Numerous studies have shown a strong association of asthma risk in children with family history of asthma and allergies.10
However, few data relate family history to the asthma subtypes of early onset transient, early onset persistent and late onset asthma which appear to have different associations with various risk factors.2,4
Consistent with reports by Martinez et al. 2
and Rusconi et al
, we found a stronger association between parental history of asthma and early onset persistent asthma as opposed to early onset transient asthma or late onset asthma. Parental history of allergy, particularly having two affected parents, also related most strongly with the risk of early onset persistent asthma. As in previous studies 1,4,7
, we observed greater associations between childhood asthma risk and family history of asthma than family history of allergy.
We found that sibling history of asthma, even in the absence of parental history, was strongly associated with asthma and, as with parental history, the association was strongest with early onset persistent asthma. A strong and independent contribution of sibling history of asthma and allergy, beyond the contribution of parental history, could be consistent with shared early life environmental factors or the interaction of genetics and the early environment.
To evaluate the possibility that genetic susceptibility, approximated by parental history of asthma and allergy, modulates the association between very early life exposures and the various asthma types, we examined maternal smoking during pregnancy.
Maternal smoking in pregnancy was mildly associated with wheezing and all three asthma types. However, among those with parental history of asthma or allergy, maternal smoking in pregnancy predominantly associated with early onset asthma that persists into later childhood. The joint effects of maternal smoking in pregnancy and parental history of asthma and allergy in relation to early onset persistent asthma were more than additive, suggestive of a possible biologic interaction.
Although it is difficult to distinguish the independent effects of prenatal and postnatal maternal smoking, early exposure to a mother who smokes clearly increases the risk of wheezy illness and asthma in children, 11
and increasing evidence implicates prenatal maternal smoking per se.12,13
Maternal smoking during pregnancy correlates with reduced lung function in newborns, measured prior to hospital discharge, who have not yet been exposed to postnatal smoking 14–16 15–17
. Maternal smoking in pregnancy has also been associated with pulmonary function decrements in school-aged children in this 18
and other studies. 19
A biologic interaction between maternal smoking in pregnancy and family history of asthma and allergy is plausible. Asthma is a chronic inflammatory disorder of the airways and airway inflammation is related to the immune response20
. The development of asthma in young children relates to the persistence of the Th-2 immune responses that characterize normal pregnancy 21
. Increasing evidence points to the influence of the in utero
environment on the developing fetal immune response 21
. T-cell priming commonly occurs transplacentally to antigens encountered by the mother in the last trimester of pregnancy; with Th-2 skewing of these primed T-cells 21
. In mice, cigarette smoke promotes release of Th-2 cytokines after antigen challenge22
. Smoking also primes human neutrophils leading to an enhanced inflammatory response to activators and production of tobacco anti-idiotypic antibodies that can continue this priming after smoking cessation 23
. Antibodies of this type could cross the placenta and stimulate fetal antibody formation 24
. In addition, during the third trimester, cigarette smoking blocks the decrease in circulating numbers of mature T-cells, particularly helper T-cells, seen in nonsmokers 24
. Infants with a family history of atopy and asthma have reduced production of interferon gamma, a Th-1 cytokine 21
. It is possible that in the infant with a genetic predisposition to asthma and allergy, the influence of maternal smoking on the subsequent development of immune responses favoring asthma could be heightened.
We are not aware of other data addressing the possible interaction of maternal smoking during pregnancy and parental history of asthma or allergy in relation to childhood asthma. Agabati et al
reported that current maternal smoking was related to current asthma among children aged 6–7 in the presence of parental asthma history, but only to wheeze in the absence of parental history.
Like many epidemiologic studies of childhood asthma, ours has several weaknesses. We classified children as asthmatic based on parental report of a doctor’s diagnosis rather than on objective measures of bronchial responsiveness. Misclassification of asthma would most likely bias results toward the null if nondifferential with respect to family history. In addition, the findings of Martinez et al
and Rusconi et al
were based on report of wheeze rather than asthma diagnosis. Unfortunately, we lacked data on the age of onset of wheezing for children without a reported doctor diagnosis of asthma. Early onset transient wheezing is reported to be very common; 2
whereas in our data early onset transient asthma was not. Classifying a large number of early transient wheezers into our category of wheeze and asthma-like illness without asthma diagnosis limits our power to study early transient illness. Further, ascertainment of a history of transient wheezing in early life among older children will likely result in misclassification of some early transient wheezers into the comparison group. Parents may not consistently report the symptoms of children whose wheezing resolved long ago. If this underreporting does not depend on family history, it would probably bias results toward the null.
The cross-sectional nature of these data also poses the danger of differential misclassification. We ascertained parental history of asthma simultaneously with report of asthma in the child. Thus, the pattern of associations seen in our study, as well as in the study of Rusconi et al. 4
, could result from biased parental reporting of childhood asthma or wheeze contingent on family history, or, conversely, from child’s asthma or wheeze influencing reporting of family history. Kulig et al
, using prospective birth cohort data, found that fathers’ reports of their atopic histories changed after their infants developed atopic dermatitis. This same distortion occurred when mothers provided the father’s history of atopy. However, the data of Kulig et al
provide reassurance in that the child’s development of atopic disease did not influence the mother’s report of her atopic history. Further, distortion in reporting of paternal history did not occur when the infant had developed atopic manifestations other than atopic dermatitis 25
. We cannot evaluate the possibility of recall bias in parental responses directly in our cross-sectional data. To decrease both differential and nondifferential misclassification, we restricted the analysis to subjects for whom a biologic parent completed the questionnaire. Because we based our assessment of parental history on the report of one parent, generally the mother, we examined whether the results were similar for questionnaires completed by mothers and fathers and found that they were.
We did not find stronger associations between childhood asthma and history of asthma in the mother versus the father. Stronger associations for maternal history have been inconsistently observed in the literature 26
. Recent data suggests that differences in risk conferred by maternal versus paternal history might depend on the specific allergen to which the asthmatic child responds 27
In summary, in this school-based study of Southern California children, we found that family history of asthma and allergy associated most strongly with the risk of early onset persistent asthma. We also found preliminary evidence that parental history of asthma and allergy may influence whether an early environmental exposure, maternal smoking during pregnancy, results in early onset asthma that persists into later childhood. If confirmed, these results may be relevant to the study of early life environmental exposures, such as air pollution, for which associations with asthma have been postulated but have been difficult to detect 28
. Other early life exposures may be differentially related to childhood asthma depending on age at onset and persistence of asthma and these relations may differ according to genetic predisposition.