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The Maternal PKU Collaborative Study

Susan E. Waisbren, PhD; William Hanley, MD; Harvey L. Levy, MD; Harvey Shifrin, MA; Elizabeth Allred, MA; Colleen Azen, PhD; Pi-Nian Chang, PhD; Sanja Cipcic-Schmidt, Dipl-Psych; Felix de la Cruz, MD; Ramona Hall, MS; Reuben Matalon, MD; Jo Nanson, PhD; Bobbye Rouse, MD; Fritz Trefz, MD; Richard Koch, MD

JAMA. 2000;283:756-762.

Context  Untreated maternal phenylketonuria (PKU) increases risk for developmental problems in offspring. The extent to which this risk is reduced by maternal dietary therapy at various stages of pregnancy is not known.

Objective  To determine whether dietary treatment during pregnancy of women with PKU affects developmental outcomes of offspring.

Design  The Maternal PKU Collaborative Study, an ongoing, longitudinal prospective study begun in 1984.

Setting  A total of 78 metabolic clinics and obstetrical offices in the United States, Canada, and Germany.

Participants  A total of 253 children of women with PKU (n=149), with untreated mild hyperphenylalaninemia (n=33), or without known metabolic problems (comparison group; n=71) were followed up to age 4 years.

Intervention  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 [605 µmol/L]). Women with mild hyperphenylalaninemia, who had plasma phenylalanine levels of no more than 10 mg/dL (605 µmol/L) on a normal diet, were not treated.

Main Outcome Measures  Children's scores on cognitive and behavioral assessments (McCarthy Scales of Children's Abilities, Test of Language Development, Achenbach Child Behavior Checklist, Vineland Adaptive Behavior Scales, and Home Observation for Measurement of the Environment), compared by maternal metabolic status at 0 to 10 weeks', 10 to 20 weeks', and after 20 weeks' gestation.

Results  Scores on the McCarthy General Cognitive Index decreased as weeks to metabolic control increased (r = -0.58; P<.001). Offspring of women who had metabolic control prior to pregnancy had a mean (SD) score of 99 (13). Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 SDs below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems.

Conclusions  Our data suggest that delayed development in offspring of women with PKU is associated with lack of maternal metabolic control prior to or early in pregnancy. Treatment at any time during pregnancy may reduce the severity of delay.

Author Affiliations: Children's Hospital, Boston, Mass (Drs Waisbren and Levy and Ms Allred); Hospital for Sick Children, Toronto, Ontario (Dr Hanley); National Institute of Child Health and Human Development, Bethesda, Md (Mr Shifrin and Dr de la Cruz); Children's Hospital, Los Angeles, Calif (Drs Azen and Koch and Ms Hall); Children's Hospital, Minneapolis, Minn (Dr Chang); University of Tuebingen, Tuebingen, Germany (Ms Cipcic-Schmidt); University of Texas Medical Branch,Galveston (Drs Matalon and Rouse); Royal University Hospital, Saskatoon, Saskatchewan (Dr Nanson); and Children's Hospital of Reutlingen, Reutlingen, Germany (Dr Trefz).

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