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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.

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbons (PAH) may increase risk of pediatric asthma, but existing human studies are limited. OBJECTIVES: We estimated associations between gestational PAHs and pediatric asthma in a diverse US sample and evaluated effect modification by child sex, maternal asthma, and prenatal vitamin D status. METHODS: We pooled two prospective pregnancy cohorts in the ECHO PATHWAYS Consortium, CANDLE and TIDES, for an analytic sample of N=1296 mother-child dyads. Mono-hydroxylated PAH metabolites (OH-PAHs) were measured in mid-pregnancy urine. Mothers completed the International Study on Allergies and Asthma in Childhood survey at child age 4–6 years. Poisson regression with robust standard errors was used to estimate relative risk of current wheeze, current asthma, ever asthma, and strict asthma associated with each metabolite, adjusted for potential confounders. We used interaction models to assess effect modification. We explored associations between OH-PAH mixtures and outcomes using logistic regression weighted quantile sum augmented by a permutation test to control Type 1 errors. RESULTS: The sociodemographically diverse sample spanned five cities. Mean (SD) child age at assessment was 4.4 (0.4) years. While there was little evidence that either individual OH-PAHs or mixtures were associated with outcomes, we observed effect modification by child sex for most pairs of OH-PAHs and outcomes, with adverse associations specific to females. For example, a 2-fold increase in 2-hydroxy-phenanthrene was associated with current asthma in females but not males (RR(female) = 1.29 [95% CI: 1.09, 1.52], RR(male) = 0.95 [95% CI: 0.79, 1.13]; p(interaction) = 0.004). There was no consistent evidence of modification by vitamin D status or maternal asthma. DISCUSSION: This analysis, the largest cohort study of gestational PAH exposure and childhood asthma to date, suggests adverse associations for females only. These preliminary findings are consistent with hypothesized endocrine disruption properties of PAHs, which may lead to sexually dimorphic effects.

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.

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.

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.

Background Prior research has demonstrated bidirectional associations between gestational diabetes mellitus (GDM) and perinatal maternal depression. However, the association between GDM, prenatal depression, and postpartum depression (PPD) has not been examined in a prospective cohort longitudinally. Methods Participants in the current analysis included 5,822 women from the National Institutes of Health’s Environmental influences on Child Health Outcomes (ECHO) Research Program: N = 4,606 with Neither GDM nor Prenatal Maternal Depression (Reference Category); N = 416 with GDM only; N = 689 with Prenatal Maternal Depression only; and N = 111 with Comorbid GDM and Prenatal Maternal Depression. The PROMIS-D scale was used to measure prenatal and postnatal maternal depressive symptoms. Primary analyses consisted of linear regression models to estimate the independent and joint effects of GDM and prenatal maternal depression on maternal postpartum depressive symptoms. Results A higher proportion of women with GDM were classified as having prenatal depression (N = 111; 21%) compared to the proportion of women without GDM who were classified as having prenatal depression (N = 689; 13%), however this finding was not significant after adjustment for covariates. Women with Comorbid GDM and Prenatal Maternal Depression had significantly increased postpartum depressive symptoms measured by PROMIS-D T-scores compared to women with Neither GDM nor Prenatal Maternal Depression (mean difference 7.02, 95% CI 5.00, 9.05). Comorbid GDM and Prenatal Maternal Depression was associated with an increased likelihood of PPD (OR 7.38, 95% CI 4.05, 12.94). However, women with GDM only did not have increased postpartum PROMIS-D T-scores or increased rates of PPD. Conclusions Our findings underscore the importance of universal depression screening during pregnancy and in the first postpartum year. Due to the joint association of GDM and prenatal maternal depression on risk of PPD, future studies should examine potential mechanisms underlying this relation.

Childhood wheeze, asthma, and allergic rhinitis are common and likely have prenatal origins. Oxidative stress is associated with respiratory disease, but the association of oxidative stress during the prenatal period with development of respiratory and atopic disease in childhood, particularly beyond the infancy period, is unknown. This study aims to investigate associations between prenatal oxidative stress, measured by maternal urinary FWe prospectively studied Black (n = 717) and White (n = 363) mother-child dyads. We measured FThe prevalence of provider-diagnosed asthma and current wheeze, asthma and allergic rhinitis was 14%, 19%, 15%, and 24%, respectively. Median (IQR) FPrenatal urinary 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.

The objective of this study was to calculate an oxidative balance score (OBS) utilizing diet and lifestyle information collected from 1322 women during the second trimester of pregnancy in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. An energy-adjusted OBS was calculated using nutrient information from a Food Frequency Questionnaire (FFQ), lifestyle measures, and plasma folate and vitamin D levels. Using the least absolute shrinkage and selection operator method, 91 food items from the FFQ were selected and they accounted for 82% of the variance in the OBS, with cruciferous vegetables, citrus fruits, fruit juice, and coffee being among the highest anti-oxidant predictors, and red meats and alcohol among the highest pro-oxidant contributors. Urinary F2-isoprostane, an objective indicator of oxidative stress, was lower with increasing OBS quintiles in a stairstep manner (p for trend = 0.0003), suggesting the possible utility of the OBS as an indicator of oxidative stress. The OBS was moderately correlated with the Healthy Eating Index (correlation coefficient = 0.6076), suggesting it provides a distinct measure of a healthy diet. In conclusion, the OBS may serve as a valid reflective indicator of urinary F2-isoprostanes and an epidemiological tool to inform intervention studies, in order to minimize oxidative stress during pregnancy.

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.

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.

Background Individuals with spina bifida are at increased risk for urinary tract infection (UTI), however there are few population-based investigations of the burden of UTI hospitalizations. Objective We assessed rates and risk factors for UTI hospitalization in individuals with and without spina bifida. Methods We conducted a retrospective cohort study to estimate rates of UTI hospitalization by spina bifida status. We included individuals enrolled in Tennessee Medicaid who lived in one of the Emerging Infections Program’s Active Bacterial Surveillance counties between 2005 and 2013. Spina bifida was primarily defined and UTI hospitalizations were identified using International Classification of Diseases, Ninth Revision diagnoses. We also studied a subset without specific health conditions potentially associated with UTI. We used Poisson regression to calculate rate ratios (RR) of UTIs for individuals with versus without spina bifida, adjusting for race, sex and age group. Results Over the 9-years, 1,239,362 individuals were included and 2,493 met criteria for spina bifida. Individuals with spina bifida had over a four-fold increased rate of UTI hospitalization than those without spina bifida-in the overall study population and in the subset without specific, high-risk conditions (adjusted rate ratios: 4.41, 95% confidence intervals: 3.03, 6.43) and (4.87, 95% CI: 2.99, 7.92), respectively. We detected differences in rates of UTI hospitalization by race and sex in individuals without spina bifida that were not seen among individuals with spina bifida. Conclusions Individuals with spina bifida had increased rates of UTI hospitalizations, and associated demographic patterns differed from those without spina bifida.

Background Previous studies of prenatal phthalate exposure and childhood asthma are inconsistent. These studies typically model phthalates as individual, rather than co-occurring, exposures. We investigated whether prenatal phthalates are associated with childhood wheeze and asthma using a mixtures approach. Methods We studied dyads from two prenatal cohorts in the ECHO-PATHWAYS consortium: CANDLE, recruited 2006–2011 and TIDES, recruited 2011–2013. Parents reported child respiratory outcomes at age 4–6 years: ever asthma, current wheeze (symptoms in past 12 months) and current asthma (two affirmative responses from ever asthma, recent asthma-specific medication use, and/or current wheeze). We quantified 11 phthalate metabolites in third trimester urine and estimated associations with child respiratory outcomes using weighted quantile sum (WQS) logistic regression, using separate models to estimate protective and adverse associations, adjusting for covariates. We examined effect modification by child sex and maternal asthma. Results Of 1481 women, most identified as White (46.6%) or Black (44.6%); 17% reported an asthma history. Prevalence of ever asthma, current wheeze and current asthma in children was 12.3%, 15.8% and 12.3%, respectively. Overall, there was no adverse association with respiratory outcomes. In sex-stratified analyses, boys’ phthalate index was adversely associated with all outcomes (e.g., boys’ ever asthma: adjusted odds ratio per one quintile increase in WQS phthalate index (AOR): 1.42; 95% confidence interval (CI): 1.08, 1.85, with mono-ethyl phthalate (MEP) weighted highest). Adverse associations were also observed in dyads without maternal asthma history, driven by MEP and mono-butyl phthalate (MBP), but not in those with maternal asthma history. We observed protective associations between the phthalate index and respiratory outcomes in analysis of all participants (e.g., ever asthma: AOR; 95% CI: 0.81; 0.68, 0.96), with di(2-ethylhexyl)phthalate (DEHP) metabolites weighted highest. Conclusions Results suggest effect modification by child sex and maternal asthma in associations between prenatal phthalate mixtures and child asthma and wheeze.

Background Prenatal and early life air pollution exposure may impair healthy neurodevelopment, increasing risk of childhood behavioral disorders, but epidemiological evidence is inconsistent. Little is known about factors that determine susceptibility. Methods Participants were mother-child dyads from the CANDLE study, an ECHO PATHWAYS Consortium birth cohort set in the mid-South United States, who completed a preschool visit. We estimated prenatal and childhood exposures to nitrogen dioxide (NO2) and particulate matter less than 10 μm (PM10) at participants' residences using a national annual average universal kriging model (land-use regression with spatial smoothing). Distance to nearest major roadway was used as a proxy for traffic-related pollution. Primary outcomes were children's internalizing and externalizing behavior problems. Regression models were adjusted for individual- and neighborhood-level socioeconomic measures, maternal IQ, and multiple other potential confounders. We tested for effect modification by select maternal and child characteristics. Results The analytic sample (N = 975 of 1503 enrolled) was 64% African American and 53% had a household annual income below $35,000; child mean age was 4.3 years (SD: 0.4). Mean prenatal NO2 and PM10 exposures were 12.0 ppb (SD: 2.4) and 20.8 μg/m3 (SD: 2.0); postnatal exposures were lower. In fully adjusted models, 2 ppb higher prenatal NO2 was positively associated with externalizing behavior (6%; 95% CI: 1, 11%). Associations with postnatal exposure were stronger (8% per 2 ppb NO2; 95%CI: 0, 16%). Prenatal NO2 exposure was also associated with an increased odds of clinically significant internalizing and externalizing behaviors. We found suggestive evidence that socioeconomic adversity and African American race increases susceptibility. PM10 and road proximity were not associated with outcomes. Conclusions Findings showed that air pollution exposure is positively associated with child behavior problems and that African American and low SES children may be more susceptible. Importantly, associations were observed at exposures below current air quality standards.

BackgroundFindings on prenatal polyunsaturated fatty acid (PUFA) intake and child wheeze and asthma have been inconsistent.ObjectiveWe sought to examine associations between prenatal PUFA status and child wheeze/asthma and modifying effects of maternal asthma/atopy, child sex, and maternal race.MethodsAnalyses included 1019 mother-child dyads with omega-3 (n-3) and omega-3 (n-6) PUFAs measured in second-trimester plasma; n-6/n-3 ratios were calculated. Child wheeze/asthma outcomes ascertained at age 4 to 6 years included ever physician-diagnosed asthma, current wheeze (symptoms past 12 months), current asthma (diagnosis and medication and/or symptoms past 12 months), and current diagnosed asthma. Each PUFA indicator and outcome was analyzed in separate models using modified Poisson regression with interaction terms.ResultsIn quartile (Q) analyses, higher n-6 PUFAs were associated with increased risk of ever (risk ratio [RR] high vs low [RR Q4 vs Q1], 1.70; 95% CI, 1.07-2.71) and current (RR Q4 vs Q1, 1.70; 95% CI, 1.07-2.71) diagnosed asthma, whereas n-3 PUFAs were associated with lower risk (RR Q4 vs Q1, 0.59; 95% CI, 0.33-1.03) of current diagnosed asthma (Ptrend< .05 for all). Higher n-6 PUFAs were associated with a higher risk of all respiratory outcomes among children born to women with asthma (Pinteraction< .05 for all outcomes). Asignificant 3-way interaction between child sex, maternal asthma, and n-6/n-3 PUFA indicated that male children born to women with asthma and a higher ratio had the highest risk across wheeze/asthma outcomes (Pinteraction< .05).ConclusionsAssociations between prenatal PUFA status and childhood wheeze/asthma were modified by maternal history of asthma and child sex.

BACKGROUND Prenatal folic acid supplementation is recommended to prevent birth defects. Some foods are fortified in the USA to ensure sufficient intake among reproductive-aged women. However, high prenatal folate exposure may be a risk factor for childhood atopic diseases. We investigated associations between prenatal folate and early childhood wheeze and atopic dermatitis in a US cohort. METHODS We studied 858 mother-child dyads, enrolled prenatally. Folate was measured in 2nd and 3rd trimester maternal plasma. Parents reported current wheeze (previous 12 months) and healthcare provider diagnosis of atopic dermatitis at 3 years. We examined associations using logistic regression, modeling folate continuously and dichotomously (< or ≥20 ng/mL), a level often considered supraphysiologic. RESULTS Over half of women were African American and on Medicaid. Median (interquartile range) folate levels were 22.6 (15.9-30.0) and 23.1 (16.1-30.0) ng/mL for 2nd and 3rd trimesters, respectively. Current wheeze and atopic dermatitis were reported for 20.4% and 26.8% of children, respectively. Second trimester folate as a continuous exposure was not significantly associated with outcomes. Decreased odds of current wheeze were observed in children born to mothers who had 2nd trimester folate ≥20 ng/mL (adjusted odds ratios = 0.67, 95% confidence interval = 0.46, 0.97) compared to children with maternal levels

Background.: Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common viruses associated with acute respiratory tract infections in infancy. Viral interference is important in understanding respiratory viral circulation and the impact of vaccines. Methods.: To study viral interference, we evaluated cases of RSV and HRV codetection by polymerase chain reaction in 2 prospective birth cohort studies (the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure [INSPIRE] study and the Tennessee Children's Respiratory Initiative [TCRI]) and a double-blinded, randomized, controlled trial (MAKI), using adjusted multivariable regression analyses. Results.: Among 3263 respiratory tract samples, 24.5% (798) and 37.3% (1216) were RSV and HRV positive, respectively. The odds of HRV infection were significantly lower in RSV-infected infants in all cohorts, with adjusted odds ratios of 0.30 (95% confidence interval [CI], .22-.40 in the INSPIRE study, 0.18 (95% CI, .11-.28) in the TCRI (adjusted for disease severity), and 0.34 (95% CI, .16-.72) in the MAKI trial. HRV infection was significantly more common among infants administered RSV immunoprophylaxis, compared with infants who did not receive immunoprophylaxis (OR, 1.65; 95% CI, 1.65-2.39). Conclusions.: A negative association of RSV on HRV codetection was consistently observed across populations, seasons, disease severity, and geographical regions. Suppressing RSV infection by RSV immunoprophylaxis might increase the risk of having HRV infection.

Dietary patterns are sensitive to differences across socio-economic strata or cultural habits and may impact programing of diseases in later life. The purpose of this study was to identify distinct dietary patterns during pregnancy in the Mid-South using factor analysis. Furthermore, we aimed to analyze the differences in the food groups and in macro- and micronutrients among the different food patterns. The study was a cross-sectional analysis of 1155 pregnant women (mean age 26.5 ± 5.4 years; 62% African American, 35% Caucasian, 3% Other; and pre-pregnancy BMI 27.6 ± 7.5 kg/m2). Using food frequency questionnaire data collected from participants in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study between 16 and 28 weeks of gestation, dietary patterns were identified using factor analysis. Three major dietary patterns, namely, Healthy, Processed, and US Southern were identified among pregnant women from the Mid-South. Further analysis of the three main patterns revealed four mixed dietary patterns, i.e., Healthy-Processed, Healthy-US Southern, Processed-US Southern, and overall Mixed. These dietary patterns were different (p < 0.001) from each other in almost all the food items, macro- and micro nutrients and aligned across socioeconomic and racial groups. Our study describes unique dietary patterns in the Mid-South, consumed by a cohort of women enrolled in a prospective study examining the association of maternal nutritional factors during pregnancy that are known to affect brain and cognitive development by age 3.

Rates of Sudden Unexplained Infant Death (SUID), bronchiolitis, and central apnea increase in winter in temperate climates. Though associations between these three conditions are suggested, more work is required to establish if there is a causal pathway linking bronchiolitis to SUID through inducing central apnea. Utilizing a large population-based cohort of infants studied over a 20-year period (n = 834,595, from birth years 1989–2009)), we analyzed ecological associations between timing of SUID cases, bronchiolitis, and apnea healthcare visits. Data were analyzed between 2013 and 2015. We used a Cox Proportional Hazards model to analyze possible interactions between maternal smoking and maternal asthma with infant bronchiolitis on time to SUID. SUID and bronchiolitis both occurred more frequently in winter. An increase in bronchiolitis clinical visits occurred within a few days prior to apnea visits. We found a temporal relationship between infant bronchiolitis and apnea. In contrast, no peak in SUID cases was seen during peaks of bronchiolitis. Among those without any bronchiolitis visits, maternal smoking was associated with an increased risk of SUID: Hazard Ratio (HR) of 2.38 (95% CI: 2.11, 2.67, p-value

Environmental exposures that occur in utero and during early life may contribute to the development of childhood asthma through alteration of the human microbiome. The objectives of this study were to estimate the cumulative effect and relative importance of environmental exposures on the risk of childhood asthma.We conducted a population-based birth cohort study of mother-child dyads who were born between 1995 and 2003 and were continuously enrolled in the PRIMA (Prevention of RSV: Impact on Morbidity and Asthma) cohort. The individual and cumulative impact of maternal urinary tract infections (UTI) during pregnancy, maternal colonization with group B streptococcus (GBS), mode of delivery, infant antibiotic use, and older siblings at home, on the risk of childhood asthma were estimated using logistic regression. Dose-response effect on childhood asthma risk was assessed for continuous risk factors: number of maternal UTIs during pregnancy, courses of infant antibiotics, and number of older siblings at home. We further assessed and compared the relative importance of these exposures on the asthma risk. In a subgroup of children for whom maternal antibiotic use during pregnancy information was available, the effect of maternal antibiotic use on the risk of childhood asthma was estimated.Among 136,098 singleton birth infants, 13.29% developed asthma. In both univariate and adjusted analyses, maternal UTI during pregnancy (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.18, 1.25; adjusted OR [AOR] 1.04, 95%CI 1.02, 1.07 for every additional UTI) and infant antibiotic use (OR 1.21, 95%CI 1.20, 1.22; AOR 1.16, 95%CI 1.15, 1.17 for every additional course) were associated with an increased risk of childhood asthma, while having older siblings at home (OR 0.92, 95%CI 0.91, 0.93; AOR 0.85, 95%CI 0.84, 0.87 for each additional sibling) was associated with a decreased risk of childhood asthma, in a dose-dependent manner. Compared with vaginal delivery, C-section delivery increased odds of childhood asthma by 34% (OR 1.34, 95%CI 1.29, 1.39) in the univariate analysis and 11% after adjusting for other environmental exposures and covariates (AOR 1.11, 95%CI 1.06, 1.15). Maternal GBS was associated with a significant increased risk of childhood asthma in the univariate analysis (OR 1.27, 95%CI 1.19, 1.35), but not in the adjusted analysis (AOR 1.03, 95%CI 0.96, 1.10). In the subgroup analysis of children whose maternal antibiotic use information was available, maternal antibiotic use was associated with an increased risk of childhood asthma in a similar dose-dependent manner in the univariate and adjusted analyses (OR 1.13, 95%CI 1.12, 1.15; AOR 1.06, 95%CI 1.05, 1.08 for every additional course). Compared with infants with the lowest number of exposures (no UTI during pregnancy, vaginal delivery, at least five older siblings at home, no antibiotics during infancy), infants with the highest number of exposures (at least three UTIs during pregnancy, C-section delivery, no older siblings, eight or more courses of antibiotics during infancy) had a 7.77 fold increased odds of developing asthma (AOR: 7.77, 95%CI: 6.25, 9.65). Lastly, infant antibiotic use had the greatest impact on asthma risk compared with maternal UTI during pregnancy, mode of delivery and having older siblings at home.Early-life exposures, maternal UTI during pregnancy (maternal antibiotic use), mode of delivery, infant antibiotic use, and having older siblings at home, are associated with an increased risk of childhood asthma in a cumulative manner, and for those continuous variables, a dose-dependent relationship. Compared with in utero exposures, exposures occurring during infancy have a greater impact on the risk of developing childhood asthma.

Background Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV-related hospitalizations and has been associated with decreased wheezing in the first years of life. Objective We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma. Methods We conducted a retrospective cohort investigation including children born from 1996-2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma-specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]–adjusted and PS-matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. Results By using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS-matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50-0.78). Conclusions This investigation of RSV immunoprophylaxis in high-risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high-risk children.

Background Risk factors for severe human rhinovirus (HRV)–associated infant illness are unknown. Objectives We sought to examine the role of HRV infection in infant respiratory tract illness and assess viral and host risk factors for HRV-associated disease severity. Methods We used a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory tract illness during the fall-spring months of 2004-2008. Illness severity was determined by using an ordinal bronchiolitis severity score, with higher scores indicating more severe disease. HRV was identified by means of real-time RT-PCR. The VP4/VP2 region from HRV-positive specimens was sequenced to determine species. Results Of 630 infants with bronchiolitis or upper respiratory tract illnesses (URIs), 162 (26%) had HRV infection; HRV infection was associated with 18% of cases of bronchiolitis and 47% of cases of URI. Among infants with HRV infection, 104 (64%) had HRV infection alone. Host factors associated with more severe HRV-associated illness included a maternal and family history of atopy (median score of 3.5 [interquartile range [IQR], 1.0-7.8] vs 2.0 [IQR, 1.0-5.2] and 3.5 [IQR, 1.0-7.5] vs 2.0 [IQR, 0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in the risk for more severe HRV-associated bronchiolitis (odds ratio, 2.39; 95% CI, 1.14-4.99; P = .02). In a similar model maternal asthma was also associated with greater HRV-associated bronchiolitis severity (odds ratio, 2.49, 95% CI, 1.10-5.67; P = .03). Among patients with HRV infection, 35% had HRVA, 6% had HRVB, and 30% had HRVC. Conclusion HRV infection was a frequent cause of bronchiolitis and URIs among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial viral genetic diversity was seen among the patients with HRV infection, and predominant groups varied by season and year. Host factors, including maternal atopy, were associated with more severe infant HRV-associated illness.

Background Asthma is a common condition during pregnancy. Objective We sought to determine the effect of asthma on the rates of adverse pregnancy and fetal outcomes. Methods We identified pregnancies among black and white women age 15 to 44 with singleton gestations enrolled in the Tennessee Medicaid program over a period of 9 consecutive years, from 1995to 2003, and used claims data to determine the relationship of maternal asthma and asthma exacerbations on pregnancy and infant outcomes. Results Among the 140,299 pregnancies, 6.5% were in women with asthma. Among women with asthma, 23% had a hospital or emergency department visit (exacerbated asthma); 40% of black and 23% of white women received hospital or emergency department care for asthma during pregnancy. After controlling for race and other covariates, birth weights among infants of women with asthma were, on average, 38 g lower, and among infants of women with exacerbated asthma they were, on average, 56 g lower. There were moderate, dose-dependent relationships between asthma alone and exacerbated asthma with hypertensive disorders of pregnancy, membrane-related disorders, preterm labor, antepartum hemorrhage, and cesarean delivery. Maternal asthma was not associated with preterm birth or birth defects. Conclusion Asthma is a risk factor for several common adverse outcomes of pregnancy, and poorly controlled asthma during pregnancy increases these risks. Clinical implications It is possible that both maternal and infant outcomes could be improved in this population with appropriate asthma care, especially among black women.

OBJECTIVE. Our goal was to determine whether maternal asthma and maternal smoking during pregnancy are associated with the incidence and severity of clinically significant bronchiolitis in term, otherwise healthy infants without the confounding factors of small lung size or underlying cardiac or pulmonary disease.PATIENTS AND METHODS. We conducted a population-based retrospective cohort study of term, non–low birth weight infants enrolled in the Tennessee Medicaid Program from 1995 to 2003. The cohort of infants was followed through the first year of life to determine the incidence and severity of bronchiolitis as determined by health care visits and prolonged hospitalization.RESULTS. A total of 101245 infants were included. Overall, 20% of infants had ≥1 health care visit for bronchiolitis. Compared with infants with neither factor, the risk of bronchiolitis was increased in infants with maternal smoking only, maternal asthma only, or both. Infants with maternal asthma only or with both maternal smoking and asthma had the highest risks for emergency department visits and hospitalizations. Infants with a mother with asthma had the highest risk of a hospitalization >3 days, followed by infants with both maternal asthma and smoking, and maternal smoking only.CONCLUSIONS. Maternal asthma and maternal smoking during pregnancy are independently associated with the development of bronchiolitis in term, non–low birth weight infants without preexisting cardiac or pulmonary disease. The risk of bronchiolitis among infants with mothers who both have asthma and smoke during pregnancy is ∼50% greater than that of infants with neither risk factor. Efforts to decrease the illness associated with these 2 risk factors will lead to decreased morbidity from bronchiolitis, the leading cause of hospitalization for severe lower respiratory tract infections during infancy.

Background Despite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections. Methods To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans. Results There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95 % confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians. Conclusions ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0229-3) contains supplementary material, which is available to authorized users.

Asthma is one of the most common chronic childhood diseases. While folic acid supplementation around conception helps prevent neural tube defects, an animal model suggests that it may be a risk factor for respiratory diseases, although epidemiologic studies have had conflicting results. We investigated the timing of folic acid-containing prescription filling during pregnancy and child asthma.In a retrospective cohort study of 104,428 children, born 1996-2005, and their mothers enrolled in Tennessee Medicaid, we investigated the association of filling folic acid-containing prescriptions during pregnancy and childhood asthma at ages 4.5-6 years. We categorized women into exposure groups based on prescription filling centered around the first trimester: no folic acid prescription exposure, exposure in first trimester only, exposure after first trimester, and exposure in first trimester and beyond. We defined asthma using asthma-specific healthcare visits and medication fills. Using logistic regression models, we investigated the relationship adjusting for potential confounders.Overall 15% of children had asthma. Compared with children born to women with no folic acid prescription exposure, children born to women with exposures in the first trimester only or first trimester and later had increased relative odds of asthma (adjusted odds ratios = 1.2, 95% confidence interval = 1.1, 1.3, and 1.2, 95% confidence interval = 1.2, 1.3); no association was seen in children born to women exposed after the first trimester.Timing of folic acid-containing prescription filling during pregnancy was associated with childhood asthma. Our findings contribute to understanding of the role of prenatal nutritional supplements on child respiratory health.

The voicing of unsolicited observations by patients and families is a form of participation in the health care system. We investigated whether visits by patients of different race/ethnicities were equally represented in unsolicited complaints filed with a medical center's Office of Patient Affairs (OPA) regarding pediatric emergency visits.We conducted a population-based retrospective study, including pediatric emergency visits, at a large academic medical center between January 1999 and December 2002. We identified complaints to the OPA and conducted bivariate and multivariable analyses to determine whether patient race/ethnicity was associated with filing a complaint.Among 105 322 total visits, the overall complaint rate was 1.22/1000 visits. Visits by white children had a complaint rate of 1.78/1000 visits compared with 0.37/1000 visits by African American children (P.001). In multivariable analysis, visits by African American children remained less likely to be associated with a complaint to the OPA compared with visits by white children (adjusted odds ratio 0.30, 95% CI 0.17-0.55) after controlling for factors such as payer status.Emergency-department visits by African American children were less likely to be associated with a complaint than visits by white children. Programs that use complaints in service recovery, quality assurance, and risk management efforts may unintentionally exclude segments of the patient population served by the institution.

Little is known about racial differences in asthma outcomes during pregnancy. We performed a cohort study to estimate racial differences in maternal asthma outcomes in a low-income population of pregnant women in which blacks and whites have similar medical care access and benefits.We conducted a population-based cohort study of asthma-related morbidity in black and white pregnant women enrolled in Tennessee's Medicaid Program, TennCare. Pregnant women were identified through TennCare enrollment files linked to birth certificates, 1995-2001. Prepregnancy, women with asthma were identified using International Classification of Diseases, 9th Revision, codes for health care visits and pharmacy files for asthma medication. Adjusted relative rates (RR) of rescue corticosteroid prescriptions, emergency department (ED) visits, and hospitalizations during pregnancy were compared by race using Poisson regression.We identified 4,315 women with asthma (4%) from a population of 112,171 pregnant women of black or white race with at least 180 days of continuous enrollment in TennCare before pregnancy. Blacks were more likely to receive a course of rescue corticosteroids than whites (14.6% versus 11.9%, adjusted RR 1.35, 95% confidence interval [CI] 1.14-1.61), have an emergency department visit (16.7% versus 8.7%, adjusted RR 1.89, 95% CI 1.57-2.27), or be hospitalized for asthma (9.0% versus 5.2%, adjusted RR 1.73, 95% CI 1.34-2.24).Pregnant women with asthma had high asthma-related morbidity. Black women had clinically significantly more morbidity than whites. There is a need to improve the medical care of low-income women with asthma, particularly black women.II-2.

Despite increased interest in promoting nutrition during pregnancy, the association between maternal dietary patterns and birth outcomes has been equivocal. We examined maternal dietary patterns during pregnancy as a determinant of offspring’s birth weight-for-length (WLZ), weight-for-age (WAZ), length-for-age (LAZ), and head circumference (HCZ) Z-scores in Southern United States (n = 1151). Maternal diet during pregnancy was assessed by seven dietary patterns. Multivariable linear regression models described the association of WLZ, WAZ, LAZ, and HCZ with diet patterns controlling for other maternal and child characteristics. In bivariate analyses, WAZ and HCZ were significantly lower for processed and processed-Southern compared to healthy dietary patterns, whereas LAZ was significantly higher for these patterns. In the multivariate models, mothers who consumed a healthy-processed dietary pattern had children with significantly higher HCZ compared to the ones who consumed a healthy dietary pattern (HCZ β: 0.36, p = 0.019). No other dietary pattern was significantly associated with any of the birth outcomes. Instead, the major outcome determinants were: African American race, pre-pregnancy BMI, and gestational weight gain. These findings justify further investigation about socio-environmental and genetic factors related to race and birth outcomes in this population.

In a cross-sectional analysis of 629 mother-infants dyads, breast-feeding (ever vs. never) was associated with decreased relative odds of a lower versus upper respiratory tract infection (adjusted odds ratio: 0.64; 95% confidence interval: 0.42-0.99). There was not a significant association between breast-feeding and bronchiolitis severity score or length of hospital stay.

Rationale: The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups.

Respiratory syncytial virus (RSV) is a major cause of worldwide morbidity and mortality in infants, primarily through the induction of bronchiolitis. RSV epidemics are highly seasonal, occurring in the winter months in the northern hemisphere. Within the United States, RSV epidemic dynamics vary both spatially and temporally. This analysis employs a retrospective space–time scan statistic to locate spatiotemporal clustering of infant bronchiolitis in a very large Tennessee (TN) Medicaid cohort. We studied infants less than 6 months of age (N = 52,468 infants) who had an outpatient visit, emergency department visit, or hospitalization for bronchiolitis between 1995 and 2008. The scan statistic revealed distinctive and consistent patterns of deviation in epidemic timing. Eastern TN (Knoxville area) showed clustering in January and February, and Central TN (Nashville area) in November and December. This is likely due to local variation in geography-associated factors which should be taken into consideration in future modeling of RSV epidemics.

Background Individuals with atopy have more severe complications of infectious diseases. We hypothesized that the importance of secondhand smoke (SHS) on lower respiratory tract infection (LRTI) severity would be greater in infants with a familial atopic predisposition. Objective To determine whether infants with a familial atopic predisposition are more susceptible to adverse effects of SHS, resulting in more severe LRTI. Methods We conducted cross-sectional analyses of mother-infant dyads enrolled during 2004 to 2008 during an infant LRTI. Predictor variables were SHS and 2 measures of a familial atopic predisposition (maternal atopic disease with allergen sensitization or familial atopy). LRTI severity was determined by bronchiolitis severity score (BSS) and hospital length of stay (LOS). We conducted multivariable regression analysis to test for a differential relationship between SHS and LRTI severity by measures of familial atopic predisposition. Results In 451 dyads, 57% of infants had SHS exposure, 36% had a mother with atopic disease, and 68% had familial atopy. We did not detect differences in BSS or LOS by SHS exposure stratified by history of maternal atopic disease. In bivariate analysis, there was a significant difference in LOS by SHS in those with familial atopy ( P = .006) but not in those without ( P = .66). In multivariable analysis, among infants with familial atopy, there was a 23% increased LOS in infants with SHS exposure ( P = .03), whereas no statistical significance was detected in those without familial atopy ( P = .07). Conclusion In infants with familial atopy, SHS was associated with longer hospital LOS for LRTI but not BSS. Because the effect was seen only among hospitalized infants, confirmation is required.

Rationale: Asthma is associated with depression, but the temporality of the association has not been established.

Background Infants hospitalized for bronchiolitis have a high rate of early childhood asthma. It is not known whether bronchiolitis severity correlates with the risk of early childhood asthma or with asthma-specific morbidity. Objectives We sought to determine whether a dose-response relationship exists between severity of infant bronchiolitis and both the odds of early childhood asthma and asthma-specific morbidity. Methods We conducted a population-based retrospective birth cohort study of term healthy infants born from 1995-2000 and enrolled in a statewide Medicaid program. We defined bronchiolitis severity by categorizing infants into mutually exclusive groups based on the most advanced level of health care for bronchiolitis. Health care visits, asthma-specific medications, and demographics were identified entirely from Medicaid and linked vital records files. Asthma was ascertained at between 4 and 5.5 years of age, and 1-year asthma morbidity (hospitalization, emergency department visit, or oral corticosteroid course) was determined between 4.5 and 5.5 years among children with prevalent asthma. Results Among 90,341 children, 18% had an infant bronchiolitis visit, and these infants contributed to 31% of early childhood asthma diagnoses. Relative to children with no infant bronchiolitis visit, the adjusted odds ratios for asthma were 1.86 (95% CI, 1.74-1.99), 2.41 (95% CI, 2.21-2.62), and 2.82 (95% CI, 2.61-3.03) in the outpatient, emergency department, and hospitalization groups, respectively. Children hospitalized with bronchiolitis during infancy had increased early childhood asthma morbidity compared with that seen in children with no bronchiolitis visit. Conclusion To our knowledge, this is the first study to demonstrate the dose-response relationship between the severity of infant bronchiolitis and the increased odds of both early childhood asthma and asthma-specific morbidity.

Rationale: Bronchiolitis during infancy is associated with an increased risk of childhood asthma. Whether winter viral infections cause asthma or are a manifestation of a predisposition to asthma development is unknown. Objectives: To study the relationship of winter virus infection during infancy and the development of childhood asthma. Methods: We studied over 95,000 infants born between 1995 and 2000 and followed through 2005 who were enrolled in the Tennessee Medicaid program from birth through early childhood to determine whether infant birth in relationship to the winter virus peak alters the risk of developing early childhood asthma. Measurements and Main Results: Among 95,310 children studied during five winter virus seasons from birth through early childhood, the risk of developing asthma tracked with the timing of infant birth in relationship to the winter virus peak. Infant birth approximately 4 months before the winter virus peak carried the highest risk, with a 29% increase in odds of developing asthma compared with birth 12 months before the peak (adjusted odds ratio, 1.29; 95% confidence interval, 1.19–1.40). Infant age at the winter virus peak was comparable to or greater than other known risk factors for asthma. Conclusions: Timing of birth in relationship to winter virus season confers a differential and definable risk of developing early childhood asthma, establishing winter virus seasonality as a causal factor in asthma development. Delay of exposure or prevention of winter viral infection during early infancy could prevent asthma.

OBJECTIVE. The purpose of this work was to estimate the incidence of medically treated thyroid disease in children with Down syndrome enrolled in Tennessee Medicaid (TennCare) during 1995–2005 and to determine whether rates increased after rerelease of American Academy of Pediatrics guidelines in 2001. PATIENTS AND METHODS. We conducted a population-based retrospective cohort study in which we identified children with Down syndrome by using TennCare files and birth certificates. We included 1- to 18-year-olds who were continuously enrolled in TennCare and did not fill a prescription for thyroid medication during a 90-day prestudy period. The rate of medically treated thyroid disease (prescription filled for thyroid medication) was the main outcome. We used Poisson regression to estimate rates of medically treated thyroid disease according to study year, age, gender, race, region of residence, and payer type. RESULTS. During the 11-year study period, 1257 children with Down syndrome (28% black, 72% white) met inclusion criteria. Overall, 10.8% filled a new prescription for thyroid medication. Rates of medically treated thyroid disease per 1000 child-years were 13.25 (1995–1997), 13.34 (1998–1999), 13.62 (2000–2001), 22.37 (2002–2003), and 22.51 (2004–2005). After adjusting for child age and race, there was an increased rate of medically treated thyroid disease in 2002–2003 and 2004–2005 compared with 1995–1997. In a comparison cohort of children without Down syndrome, there was a smaller increase in the rate of medically treated thyroid disease when comparing 2002–2003 and 2004–2005 with 1995–1997. CONCLUSIONS. Over the 11-year period, 10.8% of children with Down syndrome filled a new prescription for a thyroid medication. A 73% increase in the incidence of medically treated thyroid disease occurred after rerelease of American Academy of Pediatrics guidelines, which may have influenced screening.