Search

BACKGROUND: Phthalate exposure in pregnancy is typically estimated using maternal urinary phthalate metabolite levels. Our aim was to evaluate the association of urinary and placental tissue phthalates, and to explore the role of maternal and pregnancy characteristics that may bias estimates. METHODS: Fifty pregnancies were selected from the CANDLE Study, recruited from 2006 to 2011 in Tennessee. Linear models were used to estimate associations of urinary phthalates (2(nd), 3(rd) trimesters) and placental tissue phthalates (birth). Potential confounders and modifiers were evaluated in categories: temporality (time between urine and placenta sample), fetal sex, demographics, social advantage, reproductive history, medication use, nutrition and adiposity. Molar and quantile normalized phthalates were calculated to facilitate comparison of placental and urinary levels. RESULTS: Metabolites detectable in >80% of both urine and placental samples were MEP, MnBP, MBzP, MECPP, MEOHP, MEHHP, and MEHP. MEP was most abundant in urine (geometric mean [GM] 7.00 ×10(2) nmol/l) and in placental tissue (GM 2.56 ×10(4) nmol/l). MEHP was the least abundant in urine (GM 5.32 ×10(1) nmol/l) and second most abundant in placental tissue (2.04 ×10(4) nmol/l). In aggregate, MEHP differed the most between urine and placenta (2.21 log units), and MEHHP differed the least (0.07 log units). MECPP was positively associated between urine and placenta (regression coefficient: 0.31 95% CI 0.09, 0.53). Other urine-placenta metabolite associations were modified by measures of social advantage, reproductive history, medication use, and adiposity. CONCLUSION: Phthalates were ubiquitous in 50 full-term placental samples, as has already been shown in maternal urine. MEP and MEHP were the most abundant. Measurement and comparison of urinary and placental phthalates can advance knowledge on phthalate toxicity in pregnancy and provide insight into the validity and accuracy of relying on maternal urinary concentrations to estimate placental exposures. IMPACT STATEMENT: This is the first report of correlations/associations of urinary and placental tissue phthalates in human pregnancy. Epidemiologists have relied exclusively on maternal urinary phthalate metabolite concentrations to assess exposures in pregnant women and risk to their fetuses. Even though it has not yet been confirmed empirically, it is widely assumed that urinary concentrations are strongly and positively correlated with placental and fetal levels. Our data suggest that may not be the case, and these associations may vary by phthalate metabolite and associations may be modified by measures of social advantage, reproductive history, medication use, and adiposity.

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0–1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a “high” exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age

RATIONALE Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset. OBJECTIVES To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association. METHODS We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years). MEASUREMENTS AND MAIN RESULTS We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23). CONCLUSIONS This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Women's social experiences can have long-term implications for their offspring's health, but little is known about the potential independent contributions of multiple periods of stress exposures over time. This study examined associations of maternal exposure to adversity in childhood and pregnancy with children's anxiety and depression symptoms in a large, sociodemographically diverse sample. Participants were 1389 mother-child dyads (child age M = 8.83 years; SD = 0.66; 42% Black, 42% White; 6% Hispanic) in the ECHO-PATHWAYS Consortium's three U.S. pregnancy cohorts. Women reported their exposure to childhood traumatic events (CTE) and pregnancy stressful life events (PSLE). Children self-reported on their symptoms of anxiety and depression at age 8-9 years. Regression analyses estimated associations between maternal stressors and children's internalizing problems, adjusting for confounders, and examined child sex as a modifier. Exploratory interaction analyses examined whether geospatially-linked postnatal neighborhood quality buffered effects. In adjusted models, PSLE counts positively predicted levels of children's anxiety and depression symptoms ([ß

High maternal folic acid exposure has been studied as a risk factor for child asthma with inconclusive results. Folic acid supplementation that begins before pregnancy may propagate high exposures during pregnancy, particularly in regions with fortified food supplies. We investigated whether folic acid supplementation initiated periconceptionally is associated with childhood asthma in a US cohort.We re-contacted mother-child dyads previously enrolled in a prospective pregnancy cohort and included children age 4 to 8 years at follow-up (Approximately half of women initiated FACS use periconceptionally (49%). Nine percent of children had "ever asthma" and 6% had "current asthma." Periconceptional initiation was associated with elevated odds of ever asthma [adjusted odds ratio (95% Confidence Interval): 1.65 (0.87, 3.14)] and current asthma [1.87 (0.88, 4.01)], relative to first trimester initiation.We observed positive, but imprecisely estimated associations between periconceptional FACS initiation and child asthma. Folic acid prevents birth defects and is recommended. However, larger studies of folic acid dosing and timing, with consideration for childhood asthma, are needed.

Studies report associations between maternal mental health and adverse respiratory outcomes in children; however, the impact of timing and duration of maternal distress remains understudied. We sought to longitudinally examine associations between maternal depression and childhood asthma and wheeze, and explore sex differences.Maternal depression (n = 601) was assessed using the Edinburgh Depression Scale questionnaire, dichotomized at a clinically relevant cutoff (12) (a) during pregnancy, (b) postpartum, and (c) postpartum and subsequent time points postnatally (recurrent depression). Report of wheeze in the past 12 months (current wheeze) and asthma were obtained using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire at 48 and 72 months. Associations were analyzed using a modified Poisson regression adjusted for covariates, and in interaction models.Both postpartum and recurrent depression were associated with higher risk of current wheeze (relative risk [RR]: 1.87, 95% confidence interval [CI]: 1.21, 2.90; RR: 2.41, 95% CI: 1.53, 3.79) and asthma at 48 months (RR: 2.42, 95% CI: 1.01, 5.84; RR: 2.45, 95% CI: 1.02, 5.84). In interaction analyses, associations were stronger in females. Recurrent depression was associated with a higher risk of current wheeze at 48 months in females (RR: 4.34, 95% CI: 2.02, 9.32) when compared to males (RR: 1.89, 95% CI: 1.05, 3.39).Postpartum and recurrent depression were associated with a higher risk of wheeze and asthma in children. Understanding the temporal- and sex-specific effects of maternal depression may better inform prevention strategies.

BACKGROUND Childhood asthma is a common chronic disease that likely has prenatal origins. Gestational diabetes alters maternal physiology and may influence fetal risk for childhood-onset disease. However, the association between gestational diabetes and child asthma is not well characterized. OBJECTIVE To investigate the association between gestational diabetes and wheeze/asthma at approximately 4 years of age in a racially diverse US cohort. METHODS We studied mother-child dyads enrolled prenatally in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. Gestational diabetes was determined by medical chart review. At approximately 4 years of age, we assessed child respiratory outcomes including parent report of physician-diagnosed asthma (ever), current wheeze (symptoms within the past 12 months), and current asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used the modified Poisson regression to assess associations between gestational diabetes and child respiratory outcomes, adjusting for maternal age, race, prenatal smoking, pre-pregnancy body mass index, parity, asthma history, socioeconomic status, and infant sex. RESULTS Among 1107 women, 66% were African American/Black. Six percent (n = 62) had gestational diabetes documented during pregnancy. Gestational diabetes was associated with increased risk of physician-diagnosed asthma (adjusted risk ratio (RR) [95% Confidence Interval]: 2.13 [1.35, 3.38]; prevalence: 14%), current wheeze (RR: 1.85 [1.23, 2.78]; prevalence: 19%), and current asthma (RR: 2.01 [1.30, 3.10]; prevalence: 16%). CONCLUSIONS Gestational diabetes was associated with increased risk of asthma and wheeze outcomes. Additional studies are needed to elucidate modifiable pathways underlying this association.

Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States.We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin.This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-FApproximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of FHere, oxidative stress, as measured by 8-iso-prostaglandin-F

As the coronavirus pandemic continues to impact families and children, understanding parental attitudes and likely acceptance of the COVID-19 vaccine is essential. We conducted a statewide survey with a representative sample of parents in Tennessee focused on COVID-19 and influenza vaccine acceptance and perspectives. Data from 1066 parents were analyzed using weighted survey methods to generalize results to the state of Tennessee. About 53% of parents reported a likelihood to vaccinate their children against COVID-19, and 45% were likely to vaccinate their child against COVID-19 and influenza. Female parents were less likely to vaccinate their children against COVID-19, but the strongest predictor of likely COVID-19 vaccine acceptance was influenza vaccine acceptance (adjusted odds ratio = 5.46; 95% confidence interval: 3.20-9.30). Parental acceptance of COVID-19 vaccines for children is closely tied to influenza vaccine acceptance. Public health approaches to maximize vaccine uptake could focus on children who have not been receiving influenza vaccines.

Postnatal exposures, including breastfeeding, may influence asthma development.To investigate the association between breastfeeding duration and child asthma.We studied 2021 mother-child dyads in the ECHO PATHWAYS consortium of prospective pregnancy cohorts (GAPPS, CANDLE, TIDES). Women reported the duration of any and exclusive breastfeeding and child asthma outcomes during follow-up at child age 4 to 6 years. Outcomes included current wheeze (previous 12 months), ever asthma, current asthma (having ≥2 of current wheeze, ever asthma, medication use in past 12-24 months), and strict current asthma (ever asthma with either or both current wheeze and medication use in past 12-24 months). We used multivariable logistic regression to assess associations (odds ratios and 95% confidence intervals) between breastfeeding and asthma outcomes adjusting for potential confounders. We assessed effect modification by mode of delivery, infant sex, and maternal asthma.Among women, 33%, 13%, 9%, and 45% reported 0 to less than 2, 2 to 4, 5 to 6, and more than 6 months of any breastfeeding, respectively. The duration of any breastfeeding had a protective linear trend with ever asthma but no other outcomes. There was a duration-dependent protective association of exclusive breastfeeding and child asthma outcomes (eg, current asthma adjusted odds ratio [95% confidence interval], 0.64 [0.41-1.02], 0.61 [0.38-0.98], and 0.52 (0.31-0.87) for 2to 4 months, 5 to 6 months, and more than 6 months, respectively, compared with2 months). For exclusive breastfeeding, protective associations were stronger in dyads with children born by vaginal vs cesarean delivery although interactions did not reach statistical significance (PLonger duration of exclusive breastfeeding had a protective association with child asthma.

Background Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs). Objective In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs. Methods We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex. Results Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis. Conclusion In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.

BACKGROUND: Prenatal exposure to fine particulate matter with a diameter of ≤2.5 microns (PM(2.5)) has been linked to adverse neurodevelopmental outcomes in later childhood, while research on early infant behavior remains sparse. OBJECTIVES: We examined associations between prenatal PM(2.5) exposure and infant negative affectivity, a stable temperamental trait associated with longer-term behavioral and mental health outcomes. We also examined sex-specific effects. METHODS: Analyses included 559 mother-infant pairs enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. Daily PM(2.5) exposure based on geocoded residential address during pregnancy was estimated using a satellite-based spatiotemporal model. Domains of negative affectivity (Sadness, Distress to Limitations, Fear, Falling Reactivity) were assessed using the Infant Behavior Questionnaire-Revised (IBQ-R) when infants were 6 months old. Subscale scores were calculated as the mean of item-specific responses; the global Negative Affectivity (NA) score was derived by averaging the mean of the four subscale scores. Bayesian distributed lag interaction models (BDLIMs) were used to identify sensitive windows for prenatal PM(2.5) exposure on global NA and its subscales, and to examine effect modification by sex. RESULTS: Mothers were primarily racial/ethnic minorities (38% Black, 37% Hispanic), 40% had ≤12 years of education; most did not smoke during pregnancy (87%). In the overall sample, BDLIMs revealed that increased PM(2.5) at mid-pregnancy was associated with higher global NA, Sadness, and Fear scores, after adjusting for covariates (maternal age, education, race/ethnicity, sex). Among boys, increased PM(2.5) at early pregnancy was associated with decreased Fear scores, while exposure during late pregnancy was associated with increased Fear scores (cumulative effect estimate=0.57, 95% CI: 0.03–1.41). Among girls, increased PM(2.5) during mid-pregnancy was associated with higher Fear scores (cumulative effect estimate=0.82, 95% CI: 0.05–1.91). CONCLUSIONS: Prenatal PM(2.5) exposure was associated with negative affectivity at age 6 months, and the sensitive windows may vary by subdomains and infant sex.

Prenatal ambient particulate matter (PM2.5) exposure impacts infant development and alters placental mitochondrial DNA abundance. We investigated whether the timing of PM2.5 exposure predicts placental mitochondrial mutational load using NextGen sequencing in 283 multi-ethnic mother-infant dyads. We observed increased PM2.5 exposure, particularly during mid- to late- pregnancy and among genes coding for NADH dehydrogenase and subunits of ATP synthase, was associated with a greater amount of nonsynonymous mutations. The strongest associations were observed for participants of African ancestry. Further work is needed to tease out the role of mitochondrial genetics and its impact on offspring development and emerging disease disparities.

The prevalence of atopic dermatitis (AD) in children has steadily increased over time, yet it remains largely unknown how maternal factors during pregnancy are associated with child AD. Few studies have specifically assessed the relationship between prenatal stress and child AD, with inconsistent findings. In this prospective cohort study following 426 mother-child dyads from pregnancy to middle childhood, women reported stressful life events (SLEs) experienced during the 12 months before delivery and AD outcomes in children aged approximately 4–6 years, including current, location-specific, and ever AD. We used Poisson regression to estimate risk ratios (RRs) and corresponding 95% confidence intervals (CIs) associated with a 1-unit increase in prenatal SLEs, adjusting for potential confounders. We also assessed whether the association between prenatal SLEs and child AD was modified by child sex, history of maternal atopy, or prenatal maternal resilient coping. The mean (standard deviation) of prenatal SLEs reported in the overall sample was 1.4 (1.6), with 37.1% of women reporting none. A 1-unit increase in prenatal SLEs was not significantly associated with current AD (RR: 1.08, 95% CI: 0.89, 1.31), location-specific AD (RR: 1.09, 95% CI: 0.78, 1.52), or ever AD (RR: 0.97, 95% CI: 0.87, 1.09). We did not find evidence of effect modification. Findings from this study suggest no association between prenatal SLEs and AD in middle childhood, although larger longitudinal studies with enhanced case definition and higher variability of SLE experience may more fully inform this question.

Background Viral bronchiolitis is a common respiratory infection that often affects term, otherwise healthy infants. A small literature suggests maternal stress during pregnancy is associated with bronchiolitis. However, the association between maternal exposure to lifetime traumatic stress, including traumatic events occurring in childhood or throughout the life course, and bronchiolitis has not been studied previously. Objectives To investigate the association between maternal exposure to total lifetime and childhood traumatic stress events and infant bronchiolitis. Methods We studied mother-infant dyads enrolled in a prospective prenatal cohort, recruited 2006-2011, and Tennessee Medicaid. During pregnancy, we assessed maternal lifetime exposure to types of traumatic events by questionnaire. We captured bronchiolitis diagnoses in term, non-low birthweight infants' first 12 months using linked Medicaid data. In separate models, we assessed the association of maternal lifetime traumatic events (0 to 20 types) and a subset of traumatic events that occurred during childhood (0 to 3: family violence, sexual, and physical abuse) and infant bronchiolitis using multivariable log-binomial models. Results Of 629 women, 85% were African American. The median count (interquartile range) of lifetime traumatic events was 3 (2, 5); 42% reported ≥1 childhood traumatic event. Among infants, 22% had a bronchiolitis diagnosis (0 to 2 lifetime traumatic events: 24%; 3 events: 20%; 4 to 5 events: 18%; 6 or more events: 24%). Total maternal lifetime traumatic events were not associated with bronchiolitis in multivariable analyses. For maternal childhood traumatic events, the risk of infant bronchiolitis increased with number of event types reported: adjusted Risk ratios were 1.12 (95% confidence interval [CI] 0.80, 1.59), 1.31 (95% CI 0.83, 2.07), and 2.65 (95% CI 1.45, 4.85) for 1, 2, and 3 events, respectively, vs none. Conclusions Infants born to women reporting multiple types of childhood trauma were at higher risk for bronchiolitis. Further research is needed to explore intergenerational effects of traumatic experiences.

Supplemental Digital Content is available in the text., Background: Increasingly studies suggest prenatal exposure to air pollution may increase risk of childhood asthma. Few studies have investigated exposure during specific fetal pulmonary developmental windows. Objective: To assess associations between prenatal fine particulate matter exposure and asthma at age 4. Methods: This study included mother–child dyads from two pregnancy cohorts—CANDLE and TIDES—within the ECHO-PATHWAYS consortium (births in 2007–2013). Three child asthma outcomes were parent-reported: ever asthma, current asthma, and current wheeze. Fine particulate matter (PM2.5) exposures during the pseudoglandular (5–16 weeks gestation), canalicular (16–24 weeks gestation), saccular (24–36 weeks gestation), and alveolar (36+ weeks gestation) phases of fetal lung development were estimated using a national spatiotemporal model. We estimated associations with Poisson regression with robust standard errors, and adjusted for child, maternal, and neighborhood factors. Results: Children (n = 1,469) were on average 4.3 (SD 0.5) years old, 49% were male, and 11.7% had ever asthma; 46% of women identified as black and 53% had at least a college/technical school degree. A 2 μg/m3 higher PM2.5 exposure during the saccular phase was associated with 1.29 times higher risk of ever asthma [95% confidence interval (CI): 1.06, 1.58]. A similar association was observed with current asthma (risk ratio 1.27, 95% CI: 1.04, 1.54), but not current wheeze (risk ratio 1.11, 95% CI: 0.92, 1.33). Effect estimates for associations during other developmental windows had CIs that included the null. Conclusions: Later phases of prenatal lung development may be particularly sensitive to the developmental toxicity of PM2.5.

Background Studies evaluating effects of prenatal polyunsaturated fatty acid (PUFA) intake on childhood asthma reveal mixed results. Inconsistencies may result from not accounting for important modifying factors such as maternal asthma or child sex. Objective To evaluate whether associations between prenatal PUFA intake and childhood asthma are modified by prenatal active maternal asthma or child sex in 412 mother-child dyads. Methods Energy-adjusted prenatal dietary and supplement intakes of omega-3 (n-3) and omega-6 (n-6) PUFAs were estimated using the Block98 Food Frequency Questionnaire, administered during pregnancy. Mothers reported asthma in children followed prospectively to 4.0 plus or minus 1.7 years. Generalized additive models with smooth terms for PUFA (n-3, n-6, n-6/n-3 ratio) effects were used to investigate associations between PUFAs and child asthma, without prespecifying the form of these relationships, including effect modification by active maternal asthma or child sex. Results Among mothers (40% Black, 31% Hispanic), 22% had active asthma in pregnancy; 17.5% of children developed asthma. Lower maternal n-3 PUFA intake was significantly associated with risk of childhood asthma (P = .03), in particular among children of mothers with active asthma and low n-3 PUFA intake (P = .01). This inverse association was more apparent in girls (P = .01) compared with boys (P = .30), regardless of maternal asthma status. For n-6 PUFA and the n-6/n-3 ratio, there was a lower risk of childhood asthma in the midrange of intake and increased risk at higher intake (n-6 PUFA P = .10, n-6/n-3 ratio P = .13). Conclusion Consideration of factors that modify effects of prenatal PUFA intake on childhood asthma has implications for designing intervention strategies tailored to impact those at greatest risk.

This study identified a genotype of respiratory syncytial virus (RSV) associated with increased acute respiratory disease severity in a cohort of previously healthy term infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4th position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild-type A2 strain G gene (one stop codon preceding a wild-type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the recombinant A4G (rA4G) RSV mutant resulted in transcriptional readthrough and lower G and fusion (F) protein levels than for the wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational readthrough. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naive BALB/c mice compared to that for wild-type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of preexisting immunity than rA4G RSV. Together, these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains. IMPORTANCE Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4th position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity than a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and, potentially, immune evasion.

Purpose The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. Methods This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. Results The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants' medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. Conclusions Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

OBJECTIVES: Viral bronchiolitis is the most common cause of infant hospitalization. Folic acid supplementation is important during the periconceptional period to prevent neural tube defects. An area of investigation is whether higher prenatal folate is a risk factor for childhood respiratory illnesses. We investigated the association between maternal 2(nd) trimester plasma folate levels and infant bronchiolitis. METHODS: We conducted a retrospective cohort analysis in a subset of mother-infant dyads (n=676) enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study and Tennessee Medicaid. Maternal folate status was determined using 2(nd) trimester (16–28 weeks) plasma samples. Bronchiolitis diagnosis in the first year of life was ascertained using International Classification of Diagnosis-9 codes from Medicaid administrative data. We used multivariable logistic regression to assess the adjusted association of prenatal folate levels and infant bronchiolitis outcome. RESULTS: Half of the women in this lower-income and predominately African-American (84%) study population had high levels of folate (median 2(nd) trimester level 19.2 ng/mL) and 21% of infants had at least one bronchiolitis healthcare visit. A relationship initially positive then reversing between maternal plasma folate and infant bronchiolitis was observed that did not reach statistical significance (p(overall)=0.112, p(nonlinear effect)=.088). Additional adjustment for dietary methyl donor intake did not significantly alter the association. CONCLUSIONS FOR PRACTICE: Results did not confirm a statistically significant association between maternal 2(nd) trimester plasma folate levels and infant bronchiolitis. Further work is needed to investigate the role of folate, particularly higher levels, in association with early childhood respiratory illnesses.

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996–2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November–March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants’ protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines.

Objectives Animal studies suggest that air pollution is neurotoxic to a developing fetus, but evidence in humans is limited. We tested the hypothesis that higher air pollution is associated with lower child IQ and that effects vary by maternal and child characteristics, including prenatal nutrition. Methods We used prospective data collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. Outdoor pollutant exposure during pregnancy was predicted at geocoded home addresses using a validated national universal kriging model that combines ground-based monitoring data with an extensive database of land-use covariates. Distance to nearest major roadway was also used as a proxy for traffic-related pollution. Our primary outcome was full-scale IQ measured at age 4–6. In regression models, we adjusted for multiple determinants of child neurodevelopment and assessed interactions between air pollutants and child sex, race, socioeconomic status, reported nutrition, and maternal plasma folate in second trimester. Results In our analytic sample (N = 1005) full-scale IQ averaged 2.5 points (95% CI: 0.1, 4.8) lower per 5 μg/m3 higher prenatal PM10, while no associations with nitrogen dioxide or road proximity were observed. Associations between PM10 and IQ were modified by maternal plasma folate (pinteraction = 0.07). In the lowest folate quartile, IQ decreased 6.8 points (95% CI: 1.4, 12.3) per 5-unit increase in PM10; no associations were observed in higher quartiles. Conclusions Our findings strengthen evidence that air pollution impairs fetal neurodevelopment and suggest a potentially important role of maternal folate in modifying these effects.

Background: Maternal vitamin D status during pregnancy may influence lung development and risk of childhood wheeze and asthma. We investigated the relationship between prenatal vitamin D and child asthma in a racially diverse cohort with a high burden of vitamin D insufficiency and child asthma. Materials and methods: We included mother–child dyads in the prenatal Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort (2006–2011, Shelby County, Tennessee). Maternal plasma vitamin D [25(OH)D] was measured from second trimester (n = 1091) and delivery specimens (n = 907). At age 4–6 years, we obtained parent report of current child wheeze (symptoms within the past 12 months) and asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used multivariable logistic regression to assess associations of 25(OH)D and child wheeze/asthma, including an interaction term for maternal race. Results: Median second trimester 25(OH)D levels were 25.1 and 19.1 ng/ml in White (n = 366) and Black women (N = 725), respectively. We detected significant interactions by maternal race for second-trimester plasma 25(OH)D and child current wheeze (p = .014) and asthma (p = .011). Odds of current wheeze and asthma decreased with increasing 25(OH)D in dyads with White mothers and increased in dyads with Black mothers, e.g. adjusted odds ratio (95% confidence interval) for asthma: 0.63 (0.36–1.09) and 1.41 (1.01–1.97) per interquartile range (15–27 ng/ml 25[OH]D) increase, respectively. At delivery, protective associations in White dyads were attenuated. Conclusion: We detected effect modification by maternal race in associations between prenatal 25(OH)D and child wheeze/asthma. Further research in racially diverse populations is needed.

The prenatal period is a critical exposure window when the developing respiratory and immune systems are susceptible to damaging impacts of environmental toxicants. Several reviews have suggested adverse effects of prenatal exposure to nitrogen dioxide (NO2) and particulate matter less than 10 μm in diameter (PM10) on child airway health, though notable limitations, including suboptimal exposure assessment, were identified.1,2 More recent studies found an increased risk of childhood asthma with elevated prenatal fine particulate matter (PM2.5) exposure.3–5 The mechanisms through which air pollution may contribute to the development of asthma include increased maternal systemic inflammation, endothelial changes, and oxidative stress; reduced placental growth and nutrient transport; epigenetic changes; and direct effects of particles crossing the placental barrier.2 Factors that may amplify risk have been identified, including male fetal sex, maternal history of asthma, and high prepregnancy body mass index (BMI).3,4,6,7 To date, studies have largely assessed exposures as averages within trimesters or across the whole pregnancy period. Maturational phases with distinct morphological lung development are well recognized: terminal bronchioles are formed during the pseudoglandular phase; the canalicular phase includes distal airway formation, differentiation of epithelial cells, angiogenesis, and vascular development; formation of terminal sacs, thinning of the alveolar walls, and maturation of the pulmonary surfactant system occur during the saccular phase; and alveolarization and microvasculature maturation occur during the prenatal alveolar phase.8 However, such developmentally relevant windows of vulnerability have not been explicitly examined in previous studies of PM2.5 and pediatric lung health. We utilized finely spatiotemporally resolved exposures to examine associations between exposure to PM2.5 during established morphogenic phases of prenatal lung development and child asthma in 2 pregnancy cohorts.