We thank Bråbäck et al for their interest in our recently published review. Bråbäck et al raise important issues concerning interpretation of epidemiological findings on the role of mode of delivery in asthma risk.

Sibling-pair analysis is an effective method to control for familial confounders, and would further inform the association between mode of delivery and chronic diseases. However, because the sibling-pair design takes advantage of genetic relatedness between 2 siblings (sharing half of the genes), this analysis has limitations in complex diseases that are characterized by genetic heterogeneity, such as asthma. The reduced or null association from sibling studies may be due to shared genes, shared environment, or interaction of both of these factors.

Sibling discordance studies also assume that pairs discordant for mode of delivery are the same for all other familial factors. Previous reports have shown that birth order, years between siblings, and family size can impact the risk of immune diseases. Furthermore, mothers who give birth by elective cesarean section (CS) for the first time will most likely undergo another CS in the second birth. Clearly, the bias toward the second child born by CS compared to the first child in a sibling pair could alter susceptibility of disease. Therefore, one sibling compared to another by discordance for mode of delivery may not act as an ideal control.

The reduced or null association between mode of delivery and asthma in studies discussed by Bråbäck et al may also be because asthma was defined by dispensed asthma medication. The reported association between elective CS and asthma medication at a younger age that disappears later is not surprising because studies that use prescriptions as a proxy have shown high peaks in asthma prevalence in infants that steadily decline after 4 years of age in both boys and girls. In contrast, asthma measured by other methods such as standardized health interviews or physician diagnoses revealed the lowest prevalence in the age group 0-4 years and increased prevalence with age in children >4 years.

We agree that gestational age strongly influences the risk of chronic diseases in the offspring. This is consistent with a well-established inverse relationship between birthweight due to adverse maternal conditions and susceptibility of disease in adulthood. Because the gestational duration and mode of delivery are closely related, they should be examined together in shaping the asthma risk.