Original articleInteraction between smoking and body mass index and risk of oral clefts
Introduction
Oral clefts continue to be one of the most prevalent birth defects, affecting close to 1 of 700 births on average. Of all the environmental factors that might contribute to the risk of oral clefts, maternal smoking is the most well established [1] and was considered a causal factor for oral clefts in the 2014 US Surgeon General's Report [2]. Other factors such as body mass index (BMI) have also been supported in recent studies. Another consistent risk factor is BMI. Obese mothers have elevated risks of children with oral clefts compared with normal-weight mothers [3].
No prior study has examined whether the risk of oral clefts associated with smoking is moderated by BMI. There are several reasons why such an interaction may exist, although the direction of the interaction is theoretically ambiguous. On one hand, each of these risk factors may reinforce the effects of the other. Smoking may exacerbate metabolic problems [4], [5], whereas maternal obesity may modify the activity of drug metabolizing enzymes such as CYP1A1 [6]. Furthermore, both maternal smoking and obesity increase the risk of placental insufficiency [7], [8], [9]. Although the placenta is not fully functional until after clefts form, early synergetic and adverse effects of these risk factors on placental function could potentially exacerbate the risk of clefts.
On the other hand, carrying one risk factor may simply reduce the relative importance of the other for cleft risk. For instance, the added risk of clefts because of smoking may be lower among obese mothers who themselves have a higher risk for clefting because of metabolic problems. There may also be mechanistic interactions that offset the risk of one factor in the presence of the other. Among smokers, the interactions between lipophilic carcinogens and DNA (DNA adducts) were reported to be lower with higher BMI [10]. One may also hypothesize that, all else being equal, higher BMI provides a greater fat tissue volume for storing cigarette chemicals such as polyaromatic hydrocarbons or dioxins, thus potentially delaying fetal exposure to their metabolites during the critical first few weeks of pregnancy when clefts form. Some support for an offsetting interaction in another context comes from observational studies reporting a lower lung cancer risk among smokers with increasing BMI [11]. Similarly, other studies reported that smoking was associated with an elevated risk of postmenopausal breast cancer only in nonobese but not in obese women [12], and that smoking was related to higher cancer-related mortality among underweight young women than among women with higher weight [13].
We examined the interaction between maternal smoking and prepregnancy BMI as they influence the risk of oral clefts. Using data from a large international consortium of six population-based case–control studies, we evaluated whether the association of first-trimester smoking with oral clefts varies by BMI. Understanding this heterogeneity may help to accurately quantify the contributions of these risk factors to oral clefts.
Section snippets
Data
Our study combined samples from six population-based studies of oral clefts. Each study provided a sample of cases with oral clefts and controls and included detailed data on environmental risk factors during the first trimester through maternal interviews [1]. Together, the studies provide a sample of 4935 cases and 10,557 controls. We did not exclude any case enrolled in the participating studies based on whether the cleft was isolated or nonisolated (occurring with other birth defects or
Results
Table 1 provides the counts of cases by cleft type and smoking rates and BMI distributions for cases and controls. The sample included 4935 cases with clefts (including 4041 cases with isolated clefts) and 10,557 controls. Among cases, 1134 had cleft lip only, 2078 had cleft lip with palate, and 1723 had cleft palate only. As reported in prior studies [1], [3], smoking, underweight, and obesity rates were higher among cases than controls.
Table 2 presents the results from the logistic
Discussion
Maternal smoking is widely considered one of the most unequivocal environmental risk factors for oral clefts. Previous studies have focused mainly on average associations, with little exploration of possible heterogeneity in risk across other factors. We examined the heterogeneity in smoking associations with oral cleft risk by maternal BMI, another risk factor. We found that the increase in the risk of oral clefts associated with maternal smoking generally declines with increasing maternal
Acknowledgments
This work was supported by the National Institute of Dental and Craniofacial Research at the National Institutes of Health (grant 1 R01 DE020895). The study was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors are grateful to the Data Sharing Committee of the National Birth Defects Prevention Study for comments on earlier drafts of this article.
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