PEDIATRICS Vol. 119 No. 6 June 2007, pp. 1104-1112 (doi:10.1542/peds.2006-2837)
ARTICLE |
Maternal Asthma and Maternal Smoking Are Associated With Increased Risk of Bronchiolitis During Infancy
a Department of Pediatrics
e Department of Medicine
f Department of Preventive Medicine
d Department of Biostatistics, Divisions of
b Division of General Pediatrics
g Division of General Internal Medicine
j Division of Allergy, Pulmonary and Critical Care Medicine
c Division of Child and Adolescent Health Research Unit
h Division of Center for Education and Research on Therapeutics
k Division of Center for Health Services Research
l Division of General Clinical Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee
i Mid-South Geriatric Research Education and Clinical Center and Clinical Research Center of Excellence, Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee
m Meharry/Vanderbilt Center for Reducing Asthma Disparities, Nashville, Tennessee
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
Key Words: bronchiolitis • risk factors • infant • smoking • asthma
Abbreviations: RSV—respiratory syncytial virus • ETS— environmental tobacco smoke • EGA—estimated gestational age • ICD-9— International Classification of Diseases, Ninth Revision • ED—emergency department • HR—hazard ratio • CI—confidence interval • OR—odds ratio
Bronchiolitis, caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus, is the leading cause of lower respiratory tract infections in infants.1–4 Bronchiolitis results in significant morbidity in infants, accounting for an estimated 120000 hospitalizations annually in the United States among children <1 year of age.2, 3 It is well established that children with medical conditions such as prematurity, chronic lung disease, and congenital heart disease are at an increased risk of hospitalization for bronchiolitis.5 Risk factors implicated in the development of severe bronchiolitis include young age, birth early in the RSV season, male gender, lack of breastfeeding, and passive smoke exposure.6–9 However, 50% of hospitalizations for bronchiolitis involve term or near-term, otherwise healthy infants, among whom there are few established risk factors for bronchiolitis.5
Viruses such as RSV infect the majority of children during infancy; however, only 20% to 30% develop bronchiolitis and only 3% are hospitalized.2, 5, 10 Infants who develop severe bronchiolitis have an increased risk of recurrent wheezing and/or asthma later in life.11–15 It is unclear whether a predisposition to develop asthma is a risk factor for the development of bronchiolitis or whether the viral infection is involved in asthma inception.11, 16–19 Numerous studies, which typically had small sample sizes, have looked for an association between asthma in a first-degree relative and severe bronchiolitis in early life.11–13, 20–24 However, the majority of studies did not find an association. Maternal smoking during pregnancy and/or other environmental tobacco smoke exposure (ETS) have been associated with bronchiolitis severity.6, 7, 25–30 However, there have been no large population-based studies examining the interaction of factors, such as maternal smoking during pregnancy and maternal asthma, on the development of bronchiolitis in term, healthy infants without the confounding factors of preexisting heart or lung disease. The objectives of this study were to estimate the association of maternal asthma and maternal smoking during pregnancy with clinically significant bronchiolitis in a large population of term, otherwise healthy infants enrolled in the Tennessee Medicaid program during 1995–2003. We hypothesized that maternal smoking during pregnancy and maternal asthma are associated with the incidence and severity of bronchiolitis during infancy independently of preexisting pulmonary or cardiac disease.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We conducted a population-based retrospective cohort study of >100000 women and infants enrolled in the Tennessee Medicaid Program, during 1995–2003. In 1994, the Tennessee Medicaid Program replaced the federal Medicaid program as a state-based managed health care program that covered Medicaid-eligible individuals and the uninsured.31 Approximately 50% of infants born in Tennessee are born to women enrolled in the Tennessee Medicaid Program. Infants born to women of black or white race, aged 15 to 44 years, and continuously enrolled in the Tennessee Medicaid program were eligible for study inclusion. Infants of mothers of other races were too few to study, therefore, 2.13% of otherwise eligible infants were excluded. Infants of women with unknown smoking history (0.2%) were also excluded. We defined continuous enrollment from the year before pregnancy (last menstrual period date through 365 days) through the date of delivery with no more than 45 days of nonenrollment. To overcome potential confounding associated with preexisting cardiac or pulmonary disease, we included only healthy infants born at
37 weeks' estimated gestational age (EGA) with birth weight of 2500 g. The protocol was approved by the institutional review boards of Vanderbilt University and the Tennessee Department of Health.
Using previously described methods, we obtained study data from linked Tennessee Medicaid administrative data files and Tennessee State vital records.32, 33 Analysis files contained no personal identifiers, and study results are reported in aggregate and cannot be linked to individuals. We determined EGA in weeks by the date of the last menstrual period on the birth certificate (91.7%), or calculated based on the median gestational period in weeks for the infant's race, birth weight, and birth year (8.22%) or assigned last menstrual period as 270 days before birth (0.04%).34, 35 Infants with any of the following during the first 3 months of life were excluded: an International Classification of Diseases, Ninth Revision (ICD-9) code or Current Procedural Terminology code indicating congenital heart disease or surgery for congenital heart disease respectively, an ICD-9 code indicating chronic lung disease or a congenital anomaly of the upper airway and/or esophagus, or receipt of 1 dose of RSV prophylaxis (Palivizumab or RSV immune globulin).
Using a previously validated method,35 during the predelivery eligibility period we identified maternal asthma through health encounter and pharmacy claims. Women with an ICD-9 code of 493 (asthma) in any of the 9 diagnostic fields for inpatient, other hospital care (23 hour observation), or outpatient physician visit claims were considered to have asthma. In addition, women with 2 prescriptions for any short-acting ß-agonist or a single prescription for any other asthma medication (long-acting ß agonist, inhaled corticosteroids, leukotriene modifying agents) were considered to have asthma. Demographic characteristics identified from Tennessee Medicaid enrollment files included self-reported maternal race (black, white) and region of residence (urban, suburban, rural). Women of nonblack or nonwhite race were too few to study. Demographic variables determined from infant birth certificate data included self-reported maternal smoking during pregnancy, maternal age at delivery, maternal education level, marital status (single, married), siblings (none, 1, 2), and infant gender. We determined infant health care visits for bronchiolitis year-round using ICD-9 codes for bronchiolitis (466.1) and/or RSV pneumonia (480.1). To determine severity of bronchiolitis, we applied a hierarchy: infants with any hospitalization were categorized in the hospitalization group, infants with an emergency department (ED) visit and no hospitalization were categorized in the ED group, infants with only clinic visits were classified in the clinic group, and infants without any health care visits for bronchiolitis were categorized in the no visit group. We also determined the risk of a prolonged hospital stay defined by >3-day length of stay, based on previous reports of median length of stay for bronchiolitis for children in the United States of 3 days.2
The main predictor variables were history of maternal asthma and maternal smoking during pregnancy. Descriptive statistics for categorical variables were expressed as proportions and for continuous variables as median and interquartile ranges for nonnormally distributed variables. All infants in the study cohort were followed until 1 year of age, until they had >21 days of nonenrollment in Tennessee Medicaid, or death. To account for age at time of diagnosis, we used survival analyses with age as the time-dependent variable. We used Kaplan-Meier curves to estimate the cumulative incidence of a bronchiolitis health care visit (any clinic, ED, 23-hour observation, and/or hospitalization). We compared the cumulative incidence of clinically significant bronchiolitis by maternal asthma and smoking status using the 2-sided log-rank test. We obtained the relative risk of a bronchiolitis diagnosis using Cox's proportional hazards regression.36 We included variables in the model based on their clinical importance and association with maternal asthma, maternal smoking, and bronchiolitis including: maternal smoking during pregnancy and maternal asthma status, region of residence, maternal age, maternal education level, maternal race/ethnicity, other living siblings, infant birth weight, and gender.5, 37 We assessed for interaction between maternal asthma and maternal smoking by including a cross-product in the model. Using a multinomial logistic regression model, we estimated the risk of having a clinic visit, ED visit, or hospitalization (including 23-hour observations) compared with none by maternal asthma and smoking status. We estimated the population-based cumulative incidence of a prolonged hospitalization (>3 days) for bronchiolitis using survival analyses and obtained the relative risk of a prolonged hospitalization using Cox's proportional hazards regression. We confirmed that the proportional hazards assumption was reasonable for our data using log-log plots. R-software 2.11 (www.r-project.org), SAS 8.2 (SAS Institute, Cary, NC) and Stata 8.2 were used for data analyses. We used a 2-sided 5% significance level for all statistical inferences.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 101245 mother-infant dyads were included in the study; 42% of the mothers were black. The median age of women at delivery was 22 years, and 65% of women were single. Forty-two percent of women had less than a high school degree. The women were from urban (44%), suburban (23%), and rural regions (33%) of the state. Approximately 7% of women met the criteria for asthma during the predelivery baseline period, and 28% of women reported smoking during pregnancy. The majority of women were nonsmokers and did not have asthma (67.9%), whereas 25.3% of women smoked during pregnancy but did not have asthma, 4.4% of women had asthma and did not smoke, and 2.5% of women both smoked during pregnancy and had a diagnosis of asthma (Table 1). Among the infants, 51% were male, the median EGA was 39.6 weeks, and the median birth weight was 3289 g. Approximately 29% of infants had no living siblings, 37% had 1 sibling, and 34% had
2 siblings.
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Overall, 20% of infants had at least 1 bronchiolitis visit (clinic visit, ED visit, and/or hospitalization for bronchiolitis). Differences were seen by maternal asthma and smoking status in the frequency of having a bronchiolitis diagnosis during infancy. The proportions of infants with a bronchiolitis diagnosis in the first year of life were 18% in children with neither maternal asthma nor smoking, 24% among those with maternal asthma only, 24% among those with maternal smoking only, or 30% among those with both smoking and asthma, respectively. Differences in the unadjusted incidence of bronchiolitis are illustrated by Kaplan-Meier curves (Fig 1). Infants with both risk factors had the greatest risk of a health care encounter for bronchiolitis (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.36–1.59), adjusted for region of residence in the state, maternal age, maternal education level, maternal race, other living siblings, infant birth weight, and gender, followed by infants with maternal asthma only (adjusted HR: 1.39; 95% CI: 1.30–1.48), and maternal smoking only (adjusted HR: 1.14; 95% CI: 1.10–1.18), compared with infants with neither risk factor (Table 2).
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The risks of clinic visits, ED visits, or hospitalizations for bronchiolitis among infants whose mothers did or did not smoke during their pregnancy or have asthma are given in Table 3. Infants whose mothers both smoked and had asthma were more likely to have ED visits for bronchiolitis than infants with neither of these risk factors (adjusted odds ratio [OR]: 2.18; 95% CI: 1.87–2.54). Infants whose mothers had only 1 of these risk factors had a lower but still significantly elevated risk for ED visits. Infants whose mothers either had asthma or smoked were at significantly increased risk for clinic visits and/or hospitalizations. Maternal asthma was the more important of these 2 risk factors and was associated with ORs of 1.20 and 1.74 for clinic visits and hospitalizations, respectively. The combined effects of both of these risk factors were similar to those for maternal asthma alone.
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Table 4 gives the risks of a prolonged hospitalization for bronchiolitis classified by maternal asthma and smoking status. The median length of stay in our study was 3 days. Overall, 2.26% of the over 100000 infants in the cohort had a hospital stay of >3 days. Figure 2 illustrates that infants with 1 or both risk factors were at greater risk of having a hospital stay >3 days for bronchiolitis than were infants with neither risk factor. Compared with infants without maternal asthma or smoking, infants with maternal asthma had the highest risk of having a hospitalization >3 days (HR: 1.52; 95% CI: 1.26–1.82), followed by infants with both maternal asthma and smoking (HR: 1.38; 95% CI: 1.12–1.71), and maternal smoking only (HR: 1.19; 95% CI: 1.08–1.31; Table 4). Differences in the trend in the HRs from the trend in the cumulative incidences were because of covariate adjustment (data not shown).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In this population-based cohort of >100000 term, healthy infants, we determined that maternal asthma, which represents a predisposition to have children who develop asthma,38 and maternal smoking during pregnancy are independent risk factors for developing clinically significant bronchiolitis in the first year of life. Overall, 20% of infants had an outpatient or inpatient visit for bronchiolitis, which is consistent with previous reports of bronchiolitis incidence.10 The risk of bronchiolitis was significantly increased in patients with maternal smoking or maternal asthma, with the highest risk seen in patients with both maternal asthma and maternal smoking during pregnancy. The increased risk seen in infants with both risk factors highlights the clinical importance of the combined effects of these risk factors on the development of bronchiolitis during infancy.
Importantly, this study included only term, non–low birth weight children without preexisting heart or lung disease. We also captured both outpatient and inpatient care for bronchiolitis. Therefore, we were able to investigate the impact of a familial predisposition to develop asthma and maternal smoking during pregnancy on the spectrum of bronchiolitis severity in a population of infants without the confounding of small lung size, or underlying pulmonary or cardiac disease.
Maternal asthma, maternal smoking during pregnancy, or both also increased the risk of severe bronchiolitis in this population of term, healthy infants. Infants with 1 or both risk factors were more likely to have an ED visit or hospitalization compared with infants with neither factor. Hospitalization, in particular, is a standard measure of severe bronchiolitis used by scientists for >40 years to conduct epidemiologic studies of bronchiolitis.11–13, 21, 23, 24, 39–44 Although most infants will become infected with RSV and 20% to 30% will develop bronchiolitis, only a small percentage of infected infants will be hospitalized.5, 10 In our study cohort, infants with a mother with asthma or both maternal asthma and smoking had the highest risks of being hospitalized for bronchiolitis and having a prolonged hospitalization for bronchiolitis.
Having a mother with asthma is an easily identifiable risk factor for the development of bronchiolitis. Clarifying the association between a familial predisposition to develop asthma and bronchiolitis will guide immunologic and mechanistic studies to gain insight into differential host responses to viral infection during infancy and help define high-risk target populations for preventive efforts. In addition, providers can inform families of increased risk and further encourage the importance of avoidance measures to reduce the risk of viral infections. Regarding future interventions, several RSV vaccines are being evaluated, and if approved, could be used to prevent disease, particularly in high-risk children.
Maternal smoking during pregnancy is a preventable factor in bronchiolitis morbidity to which >25% of our study cohort was exposed. We focused only on non–low birth weight infants in this study and found that infants with maternal smoking during pregnancy have an increased risk of developing clinically significant bronchiolitis and of more severe bronchiolitis independent of the effects of low birth weight.45–47 The increased incidence and severity of bronchiolitis in infants with maternal smoking highlights the importance of efforts to prevent tobacco use and promote smoking cessation in pregnant women and women of childbearing age.
There are several potential limitations of this work. We defined maternal asthma using ICD-9 diagnosis codes and medication use and thus may not detect individuals with intermittent disease. However, the asthma prevalence in the study cohort was similar to the reported asthma prevalence in Tennessee.48 Our definition of asthma has been demonstrated to be specific, with previous work showing that similarly defined individuals had definite asthma (62%) or probable asthma (38%) by chart review.35, 49, 50 We determined 1 measure of a genetic predisposition to develop asthma, namely maternal asthma; however, we were not able to obtain the asthma history of other first-degree relatives. Therefore, there are likely individuals in the group of infants without maternal asthma who have a familial predisposition to develop asthma. This misclassification would lead to an attenuation of the association between familial predisposition to develop asthma and bronchiolitis. This suggests, for example that the 74% increased odds for infants with maternal asthma to be hospitalized for bronchiolitis compared with infants without maternal asthma or smoking is a real difference and potentially an underestimation of the impact of familial predisposition. One might also question whether assessing maternal smoking from birth certificates would be accurate. However, previous reports from our research group have demonstrated good concordance of the birth certificate data with medical chart data.51 In addition, maternal smoking history is determined before the infant's birth and any misclassification would be nondifferential for those infants that develop subsequent respiratory symptoms. We did not have access to the smoking history of others in the infants' households nor could we separate in utero tobacco smoke exposure from maternal smoking during the postnatal period. Therefore, maternal smoking during pregnancy is likely a measure of prenatal and postnatal ETS. In this case, the association of ETS and bronchiolitis during infancy would be underestimated because there will be misclassification. We identified bronchiolitis by using administrative data, and ICD-9 diagnoses represent objective physician-characterized outcomes at the time of illness that would not be influenced by recall bias. We used ED visits as a measure of bronchiolitis severity, and it is possible that some infants were taken to the ED that could have been cared for in outpatient clinics. However, the increased risk of an ED visit was consistent with other measures of bronchiolitis severity including hospitalization and prolonged length of stay. Because of the retrospective nature of this cohort study, it is possible that study findings were influenced by other unmeasured factors. In addition, we cannot rule completely that we have eliminated all possible bias in our multivariable statistical analyses. Although the generalizability of our findings to non-Medicaid populations may be questioned, half of the infants born in Tennessee are enrolled in the Medicaid program. Therefore, infants in Tennessee Medicaid are highly representative of the state's population and a substantial proportion of children born in other areas in the United States.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In a population-based cohort of >100000 healthy, non–low birth weight infants, maternal asthma and maternal smoking during pregnancy were both associated with an increased incidence and severity of bronchiolitis during infancy. Study findings suggests that a familial predisposition to develop asthma and maternal smoking during pregnancy are independent risk factors for the development of the leading cause of lower respiratory tract infections during infancy. Because viruses such as RSV are ubiquitous, the association of severe bronchiolitis and maternal asthma suggests that genetic/host factors influence infant response to viral infection and confer increased risk for viral lower respiratory tract infections. The work in understanding differences in the immune response to viral infections will increase our understanding of the etiology of the increased illness experienced by children with maternal asthma.17, 52–54 In addition, the study findings support future investigations aimed at decreasing bronchiolitis severity in high-risk populations by targeting infants whose mothers smoke during pregnancy and/or have a familial predisposition to develop asthma.
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ACKNOWLEDGMENTS |
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This study was supported by the National Institutes of Health (grants UO1 HL 72471, MO1 RR00095, KO8 AI01582, and K12 RR17697); the Agency for Healthcare Research and Quality, Centers for Education and Research (grant U18-HS10384); the Geriatric Research Education and Clinical Center, Department of Veterans Affairs; and the Thrasher Research Fund.
We thank the Tennessee Bureau of TennCare (Department of Finance and Administration) and the Tennessee Department of Health (Office of Policy, Planning and Assessment) for providing the data.
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FOOTNOTES |
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Accepted Feb 12, 2007.
Address correspondence to Tina V. Hartert, MD, MPH, Division of Allergy, Pulmonary and Critical Care Medicine, Center for Health Services Research, 6107 MCE, Vanderbilt University School of Medicine, Nashville, TN 37232-8300. E-mail: tina.hartert{at}vanderbilt.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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