title: Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, and Center for Asthma and Environmental Sciences Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, and Center for Asthma and Environmental Sciences Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Feldman
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Rosas-Salazar
authors.affiliation: Peninsula Allergy & Asthma Center, Soldotna, Alaska, United States of America.
authors.forename: Kristina
authors.initials: K
authors.lastname: James
authors.affiliation: Kaiser Permanente Medical Care Program, Oakland, California, United States of America.|Kaiser Permanente Northern California, Perinatal Research Unit, Division of Research, Oakland, California, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Escobar
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Tebeb
authors.initials: T
authors.lastname: Gebretsadik
authors.affiliation: Kaiser Permanente Northern California, Perinatal Research Unit, Division of Research, Oakland, California, United States of America.
authors.forename: Sherian Xu
authors.initials: SX
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Kecia N
authors.initials: KN
authors.lastname: Carroll
authors.affiliation: Kaiser Permanente Northern California, Perinatal Research Unit, Division of Research, Oakland, California, United States of America.
authors.forename: Eileen
authors.initials: E
authors.lastname: Walsh
authors.affiliation: Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Mitchel
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Suman
authors.initials: S
authors.lastname: Das
authors.affiliation: The Ann and Robert H. Lurie Children's Hospital of Chicago and Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Dupont
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, and Center for Asthma and Environmental Sciences Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Tina V
authors.initials: TV
authors.lastname: Hartert
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001249:Asthma / Q000453:epidemiology*; D002585:Cesarean Section / Q000009:adverse effects; D036861:Delivery, Obstetric / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects*; D064307:Microbiota / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D035781:Siblings; D014552:Urinary Tract Infections / Q000150:complications
chemical_list: D000900:Anti-Bacterial Agents