Family Size, Day-Care Attendance, and Breastfeeding in Relation to the Incidence of Childhood Asthma

Claire Infante-Rivard1,2, Devendra Amre1, Denyse Gautrin3 and Jean-Luc Malo3

1 Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
2 Department of Pediatrics, Hôpital Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
3 Department of Chest Medicine, Hôpital Sacré-Coeur, Université de Montréal, Montréal, Québec, Canada.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A hypothesis has been suggested stating that children exposed early to infections are less likely to develop atopy or asthma. The authors investigated the relation between risk of childhood asthma and number of siblings as well as day-care attendance, as factors possibly increasing the likelihood of early infections, and breastfeeding as a factor reducing them. A case-control study was carried out in Montréal, Canada, between 1988 and 1995 that included 457 children diagnosed with asthma at 3–4 years of age and 457 healthy controls. Cases followed for 6 years were later classified as persistent or transient by the symptoms and use of medication after diagnosis. Among cases diagnosed at 3–4 years of age, the adjusted odds ratio for asthma was 0.54 (95% confidence interval (CI): 0.36, 0.80) for one sibling and 0.49 (95% CI: 0.30, 0.81) for two or more. The adjusted odds ratio for day-care attendance before 1 year of age was 0.59 (95% CI: 0.40, 0.87). Results were similar with persistent cases. Among transient cases (who possibly had an infection with wheezing at 3–4 years of age), day-care attendance and a short duration of breastfeeding resulted in increased risk. The results support the hypothesis that opportunity for early infections reduces the risk of asthma.

asthma; breast feeding; child; day care; family

Abbreviations: CI, confidence interval; OR, odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Over the last few decades, the prevalence of childhood allergic disorders such as hay fever, eczema, and asthma has been on the rise, especially in the developed countries (1GoGo–3Go). Concurrently, there has been a decrease in more severe childhood infections such as measles, rubella, pertussis, and mumps. Observations of an inverse relation between the risk of hay fever and birth order (4Go) led investigators to the hypothesis that an increase in childhood infections from contact with either older siblings or the mother who was infected by her other children may decrease the risk of this and other allergic diseases. It has been suggested that early childhood infections could alter the development of T-cell clones toward an increase in production of TH1 lymphocytes, conferring a protection from immunoglobulin E-mediated allergic conditions (5Go). From these observations, it is hypothetized that the increasing prevalence of allergic conditions may result from a concurrent decrease in childhood infections. A number of studies have now consistently reported an inverse relation between the risk of allergic conditions (such as hay fever, eczema, and atopy) and sibship size and/or birth order (sibling effect) (6GoGoGo–9Go). Recently, this evidence was briefly reviewed (10Go). For asthma, the sibling effect has not been as consistently observed (5Go, 11GoGoGoGoGoGoGoGoGoGo–21Go).

Other risk factors could be markers for the infectious hypothesis underlying the sibling effect; these are day-care attendance and breastfeeding. Children who attend day care have more infections and, in particular, infections of the respiratory tract (22Go); if the hypothesis previously stated holds true, a reduction in atopy and asthma is possible with early day-care attendance. However, most studies have found an increased risk of asthma with day-care attendance (17Go, 21Go, 23GoGo–25Go); on the other hand, another study reported an increase in risk for cases of transient early wheezing, no increase for cases of persistent wheezing, and a protective effect for cases of late-onset wheezing (20Go). Breastfeeding may be critical to the development of the immune system; by contributing to the prevention of early infections, it may work against the hypothesized effect of family size and day-care attendance on the incidence of asthma. However, a recent study reported an increased risk of developing asthma when milk other than breast milk was introduced before 4 months of age (26Go).

A previous case-control study of the incidence of asthma in children aged 3–4 years in Montréal (27Go), as well as a follow-up of cases in this study (28Go), gave us the opportunity to study the effect of family size, day-care attendance, and breastfeeding on the incidence of asthma.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study design and measures
The methods have been described in detail elsewhere (27Go). Briefly, 457 cases diagnosed for the first time by a pediatrician were recruited from the emergency room of a university-affiliated pediatric hospital in Montréal, Canada, between 1988 and 1990. Cases were between 3 and 4 years of age. Diagnostic criteria for asthma described in periodically reviewed protocols were used by emergency room pediatricians. We did not review the diagnosis for this study. For each case, one control matched for age (±1 month) and census tract of residence at the time of diagnosis was recruited from the family allowance files. At the time of the study, these files included all families of legal residents and citizens with children under the age of 18 years. Information from these cases was collected from medical records and with a structured telephone interview. During the first contact with parents of potential controls, we verified the absence of a history of asthma in the sampled child; we asked about a previous diagnosis of asthma by a physician. Parents were later administered the structured interview by interviewers who were blind to the case-control status. Information was collected on the number of siblings at diagnosis (or at the time of the case's diagnosis for controls), day-care attendance from birth, and breastfeeding duration.

Follow-up of cases
We carried out a follow-up of the 457 cases included in the initial study 6–7 years after diagnosis. Controls were not followed. The methods were also previously described (28Go). We were able to track 407 families of which 404 (88.4 percent of the original case group) agreed to a telephone interview. For yearly periods from the time of diagnosis to the time of the survey we asked, "After the diagnosis of asthma, has your child continued to have asthma in the form of episodes of wheezing that caused breathing difficulty or shortness of breath?" We also asked if these episodes were treated by medication. Independently of episodes, we asked if during the study period the child had taken medication prescribed by a physician to control asthma. Cases who neither reported symptoms nor used asthma medication during the follow-up period were defined as transient; there were 110 of these. Cases who continued to have symptoms or to use asthma medication were called persistent; we identified 294 such cases.

Analysis
Conditional logistic regression was used to analyze the matched sets of cases and controls using 1) all sets from the original study (457 cases and 457 controls); 2) the sets that included persistent cases and their original controls (294 subjects in each group); and 3) those including transient cases and their original controls (110 subjects in each group). The main explanatory variables were family size (number of siblings), day-care attendance (defined two ways: before 1 year of age or at any time before diagnosis), and breastfeeding (defined two ways: a duration of 4 months or more or any duration). Paternal and maternal asthma, asthma in siblings, history of allergy and eczema, past infections defined as pneumonia diagnosed by a physician and tonsillectomy, maternal smoking and level of schooling, sex, and persons per room (occupant density) were considered confounding variables. Odds ratios and 95 percent confidence intervals were estimated.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 shows the case-control comparisons for all cases, persistent cases, and transient cases with respect to the main explanatory variables. When using all cases diagnosed at 3–4 years of age, we found that a greater number of siblings and day-care attendance before 1 year of age were protective; risk was reduced by 41 percent with more than one sibling and by 35 percent with day-care attendance before 1 year of age. Breastfeeding was not associated with asthma. Among persistent cases, similar results were observed; in addition, no statistically significant interaction was observed in this group between maternal asthma and breastfeeding. Among transient cases, attending day care at any time before diagnosis was associated with a subtantial risk increase (odds ratio (OR) = 2.37; 95 percent confidence interval (CI): 1.32, 4.25). In the same group, contrary to the two others, breastfeeding for less than 4 months was associated with an increase in risk but it was not statistically significant.


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TABLE 1. Conditional logistic regression* for family size, day-care attendance, and breastfeeding in a case-control study of childhood asthma, Montréal, Canada, 1988–1995

 
Table 2 shows the results of separate analyses for family size, day-care attendance, and duration of breastfeeding, adjusting for confounding variables. The protective effect of family size was more pronounced in the adjusted than in the unadjusted analysis in the group including all cases and in the group of persistent cases but tended more toward the null in the transient case group. The protective effect of day-care attendance before 1 year of age and the effect of attendance before 3–4 years of age remained materially unchanged after adjustment, except that in the transient case group the higher risk associated with the latter was only marginally significant. The risk associated with absence of breastfeeding did not change much after adjustment, whereas that associated with a duration of less than 4 months was somewhat increased in the transient case group (OR = 2.42; 95 percent CI: 0.91, 6.47).


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TABLE 2. Adjusted conditional logistic regression* for family size, day-care attendance, and breastfeeding in a case-control study of childhood asthma, Montréal, Canada, 1988–1995

 
Noteworthy in the analysis of these data are two additional observations that are shown in table 3. The first is that, among persistent cases, all familial factors were strong risk factors, whereas this was not the case among transient cases. The second observation is that, in both groups, a past history of infections (in particular, pneumonia confirmed by radiographic examination but also tonsillectomy) was associated with increased risk.


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TABLE 3. Adjusted conditional logistic regression* for family factors and past infections in a case-control study of childhood asthma, Montréal, Canada, 1988–1995

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The risk of asthma in children was found to decrease with an increasing number of siblings after controlling for confounding variables. This was true for the group of cases diagnosed at 3–4 years of age and also for the persistent cases although in the latter, the protective effect was not more pronounced with more than one sibling in comparison with the effect for one sibling. Day-care attendance before 1 year of age was also protective in the two previous groups but with borderline statistical significance in the persistent cases after adjustment for confounders. Among transient cases, however, different results were observed. The most important observation was that attendance at day care at any time before diagnosis was associated with a greater than twofold increase in risk. With respect to breastfeeding for less than 4 months, there was no effect among persistent cases but an increased risk (although not statistically significant) among transient ones.

Almost all previous studies have considered family size (number of siblings) as well as birth order when studying the association with asthma. Unfortunately in our initial study we did not collect the latter information. In some previous studies when birth order was considered and an inverse relation with asthma was found, it was with the number of older siblings (11Go, 12Go, 15Go). Other studies have not found a relation with the number of older siblings or being born first (5Go, 13Go, 14Go, 16GoGoGo–19Go). The number of siblings was also considered as such and found related in most studies (5Go, 17GoGoGo–20Go) but not in all (21Go). Rusconi et al. (20Go) reported that having siblings increased the risk among transient early wheezing cases, did so slightly in persistent wheezing cases, and was protective in late-onset wheezers. The previous groups were defined among children aged 6 and 7 years the following way: at least one lower respiratory tract illness with wheezing in the first 2 years of life and none in the last 12 months (transient early wheezers); at least one lower respiratory tract illness with wheezing in the first 2 years of life and again in the last 12 months (persistent wheezers); and finally, no symptoms in the first 2 years of life but wheezing in the last 12 months (late-onset wheezers). In comparison with most previous studies, ours included cases that were younger and incident rather than prevalent. In addition, time confirmed the diagnosis in the so-called persistent cases over a 6-year period. Among them, the sibling effect was present, whereas this effect was suggested but not clear in the transient cases where the sample size was not large.

It has been suggested that the sibling effect may be the result of common childhood infections (in particular, viral infections) (6Go) that confer a protective effect toward the development of asthma. Children who have no siblings are usually exposed to common infections later in life than are children with siblings. This hypothesis is supported by recent studies showing that recurrent viral infections induce down-regulation of immunoglobulin E production and a predominant activation of TH1-like helper cells as opposed to TH2 cells (29GoGo–31Go). It is as yet unclear which infections could be protective. Although, on the one hand, viral infections such as measles are thought to be associated with a decreased risk of asthma, infections such as pertussis, rubella, and mumps have not been shown to decrease this risk (4Go). Our results show that having had pneumonia or tonsillitis was associated with an increased risk of asthma. This may perhaps argue against the protective role played by viral infections. However, pneumonia in particular and tonsillitis in some cases are likely to be infections that result in severe tissue damage, which may promote the development of allergy. In addition, a bacterial etiology is not unlikely for pneumonia given that these clinical events took place before the widespread use of Haemophilus influenzae vaccination (32Go); as for tonsillitis, it is not uncommon to find in this age group a mix of bacteria and viruses as reponsible agents (33Go).

Most studies evaluating the relation between day-care attendance and asthma found that risk increased with attendance or that there was no association (17Go, 21Go, 23GoGo–25Go, 34Go) regardless of the definition that varied from any attendance to attendance at specific ages. This suggests that childhood infections may not explain the protective sibling effect. However, Rusconi et al. (20Go) found that day-care attendance in the first 2 years of life was associated with an increase in risk among transient wheezers (as previously defined), no increase in the persistent cases, and a protective effect in the late-onset cases. Another study showed that the risk of asthma later in life (children 5–14 years of age) increased as entry into day care was later (trend marginally significant) in comparison with entry between 6 and 11 months of age (22Go). In our study, we observed that the risk among persistent cases was lower in children who attended day care, but only before 1 year of age; attendance defined as at any time before diagnosis had no effect on persistent cases but substantially increased the risk among transient cases. These observations support the infectious hypothesis for asthma. Assuming that transient cases either have a less severe form of asthma or do not have asthma but were diagnosed as such at 3–4 years of age because of an infectious episode with some wheezing, it makes sense that exposure to infections in day care would increase risk, whereas among true cases early exposure to infection is protective.

All recent studies that have considered the association between breastfeeding and asthma have found a relation suggesting that breastfeeding is protective (15Go, 20Go, 21Go, 24Go, 26Go); however, Wright et al. (35Go) reported that among schoolchildren this was true only when the mother had no asthma. Our data did not confirm this latter observation among persistent cases aged 3 and 4 years. Oddy et al. (26Go) report an odds ratio of 1.25 (95 percent CI: 1.02, 1.52) for asthma at 6 years of age when milk other than breast milk was introduced before 4 months of age. We cannot determine from our data if breastfeeding was exclusive. However, in an effort to compare our results with the ones by Oddy et al. (26Go), we used a cutoff at 4 months of duration; with this definition, only the adjusted risk among transient cases was substantially increased (OR = 2.42; 95 percent CI: 0.91, 6.47). This tends to suggest that breastfeeding is likely to have an impact on later infections (assuming transient cases were such) but none on the incidence of asthma. These observations do not contradict the hypothesis stating that more opportunity for infections at an earlier age protects from asthma.

The strengths of this study were that cases were incident, diagnosed by a pediatrician, and that a follow-up with a high percentage of tracing was carried out among cases to confirm diagnosis. Asthma is a familial disease with a genetic basis (36Go). In addition, maternal asthma in particular has been associated with asthma in children (37Go). The fact that our data suggest a strong relation between familial factors and persistent asthma that is not present for maternal and sibling asthma in transient cases is in support of the validity of the classification of cases.

Nevertheless, our study has weaknesses. Whereas time helped to confirm the diagnosis of cases, we cannot be fully assured that all persistent cases are true cases because of misdiagnosis by their physicians. In addition, we did not have the opportunity to confirm the healthy status of controls. Assuming that 80 percent of the children who develop asthma will experience their first episode of wheeze before the age of 3 years (38Go), we believe that most controls should remain disease-free. However, if some controls have become true cases and are compared with persistent cases, this would result in a bias toward the null. In the comparison with transient cases, it is more difficult to speculate because the nature of this group is uncertain (infectious episodes with wheezing or an alternate form of asthma).

In conclusion, the findings from our study provide additional support for the hypothesis that early infections (likely viral in nature) measured with proxy variables, such as the number of siblings and early day-care attendance, are protective of asthma, while breastfeeding that reduces the opportunity for early infection is not. These relations were independent of such common childhood infections as pneumonia and tonsillitis. Further elucidation of the mechanisms supporting the main observations of this study that have now been reported quite frequently is needed.


    ACKNOWLEDGMENTS
 
This project was supported by grants from the "Fonds de la Recherche en Santé du Québec (FRSQ)" (grant 970965) and from the "Association pulmonaire du Québec." D. Gautrin is a research scholar with FRSQ.


    NOTES
 
Correspondence to Dr. Claire Infante-Rivard, Department of Epidemiology, Biostatistics, and Occupational Health, 1130 Pine Avenue West, Montréal, PQ, Canada H3A 1A3 (e-mail: cirivard{at}epid.lan.mcgill.ca).


    REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Received for publication September 21, 1999. Accepted for publication July 27, 2000.