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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.

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 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.

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.

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.

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.

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.

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: Infants with lower respiratory tract infections (LRTIs) are at an increased risk of developing childhood wheezing illnesses (including asthma), but it is not currently possible to predict those at risk for these long-term outcomes. The current objective was to examine whether urine levels of club cell 16-kDa secretory protein (CC16) at the time of an infant LRTI are associated with the development of childhood wheezing illnesses. Methods: Prospective study of 133 previously healthy infants enrolled during a healthcare visit for a LRTI and followed longitudinally for childhood wheezing illnesses. Urine levels of CC16 at the time of enrollment were measured after validating a commercially available enzyme-linked immunosorbent assay kit for serum. The outcome of interest was parental report of subsequent childhood wheeze (defined as ≥1 episode of wheezing following the initial LRTI) at the 1-year follow-up visit. Logistic regression was used for the main analysis. Results: The median (interquarti...

Background: A respiratory severity score (RSS) describing acute respiratory illness (ARI) severity would be useful for research and clinical purposes. Methods: A total of 630 term infants presenting with ARI had their RSS measured. Results: RSS was higher in those with lower respiratory tract infection (LRTI) compared with those with upper respiratory infection (URI; LRTI 6.5 [4–8.5]; URI 1 [0–2], p

It is unknown whether gastroesophageal reflux disease (GERD) during infancy affects infant bronchiolitis severity or childhood asthma inception. Four hundred thirty-two infants presenting with acute respiratory illness due to bronchiolitis or upper respiratory infection were studied. The primary exposure was the parental report of a previous GERD diagnosis. Outcomes included bronchiolitis severity at initial presentation and childhood asthma diagnosis at age 4. Infants with parentally reported GERD had a higher bronchiolitis severity score (range=0–12, clinically significant difference=0.5), indicating more severe disease, than infants without reported GERD (median 5.5 [interquartile range 3.5–9.0] among those with reported GERD versus 4.0 [1.0–7.0] among those without, P=0.005). This association persisted after adjusting for infant age, race, gender, and secondhand smoke exposure by a propensity score (adjusted odds ratio [OR] 1.99, 95% confidence interval [CI] 1.14–3.46, P=0.02). The parental report of GERD during infancy was not associated with the parental report of asthma diagnosis at age 4. GERD during infancy may contribute to acute respiratory illness severity, but is not associated with asthma diagnosis at age 4. Future prospective studies are needed to confirm these findings.

Objective To examine healthcare resource utilization for acute respiratory illness in Latino infants compared with other racial/ethnic groups. Study design We studied 674 term-born, previously healthy infants brought in for an unscheduled healthcare visit for an acute respiratory illness. The predictor variable was infant race/ethnicity, and the primary outcome was healthcare resource utilization, adjusted for age and disease severity. Results The cohort was 14% Latino, 52% white, 22% African American, and 12% other race/ethnicity. More than one-third (37%) of the mothers of Latino infants were Spanish-speaking. The bronchiolitis severity score was higher (indicating more severe disease) in white infants (median, 6.0; IQR, 3.0-9.0 on a scale of 0-12) compared with Latino (median, 3.0; IQR, 1.0-6.0) and African American (median, 3.5; IQR, 1.0-6.0) infants ( P P = .96). Latino infants were the most likely to receive antibiotics (58%, compared with 47% of whites and 34% of African Americans; P = .005) and to have body fluid cultures drawn. Latino infants also were more likely than African American infants to undergo chest radiography and respiratory virus rapid antigen testing ( P ≤ .01). Latino infants from Spanish-speaking families had a higher rate of respiratory syncytial virus testing compared with those from English-speaking families (76% vs 51%; P = .016). Conclusion Providers caring for Latino infants with acute respiratory illness ordered more antibiotics and diagnostic testing for this group, particularly compared with African Americans, even though the 2 groups had similar disease severity and socioeconomic disparities. Language barrier may be a possible explanation for these differences.

Background—Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness in infants is limited. Methods—This prospective cohort enrolled previously healthy term infants during inpatient or outpatient visits for acute upper respiratory illness (URI) or bronchiolitis during September - May 2004–2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time RT-PCR. Results—Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup, and 27% URI. Among infants with bronchiolitis, 76% had RSV, 18% HRV, 10% influenza, 2% coronavirus, 3% HMPV, and 1% PIV. Among infants with croup, 39% had HRV, 28% PIV, 28% RSV, 11% influenza, 6% coronavirus, and none HMPV. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% PIV, and 4% HMPV. Individual viruses exhibited distinct seasonal, demographic, and clinical expression. Conclusions—The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.

Introduction: Bronchiolitis, a viral lower respiratory tract infection, affects 20-30% of infants and is a leading cause of hospitalizations. Identifying and mitigating risk factors has public heal...

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 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. Methods 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. Results 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. Conclusion 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 Urban children represent a group at high risk for asthma development and adverse asthma outcomes. Although rural children also encounter sociodemographic disparities that might be expected to worsen asthma, asthma in the rural United States is poorly studied. Objectives To determine rural-urban differences in childhood asthma diagnosis and morbidity. Methods We studied a statewide population of 117,080 children continuously enrolled in Tennessee Medicaid from birth through the sixth year of life, using linked Tennessee Medicaid, vital records, and pharmacy claims databases to determine asthma diagnosis and residence. Results The cohort was 45% urban, 23% suburban, and 33% rural. Compared with urban children, rural children were more likely to be white, have a history of bronchiolitis, and have mothers who smoked. Eleven percent of urban, 12% of suburban, and 13% of rural children met study criteria for asthma diagnosis (adjusted odds ratio for rural children, 1.16; 95% confidence interval, 1.09–1.24; adjusted odds ratio for suburban children, 1.22; 95% confidence interval, 1.14–1.30; with urban as the referent; P Conclusion In this pediatric Medicaid population, rural children had increased asthma prevalence and similar asthma morbidity compared with urban children but differences in patterns of asthma care and resource use, suggesting that optimal interventions for asthma may differ in rural compared with urban populations.

Aim We sought to determine the proportion of bronchiolitis episodes attributable to respiratory syncytial virus (RSV) among ICD‐9 coded infant bronchiolitis episodes which were tested for RSV. Methods Bronchiolitis healthcare encounters were extracted from Kaiser Permanente Northern California databases for years 2006 to 2009. We used ICD‐9 codes for bronchiolitis to capture bronchiolitis‐related healthcare encounters including hospital admissions (Hospitalization), emergency department visits (EDV), and outpatient visits (OPV). We reported the monthly proportion of RSV‐positive bronchiolitis episodes among tested bronchiolitis episodes. We used logistic regression to assess association between bronchiolitis episodes and patient demographic and health care characteristics. We also used logistic regression to assess association between decision to test and patient demographics and health care characteristics. Results Among 10,411 ICD‐9 coded infant bronchiolitis episodes, 29% were RSV tested. Fifty one percent of those tested were RSV positive. Between December and February, and in infants ≤6 months, the proportion of bronchiolitis episodes that were attributable to RSV was 77.2% among hospitalized episodes, 78.3% among EDV episodes, and 60.9% among OPV episodes, respectively. The proportion of RSV‐positive bronchiolitis episodes varied based upon infant age at diagnosis, level of health care service used, and time of the year of the episode. Conclusion Estimation of the proportion of ICD‐9 coded bronchiolitis episodes attributable to RSV is more specific when restricting to bronchiolitis episodes during peak months, younger infant age, and those requiring higher level of healthcare., Perspective on this article: Is it RSV?

Background and objective: The ‘attack rate’ of asthma following viral lower respiratory tract infections (LRTI) is about 3–4 fold higher than that of the general population; however, the majority of children who develop viral LRTI during infancy do not develop asthma, and asthma incidence has been observed to continuously decrease with age. Thus, we do not understand how viral LRTI either predispose or serve as a marker of children to develop asthma. The Tennessee Children's Respiratory Initiative has been established as a longitudinal prospective investigation of infants and their biological mothers. The primary goals are to investigate both the acute and the long-term health consequences of varying severity and aetiology of clinically significant viral respiratory tract infections on early childhood outcomes. Methods: Over four respiratory viral seasons, 2004–2008, term, non-low birth weight previously healthy infants and their biological mothers were enrolled during an infant's acute viral respiratory illness. Longitudinal follow up to age 6 years is ongoing. Results: This report describes the study objectives, design and recruitment results of the over 650 families enrolled in this longitudinal investigation. The Tennessee Children's Respiratory Initiative is additionally unique because it is designed in parallel with a large retrospective birth cohort of over 95 000 mother–infant dyads with similar objectives to investigate the role of respiratory viral infection severity and aetiology in the development of asthma. Conclusions: Future reports from this cohort will help to clarify the complex relationship between infant respiratory viral infection severity, aetiology, atopic predisposition and the subsequent development of early childhood asthma and atopic diseases.

The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections.[1-7] Although it is unclear whether respiratory viral infections cause asthma, observational studies have demonstrated a high rate of asthma in children with a history of severe viral lower respiratory tract infections during infancy, and viruses are the associated with the majority of asthma exacerbations among both children and adults. This review will discuss the pathogens associated with virus-induced wheezing illnesses during infancy and early childhood, the association of bronchiolitis during infancy with an increased risk of childhood asthma, and the association of respiratory viruses with asthma exacerbations in older children and adults.

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.

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.

Background: Infant temperament predicts a range of developmental and behavioral outcomes throughout childhood. Both maternal fatty acid intake and psychosocial stress exposures during pregnancy may influence infant temperament. Furthermore, maternal race may modify prenatal diet and stress effects. The goals of this study are to examine the joint effects of prenatal diet and stress and the modifying effects of race on infant behavior. Methods: Analyses included N=255 mother-infant dyads, primarily minorities (21% Blacks; 42% Hispanics), enrolled in an urban pregnancy cohort. Maternal prenatal stress was indexed by a negative life events (NLEs) score on the Crisis in Family Systems-Revised survey. Prenatal total daily intakes of polyunsaturated fatty acids (PUFAs) (n3, n6) were estimated from a food frequency questionnaire; n3:n6 ratios were calculated. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), a measure of infant temperament, when the children were 6 months old. Three commonly used dimensions were derived: Orienting & Regulation, Extraversion, and Negative Affectivity.?Associations among prenatal stress, maternal n3:n6 ratio, and race/ethnicity on infant temperament, controlling for maternal education and age and child sex, were examined. Results: Among Blacks, prenatal stress effects on infant Orienting & Regulation scores were modified by maternal n3:n6 ratios (p = 0.03):?As NLEs increased, lower n3:n6 ratios predicted lower infant Orienting & Regulation scores, whereas higher n3:n6 ratios attenuated the effect of prenatal stress. There were no main or interaction effects predicting Extraversion or Negative Affectivity. Conclusions: An optimal PUFA ratio may protect the fetus from stress effects on infant behavior, particularly among Blacks. These findings may have implications for later neurodevelopment and social functioning predicted by early temperamental characteristics.

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts. Supported by MeDALL (Mechanisms of the Development of Allergy, EU FP7 Grant agreement no. 261357)

There is a population-based increased risk of early childhood asthma following infant bronchiolitis occurring during rhinovirus-predominant months compared to asthma following infant bronchiolitis during RSV-predominant months.

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.

Among infants with prematurity and/or chronic lung disease for whom respiratory syncytial virus immunoprophylaxis is recommended, we examined adherence in infants enrolled during healthcare visits for acute respiratory illness in 3 U.S. counties from 2001 to 2007. Immunoprophylaxis among infants who met national criteria for prophylaxis increased from 33% to 83% over the 6-year period; 17% (11/65) of infants who received immunoprophylaxis did not meet eligibility criteria.

Background The ability to measure 25-hydroxyvitamin D (25OHD) levels from blood spot cards can simplify sample collection versus samples obtained by venipuncture, particularly in populations in whom it is difficult to draw blood. We sought to validate the use of blood spot samples for the measurement of 25OHD compared to serum or whole blood samples and correlate the measured levels with intake estimated from dietary recall. Methods Utilizing 109 biological mothers of infants enrolled in the Tennessee Children's Respiratory Initiative cohort, we measured 25OHD levels through highly selective liquid chromatography–tandem mass spectrometry on samples from blood spot cards, serum, and whole blood collected at enrollment. Dietary questionnaires (n = 65) were used to assess 25OHD intake by dietary recall. Sample collection measures were assessed for agreement and 25OHD levels for association with dietary 25OHD intake. Results The mean absolute differences (95%CI) in 25OHD levels measured between whole blood and blood spot (n = 50 pairs) or serum and blood spot (n = 20) were 3.2 (95%CI:1.6, 4.8) ng/ml and 1.5 (95%CI:−0.5,3.4) ng/mL. Intake by dietary recall was marginally associated with 25OHD levels after adjustment for current smoking and race in linear regression. Discussion 25OHD levels determined by mass spectrometry from blood spot cards, serum and whole blood show relatively good agreement, although 25OHD levels are slightly lower when measured by blood spot cards. Blood spot samples are a less invasive means of obtaining 25OHD measurements, particularly in large population-based samples, or among children when venipuncture may decrease study participation.

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.

Objective The objective of the study was to determine whether women alter their use of asthma medications during pregnancy. Study design Weekly asthma medication use was determined from prescription claims data in a cohort of 112,171 pregnant women aged 15 to 44 years who were continuously enrolled in the Tennessee Medicaid program prior to their singleton pregnancy and who delivered a singleton birth during 1995 to 2001. Change in asthma medication use was evaluated using generalized estimating equation analyses. Results Women with asthma significantly ( P ≤ 0.0005) decreased their asthma medication use from 5 to 13 weeks of pregnancy. During the first trimester, there was a 23% decline in inhaled corticosteroid prescriptions, a 13% decline in short-acting beta-agonist prescriptions, and a 54% decline in rescue corticosteroid prescriptions. Conclusions Utilization of all categories of asthma medications decreased in early pregnancy, with the largest declines occurring for inhaled and rescue corticosteroids.

To the Editor: The etiology of asthma remains unclear but is thought to include non-modifiable risk factors such as family history and genetic predisposition, as well as potentially modifiable risk factors including viral bronchiolitis in infancy(1;2). During the winter months, the predominant virus detected in infants with viral bronchiolitis is respiratory syncytial virus (RSV)(3). By 1 year of age approximately 70% of children have been infected with RSV, and this increases to almost 100% by 2 years of age(4). Infant RSV bronchiolitis is associated with recurrent wheeze or asthma throughout childhood and even into early adulthood(5;6), with a dose-response relationship identified between the severity of the bronchiolitis and the risk of developing asthma(7), and evidence for a causal relationship(8). The aim of our study was to determine what proportion of childhood asthma is associated with infant bronchiolitis during RSV season. We analyzed cohort data of children born from 1996–2003 cared for at Northern California Kaiser Permanente (KPNC), an integrated healthcare delivery system, and children born from 1995–2003 enrolled in Tennessee Medicaid (TennCare). KPNC and TennCare provide health insurance for approximately one-third of Northern California residents and approximately one-half of infants born in Tennessee, respectively. Eligible infants had a minimum gestation age of 32 weeks, no chronic lung disease, and were continuously enrolled in either TennCare or KPNC during the first year of life. The main predictor variable was infant bronchiolitis during RSV season defined by ICD-9 codes for bronchiolitis and limited to the RSV season, October through March, during the first year of life. The main outcome variable was early childhood asthma determined using an algorithm of ICD-9 codes for asthma and asthma-specific medication utilization between ages 4.5–6 years. The Vanderbilt University Institutional Review Board and the KPNC Institutional Board for the Protection of Human Subjects approved the study. The Bureau of TennCare approved use of Tennessee Medicaid data. To ascertain the proportion of childhood asthma in the TennCare or KPNC population that is associated with bronchiolitis exposure during RSV season, we calculated both the attributable risk of infants with a bronchiolitis event during infancy, and the population attributable risk. We estimated the attributable fraction of bronchiolitis from adjusted risk ratios that were calculated from multivariable Poisson regression models with a robust error variance for the early childhood asthma outcome. Adjustment covariates included gender, race, gestational age, birthweight, siblings, maternal age, and maternal smoking. Statistical analyses were performed with R version 2.12.1 software. A total of 264,010 infant births (KPNC 81,550, TennCare 182,460) were included in this study and followed until 6 years of age. Table I highlights key characteristics of the two cohorts. Compared to the TennCare population, the KPNC population had more Hispanic and Asian participants, less African American participants, higher rates of maternal education beyond high school, and lower rates of maternal smoking. Overall, 15% of infants had bronchiolitis during RSV season. The proportion of children diagnosed with asthma among the KPNC and TennCare cohorts was 8% and 12%, respectively, for those without a history of infant bronchiolitis during RSV season, and 16% and 23%, respectively, for those with a history of infant bronchiolitis during RSV season. The population attributable risk for asthma contributed by infant bronchiolitis during RSV season was 10% for the KPNC cohort, and among the subset of children with infant bronchiolitis during RSV season, the attributable risk was 49% (95% CI:47%,52%); in TennCare, it was 13% and 47% (95% CI:45%,48%), respectively (See Fig 1). The unadjusted risk ratio of childhood asthma following infant bronchiolitis during RSV seaso100 n for KPNC was 1.97 (95% CI:1.87,2.09) and the multivariate adjusted risk ratio of childhood asthma following infant bronchiolitis during RSV season was 1.94 (95% CI:1.84,2.05); for TennCare it was 1.87 (95% CI:1.82,1.92) and 1.81 (95% CI:1.77,1.86), respectively. In our analysis restricting to term infants (gestational age ≥37 weeks), results remain unchanged (data not shown). FIG 1 Attributable risk of asthma due to infant bronchiolitis during RSV season. *Multivariable Poisson regression analyses were used to calculate risk ratios within the KPNC and TennCare populations. In both the KPNC and TennCare cohorts, the proportion of children who developed asthma was almost two times higher in children with a history of infant bronchiolitis during RSV season as compared to the children who did not have a history of infant bronchiolitis during RSV season. The almost identical attributable risk and population attributable risk findings are notable given the significant differences between the two populations. Adjustment of risk ratios for potential confounders did not change the results. Despite the strengths of our large population-based study, several limitations deserve mention. This study relied on existing electronic data; however, the use of electronic data has been previously validated as both sensitive and specific(9). Secondly, the study was unable to detect infants with asymptomatic or mild bronchiolitis during RSV season as well as those who did not seek treatment. In addition, we were unable to confirm the diagnosis of RSV as the etiology of bronchiolitis events although prior studies support that the majority of infant bronchiolitis events during RSV season are attributable to RSV(3). In a retrospective study by Stemple et al. in which bronchiolitis was defined by ICD-9 codes for bronchiolitis, RSV was detected in the nasal wash samples of 77% of children under 2 years of age collected between October and April(10). By limiting our study to bronchiolitis episodes during the winter months, RSV is likely to be the associated viral pathogen. Lastly, while human rhinovirus (RV) infection has also been implicated in asthma inception, infant RV bronchiolitis is far less common than infant RSV bronchiolitis, and occurs in older infants, those born to parents with asthma, or those who have already been allergically sensitized, suggesting that rather than being causal, that RV bronchiolitis is a clinical biomarker of future asthma risk(11–13). In summary, in two representative US populations with significantly varying baseline characteristics, there were consistent findings that nearly 50% of asthma cases in children with a history of infant bronchiolitis during RSV season were associated with bronchiolitis. On a population level, 13% of asthma was associated with infant bronchiolitis during RSV season. The mechanism to explain how infant RSV infection results in the subsequent development of asthma remains unclear, but if truly causal in nature as supported by observational(8) and mechanistic(14) studies, our findings indicate up to 13% of asthma cases could be prevented by eliminating infant bronchiolitis during RSV season. Thus, next steps are to determine if preventing or altering host response to infant RSV infections decreases both the incidence and severity of childhood asthma as a primary asthma prevention strategy.

Objective The objective of the study was to investigate the association of maternal vitamin D and maternal asthma and infant respiratory infection severity. Study Design The study included cross-sectional analyses of 340 mother-infant dyads enrolled from September to May 2004-2008 during an infant viral respiratory infection. Maternal vitamin D levels were determined from enrollment blood specimens. At enrollment, we determined self-reported maternal asthma and infant respiratory infection severity using a bronchiolitis score. We assessed the association of maternal vitamin D levels and maternal asthma and infant bronchiolitis score in race-stratified multivariable regression models. Results The cohort was 70% white, 19% African American, and 21% had asthma. Overall, the median maternal vitamin D level was 20 ng/mL (interquartile range, 14–28). Among white women, a 14 ng/mL increase in vitamin D was associated with a decreased odds of asthma (adjusted odds ratio, 0.54; 95% confidence interval, 0.33–0.86). Maternal vitamin D was not associated with infant bronchiolitis score. Conclusion Higher maternal vitamin D levels were associated with decreased odds of asthma.

Background Acute respiratory infections are ubiquitous and may have long-term implications on respiratory health. There are many scoring systems used to objectively measure severity of respiratory infections in clinical and research settings. A respiratory severity score derived exclusively from physical exam components (RSS-HR) was studied as an objective measure of disease severity and was compared to a previously described score that uses pulse oximetry as a component of its score (RSS-SO). Findings A score was derived from 497 infants. The RSS-HR median score was higher in infants that were hospitalized (8.0) versus outpatient (4.0, p