Association between prenatal alcohol exposure and children’s facial shape. A prospective population-based cohort study
Authors: Liu X. , Kayser M. , Kushner S. A. , Tiemeier H. , Rivadeneira F. , Jaddoe V. W. V. , Niessen W. , Wolvius E.B. , Roshchupkin G. V. 
Published: July 2021

ABSTRACTIMPORTANCEChildren exposed to a high level of prenatal alcohol exposure (PAE) are more likely to develop fetal alcohol spectrum disorder with adverse phenotypes on their faces. However, it is still poorly understood, which level of PAE is associated with facial manifestation and if such associations persist during childhood.OBJECTIVETo examine the association between PAE and children’s facial phenotype in a prospective multi-ethnic population-based study.DESIGN, SETTING, AND PARTICIPANTSThis study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. Children had a 3D facial image taken at ages 9 (n=3160) and 13 years (n=2492).EXPOSURESWe defined 6 levels of PAE based on the frequency and dose of alcohol consumption, and defined three tiers based on the timing of alcohol exposure of the unborn child.MAIN OUTCOMES AND MEASURESFor image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 endophenotypes representing facial morphology. These facial endophenotypes were used as dependent variables in a linear regression analysis to search for associations with PAE. Finally, to detect specific facial components associated with PAE, we mapped statistically significant endophenotypes back to the 3D facial shape. We generated heatmaps to display the facial changes associated with PAE. PAE prediction based on facial shape was also performed; the prediction accuracy was estimated by area under the receiver operating characteristic curve (AUC).RESULTSA significant association between PAE and facial shape was found in the 9-year-old children, at all levels of alcohol exposure: the higher the level of exposure, the stronger the association. Moreover, PAE before and during pregnancy was associated with facial shape. The most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out jaw and turned-in lower-eyelid-related regions. For the 13-year-old children, the associations were weaker and the AUCs lower than those of the 9-years-old children.CONCLUSIONS AND RELEVANCEPAE before and during pregnancy, even at low level, is associated with the facial shape of children, and these associations become weaker as children grow older.Key pointsQuestionsWhich level of prenatal alcohol exposure (PAE) is associated with children’s facial shape at different lifetimes?FindingsA 3D facial phenotype analysis of 9- (N=3160) and 13- (N=2492) year-old children was conducted. PAE before and during pregnancy, even at low level, associates with the children’s facial shape; the association becomes weaker as children grow older.MeaningThe results suggest avoiding drinking alcohol at least three months before and during pregnancy is the safest option for the child. More research is needed to investigate the consequences of PAE on children; the discovered facial phenotypes could be used as a biomarker for further investigations.