Maternal factors increase risk of orofacial cleft: a meta-analysis

Orofacial clefts are among the most prevalent birth defects, with severe medical and psychosocial consequences. Cleft lip with or without cleft palate (CL ± P) and cleft palate only (CPO) affect on average nearly 1/700 births worldwide. The cause of most non-syndromic cases is unknown. Maternal factors and disorders are assumed to modify the risk of orofacial clefting. In the present study, we performed a systematic review and meta-analysis to analyze the effects of maternal underweight, obesity, hypertension, diabetes, as well as smoking, and alcohol consumption on the development of orofacial clefts. As CL ± CP and CPO have distinct pathogenetic backgrounds, these cleft subtypes were assessed separately. Altogether, 5,830 studies were identified and 64 of them met the inclusion and exclusion criteria. Obesity significantly elevated the odds of clefting (OR = 1.28, CI:1.08-1.51) (OR_CL±CP = 1.23, CI:1.01-1.50; OR_CPO = 1.31, CI:0.97-1.77). Maternal underweight also significantly increased the odds of clefting (OR = 1.21 CI:1.06-1.38). In mothers with type 1 diabetes, the odds of cleft development were significantly elevated (OR = 1,75, CI:1.45-2.12). Essential hypertension was also associated with higher odds of developing cleft (OR = 1.55, CI:1.18-2.03). Smoking during pregnancy significantly elevated the odds of cleft development (OR = 1.55, CI:1.34-1.79) (OR_CL±CP = 1.58, CI:1.36-1.83; OR_CPO = 1.50, CI:1.15-1.96). Passive smoking was even more damaging than active tobacco use, but alcohol consumption had no effect. In conclusion, this study clearly showed the importance of maintaining normal maternal body weight and emphasized the importance of hypertension and type 1 diabetes care in the first months of pregnancy. It also highlighted similarnegative effects of passive and active smoking, while alcohol consumption did not seem to be a significant risk factor for cleft development. However, there is a complete lack of available studies on the interactions of these factors, which is an essential direction for improving prevention.