Siblings, Day-Care Attendance, and the Risk of Asthma and Wheezing during Childhood
Thomas M. Ball, M.D., M.P.H., Jose A. Castro-Rodriguez, M.D., Kent A. Griffith, M.P.H., Catharine J. Holberg, Ph.D., Fernando D. Martinez, M.D., and Anne L. Wright, Ph.D.
Background Young children with older siblings and those whoattend day care are at increased risk for infections, whichin turn may protect against the development of allergic diseases,including asthma. However, the results of studies examiningthe relation between exposure to other children and the subsequentdevelopment of asthma have been conflicting.
Methods In a study involving 1035 children followed since birthas part of the Tucson Children's Respiratory Study, we determinedthe incidence of asthma (defined as at least one episode ofasthma diagnosed by a physician when the child was 6 to 13 yearsold) and the prevalence of frequent wheezing (more than threewheezing episodes during the preceding year) in relation tothe number of siblings at home and in relation to attendanceat day care during infancy.
Results The presence of one or more older siblings at home protectedagainst the development of asthma (adjusted relative risk foreach additional older sibling, 0.8; 95 percent confidence interval,0.7 to 1.0; P=0.04), as did attendance at day care during thefirst six months of life (adjusted relative risk, 0.4; 95 percentconfidence interval, 0.2 to 1.0; P=0.04). Children with moreexposure to other children at home or at day care were morelikely to have frequent wheezing at the age of 2 years thanchildren with little or no exposure (adjusted relative risk,1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) butwere less likely to have frequent wheezing from the age of 6(adjusted relative risk, 0.8; 95 percent confidence interval,0.6 to 1.0; P=0.03) through the age of 13 (adjusted relativerisk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001).
Conclusions Exposure of young children to older children athome or to other children at day care protects against the developmentof asthma and frequent wheezing later in childhood.
Both the incidence and the prevalence of asthma among childrenhave increased dramatically in the past three decades,1,2 makingit the most common chronic disease of childhood in the UnitedStates.3 Although the cause of this epidemic remains unclear,one hypothesis is that a decrease in infections during earlychildhood may be partly responsible.4 In support of this hypothesis,the frequency of several allergic disorders has been found tobe inversely associated not only with childhood infections5,6,7but also with the number of siblings,8,9,10,11,12,13 a purportedmeasure of exposure to infections.
If the presence of older siblings protects children againstthe subsequent development of allergic disease by exposing themto more infections during early childhood, then attendance atday care should have a similar effect. Children attending daycare are known to have more frequent infections than those whoremain at home.14,15,16 However, the results of studies examiningthe effect of attendance at day care on the development of allergicdisease are conflicting. In one study, day-care attendance duringinfancy was found to protect against the development of asthma,hay fever, and skin-test reactivity among children with fewsiblings,17 but in several other studies no association wasfound between attendance at day care and the subsequent developmentof allergic diseases.9,13,18
Interpretation of the available data regarding day-care attendanceand the subsequent development of asthma is further complicatedby the existence of multiple possible causes of wheezing duringchildhood.19 Wheezing in preschool children is primarily associatedwith infections, whereas in school-age children it is primarilyassociated with atopy.19,20 Although many children have wheezingduring their preschool years, it is difficult to identify thosewho will later have asthma.21 Therefore, increased exposureto other children may place preschool children at increasedrisk for wheezing associated with respiratory infections, butit may also help to protect them from IgE-associated wheezinglater in childhood. Attendance at day care was found to be arisk factor for recurrent wheezing and asthma in children lessthan 5 years of age,16,22 but among children 5 to 14 years oldthe frequency of asthma was inversely associated with previousday-care attendance.17 In this study, we examined exposure tochildren at home and attendance at day care during infancy inrelation to the subsequent development of asthma and frequentwheezing in a cohort of children followed prospectively frombirth.
Methods
Study Population
We enrolled 1246 normal newborn infants in the Tucson Children'sRespiratory Study between 1980 and 1984.23 Detailed informationon the enrollment process and study design has been publishedelsewhere.23,24 Information about the mother's level of education,whether there was a history of asthma in either parent, thesmoking status of the mother during the prenatal period, andthe race of each parent was obtained from responses on questionnairesadministered to parents soon after their child's birth. Informationabout breast-feeding status was obtained from two sources: prospectivelyfrom data gathered at health-supervision visits and retrospectivelyfrom responses on a follow-up questionnaire.25
The study was approved by the Human Subjects Committee of theUniversity of Arizona. Written informed consent was obtainedfrom parents at the time of enrollment and at each in-depthevaluation (which took place at years 6 and 11 of the study).
Siblings and Day Care
Parents reported information on all household members shortlyafter their child's birth. Because 95 percent of the childrenless than 18 years of age who were living at home were siblingsof the enrolled child, all such children were considered siblings.Information about attendance at day care and about the numberof unrelated children present in the day-care setting duringthe first three years of life was obtained for 996 childrenby means of a questionnaire administered to the parents from1988 to 1990, when the mean (±SD) age of the childrenwas 6.7±1.5 years.14 Day care was defined as a child-caresetting where six or more unrelated children were present.
Asthma and Frequent Wheezing
The parents of the enrolled children completed questionnairesrelated to their children's respiratory status at years 6, 8,11, and 13 of the study (mean age of the children, 6.3±0.9,8.6±0.7, 10.9±0.6, and 13.5±0.6 years,respectively). Children who had been given a diagnosis of asthmaby a physician and who had had an exacerbation of their asthmaduring the previous year, as indicated by the responses on thequestionnaires at any of these times, were categorized as havingasthma. Parents were also asked on the questionnaires at years6, 8, 11, and 13 whether their child's chest had ever sounded"wheezy" or "whistling" during the previous year and, if so,how often this had occurred.
Frequent wheezing was defined as the occurrence of more thanthree episodes of wheezing during the previous year. Data onfrequent wheezing at years 2 and 3 (mean age of the children,1.6±0.8 and 2.9±0.9 years, respectively) werealso obtained, in a slightly different format: the parents wereasked whether their child had had wheezing during the previousyear and, if so, how often he or she had wheezed on a scalefrom 1 to 5, on which 1 indicated "very rarely" and 5 "on mostdays." Children with scores of 2 or higher in either year 2or 3 were defined as having frequent wheezing during that year.Data on the frequency of upper respiratory tract infectionswere also obtained from these six questionnaires by asking parentsthe question, "During the past year, how many head colds (commoncolds) did this child have?"
Skin-Test Reactivity and Serum IgE Measurement
At years 6 and 11, skin tests were conducted with extracts ofallergens common in the Tucson area (Hollister–Stier Laboratories,Everett, Wash.). At year 6, 737 children underwent skin testingwith extracts of house-dust mix, the mold alternaria, Bermudagrass, careless weed (Amaranthus palmeri), mesquite, mulberry,and olive. At year 11, 663 children, 585 of whom had been testedat year 6, were tested with the same allergens as well as extractsof cat dander and Dermatophagoides farinae. The skin tests wereread after 20 minutes, and the results were considered positiveif a wheal at least 3 mm larger than the control wheal was produced.Children with a positive result on skin testing at either year6 or year 11 were considered to have skin-test reactivity.
Serum IgE concentrations were measured at years 6 and 11 withpaper radioimmunosorbent assays (Pharmacia Diagnostics, Piscataway,N.J.). Serum IgE concentrations above the 95th percentile forage (161 IU per milliliter at year 6 and 570 IU per milliliterat year 11) were considered high.26 Children with a high serumIgE value at either year 6 or year 11 were considered to havea high serum IgE concentration.
Statistical Analysis
We used chi-square tests to assess statistical significancein bivariate analyses. Because significant linear trends inthe incidence of asthma according to the number of siblingswere identified in cross-sectional analysis, the number of siblingswas considered a single ordinal variable in Cox regression analysis,and the crude relative risk of asthma according to the numberof siblings was calculated. Adjusted relative risks of asthmawere calculated in Cox regression analysis that included allpotential confounding variables (sex, whether there was a historyof asthma in either parent, the race of the parents, the mother'slevel of education, the mother's smoking status during the prenatalperiod, and breast-feeding status). In separate Cox regressionanalyses that included the same confounding variables, the adjustedrelative risks of asthma and of frequent wheezing at years 6,8, 11, and 13 were calculated.
We used the generalized estimating equation to assess the longitudinaleffects of the number of siblings and day-care attendance onthe prevalence of frequent wheezing from years 2 through 13.The generalized estimating equation is a statistical procedurethat yields estimates of risk for longitudinal dichotomous datain mixed-effects regression models.27 To be included in thelongitudinal analysis, children were required to have completeinformation on at least one of the six questionnaires. To testthe main hypothesis, we used a model in which frequent wheezingin each of the six questionnaire intervals was the outcome variableand day-care attendance or the presence of two or more oldersiblings was the exposure variable, with adjustment for thepotential confounding variables listed above. To assess age-dependentassociations, age was entered into the model as an independentvariable, along with an interaction term for the degree of exposureto other children and the age of the child at the time the questionnairewas administered. All statistical tests were two-sided.
Results
The parents of 1035 of the 1246 children in the original cohortcompleted at least one of the questionnaires at years 6, 8,11, and 13, and these 1035 children were therefore includedin the cross-sectional analyses of the development of asthmaand frequent wheezing. The children included in these analyseswere significantly more likely to have one sibling or no siblings,a mother with a high level of education, and white parents thanwere the children who were excluded because of missing information(data not shown). The parents of 875 children completed at least1 questionnaire (mean, 5.3 questionnaires) and provided informationon day-care attendance, and these 875 children were thereforeincluded in the longitudinal analysis of frequent wheezing.The children included in the longitudinal analysis were similarto the 1035 children included in the cross-sectional analyses,except that they were significantly more likely to have whiteparents than were those excluded because of missing information(data not shown).
There was an inverse association between the incidence of asthmaand both the number of older siblings present in the home atbirth and the age at entry into day care (Table 1). This relationdid not vary according to the sex of the siblings. Since therewas no significant difference between day-care entry betweenthe ages of 7 and 12 months and entry after the age of 12 months,these two categories were combined in subsequent analyses.
Table 1. Percentage of Children with Asthma According to the Number of Older Siblings and the Age at Entry into Day Care.
The incidence of asthma among children who had two or more oldersiblings or who attended day care during the first six monthsof life was significantly lower than that among children whohad one sibling or no siblings and who did not attend day care(Table 2). The same children had a significantly lower prevalenceof high serum IgE concentrations, skin-test reactivity to anyallergen, and skin-test reactivity to alternaria, the allergenmost commonly associated with asthma in the Tucson area.28
Table 2. Percentage of Children with Asthma, High Serum IgE Concentrations, and Skin-Test Reactivity, According to the Number of Siblings and Day-Care Attendance before the Age of Six Months.
In a multivariate analysis, each additional older sibling andattendance at day care during the first six months of life remainedinversely associated with the development of asthma (Table 3).Male sex and a history of asthma in the mother or the fatherwere positively associated with the development of asthma inthe child.
Table 3. Significant Predictors of Asthma in 926 Children.
We also calculated the adjusted relative risks of asthma andfrequent wheezing at years 6, 8, 11, and 13 among children whohad two or more older siblings or who attended day care duringthe first six months of life, as compared with children whohad one or no older siblings and who did not attend day care(Figure 1). The protective effect of greater exposure to otherchildren at home or at day care was similar for the two outcomesand appeared to be greater in the later years.
Figure 1. Adjusted Relative Risk of Asthma or Frequent Wheezing among Children Who Had Two or More Older Siblings or Who Attended Day Care during the First Six Months of Life, as Compared with Those with Less Exposure to Other Children.
Children with less exposure to other children were those who had one or no older siblings and who did not attend day care during the first six months of life. Relative risks were adjusted for sex, whether there was a history of asthma in the mother or the father, the mother's smoking status during the prenatal period, breast-feeding status, the parents' race, and the mother's level of education. The I bars represent the 95 percent confidence intervals. P values are for the comparisons between the children with greater exposure to others at home or at day care and those with less exposure. The adjusted relative risks are shown on a natural-log scale.
The occurrence of frequent wheezing among children in thesetwo groups was also examined longitudinally for the entire studyperiod. At year 2, the prevalence of frequent wheezing was significantlyhigher among children with greater exposure to other childrenat home or at day care than among those with less exposure toother children (24 percent vs. 17 percent, P=0.02), but at year11 and year 13 it was significantly lower in the group withgreater exposure (6 percent vs. 11 percent [P=0.02] and 5 percentvs. 10 percent [P=0.04], respectively) (Figure 2).
Figure 2. Prevalence of Frequent Wheezing among Children Who Had Two or More Older Siblings or Who Attended Day Care during the First Six Months of Life and among Children with Less Exposure to Other Children.
Children with less exposure to other children were those who had one or no older siblings and who did not attend day care during the first six months of life. P values are for the comparisons between the two groups of children. The results are shown on a logit scale.
The model based on the generalized estimating equation was usedto examine the relative risk of frequent wheezing during theentire study period among those with greater exposure to otherchildren at home or at day care as compared with those withless exposure, after adjustment for all potential confoundingvariables. Children who had greater exposure to others weremore likely than those with less exposure to have frequent wheezingat year 2 (relative risk, 1.4; 95 percent confidence interval,1.1 to 1.8; P=0.01) but were significantly less likely to havefrequent wheezing at year 6 (relative risk, 0.8; 95 percentconfidence interval, 0.6 to 1.0; P=0.03), year 8 (relative risk,0.6; 95 percent confidence interval, 0.4 to 0.8; P=0.001), year11 (relative risk, 0.4; 95 percent confidence interval, 0.3to 0.6; P<0.001), and year 13 (relative risk, 0.3; 95 percentconfidence interval, 0.2 to 0.5; P<0.001) (Figure 3). Whenthe data were analyzed in a separate model based on the generalizedestimating equation, with the number of siblings and day-careattendance during the first six months of life entered as independentvariables, similar trends for each variable were observed (datanot shown).
Figure 3. Adjusted Relative Risk of Frequent Wheezing among Children Who Had Two or More Older Siblings or Who Attended Day Care during the First Six Months of Life, as Compared with Children Who Had Less Exposure to Other Children, According to Analysis with the Generalized Estimating Equation.
Relative risks were adjusted for sex, whether there was a history of asthma in the mother or father, the mother's smoking status during the prenatal period, breast-feeding status, the race of the parents, and the mother's level of education. The I bars represent the 95 percent confidence intervals. P values are for the comparisons between the children with greater exposure to others at home or at day care and those with less exposure. The adjusted relative risks are shown on a natural-log scale.
Discussion
The main finding of this study is that the development of asthmais less common among children with more exposure to other childrenat home or at day care during the first six months of life thanamong children with little or no exposure to other childrenat home or at day care. However, the children with more exposurehad more frequent wheezing during the preschool years.
Decreasing family sizes and higher standards of personal hygiene,both of which result in a lower rate of cross-infection withinhouseholds, have been suggested as explanations for the increasein allergic disease seen during the past 30 years.10 While thefrequency of asthma has increased, the percentage of young familiesin the United States with more than two children has declined,from 36 percent in 1970 to 21 percent in 1998.29,30 During thissame period, day-care attendance has increased, involving 60percent of preschool children in 1995.31 However, whereas 65percent of four-year-old children attended a day-care centerin 1995, only 7 percent of infants less than a year old didso.31 Day-care attendance is also lowest among children fromlow-income families, among whom morbidity from asthma is high.32
Although children attending day care are at increased risk formany types of infections, the results of previous investigationsof day-care attendance and the risk of asthma or recurrent wheezingare conflicting. However, when those results are viewed accordingto the ages at which the children were studied, they are consistentwith the results of our study and with each other. Among two-year-oldchildren, day-care attendance increased the risk of recurrentwheezing, and among four-to-five-year-old children, day-careattendance also increased the risk of asthma.16,22 Among seven-year-oldchildren, asthma was not associated with previous day-care attendance.13,18Among 5-to-14-year-old children, asthma was inversely associatedwith previous day-care attendance.17 The current results demonstratethe same age-dependent relation between exposure to other childrenat home or at day care and the development of wheezing illnesseslater in childhood. Although day-care attendance during thefirst six months of life is a risk factor for wheezing associatedwith lower respiratory tract infections early in life, it appearsto protect against wheezing associated with atopy later in childhood.
The mechanism by which exposure to other children early in lifemight prevent the development of allergic disease, includingasthma, is not known. Bacterial or viral infections occurringduring infancy as a result of exposure to numerous childrenmay provide important signals to the newborn's maturing immunesystem.4 Within the first six months of life, the immune responseof children without atopy shifts from one associated predominantlywith type 2 helper T cells (Th2 cells), like that in adultswith atopic illnesses, toward one based more on cytokines derivedfrom type 1 helper T cells (Th1 cells), like that in adultswithout atopy.33 Th1-like response includes the production ofinterferon-, which inhibits the proliferation of Th2 cells.Therefore, infections that stimulate a Th1-like response duringthis critical period of maturation may play an important partby inhibiting the predominantly Th2 response that is presentin newborn infants.4,33 The absence of such inhibitory signalsduring infancy may allow the expansion and maturation of Th2memory cells, resulting in the persistence of a more atopicphenotype.
Alternative explanations for our results appear to be less plausible.Parents participating in our study may have confused symptomsof upper respiratory tract infections in their children withwheezing, in which case the excess wheezing during the schoolyears among children who had had less contact with other childrenduring infancy may simply represent "catch-up" infections thatare due to their lower degree of acquired immunity. However,the findings reported here are specific to asthma and frequentwheezing: although children with one or no siblings and no earlyattendance at day care had more upper respiratory tract infectionsat year 6 than children with greater exposure to others duringthe preschool years, this difference gradually disappeared,becoming nonexistent by year 13 (data not shown). It is alsopossible that the two groups of children differed accordingto the presence of some other putative risk factor for asthma,such as exposure to allergens.34 However, the primary allergenassociated with asthma in this region of Arizona, alternaria,is ubiquitous. It also seems unlikely that allergen exposurewould vary according to sibling order.
There are two possible weaknesses of this study. First, dataon the occurrence of asthma and frequent wheezing were basedon parents' responses on questionnaires. However, in other analysesof the same cohort, we found that these outcome measures correlatedwell with objective measures of bronchial hyperresponsiveness,such as peak-flow variability and the results of cold-air challengeor methacholine challenge.19,35 Second, the data regarding day-careattendance were obtained retrospectively. However, the decisionto enroll an infant in day care, the selection of a site, andoften the mother's accompanying return to work usually makethese events very memorable to the parents. Nevertheless, ifmisclassification of day-care status did occur, it would mostlikely have skewed our results toward the null hypothesis.
In conclusion, the results of this prospective, longitudinalstudy indicate that a young child's exposure to other childrenin or out of the home leads to more frequent wheezing duringthe first few years of life. However, such exposure protectsagainst the development of asthma and frequent wheezing laterduring childhood.
Presented in part at the 39th Annual Meeting of the AmbulatoryPediatric Association, San Francisco, May 3, 1999.
Supported by grants from the National Heart, Lung, and BloodInstitute (HL 56177, HL 14136, and HL 03154).
We are indebted to the study families for their participation;to the study nurses, M.A. Smith, R.N., and L.L. De La Ossa,R.N., for their work; to Bruce W. Saul, M.S., for his assistancewith data analysis; and to Andrew T. Ball and Debra A. Stern,M.S., for their review of the manuscript.
Source Information
From the Department of Pediatrics (T.M.B., C.J.H., F.D.M., A.L.W.) and the Respiratory Sciences Center (J.A.C.-R., K.A.G., C.J.H., F.D.M., A.L.W.), University of Arizona College of Medicine, Tucson.
Address reprint requests to Dr. Wright at the Respiratory Sciences Center, University of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245073, Tucson, AZ 85724-5073, or at awright{at}resp-sci.arizona.edu.
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, which inhibits the proliferation of Th2 cells. Therefore, infections that stimulate a Th1-like response during this critical period of maturation may play an important part by inhibiting the predominantly Th2 response that is present in newborn infants.4,33 The absence of such inhibitory signals during infancy may allow the expansion and maturation of Th2 memory cells, resulting in the persistence of a more atopic phenotype. 
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