Results

The cumulative incidence of asthma in the adolescents was 3.9% (179 affected of 4578 twins with asthma data available). Comparison of their perinatal characteristics showed that asthmatic adolescents had a slightly higher mean ponderal index (p<0.05) and their mothers were younger at their birth (p<0.05) than was the case for unaffected adolescents (table 1). Of the asthmatic adolescents 34.5% had been admitted to hospital during the neonatal period compared with 29.3% of the non-asthmatic subjects. No significant differences were found when mean values for perinatal variables in those responding to the asthma question were compared with those of non-responders, except for higher maternal age in the families of non-responders (28.2 years versus 29.1 years, p<0.001, t test).

In the univariate analysis of categorised individual perinatal factors the risk for asthma increased with increasing ponderal index (table 2). Among those in the highest 25% of the ponderal index the risk for asthma was 82% higher than in those in the lowest 25%. Assuming the median birth length for both twins to be 47 cm, the mean ponderal index in the lowest and highest groups corresponded to length adjusted birth weights of 2260 g and 2970 g. This in turn corresponds to an increase of approximately 10% in the risk per 100 g increase in birth weight. A high ponderal index remained a significant risk factor after adjustment for confounding variables (table 2). The risk of asthma also increased with gestation adjusted birth weight (crude OR for the highest fifth = 1.38, 95% CI 0.82 to 2.31, adjusted OR = 1.55, 95% CI 0.84 to 2.83), though the trend was not significant. When individual perinatal factors were adjusted for the corresponding perinatal factor of the co-twin the ORs decreased slightly but the result remained unchanged (table 2). The regression estimates of the perinatal factors in the co-twin showed patterns similar to those in the index twin but were not significant (data not shown). Among the co-twins within the highest fourth of the ponderal index, the OR for asthma was 1.50 (95% CI 0.87 to 2.59) indicating that a high ponderal index is a risk factor on an individual level rather than due to shared environment.

In the univariate analysis of shared perinatal factors the risk of asthma increased with decreasing maternal age (table 2). The offspring of mothers under the age of 25 at the time of their birth were at a significantly higher risk for developing asthma than were the offspring of older mothers. Because both members of the pair share the values for common birth factors, adjustment for co-twin values was not performed.

Testing suggested interactions between parental asthma status and categorised ponderal index (p for Wald statistic of the interaction term = 0.08) and gestation adjusted birth weight (categorised as continuous p = 0.04 and categorised p = 0.10). In the analysis stratified by parental asthma status the risk for asthma in adolescents with unaffected parents increased with increasing ponderal index (p for trend <0.01 when adjusted for confounders), whereas among adolescents with asthmatic parent(s) a similar trend was found for gestation adjusted birth weight (p for trend <0.01 when adjusted for confounders) (data not shown). In the latter families those with a higher ponderal index had, in addition, a higher risk for asthma (OR 2.33, 95% CI 0.84 to 6.48) than did those with the lowest ponderal index. However, there was no significant trend and the confidence intervals included unity as there were few cases in each category (data not shown).

After assessment of the perinatal risk factors, non-perinatal factors were assessed separately. Because the occurrence of asthma in the offspring of farmers was distinct from that in any other occupational group, other occupational categories were pooled. Sex, hay fever in the adolescent, parental asthma, parental hay fever, sibship size, father's occupation, and maternal smoking were all associated with asthma (table 3). Because the ORs of adolescent's own smoking and exposure to ETS were close to unity, only maternal smoking among the smoking variables was included in the subsequent analysis. When non-perinatal variables were included in the same model, parental asthma, sibship size, and maternal smoking remained significant determinants of asthma, and further adjustment with adolescent's hay fever changed the ORs only slightly (table 3).

When significant perinatal and non-perinatal risk factors (ponderal index, neonatal hospitalisation, maternal age, sex, parental asthma, parental hay fever, number of older siblings, father's occupation, and maternal smoking) were combined in a single model, the following remained independent determinants of asthma: ponderal index, maternal smoking, parental asthma, and number of older siblings (table 4). The model additionally adjusting for hay fever in the adolescent showed a similar result except for sibship size which was replaced by neonatal hospitalisation (OR 1.60, 95% CI 1.00 to 2.47) (data not shown).

Inclusion of subjects with missing data for the independent variables (perinatal and non-perinatal) in the analysis as an additional category for each variable did not change the results.

Among asthma discordant MZ pairs (n = 32) twins with asthma tended to have a lower birth weight, lower ponderal index, and lower Apgar score than did their unaffected co-twins, whereas among asthma discordant DZ pairs (n = 101) twins with asthma had a higher birth weight and ponderal index than the unaffected co-twins (table 5). The difference in ponderal index among DZ discordant pairs was significant, but the differences between MZ and DZ pairs were not (table 5). There were no significant associations between categorised birth weight, ponderal index, gestation adjusted birth weight, or neonatal hospitalisation and the disease status in the asthma discordant pairs overall or when stratified by zygosity (data not shown).

Discussion

The major strength of this study is that it was conducted in a nationwide population based twin cohort with high response rates.19 This minimises selection bias, except for the effect due to twinning. In addition, because the FinnTwin16 study assessed multiple aspects of the health and behaviour of adolescents, bias towards over-reporting of allergic disorders is unlikely. Multiple birth itself has been suggested to decrease the risk for asthma and hay fever,5 but very few studies have compared the occurrence of asthma in twins with that in singletons. However, the prevalence rates for asthma and hay fever among Finnish adolescent singletons in studies which used methods similar to ours have been very similar to those among the twins of this study.19 ,29-31

Among adolescent twins there was no apparent association between the occurrence of asthma and absolute birth weight, although those at the extremes of birth weight had slightly higher ORs than those with intermediate birth weights. Previous studies have found a negative association between birth weight and asthma even until young adulthood,4-6 ,32 but a lack of association has also been reported in a large cohort study.7 Low birth weight may be due to premature birth, inadequate nutrient supply to the fetus, or multiple pregnancy. Prematurity with its pulmonary complications has been reported to contribute to an increased risk for wheezing illness, particularly in childhood.8 In twins, growth retardation in the third trimester of pregnancy is a common cause of lower birth weight.33 With such a large proportion of low birth weights among twins, one would expect a higher rate of asthma if the birth weight in itself was a cause of asthma. However, maturation, especially of the lungs and central nervous system, takes place at the same stage of pregnancy in twins as in singletons, if not earlier,16 and for most twins the catch-up growth after birth is often rapid and is complete by school age.33Birth weight may be an indicator of another underlying cause for asthma, or there may be mechanisms in the maturation and growth of twins which are still unknown and may be protective against the development of asthma among twins.

A novel finding in this study was the increasing risk for asthma with increasing ponderal index. Comparison of our result with other studies is difficult as only a few of the previous studies on the perinatal determinants of asthma have applied adjusted measures of birth weight. Among almost 900 adolescents from New Zealand a head circumference of 37 cm or over was the only factor predictive of asthma among several perinatal crude and ratio measures including the ponderal index.2 In the study by Fergusson et al the lack of association between ponderal index and asthma may have been due to a smaller sample size and different distribution of birth characteristics and asthma (13–27% had asthma, depending on the definition). However, their finding of large head circumference is in accordance with our finding on ponderal index, since both measures indicate advanced fetal growth requiring a well functioning placenta and a nutrient surplus. In both studies the effect appeared independent since several individual, familial, and social factors were accounted for. A similar association between adjusted birth weight and asthma among both adolescents with (gestation adjusted birth weight) and without a parental history of asthma (ponderal index) may suggest that the effect of adjusted birth weight is independent of the genetic background of asthma.

Because others have suggested a positive association between birth factors and hay fever,5 ,32 our observations may reflect the well known association of asthma and atopy in adolescence. Unfortunately, clinical measurements such as serum IgE were not available in the present nationwide cohort of adolescents. However, the association between ponderal index and asthma remained after adjustment for hay fever. Another possible explanation is that a high ponderal index may predict obesity in adolescence34 which, in turn, may be associated with asthma and bronchial reactivity.6 ,35 However, Shaheen et al found an association between low birth weight and asthma on the one hand and, on the other, between a high body mass index and asthma at 26 years of age.6 The association of birth weight, later body weight, and asthma deserves further study and longitudinal studies are needed to tease out causal relationships.

The result of the discordant pair analysis supports the logistic regression analysis of perinatal factors on all pairs. In DZ pairs the ponderal index was significantly higher in the affected twin, indicating an association between ponderal index and asthma. Further, the greater intrapair difference in DZ twins than in MZ twins may indicate a genetic contribution to the association between ponderal index and asthma. On the other hand, the finding that the intrapair difference between birth weight and ponderal index was negative in MZ pairs and positive in DZ pairs suggests that the mechanisms between birth characteristics and asthma may differ in MZ and DZ twins. However, because of the relatively small number of asthma-discordant pairs, the results of the discordant-pair analysis are vulnerable to recall bias with respect to birth measurements. This bias would generally tend to obscure relationships. The apparent lack of an association in the MZ pairs should therefore be interpreted with caution.

Maternal smoking increased the risk for asthma in the adolescents by over 50%. This is in agreement with current knowledge of the effect of parental smoking on the risk of asthma in their children.36 Maternal smoking in pregnancy impairs the growth of the fetus37 and may contribute further to the increased risk for wheezing in early childhood.7 It is practically impossible to make a complete distinction between the effects of smoking during pregnancy and smoking before or after, as most smoking mothers continue to smoke throughout pregnancy. Even with a relatively crude measure of maternal smoking (never versus ever) an association with asthma in the adolescents was apparent. This result may be accounted for by smoking during pregnancy but, alternatively, it may indicate some unmeasured life style factor. This, however, receives no support from the finding that the other smoking variables analysed—environmental tobacco smoke at home and the adolescents' own smoking—showed no association with asthma in these adolescents.

In this study of adolescent twins hay fever in the adolescent and parental asthma were the strongest determinants of asthma at the age of 16 as judged by the odds ratios. However, at the population level the effect of a risk factor depends also on the prevalence of the exposure—that is, how common is the risk factor. Attributable proportion combines the effects of both the relative risk and the prevalence of the exposure. The attributable proportion of high ponderal index, almost as large as that of parental asthma, suggests that, at the population level, the effect of the ponderal index on the risk of asthma is of the same magnitude as the effect of parental asthma.