Prenatal exposure to H₂blockers and to proton pump inhibitors and asthma development in offspring

Abstract

Fetal exposure to H2 blockers (H2 Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2 Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998-2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2 Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2 Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2 Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative.

Acid-Suppressive Drug Use During Pregnancy and the Risk of Childhood Asthma: A Meta-analysis

“…The study did not address GERD and may be confounding the association. Yitshak-Sade et al 14 The main possible bias in the study was confounding by indication, which was supported by a statistically signifi cant association between maternal consumption of the medications 2 y after delivery and childhood asthma. Residual confounding factors associated with asthma could exist in their databases.…”

“…We further assessed heterogeneity by using the sensitivity analyses and removing each study from the analysis to assess the changes in the I 2 values and determine which studies contributed most significantly to the heterogeneity. The number of patients in the study by Hak et al 16 was lower compared with other studies, and Yitshak-Sade et al 14 investigated the use of H 2 RA or PPIs rather than the use of any acid-suppressive drug. We found that when the studies by Yitshak-Sade et al 14 and Hak et al 16 were removed, the I 2 values decreased from 88% to 0% (P = .68), but the effect remained significant (RR = 1.45; 95% CI 1.35-1.56; P < .00001; Fig 3).…”

“…Researchers in 3 studies tried to assess maternal GERD. 12,14,18 We summarized the confounders in the studies during the meta-analysis ( Table 3). The methodological quality of the 8 studies was assessed according to the NOS ( Table 4).…”

“…26 Of the 8 studies identified in the metaanalysis, researchers in only 3 tried to assess this issue. 12,14,18 Andersen et al 12 reported that maternal GERD could explain the association observed for maternal postnatal use of PPIs. Although they adjusted the analysis for maternal asthma, maternal GERD may be associated with asthma in offspring also, but this has not yet been investigated.…”

“…Yitshak-Sade et al 14 showed that the main possible bias in a study of this kind is confounding by indication. This finding raises a question of the causality of the effect at study.…”