the step-down vs. 74 [54.8%] in the no change group), exhibited less activity limitation (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and experienced fewer asthma attacks (RR: 0.53, 95% CI: 0.34-0.84) during pregnancy. The step-down group had a nonsignificant increase in overall odds of experiencing an adverse pregnancy outcome (odds ratio: 1.62, 95% CI: 0.97-2.72). CONCLUSION: Over half of women with asthma reduce asthma medication in the periconceptional period. Although these women typically have milder disease, a step down in medication may be associated with an increased risk of adverse pregnancy outcomes. KEY POINTS: · Many women reduce their asthma medication in pregnancy.. · Reduction is more common among those with mild disease.. · Medication reduction may lead to adverse pregnancy outcomes..

The dose-response association between LEAP 1000 and birthweight - no clear mechanisms: a structural equation modeling approach.

BACKGROUND: Birthweight is an important indicator of maternal and fetal health globally. The multifactorial origins of birthweight suggest holistic programs that target biological and social risk factors have great potential to improve birthweight. In this study, we examine the dose-response association of exposure to an unconditional cash transfer program before delivery with birthweight and explore the potential mediators of the association. METHODS: Data for this study come from the Livelihood Empowerment Against Poverty (LEAP) 1000 impact evaluation conducted between 2015 and 2017 among a panel sample of 2,331 pregnant and lactating women living in rural households of Northern Ghana. The LEAP 1000 program provided bi-monthly cash transfers and premium fee waivers to enroll in the National Health Insurance Scheme (NHIS). We used adjusted and unadjusted linear and logistic regression models to estimate the associations of months of LEAP 1000 exposure before delivery with birthweight and low birthweight, respectively. We used covariate-adjusted structural equation models (SEM) to examine mediation of the LEAP 1000 dose-response association with birthweight by household food insecurity and maternal-level (agency, NHIS enrollment, and antenatal care) factors. RESULTS: Our study included a sample of 1,439 infants with complete information on birthweight and date of birth. Nine percent of infants (N = 129) were exposed to LEAP 1000 before delivery. A 1-month increase in exposure to LEAP 1000 before delivery was associated with a 9-gram increase in birthweight and 7% reduced odds of low birthweight, on average, in adjusted models. We found no mediation effect by household food insecurity, NHIS enrollment, women's agency, or antenatal care visits. CONCLUSIONS: LEAP 1000 cash transfer exposure before delivery was positively associated with birthweight, though we did not find any mediation by household- or maternal-level factors. The results of our mediation analyses may serve to inform program operations and improve targeting and programming to optimize health and well-being among this population. TRIAL REGISTRATION: The evaluation is registered in the International Initiative for Impact Evaluation's (3ie) Registry for International Development Impact Evaluations (RIDIESTUDY- ID-55942496d53af) and in the Pan African Clinical Trial Registry (PACTR202110669615387).