Sex Disparities in Asthma Related to Parental and Grandmaternal Smoking Habits—A Population-Based Register Study

There is a mounting body of evidence that grandmaternal smoking increases the risk of asthma not only in their children but also in nonexposed grandchildren [1]. Effects of in utero exposure to tobacco smoke might be transmitted over generations via epigenetic modification of the foetal germ cells suggesting that the effects could be sex specific [2].

Using prospectively collected data over three generations from Swedish national registries, we have demonstrated that maternal [3] but not paternal [4] grandmother's smoking during pregnancy was related to an increased risk of grandchild asthma. We have now set up a much bigger registry-based cohort also comprising data on paternal smoking from the Swedish conscript registry. Our aim was to assess whether potential effects of grandmaternal and parental smoking were sex specific and whether paternal smoking affected the associations.

We have used dispensed prescriptions of leukotriene antagonists (Anatomic Therapeutic Chemical (ATC) code R03) and/or inhaled steroids (ATC codes R03AK06, R03AK07, R03AK08, R03AK11, R03BA) as a proxy for asthma. We have defined three phenotypes of asthma during the first 6 years of life as suggested by Martinez et al [5]:

Early transient asthma was defined as purchase of at least two prescriptions of asthma medication before 3 years of age and no or less than two purchases after 3 years of age, early persistent as at least two purchases also after 3 years of age and late onset as at least two prescriptions after 3 years of age but no or less than two before.

The study cohort comprised 28,723 children together with their parents and grandmothers. The prevalence of asthma was 7.8%. Grandchild asthma was almost twice as common in boys as in girls. Smoking during pregnancy has declined over the years, and maternal and grandmaternal smoking habits in early pregnancy were closely associated with maternal age. Additional information: https://zenodo.org/doi/10.5281/zenodo.12610766.

The effects of smoking variables on asthma risk were studied using multinomial logistic regression, with crude, adjusted and interaction models defined in Table 1.

In the final model with all adjustments allowing interaction between sex and smoking variables, the associations with maternal grandmother's smoking on late onset and early persistent asthma were statistically significantly larger in girls than in boys. Paternal grandmother's smoking had no association with grandchild asthma. However, paternal smoking increased early transient asthma and late-onset asthma in boys, with statistically significantly lower odds ratio (OR) in girls.

We have also assessed the outcome with a wider definition of asthma based on any asthma medication also including an inhaled beta₂-agonist (ATC codes R03AC and R03AL). When this asthma definition was considered, maternal grandmother's smoking was associated with an increased but similar risk of asthma in granddaughters and grandsons. Paternal smoking had a strong association with early transient asthma in boys, but not at all in girls. Additional information: see above!

This study supports our previous findings that maternal but not paternal grandmother's smoking is associated with an increased risk of grandchild asthma in early life. Maternal grandmother's smoking had a stronger association with early persistent and late-onset asthma in the granddaughters than in the grandsons but only when we used the more restricted definition of asthma. Interestingly, maternal smoking and maternal grandmother's smoking in pregnancy were associated with different phenotypes of asthma. Grandmaternal smoking has been associated with DNA methylation in the grandchildren and a recent study indicated that epigenetic modifications induced by grandmaternal smoking seem to differ from those induced by maternal smoking [6].

Maternal smoking in pregnancy was a risk factor for early onset transient asthma in both boys and girls whereas paternal smoking at the age of 18 was related to early onset transient asthma only in boys. However, the sex-specific association between paternal smoking and offspring asthma may suggest that father's smoking before conception is important. It has been hypothesised in men that this is a developmental window in early puberty with an increased vulnerability to epigenetic modifications caused by environmental exposures [7]. However, paternal smoking in our study is based on reported smoking habits at conscription and we do not know who had started smoking already in early puberty.

Diagnosing asthma is challenging in children less than 5 years [8]. We have used dispensed prescribed medication as a proxy for asthma. However, the broad definition based on any asthma medication is likely to be less specific including many children with viral-induced wheezing and inhaled beta₂-agonists as the only treatment.

Not only the genes but also the impact of lifestyle and environmental exposures are transmitted over the generations. We have adjusted for parental and grandparental educational levels in our analyses. However, data on lifestyle factors (except for smoking) are missing in the registries and we cannot fully exclude that residual confounding due to, for example breast feeding and dietary habits may have affected our findings. Our definition of phenotypes may be subject to misclassification as it is based only on child age at onset since information on atopic status is missing in the registries. Therefore, we should be cautious in interpreting the differences by phenotype.

To summarise, we found that the risk of asthma related to grandmaternal smoking is transmitted to the grandchildren via the maternal line. There is some evidence that the risk of grandchild asthma is stronger in girls than in boys. The sex-specific association between paternal smoking and offspring asthma is a new finding which should be further investigated in epidemiological and mechanistic studies.

All authors on this paper fulfil the criteria for authorship. L.B., K.M. and B.F. acquired the data. All authors contributed substantially to the conception, design and interpretation of the work. L.B. produced the initial draft which was revised following the input of all authors. All authors have approved the final version for publication.

The authors declare no conflicts of interest.