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.

Exposure to organophosphate ester flame retardants and plasticizers and associations with preeclampsia and blood pressure in pregnancy.

BACKGROUND: Organophosphate esters (OPEs), flame retardants and plasticizers found widely in consumer products, may impact vascularization processes in pregnancy. Yet, the association between maternal exposure to OPEs and both preeclampsia and blood pressure during pregnancy remains understudied. METHODS: Within the LIFECODES Fetal Growth Study (N = 900), we quantified 8 OPE metabolites from maternal urine collected at up to 3 time points during pregnancy and created within-subject geometric means. Outcomes included diagnosis of preeclampsia and longitudinal systolic (SBP) and diastolic (DBP) blood pressure measurements (mean = 14 per participant). Cox proportional hazards models were used to estimate associations between OPE metabolites and preeclampsia. Associations between average OPE metabolite concentrations and repeated blood pressure measurements were estimated using generalized estimating equations. RESULTS: Five OPE metabolites were detected in at least 60% of samples; 3 metabolites detected less frequently (5-39%) were examined in an exploratory analysis as ever vs. never detectable in pregnancy. There were 46 cases of preeclampsia in our study population. Associations between OPE metabolites and preeclampsia were null. We noted several divergent associations between OPE metabolites and longitudinal blood pressure measurements. An interquartile range (IQR) difference in average bis(2-chloroethyl) phosphate concentrations was associated with a decrease in SBP (-0.81 mmHg, 95% confidence interval [CI]: -1.62, 0.00), and, conversely, bis(1-chloro-2-propyl) phosphate was associated with a slight increase in SBP (0.94 mmHg, 95% CI: 0.28, 1.61). We also noted a decrease in SBP in association with several metabolites with low detection frequency. CONCLUSIONS: We observed null associations between OPE metabolites and preeclampsia, but some positive and some inverse associations with blood pressure in pregnancy. While our study was well-designed to assess associations with blood pressure, future studies with a larger number of preeclampsia cases may be better poised to investigate the association between OPE metabolites and phenotypes of this heterogenous hypertensive disorder of pregnancy.

Prenatal exposure to non-persistent chemicals and fetal-to-childhood growth trajectories.

INTRODUCTION: Prenatal exposure to non-persistent chemicals, including organophosphate pesticides, phthalates, and bisphenols, is associated with altered fetal and childhood growth. Few studies have examined these associations using longitudinal growth trajectories or considering exposure to chemical mixtures. METHODS: Among 777 participants from the Generation R Study, we used growth mixture models to identify weight and body mass index (BMI) trajectories using weight and height measures collected from the prenatal period to age 13. We measured exposure biomarkers for organophosphate pesticides, phthalates, and bisphenols in maternal urine at three timepoints during pregnancy. Multinomial logistic regression was used to estimate associations between averaged exposure biomarker concentrations and growth trajectories. We used quantile g-computation to estimate joint associations with growth trajectories. RESULTS: Phthalic acid (OR: 1.4, 95% CI: 1.01, 1.9) and bisphenol A (BPA; OR: 1.5, 95% CI: 1.0, 2.2) were associated with higher odds of a growth trajectory characterized by smaller prenatal and larger childhood weight relative to a referent trajectory of larger prenatal and average childhood weight. Biomarkers of organophosphate pesticides, individually and jointly, were associated with lower odds of a growth trajectory characterized by average prenatal and lower childhood weight. CONCLUSIONS: Exposure to phthalates and BPA was positively associated with a weight trajectory characterized by lower prenatal and higher childhood weight, while exposure to organophosphate pesticides was negatively associated with a trajectory of average prenatal and lower childhood weight. This study is consistent with the hypothesis that non-persistent chemical exposures disrupt growth trajectories from the prenatal period through childhood.

Fetal and Maternal Factors Predictive of Primary Cesarean Delivery at Term in a Low-Risk Population: NICHD Fetal Growth Studies-Singletons.

OBJECTIVE: This study aimed to examine associations of fetal biometric and amniotic fluid measures with intrapartum primary cesarean delivery (PCD) and develop prediction models for PCD based on ultrasound parameters and maternal factors. STUDY DESIGN: Secondary analysis of the National Institute of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-singleton cohort (2009-2013) including patients with uncomplicated pregnancies and intent to deliver vaginally at ≥370/7 weeks. The estimated fetal weight, individual biometric parameters, fetal asymmetry measurements, and amniotic fluid single deepest vertical pocket assessed at the final scan (mean 37.5 ± 1.9 weeks) were categorized as <10th, 10th to 90th (reference), and >90th percentiles. Logistic regression analyses examined the association between the ultrasound measures and PCD. Fetal and maternal SuperLearner prediction algorithms were constructed for the full and nulliparous cohorts. RESULTS: Of the 1,668 patients analyzed, 249 (14.9%) had PCD. The fetal head circumference, occipital-frontal diameter, and transverse abdominal diameter >90th percentile (adjusted odds ratio [aOR] = 2.50, 95% confidence interval [95% CI]: 1.39, 4.51; aOR = 1.86, 95% CI: 1.02, 3.40; and aOR = 2.13, 95% CI: 1.16, 3.89, respectively) were associated with PCD. The fetal model demonstrated poor ability to predict PCD in the full cohort and in nulliparous patients (area under the receiver-operating characteristic curve [AUC] = 0.56, 95% CI: 0.52, 0.61; and AUC = 0.54, 95% CI: 0.49, 0.60, respectively). Conversely, the maternal model had better predictive capability overall (AUC = 0.79, 95% CI: 0.75, 0.82) and in the nulliparous subgroup (AUC = 0.72, 95% CI: 0.67, 0.77). Models combining maternal/fetal factors performed similarly to the maternal model (AUC = 0.78, 95% CI: 0.75, 0.82 in full cohort, and AUC = 0.71, 95% CI: 0.66, 0.76 in nulliparas). CONCLUSION: Although a few fetal biometric parameters were associated with PCD, the fetal prediction model had low performance. In contrast, the maternal model had a fair-to-good ability to predict PCD. KEY POINTS: · Fetal HC >90th percentile was associated with cesarean delivery.. · Fetal parameters did not effectively predict PCD.. · Maternal factors were more predictive of PCD.. · Maternal/fetal and maternal models performed similarly.. · Prediction models had lower performance in nulliparas..

Longitudinal associations between urinary biomarkers of phthalates and replacements with novel in vivo measures of placental health.

STUDY QUESTION: What is the longitudinal association between gestational phthalate exposure and in vivo placental outcomes? SUMMARY ANSWER: Phthalates were adversely associated with placental microvasculature, stiffness, and presence of calcification, with different metabolites associated with different outcomes. WHAT IS KNOWN ALREADY: Phthalate exposure is ubiquitous and implicated as a contributor to adverse pregnancy outcomes, possibly through impacts on the placenta. STUDY DESIGN, SIZE, DURATION: A total of 303 women were recruited in early pregnancy and prospectively followed for up to eight visits across gestation in the Human Placenta and Phthalates study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At each visit, women provided urine samples and underwent placental ultrasounds. Urine was analyzed for 18 metabolites of phthalates and replacements. We took the geometric mean of repeated measurements to reflect pregnancy-averaged phthalate or replacement exposure for each participant (n = 303). Placental microvasculature, stiffness, and microcalcification presence were quantified from ultrasounds at each visit. Higher scores reflected worse placental function for all measures. Generalized linear mixed models were created to estimate the association between pregnancy-averaged exposure biomarker concentrations and repeated outcome measurements for microvasculature and stiffness. Gestational age at the time of calcification detection was modeled using Cox proportional hazards models. MAIN RESULTS AND THE ROLE OF CHANCE: Monocarboxyisononyl phthalate and summed di(2-ethylhexyl) phthalate metabolites were associated with impaired microvasculature development, such that an interquartile range increase in concentration was associated with 0.11 standard deviation increase in the microvasculature ratio, indicating poorer vascularization (95% CI: 0.00, 0.22); 0.11 [95% CI: -0.01, 0.22], respectively. Monoethyl phthalate was associated with increased placental stiffness (0.09 [95% CI: -0.01, 0.19]) while summed di-iso-butyl phthalate metabolites and monobenzyl phthalate were associated with increased hazard of calcification detection (hazard ratios: 1.18 [95% CI: 0.98, 1.42]; 1.13 [95% CI: 0.96, 1.34]). LIMITATIONS, REASONS FOR CAUTION: Outcomes used in this study are novel and further investigation is needed to provide clinical context and relevance. WIDER IMPLICATIONS OF THE FINDINGS: We found evidence of associations between select phthalate biomarkers and various aspects of in vivo placental health, although we did not observe consistency across placental outcomes. These findings could illustrate heterogeneous effects of phthalate exposure on placental function. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES103344), and NIEHS T32ES007018. The authors declare that they have no competing interests to disclose. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services. TRIAL REGISTRATION NUMBER: N/A.

Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study.

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. OBJECTIVES: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. METHODS: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Prenatal exposure to environmental phenols and fetal growth across pregnancy in the LIFECODES fetal growth study.

INTRODUCTION: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy. OBJECTIVE: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth. METHODS: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth. RESULTS: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98). DISCUSSION: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period.

Environmental phenol exposures in 6- to 12-week-old infants: The Infant Feeding and Early Development (IFED) study.

BACKGROUND: Exposure to phenols, endocrine-disrupting chemicals used in personal care and consumer products, is widespread. Data on infant exposures are limited despite heightened sensitivity to endocrine disruption during this developmental period. We aimed to describe distributions and predictors of urinary phenol concentrations among U.S. infants ages 6-12 weeks. METHODS: The Infant Feeding and Early Development (IFED) study is a prospective cohort study of healthy term infants enrolled during 2010-2013 in the Philadelphia region. We measured concentrations of seven phenols in 352 urine samples collected during the 6- or 8- and/or 12-week study visits from 199 infants. We used linear mixed models to estimate associations of maternal, sociodemographic, infant, and sample characteristics with natural-log transformed, creatinine-standardized phenol concentrations and present results as mean percent change from the reference level. RESULTS: Median concentrations (µg/L) were 311 for methylparaben, 10.3 for propylparaben, 3.6 for benzophenone-3, 2.1 for triclosan, 1.0 for 2,5-dichlorophenol, 0.7 for BPA, and 0.3 for 2,4-dichlorophenol. Geometric mean methylparaben concentrations were approximately 10 times higher than published estimates for U.S. children ages 3-5 and 6-11 years, while propylparaben concentrations were 3-4 times higher. Infants of Black mothers had higher concentrations of BPA (83%), methylparaben (121%), propylparaben (218%), and 2,5-dichorophenol (287%) and lower concentrations of benzophenone-3 (-77%) and triclosan (-53%) than infants of White mothers. Triclosan concentrations were higher in breastfed infants (176%) and lower in infants whose mothers had a high school education or less (-62%). Phenol concentrations were generally higher in summer samples. CONCLUSIONS: Widespread exposure to select environmental phenols among this cohort of healthy U.S. infants, including much higher paraben concentrations compared to those reported for U.S. children, supports the importance of expanding population-based biomonitoring programs to infants and toddlers. Future investigation of exposure sources is warranted to identify opportunities to minimize exposures during these sensitive periods of development.

Environmental Phenols and Growth in Infancy: The Infant Feeding and Early Development Study.

CONTEXT: Higher mean and rapid increases in body mass index (BMI) during infancy are associated with subsequent obesity and may be influenced by exposure to endocrine-disrupting chemicals such as phenols. OBJECTIVE: In a prospective US-based cohort conducted 2010-2014, we investigated associations between environmental phenol exposures and BMI in 199 infants. METHODS: We measured seven urinary phenols at ages 6-8 and 12 weeks and assessed BMI z-score at up to 12 study visits between birth and 36 weeks. We examined individual and joint associations of averaged early infancy phenols with level of BMI z-score using mean differences (ß [95% confidence intervals (CI)]) and with BMI z-score trajectories using relative risk ratios (RR [95% CI]). RESULTS: Benzophenone-3, methyl and propyl paraben, and all phenols jointly were positively associated with higher mean BMI z-score (0.07 [-0.05, 0.18], 0.10 [-0.08, 0.27], 0.08 [-0.09, 0.25], 0.17 [-0.08, 0.43], respectively). Relative to a Stable trajectory, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, and all phenols jointly were positively associated with risk of a Rapid Increase trajectory (1.46 [0.89, 2.39], 1.33 [0.88, 2.01], 1.66 [1.03, 2.68], 1.41 [0.71, 2.84], respectively). CONCLUSION: Early phenol exposure was associated with a higher mean and rapid increase in BMI z-score across infancy, signaling potential long-term cardiometabolic consequences of exposure.

Personal care product use patterns in association with phthalate and replacement biomarkers across pregnancy.

BACKGROUND: Humans are exposed to phthalates, a class of non-persistent chemicals, through multiple products, including personal care and cosmetics. Associations between specific phthalates and product use have been inconsistent. However, determining these connections could provide avenues for exposure reduction. OBJECTIVE: Examine the association between patterns of personal care product use and associations with phthalate and replacement biomarkers. METHODS: In the Human Placenta and Phthalates Study, 303 women were enrolled in early pregnancy and followed for up to 8 visits across gestation. At each visit, women completed a questionnaire about product use in the prior 24 hours and contributed urine samples, subsequently analyzed for 18 phthalate and replacement metabolites. At early, mid-, and late pregnancy, questionnaire responses were condensed and repeated metabolite concentrations were averaged. Latent class analysis (LCA) was used to determine groups of women with similar use patterns, and weighted associations between group membership and biomarker concentrations were assessed. RESULTS: LCA sorted women into groups which largely corresponded to: (1) low fragranced product use (16-23% of women); (2) fragranced product and low body wash use (22-26%); 3) fragranced product and low bar soap use (26-51%); and (4) low product use (7-34%). Monoethyl phthalate (MEP) urinary concentrations were 7-10% lower and concentrations of summed di(2-ethylhexyl) terephthalate metabolites were 15-21% lower among women in the "low fragranced product use" group compared to the population mean. Few other consistent associations between group and biomarker concentrations were noted. IMPACT STATEMENT: Personal care products and cosmetics are a known exposure source for phthalates and potentially represent one of the most accessible intervention targets for exposure reduction. However, in this analysis accounting for concurrent use and fragranced status of products, we did not find any use patterns that corresponded to universally lower levels.

Midpregnancy Phthalate and Phenol Biomarkers in Relation to Infant Body Composition: The Healthy Start Prospective Cohort.

BACKGROUND: Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans. OBJECTIVE: We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age. METHODS: Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24-28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex. RESULTS: In single-pollutant models, mono-benzyl phthalate and di-n-butyl phthalate were inversely associated with percentage fat mass [ß: -0.49 (95% CI: -0.91, -0.08) and -0.51 (95% CI: -1.02, 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [-1.06 (95% CI: -2.21, 0.1)] and at 5 months of age [-2.14 (95% CI: -3.88, -0.39)] among males, but associations were null among females [0.48 (95% CI: -0.78, 1.75) and -0.64 (95% CI: -2.68, 1.41), respectively]. Similar associations were observed with infant weight. CONCLUSION: In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. https://doi.org/10.1289/EHP12500.

Variability and Longitudinal Trajectories of Phthalate and Replacement Biomarkers across Pregnancy in the Human Placenta and Phthalates Study.

Human exposure to phthalates is widespread, but assessment of variability across pregnancy has been hampered by short half-lives of phthalate biomarkers and a few repeated measures in prior studies. We aimed to characterize the variability and longitudinal profiles of phthalate and replacement biomarkers across pregnancy. Within the Human Placenta and Phthalates Study, 303 pregnant women provided urine samples at up to 8 visits across gestation. Concentrations of 14 metabolites of phthalates and 4 metabolites of replacements were quantified in each sample, and subject-specific averages within each trimester were calculated. We examined variability in individual biomarker concentrations across the 8 visits, within trimesters, and across trimester-specific averages using intraclass correlation coefficients (ICCs). To explore longitudinal exposure biomarker profiles, we applied group-based trajectory modeling to trimester-specific averages over pregnancy. Pooling multiple visits into trimester-specific averages improved the ICCs for all biomarkers. Most biomarkers generally showed stable concentrations across gestation, i.e., high-, medium-, and low-concentration profiles, with small proportions of participants falling into the "high"-exposure groups. Variability over pregnancy is likely attributable to random fluctuations around a baseline exposure rather than true changes in concentrations over time.

Fetal Organophosphate Pesticide Exposure and Child Adiposity Measures at 10 Years of Age in the General Dutch Population.

BACKGROUND: Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life. OBJECTIVE: We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age. METHODS: Between 2002 and 2006, we included 642 mother-child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid- and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging. RESULTS: Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y. CONCLUSION: We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied. https://doi.org/10.1289/EHP12267.

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..

Early pregnancy phthalates and replacements in relation to fetal growth: The human placenta and phthalates study.

BACKGROUND: Pregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals. OBJECTIVE: Characterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes. METHODS: Analyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017-2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers. RESULTS: Mono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (ß: -0.36 [95% confidence interval: -0.56, -0.15]) and abdominal circumference (-0.31 [-0.49, -0.12]) z-scores. This association was mainly driven by phthalate biomarkers. CONCLUSIONS: Urine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.

Asthma Medication Regimens in Pregnancy: Longitudinal Changes in Asthma Status.

OBJECTIVE: This study aimed to assess the impact of common asthma medication regimens on asthma symptoms, exacerbations, lung function, and inflammation during pregnancy. STUDY DESIGN: A total of 311 women with asthma were enrolled in a prospective pregnancy cohort. Asthma medication regimen was categorized into short-acting ß agonist (SABA) alone, SABA + inhaled corticosteroid (ICS), SABA + ICS + long-acting ß agonist (LABA), and no asthma medications (reference). We evaluated asthma control at enrollment (< 15 weeks' gestation) and its change into trimesters 2 and 3, including per cent predicted forced expiratory volume in 1 second (%FEV1) and peak expiratory flow (%PEF), pulse oximetry, fractional exhaled nitric oxide (FeNO), asthma symptoms (asthma attacks/month, night symptoms/week), and severe exacerbations. Linear mixed models adjusted for site, age, race, annual income, gestational age, body mass index, and smoking, and propensity scores accounted for asthma control status at baseline. RESULTS: Women taking SABA + ICS and SABA + ICS + LABA had better first trimester %PEF (83.5% [75.7-91.3] and 84.6% [76.9-92.3], respectively) compared with women taking no asthma medications (72.7% [66.0-79.3]). Women taking SABA + ICS + LABA also experienced improvements in %FEV1 (+11.1%, p < 0.01) in the third trimester and FeNO in the second (-12.3 parts per billion [ppb], p < 0.01) and third (-11.0 ppb, p < 0.01) trimesters as compared with the trajectory of women taking no medications. SABA + ICS use was associated with increased odds of severe exacerbations in the first (odds ratio [OR]: 2.22 [1.10-4.46]) and second (OR: 3.15 [1.11-8.96]) trimesters, and SABA + ICS + LABA use in the second trimester (OR: 7.89 [2.75-21.47]). Women taking SABA alone were similar to those taking no medication. CONCLUSION: Pregnant women taking SABA + ICS and SABA + ICS + LABA had better lung function in the first trimester. SABA + ICS + LABA was associated with improvements in lung function and inflammation across gestation. However, both the SABA + ICS and SABA + ICS + LABA groups had a higher risk of severe exacerbation during early to mid-pregnancy. KEY POINTS: · Medication regimens may affect perinatal asthma control.. · Intensive regimens improved lung function/inflammation.. · Women on intensive regimens had more acute asthma events..

Fetal growth trajectories of babies born large-for-gestational age in the LIFECODES Fetal Growth Study.

BACKGROUND: Babies born large-for-gestational age have an increased risk of adverse health outcomes, including birth injuries, childhood obesity, and cardiometabolic disorders. However, little work has been done to characterize patterns of fetal growth among large-for-gestational age births, which may further elucidate high- and low-risk subgroups. OBJECTIVE: This study aimed to identify subgroups of large-for-gestational age births based on trajectories of fetal growth derived from prenatal ultrasound measurements and explore differences in sociodemographic, pregnancy, and birth outcome characteristics across subgroups. STUDY DESIGN: This study identified and described trajectories of fetal growth among large-for-gestational age births (n=235) in the LIFECODES Fetal Growth Study. Ultrasound measurements of fetal growth in middle to late pregnancy were abstracted from health records. Group-based multi-trajectory modeling was applied to measurements of head circumference, abdominal circumference, and femur length z-scores to identify multivariate trajectories of fetal growth. Moreover, sociodemographic variables, pregnancy characteristics, and birth outcomes based on trajectory membership were summarized. RESULTS: This study identified 4 multivariate trajectories of fetal growth among large-for-gestational age births: catch-up growth (n=28), proportional abdominal circumference-to-femur length growth (n=67), disproportional abdominal circumference-to-femur length growth (n=96), and consistently large (n=44). Fetuses in the "catch-up growth" group exhibited small relative sizes in midpregnancy (ie, below average head circumference, abdominal circumference, and femur length z-scores) and large relative sizes in late pregnancy. Growth among these births was driven by increases in relative abdominal circumference and head circumference sizes. Participants who delivered births assigned to this group were less likely to have normal glucose control (40% vs 65%-75%) and more likely to have pregestational diabetes mellitus (36% vs 10%-17%) than other large-for-gestational age subgroups. In addition, the babies in this trajectory group were more likely to have macrosomia (86% vs 67%-73%) and to be admitted to the neonatal intensive care unit (32% vs 14%-21%) than other large-for-gestational age subgroups. In contrast, babies in the "consistently large" group had the largest relative size for all growth parameters throughout gestation and experienced a lower risk of adverse birth outcomes than other large-for-gestational age subgroups. CONCLUSION: This study characterized several trajectories of fetal growth among large-for-gestational age births, which were related to different pregnancy characteristics and the distribution of adverse birth outcomes. Although the number of individuals within some trajectories was small, a subgroup that exhibited a catch-up growth phenotype during gestation was identified, which may be uniquely associated with exposure to pregestational diabetes mellitus and a higher risk of admission to the neonatal intensive care unit. These results have highlighted that the risk of adverse outcomes may not be evenly distributed across all large-for-gestational age births.

An application of group-based trajectory modeling to define fetal growth phenotypes among small-for-gestational-age births in the LIFECODES Fetal Growth Study.

BACKGROUND: Reductions in fetal growth are associated with adverse outcomes at birth and later in life. However, identifying fetuses with pathologically small growth remains challenging. Definitions of small-for-gestational age are often used as a proxy to identify those experiencing pathologic growth (ie, fetal growth restriction). However, this approach is subject to limitation as most newborns labeled small-for-gestational age are constitutionally, not pathologically, small. Incorporating repeated ultrasound measures to examine fetal growth trajectories may help distinguish pathologic deviations in growth from normal variability, beyond a simple definition of small-for-gestational age. OBJECTIVE: This study aimed to characterize phenotypes of growth using ultrasound trajectories of fetal growth among small-for-gestational-age births. STUDY DESIGN: This study identified and described trajectories of fetal growth among small-for-gestational-age births (<10th percentile weight for gestational age; n=245) in the LIFECODES Fetal Growth Study using univariate and multivariate trajectory modeling approaches. Available ultrasound measures of fetal growth (estimated fetal weight, head circumference, abdominal circumference, and femur length) from health records were abstracted. First, univariate group-based trajectory modeling was used to define trajectories of estimated fetal weight z scores during gestation. Second, group-based multi-trajectory modeling was used to identify trajectories based on concurrent measures of head circumference, abdominal circumference, and femur length z scores. Last, how these trajectories were related to patient demographics, pregnancy characteristics, and birth outcomes compared with those observed among appropriate-for-gestational-age controls was described. RESULTS: Of note, 3 univariate trajectories of estimated fetal weight and 4 multivariate trajectories of fetal growth among small-for-gestational-age births were identified. In our univariate approach, infants with the smallest estimated fetal weight trajectory throughout pregnancy had poorer outcomes, including the highest risk of neonatal intensive care unit admission. The remaining univariate trajectory groups did not have an elevated risk of adverse birth outcomes relative to appropriate-for-gestational-age controls. In our multivariate approach, 2 groups at increased or moderately increased risk of neonatal intensive care unit admission were identified, including infants that remained extremely small for all parameters throughout pregnancy and those who had disproportionately smaller femur length and abdominal circumference compared with head circumference. The remaining multivariate trajectory groups did not have an elevated risk of adverse birth outcome relative to appropriate-for-gestational-age controls. CONCLUSION: Latent class group-based trajectory modeling applied to ultrasound measures of fetal growth may help distinguish pathologic vs constitutional growth profiles among newborns born small-for-gestational age. Although trajectories cannot be fully characterized until delivery, limiting the direct clinical application of these methods, they may still contribute to the development of approaches for separating growth restriction from constitutional smallness.