The threshold for teratogenic effects on child intelligence of prenatal exposure to phenylalanine

Abstract

The primary aim of this study was to model the form of the relation between prenatal phenylalanine exposure and offspring cognitive outcomes and thereby identify the threshold for teratogenic effects of prenatal phenylalanine exposure. The participants were the 413 children and their mothers from the International Maternal Phenylketonuria Collaborative (MPKUC) Study. Consistent with prior research, average phenylalanine (PHE) level in the mother's blood throughout the pregnancy was the strongest predictor of later developmental status. Both linear regression and two-piece linear spline models were fit to the offspring outcome data, using average prenatal PHE exposure as independent variable. Results supported a nonlinear relation between prenatal PHE exposure and offspring cognitive outcomes, with damage to the developing fetus if average PHE levels were above approximately 6 to 7 mg/dL (360 to 420 μmol/L). Interestingly, prenatal PHE exposure had a moderately strong effect on offspring outcomes at 1 year of age and then had stronger effects on offspring outcomes at 2 years, even stronger at 4 years, and then stronger still at 7 years of age. The results of this study have major implications for dietary treatment of pregnant women with PKU and for conceptions of the interplay of genetic and environmental factors in affecting children's intellectual development.