Follow-Up Of Offspring Of Women With Maternal Phenylketonuria

Nutrition Research Newsletter, March, 2000

Phenylketonuria (PKU) in women increases the risk for adverse outcomes in their offspring. Children of women with untreated PKU have a 92% chance of mental retardation, a 73% risk for microcephaly, a 40% risk for low birth weight, and 12% risk for congenital heart disease. Treatment of PKU with a phenylalanine-restricted diet begun prior to pregnancy reduces these risks. The extent to which these risks are reduced in late or inadequately treated pregnancies has not been clearly established. The Maternal PKU Collaborative Study is an ongoing, longitudinal prospective study that began in 1984 in a total of 78 metabolic clinics in obstetrical offices in the United States, Canada, and Germany. The outcomes at age four years in offspring were reported in the February 9, 2000, issue of the Journal of the American Medical Association.

Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine = 10 mg/dL). Women with mild hyperphenylalaninemia (MHP) were also invited to participate in the study, and they remained on a normal diet as treatment was not recommended. The final study included 572 pregnancies, of which 412 were completed. Eight children died of complications associated with PKU. At the time of the report, 368 children from the United States and Canada had reached their four-year birthday. Four offspring were excluded from the study after being diagnosed with PKU or MHP and the children in Germany were excluded because a different test battery was used. Of the 253 offspring receiving the preschool psychological test battery, 149 were born to mothers with PKU, 33 had mothers with untreated MHP, and 71 had mothers in a comparison group. All of the children received the McCarthy Scales of Children's Abilities test, 183 received the full battery of tests to assess language, behavior, and adaptive behavior, and the IQ of the mothers was also measured.

The majority of women with PKU attained metabolic control after 10 gestational weeks. Maternal IQ was lower in these women, their assigned plasma phenylalanine level was higher, and their education and level of social position was lower. The children's scores on the McCarthy Scales declined as the number of weeks to metabolic control increased. A group of 10 children had mothers who attained metabolic control after pregnancy but within six weeks of gestation. These children did not perform as well as those whose mothers had been treated prior to conception. Treatment at any time during pregnancy appears to reduce the risks of cognitive impairment and developmental delay associated with untreated PKU. The children are best protected when metabolic control is achieved prior to pregnancy. There is no evidence for a "safe zone" once pregnancy begins that would mark a period in which the fetus is fully protected. It is well documented that maternal phenylalanine levels higher than 10 mg/dL during pregnancy affect the fetus. The developmental profile of maternal PKU offspring shows a distinct trend toward lower scores on tests of language, memory, and quantitative abilities, while motor skills and behavior are relatively less affected.

This cohort of women with PKU had difficulty complying with dietary restrictions and monitoring metabolic status. Adhering to the diet did not become easier with successive pregnancies. The women were often less able to maintain metabolic control because of lack of resources, time, motivation, support, or organization. This finding underscores the relevance of psychosocial factors in maternal PKU. Interventions directed at reducing the risks at each step in the maternal PKU cycle may prove to be the most effective. In terms of outcome, every week counts.

S. Waisbren, W. Hanley, H. Levy, et al., Outcome at Age 4 Years in Offspring of Women with Maternal Phenylketonuria, JAMA 283 (6): 756-762 (February 2000) [Correspondence: Susan E. Waisbren, PhD, Genetic Services, Childrens Hospital, 300 Longwood Ave., 1C-107, Boston, MA 02115. E-mail: waisbren@al.tch.harvard.edu.]