1 Division of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
Correspondence to Dr. Tine Westergaard, Division of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark (e-mail: twe{at}ssi.dk).
Received for publication December 6, 2002. Accepted for publication January 5, 2005.
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ABSTRACT |
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asthma; birth order; hypersensitivity; rhinitis, allergic, perennial; rhinitis, allergic, seasonal; risk factors; siblings
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INTRODUCTION |
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Results from studies on the association between asthma and sibship size have, on the other hand, lacked consistency (4, 10
). However, few have taken into account whether they studied asthma with or without an allergic component, such as allergic sensitization or other allergic diseases. Regarding sibship characteristics other than sibship size, the literature is furthermore sparse on studies addressing whether, for example, age interval to siblings (2
, 3
) and gender of siblings (7
, 11
) might affect the risk of allergy or asthma. Studying sibship characteristics and associations with allergy and asthma in more detail could contribute to our understanding of the underlying mechanism behind allergy and asthma and bring new clues to their etiology.
In this study, we investigated among pregnant women whether the risk of allergic rhinitis and the risk of asthma with and without allergic rhinitis were associated with sibship characteristics, including the total number of siblings, the number of older and younger siblings, and the number of brothers and sisters. Furthermore, the possible association of allergic rhinitis and of asthma with and without allergic rhinitis with the interval to closest older and younger sibling was studied.
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MATERIALS AND METHODS |
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The Danish National Birth Cohort Study is an ongoing study conducted in Denmark, with the main focus on studying the importance of exposures in utero and during the first years of life for later development of disease (12). Pregnant women were invited to participate in this study when they visited their general practitioner for the first time during their pregnancy. Women were eligible for inclusion if they wanted to carry their pregnancy to term and spoke Danish well enough to take part in telephone interviews. The first of four telephone interviews was conducted around weeks 1216 of pregnancy. In this interview, the women were asked a wide variety of questions, including questions on allergic rhinitis and asthma.
Overall, 39,154 women participating in the Danish National Birth Cohort for the first time had completed their first telephone interview between September 29, 1997, and March 14, 2000. These women were linked with the Civil Registration System, which is a mandatory national register containing updated demographic information on all residents in Denmark (13). From the Civil Registration System, complete information on date of birth, place of birth, and vital status of their mothers and all their siblings could be obtained as long as their mothers and siblings were born in Denmark on April 1, 1935, or later (14
) and were alive or born later than April 1, 1968, when the Civil Registration System was established. The study was restricted to the 31,749 women whose mothers fulfilled these criteria. In addition, women were excluded if they were born abroad or had missing information on the place of birth or the place of residence (n = 520) or if they did not know whether they had allergy (n = 84), leaving 31,145 women in the study.
Definitions
The study is based on the lifetime prevalence of allergic rhinitis and asthma as defined below. During the first telephone interview, all women were asked, "Have you ever had asthma?" and, if so, "Have you had the disease diagnosed by a doctor?" Women who answered affirmatively to these two questions were considered as cases with asthma. All women were furthermore asked, "Have you ever had allergy?" and, if so, "Have you had the disease diagnosed by a doctor?" Women who answered affirmatively to these two questions were further asked what kind of allergy they had. Women who reported allergic rhinitis and/or hay fever were considered as cases with allergic rhinitis.
Statistical analyses
The odds of allergic rhinitis and of asthma with and without allergic rhinitis were estimated using logistic regression models. Maximum likelihood estimation was performed using the GENMOD procedure in the SAS 6.12 statistical software package (15). Two-sided p values were based on likelihood ratio tests, and 95 percent confidence intervals were based on Wald's tests. Trends were estimated as the slope when the categorical variables of interest were treated as quantitative variables.
First, possible associations were investigated between the studied outcomes and the total number of siblings at the age of 10 years, the numbers of older and younger siblings, the numbers of brothers and sisters, and the numbers of older and younger brothers and sisters, respectively. Tests for trend were performed to study the potential effect of the number of siblings, and the slope estimates were used to test for a potential difference between having older and younger siblings and having brothers and sisters.
Second, possible associations between the interval to the closest older and younger sibling and the studied outcomes were investigated. The possible association between allergic rhinitis and the interval to siblings was furthermore studied in more detail in a subanalysis on a data set restricted to women with zero, one, or two siblings and with intervals of less than 10 years to their siblings (n = 24,540).
In all models, we included the age at interview (<20, 2024, 2529, 3034, 35 years), the age of the mother at the woman's birth (<20, 2024, 2529, 3034,
35 years), the degree of urbanization of the place of birth (five categories) and the place of residence (five categories), and occupation (six categories) (16
).
Finally, we used polytomous logistic regression to investigate whether an effect of having siblings on the risk of asthma with allergic rhinitis could be due to a protective effect of siblings on the risk of allergic rhinitis alone. These analyses were done using Stata software, release 8 (17). Cases were categorized in three groups (asthma with allergic rhinitis, asthma without allergic rhinitis, allergic rhinitis without asthma) and compared with women who had neither asthma nor allergic rhinitis. The effect of confounders was allowed to be different for the three outcomes. The hypothesis was investigated by testing whether the parameters corresponding to the outcomes allergic rhinitis without asthma and asthma with allergic rhinitis could be considered identical.
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RESULTS |
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Allergic rhinitis
As seen in table 1, the odds ratio of allergic rhinitis decreased with the increasing number of siblings (ptrend < 0.0001). There was an inverse association between allergic rhinitis and the number of older siblings (ptrend < 0.0001), as well as the number of younger siblings (ptrend = 0.0008) (table 1). For each additional older sibling, the odds of allergic rhinitis decreased by a factor of 0.80 (95 percent confidence interval (CI): 0.76, 0.84), while for each additional younger sibling the risk decreased by a factor of 0.92 (95 percent CI: 0.87, 0.97). The effect of having older siblings was significantly stronger than the effect of having younger siblings (p = 0.0001). The odds ratio of allergic rhinitis for combinations of the numbers of older and younger siblings can be seen in table 2. The table shows that the protective effect of younger siblings primarily was in subjects with additional older siblings, whereas the protective effect of older siblings was observed regardless of the number of younger siblings. The association between the number of siblings and the risk of allergic rhinitis was not modified by birth cohort.
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There was no association between allergic rhinitis and the interval to closest older sibling or the interval to closest younger sibling (table 3), and the gender of the sibling did not affect the risks (data not shown). The subanalysis on the data restricted to the 24,540 women with zero, one, or two siblings and with intervals of less than 10 years to their siblings showed a tendency of lower odds ratios for intervals to older siblings than to younger siblings but did not show any consistent pattern of association between specific age intervals to younger or older siblings, respectively, and the risk of allergic rhinitis (table 4).
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Asthma with allergic rhinitis.
As seen in table 5, the risk of asthma with allergic rhinitis decreased with the increasing number of siblings (ptrend = 0.0006). There were a significant inverse association with the number of older siblings (ptrend = 0.0004) and a borderline significant association with the number of younger siblings (ptrend = 0.06) (table 5). The trends of 0.86 (95 percent CI: 0.79, 0.94) for number of older siblings and of 0.92 (95 percent CI: 0.84, 1.00) for number of younger siblings did not differ significantly from each other (p = 0.20).
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There was no association between the interval to the closest older or younger sibling and the risk of asthma with allergic rhinitis (table 3). Furthermore, there was no interaction between the intervals and the gender of the sibling (data not shown).
Asthma without allergic rhinitis.
There was no significant association between having had asthma without allergic rhinitis and the number of siblings or the number of brothers or sisters (table 5). However, the odds of asthma without allergic rhinitis increased significantly with the number of older siblings (ptrend = 0.02), while there was no association with the number of younger siblings (ptrend = 0.92) (table 5), but the trends for the numbers of older and younger siblings were not significantly different. The odds of asthma without allergic rhinitis increased significantly with the number of older brothers but not with the number of older sisters (table 5). The trends, however, did not differ significantly from each other. There was no association with having younger brothers or sisters (table 5).
The risk of asthma without allergic rhinitis was higher for intervals of 2 or more years to the closest older sibling (odds ratio = 1.25, 95 percent CI: 1.02, 1.53) compared with intervals of less than 2 years (table 3). There was no association with the interval to the closest younger sibling. There was no interaction between the interval to the closest older or younger sibling and gender (data not shown).
Comparisons of the effects of having siblings
The observed protective effect of having siblings on the risk of asthma with allergic rhinitis could potentially be due to the protective effect of siblings on the risk of allergic rhinitis alone. To investigate this, we used polytomous logistic regression. The analysis revealed that, when categorizing cases in three outcomes (asthma with allergic rhinitis, asthma without allergic rhinitis, allergic rhinitis without asthma) and compared with women with neither asthma nor allergic rhinitis, the differences in the effect of having siblings could be ascribed to the presence of allergic rhinitis in the case definition or not. In other words, the fitted model showed that the associations between having siblings and allergic rhinitis without asthma and allergic rhinitis with asthma were similar when compared with women with neither asthma nor allergic rhinitis. Thus, one can interpret the protective effect of having siblings on the risk of asthma with allergic rhinitis as due to the protective effect of siblings on the risk of allergic rhinitis alone.
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DISCUSSION |
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We found that having both older and younger siblings was associated with a protective effect on allergic rhinitis but that the effect of having older siblings was stronger than the effect of having younger siblings. According to the theory that in particular having infections during the first few years of life should protect against allergic sensitization, we would also expect that among younger siblings only younger siblings very close in age to the subject would have a protective effect. However, no specific age interval either to the closest younger or older sibling, respectively, was found to be associated with a particularly protective effect on allergic rhinitis. This suggests that exposures later in childhood also may be involved in the etiology.
Some studies have suggested that the association between allergy and the number of older siblings as measured by birth order might rather be explained by an association with immune development in utero than by postnatal exposure. One study found a tendency of a decrease (18), and another more recent study reported a significant decrease in cord blood immunoglobulin E with increasing birth order and found the cord blood immunoglobulin E concentration to be a significant predictor of allergic sensitization in childhood (19
). Furthermore, proliferative responses of cord blood mononuclear cells to allergens have recently been found to decrease significantly with increasing birth order (20
). Such findings do not, however, explain the independent association between allergy and the number of younger siblings that has been found in the present study and in previous large studies on allergic rhinitis and allergic sensitization (1
, 2
, 6
, 7
).
Interestingly, Strachan et al. (11) found in a study of 11,042 pregnant women that the inverse association between having many siblings and the risk of inhalant allergy was restricted to the number of brothers the women had, while there was no association with having sisters. This finding was supported by a study of 13,932 subjects by Svanes et al. (7
), who found a stronger protective effect of having brothers than sisters on the risk of atopy among women as well as men. Svanes et al. suggested that having brothers compared with sisters may have a particularly protective effect on developing allergy, perhaps because boys are more likely to contract serious respiratory infections and thereby provide a stronger exposure to infectious agents (7
). There was a slight tendency in our data of a more protective effect of having brothers than sisters, but none of the trend estimates differed significantly from each other.
Information on allergic rhinitis and asthma in our study was based on self-reported information obtained in young adult life. It cannot be excluded that some misclassification of the outcomes could have occurred. However, bias from self-reporting was reduced by using questions on physician-diagnosed conditions, which have been found suitable for risk factor studies because of their high specificity and positive predictive value (21). In addition, in Denmark, asthma-like symptoms that occur only in the presence of colds during early childhood and are not due to allergy are usually not diagnosed as asthma but as asthmatic bronchitis. This is likely to have reduced misclassification of the asthma outcome, since asthma and asthmatic bronchitis in most cases are likely to be different diseases with different etiologies (22
).
Overall, it has been estimated that approximately one half of the pregnant women in Denmark were invited to participate in the Danish National Birth Cohort, since not all general practitioners wished to be involved in the recruitment. Among women who were invited to participate, approximately two thirds did so. We have no reason to believe that selection mechanisms into the Danish National Birth Cohort should have influenced the internal validity of this study.
In conclusion, we found that having siblings was associated with a protective effect on allergic rhinitis but not on asthma. Our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Although the protective effect on allergic rhinitis was stronger for older than younger siblings, the finding that allergic rhinitis was associated with the number of younger siblings, but not with the age interval to younger siblings, supports the hypothesis of an influence of postnatal mechanisms and suggests that these mechanisms may not necessarily be operating only in early life.
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ACKNOWLEDGMENTS |
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Conflict of interest: none declared.
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NOTES |
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References |
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