Adverse Effect of Maternal Phenylketonuria on Offspring

Stimulated by the original observations of Mabry and his colleagues in the early 1960's, Dr. Harvey Levy in this IDDRC had a central role in the study of the effect of untreated maternal PKU during pregnancy on the offspring (Transplacental Effects on Fetal Health, 1988). An international survey found that when mothers had classic PKU and their pregnancies were untreated, 92% of the offspring were mentally retarded. In a further followup study of 435,000 women screened in Massachusetts, Levy identified 22 with persistent hyperphenylalaninemia; two of these women had classic PKU and all four of their children were adversely affected. Of the remaining 20 with atypical PKU or non-PKU, mild hyperphenylalaninemia, it was found that in those with concentrations between 10 and 20 mg/ml, there was a roughly linear correlation with mental retardation. It was also learned that if dietary treatment is instituted prior to pregnancy, the offspring are normal, and that if treatment is instituted in the middle of the first trimester, mentation is preserved but there is a greater than expected incidence of cardiac malformations. An additional finding of great interest was the fact that the human placenta concentrates phenylalanine, and thereby umbilical cord blood concentrations are higher than maternal blood concentrations, thus exposing the fetus to a higher concentration during pregnancy. Dr. Susan Waisbren has pursued this work in the current IDDRC with great vigor and has delineated the importance of timing of intrauterine exposure to hyperphenylalaninemia in the pathogenesis of the adverse effects in offspring.