Maternal smoking during pregnancy, prematurity and recurrent wheezing in early childhood.

BACKGROUND: Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood. OBJECTIVE: We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing. METHODS: We evaluated 1,448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm < 37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates. RESULTS: In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% confidence interval [CI], 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (P = 0.049). CONCLUSIONS: We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.

Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood.

BACKGROUND: The effect of breast-feeding on the development of allergic disease is uncertain. There are no data that show whether this relationship varies by individual genotypes. OBJECTIVE: We sought to evaluate the effect of breast-feeding and gene-breast-feeding interactions on food sensitization (FS) in a prospective US birth cohort. METHODS: This study included 970 children who were prospectively followed since birth. Breast-feeding history was obtained from a standardized questionnaire interview. FS was defined as a specific IgE level of 0.35 kU(A)/L or greater to any of 8 common food allergens. Eighty-eight potentially functional single nucleotide polymorphisms (SNPs) were genotyped from 18 genes involved in innate immunity or T(H)1/T(H)2 balance. Logistic regression models were used to test the effects of breast-feeding and gene-breast-feeding interactions on FS, with adjustment for pertinent covariates. RESULTS: Children who were ever breast-fed (n = 739), including exclusively breast-fed children, were at a 1.5 (95% CI, 1.1-2.1; P = .019) times higher risk of FS than never breast-fed children (n = 231). This association was significantly modified by rs425648 in the IL-12 receptor ß1 gene (IL12RB1; P for interaction = .0007): breast-feeding increased the risk of FS (odds ratio, 2.0; 95% CI, 1.4-3.1; P = .0005) in children carrying the GG genotype but decreased the risk (odds ratio, 0.6; 95% CI, 0.3-1.4; P = .252) in children carrying the GT/TT genotype. Similar interactions were observed for SNPs in the Toll-like receptor 9 (TLR9; rs352140) and thymic stromal lymphopoietin (TSLP; rs3806933) genes. The interaction between the combined genotypes of the 3 SNPs and breast-feeding on FS was even stronger (P for interaction < 10⁻5). CONCLUSION: Our data suggest that the effect of breast-feeding on FS was modified by SNPs in the IL12RB1, TLR9, and TSLP genes both individually and jointly. Our findings underscore the importance of considering individual genetic variations in assessing this relationship.

Does genetic regulation of IgE begin in utero? Evidence from T(H)1/T(H)2 gene polymorphisms and cord blood total IgE.

BACKGROUND: Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast with numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. OBJECTIVE: To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the T(H)1/T(H)2 pathway and CBIgE in a large US inner-city birth cohort. METHODS: CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the 2 outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. RESULTS: Three SNPs (rs1800925, rs2069743, and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (P ≤ 6 × 10(-4), FDR-corrected P < .05). These SNPs jointly influenced CBIgE in a dose-response manner (P for trend = 9 × 10(-8)). Significant associations also were observed for SNPs in the IL-13 receptor α1 (rs5956080) and signal transducer and activator of transcription 6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4 receptor and IL13-signal transducer and activator of transcription 6 interactions) were detected in relation to CBIgE. CONCLUSION: Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in utero.

Maternal Pre-Pregnancy Obesity and Recurrent Wheezing in Early Childhood.

A number of studies have linked obesity with asthma in adults and children. Few longitudinal studies have evaluated the effect of maternal pre-pregnancy obesity on either asthma or early childhood respiratory morbidity, and these have not been in urban, nonwhite populations. We sought to determine whether pre-pregnancy obesity was associated with recurrent wheezing in an urban, nonwhite population. This study includes 1,191 children from the Boston Birth Cohort (1998-present) followed prospectively to a mean age of 3.0 ± 2.4 years with study visits aligned with the pediatric primary care schedule. Multivariate logistic regression was used to evaluate the associations of maternal pre-pregnancy obesity (body mass index ≥30) with recurrent wheezing (≥4 lifetime episodes). Secondary outcomes included log-transformed cord-blood immunoglobulin E (Phadia), and physician diagnoses of eczema and food allergy. Pre-pregnancy obesity was present in 20.7% of mothers. Of the 1,191 children, 60 (5%) developed recurrent wheezing. Children of obese mothers had an increased risk of recurrent wheezing (adjusted odds ratio, 95% confidence interval: 3.51, 1.68-7.32). These associations persisted even after adjustment for fetal growth status. In contrast, maternal obesity was not associated with eczema or food allergy, and was inversely associated with log cord-blood immunoglobulin E (ß, 95% confidence interval: -0.34, -0.66 to -0.02). In this predominantly urban, multiracial/ethnic birth cohort, maternal pre-pregnancy obesity was associated with an increased risk of recurrent wheezing. This association was not explained by fetal growth or increased atopy. Maternal pre-pregnancy obesity is a prevalent risk factor for respiratory morbidity in this urban, nonwhite population.

Gestational diabetes, atopic dermatitis, and allergen sensitization in early childhood.

BACKGROUND: The relationship between the prenatal environment, maternal-fetal interaction, and allergic disease in the offspring remains understudied. OBJECTIVE: We sought to determine whether gestational diabetes (GDM) modifies the risk of early childhood atopic manifestations, including atopic dermatitis and allergen sensitization. METHODS: This study includes 680 children from the Boston Birth Cohort. Mother-child dyads were recruited at birth and followed prospectively to a mean age of 3.2 +/- 2.3 years, with study visits aligned with the pediatric primary care schedule. The primary outcomes were physician-diagnosed atopic dermatitis on standardized medical record abstraction and allergen sensitization based on ImmunoCAP to 7 common foods and 5 common aeroallergens (specific IgE, >or=0.10 kUA/L; Phadia, Uppsala, Sweden). GDM was determined by means of standardized medical record review. Logistic regression analysis, stratified by term/preterm status, evaluated the association of GDM with atopic dermatitis and allergen sensitization, respectively, controlling for maternal prepregnancy body mass index, fetal growth, and pertinent covariates. RESULTS: Of the 680 children, 488 were term, and 192 were preterm (<37 weeks' gestation). Overall, 4.9% of the mothers had GDM. Among the 680 children, 34.4% had atopic dermatitis, and 51% had allergen sensitization. In term births GDM was significantly associated with atopic dermatitis (odds ratio [OR], 7.2; 95% CI, 1.5-34.5) and allergen sensitization (OR, 5.7; 95% CI, 1.2-28.0). Adjusting for fetal growth had little effect. The association with sensitization was driven primarily by food sensitization (OR, 8.3; 95% CI, 1.6-43.3). The above associations were not observed in preterm births. CONCLUSIONS: In term births GDM increased the risk of atopic dermatitis and early childhood allergen sensitization independently of maternal prepregnancy body mass index and fetal growth.

Prematurity, chorioamnionitis, and the development of recurrent wheezing: a prospective birth cohort study.

BACKGROUND: Prematurity (< 37 weeks) has been inconsistently associated with asthma and wheezing. Chorioamnionitis may promote both prematurity and inflammatory pathways in infants' airways. OBJECTIVE: To investigate the relationship of prematurity and chorioamnionitis with the development of early childhood recurrent wheezing. METHODS: The Boston Birth Cohort (n = 1096) were followed prospectively from birth to a mean age of 2.2 +/- 2 years. Perinatal and postnatal clinical data and placental pathology were collected. The primary outcome was recurrent wheezing (> or =2 physician documented episodes). Secondary outcomes included physician-diagnosed asthma, food allergy, and eczema. Preterm children were grouped by gestational age into moderately (33-36.9 weeks) and very preterm (< 33 weeks) with and without chorioamnionitis, and compared with term children without chorioamnionitis (reference group). Chorioamnionitis was diagnosed either by intrapartum fever or by placental histology findings. Logistic regression models were performed to investigate the independent and joint associations of degree of prematurity and chorioamnionitis. RESULTS: Prematurity was associated with recurrent wheezing (odds ratio [OR], 1.7; 95% CI, 1.2-2.6). However, when subjects were grouped by degree of prematurity with or without chorioamnionitis, the highest risk of wheezing (OR, 4.0; 95% CI, 2.0-8.0) and physician-diagnosed asthma (OR, 4.4; 95% CI, 2.2-8.7) was present in the very preterm children with chorioamnionitis. The effect on both wheezing (OR, 5.4; 95% CI, 2.4-12.0) and asthma (OR, 5.2; 95% CI, 2.3-11.9) was greater in African Americans. Neither prematurity nor chorioamnionitis was associated with food allergy or eczema. CONCLUSION: We found a strong joint effect of prematurity and chorioamnionitis on early childhood wheezing. This effect was stronger in African American subjects.