Shape analysis of the craniofacial skeleton in children prenatally exposed to anticonvulsant medications using geometric morphometrics

Abstract

Children exposed prenatally to antiepileptic drugs may have a typical facies characterized by midfacial retrusion, a short nose, and anteverted nares. Our aim was to determine whether the shape of the maxilla was altered in its sagittal displacement, or whether the defect in the underlying articulation with the cranial base was responsible for the appearance of midface retrusion. Our hypothesis was that the sphenoid bone as well as the maxilla and other bones in the cranial base were affected by the anticonvulsant medication. The lateral cephalograms of 65 children exposed prenatally to monotherapy (phenobarbital, phenytoin, or carbamazepine) were evaluated using various analyses derived from geometric morphometrics (GM) on different studied areas (maxilla, entire cranial base, spheno‐occipital region, and the total study area) and the resulting configurations compared with those of control children. Procrustes ANOVA suggested that shape variation for all the regions correlated significantly (p < 0.0001) with exposure to antiepileptic drugs, and principal component analysis revealed a noticeable separation between the means of the two groups when PC1 was plotted against PC2 for all the areas studied. The cross‐validation resulting from the discriminant function analysis accurately classified between 79.5% and 88.6% of the control group and between 73.8% and 90.7% of the study group when looking at the different anatomic regions. Canonical variate analysis, applied to the sample after its separation following biological sex and stratification into two age groups, showed unequal results between males and females as well as during circumpubertal growth of the cranial base. Thus, in the exposed subjects, while the glabella was projected forward with a similar prominence in males and females, the rhinion, which is relocated more posteriorly, was more severely displaced in females as opposed to the sella, where the most important displacement occurred in males. Regarding the age groups, it revealed that patients in the younger group of both sexes exhibited a facial shape difference very early (p < 0.0001) when the comparison was performed between exposed and non‐exposed subjects. This difference was maintained in females at older ages but not in males. These details may help isolate the mechanism for the anomalies because of GM's use of shape instead of traditional linear and angular cephalometric measurements.