Effect of Maternal Prepregnancy/Early‐Pregnancy Body Mass Index and Pregnancy Smoking and Alcohol on Congenital Heart Diseases: A Parental Negative Control Study

Abstract

Background Congenital heart diseases (CHDs) are the most common congenital anomaly. The causes of CHDs are largely unknown. Higher prenatal body mass index (BMI), smoking, and alcohol consumption are associated with increased risk of CHDs. Whether these are causal is unclear. Methods and Results Seven European birth cohorts, including 232 390 offspring (2469 CHD cases [1.1%]), were included. We applied negative exposure paternal control analyses to explore the intrauterine effects of maternal BMI, smoking, and alcohol consumption during pregnancy, on offspring CHDs and CHD severity. We used logistic regression, adjusting for confounders and the other parent's exposure and combined estimates using a fixed‐effects meta‐analysis. In adjusted analyses, maternal overweight (odds ratio [OR], 1.15 [95% CI, 1.01–1.31]) and obesity (OR, 1.12 [95% CI, 0.93–1.36]), compared with normal weight, were associated with higher odds of CHD, but there was no clear evidence of a linear increase in odds across the whole BMI distribution. Associations of paternal overweight, obesity, and mean BMI were similar to the maternal associations. Maternal pregnancy smoking was associated with higher odds of CHD (OR, 1.11 [95% CI, 0.97–1.25]) but paternal smoking was not (OR, 0.96 [95% CI, 0.85–1.07]). The positive association with maternal smoking appeared to be driven by nonsevere CHD cases (OR, 1.22 [95% CI, 1.04–1.44]). Associations with maternal moderate/heavy pregnancy alcohol consumption were imprecisely estimated (OR, 1.16 [95% CI, 0.52–2.58]) and similar to those for paternal consumption. Conclusions We found evidence of an intrauterine effect for maternal smoking on offspring CHDs, but no evidence for higher maternal BMI or alcohol consumption. Our findings provide further support for the importance of smoking cessation during pregnancy.

The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomization study

“…However, as noted above our imprecise MR results do not rule out an effect, and future larger MR studies are important. Due to the lack of information on alcohol consumption around the time of their partners pregnancy, previous analyses using a negative control design were inconclusive 10 . Recent meta-analyses found consistent modest increases in risk of offspring CHD in mothers reporting alcohol consumption in pregnancy, however, many of the included studies did not adjust for confounders 9,45 , meaning that it is difficult to determine whether the association is a result of alcohol or other characteristics that are related to alcohol and offspring CHDs.…”

“…The causal relevance of the results from meta-analyses is unclear, due to many studies not controlling for key confounders and for the risk of residual confounding. Previously, using parental negative exposure control analyses, we found that positive associations between maternal overweight and obesity with offspring CHDs may be being driven by confounding factors 10 . This work found some evidence of an intrauterine effect of maternal smoking on offspring CHDs.…”

“…This work found some evidence of an intrauterine effect of maternal smoking on offspring CHDs. For alcohol consumption, results were inconclusive due to limited data 10 . Negative control analyses attempt to address the issue of residual confounding in observational studies 10,11 , but rely on assumptions that cannot be empirically verified, such as it being implausible that the exposure in the father (e.g.…”

“…For alcohol consumption, results were inconclusive due to limited data 10 . Negative control analyses attempt to address the issue of residual confounding in observational studies 10,11 , but rely on assumptions that cannot be empirically verified, such as it being implausible that the exposure in the father (e.g. their smoking) could influence offspring CHD risk to a similar magnitude of any effect in mothers.…”

The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study

“…Considering these two criteria, we used paternal exposures measured around the time of pregnancy as a negative exposure control ( Figure 1A ), and offspring dental trauma as a negative control outcome ( Figure 1B ). Parental negative exposure controls have been used previously to explore the intrauterine effects of maternal exposures and offspring outcomes (Brand et al, 2019; K. Taylor et al, 2021).…”