Results from the International Maternal PKU Study

By Virginia Schuett

From the Fall 2002 issue of National PKU News

This spring (April 11-12, 2002), more than 150 people from all over the world met in Bethesda, Maryland to discuss research findings of the most important study of maternal PKU that has ever been done: The Maternal PKU International Collaborative Study. The study, which began in 1984, has provided us with reams of data and an emerging understanding of the syndrome that was first suggested 45 years ago. At one time, PKU clinicians wondered if the benefits of newborn screening for PKU might be overshadowed by the mental retardation and birth defects associated with maternal PKU. Fortunately, with good diet treatment throughout pregnancy, we now know that the "Maternal PKU Syndrome" can be largely eliminated.

A Brief History of MPKU

In 1957, a London physician who was a pioneer in identifying metabolic diseases through urine amino acid analysis, first mentioned "maternal PKU." He described a mentally retarded woman with PKU who had 3 severely retarded children, all without PKU, and speculated that the mother's high blood phenylalanine levels had caused brain damage to the developing fetus. Several years later, Dr. Charlton Mabry and his colleagues in Kentucky described an additional 14 children, who were mentally retarded but did not have PKU-but were the offspring of 3 women with PKU. The Maternal PKU Syndrome was more fully characterized in the following years to include intrauterine growth retardation, small heads, and a variety of congenital abnormalities (most notably heart defects). In 1980, Dr. Harvey Levy and Dr. Roger Lenke of Boston reported the results of an international survey of maternal PKU cases. This seminal study of more than 500 pregnancies served to focus worldwide medical attention on the problem.

Shortly afterwards, in 1984, Dr. Richard Koch at Children's Hospital of Los Angeles became the principal investigator of the Maternal PKU Collaborative Study (MPKUCS). This multi-center study was funded by the National Institute of Child Health and Human Development (NICHD). The study was designed to thoroughly research important aspects of maternal PKU and sought to prevent the problems described in offspring of women with PKU.

Organization of the Study

Coordinated by Children's Hospital of Los Angeles under the direction of Dr. Richard Koch, this large study has drawn participants from all over the U.S. as well as several other countries. It has been a massive and intense effort.

The study began with four coordinating centers in Boston, Chicago, Texas and Los Angeles. In 1985, Canada joined the group. In 1992, Germany, Austria, and Switzerland entered the study to increase the number of pregnancies that would be treated preconceptually (since by 1988 it was clear that about 80% of enrollees in the study were not on the PKU diet when they became pregnant). These countries were selected since they provided the diet for all adults. The idea was to enroll and follow all pregnancies occurring in women with PKU and hyper-phenylalaninemia in these countries during the study time period. Any woman of childbearing age with blood phe levels above 4 mg/dl (240 µmol/L) was eligible, as long as she had the intellectual capacity to follow diet treatment recommendations.

Enrollment began in 1984 and ended in 1995. The study followed 574 pregnancies in women with PKU or hyperphenylalaninemia, and 100 non-PKU control women matched on a number of important characteristics. The sample included 416 live births. Extensive evaluations of the babies began at birth and continued each year thereafter. These included medical, physical, psychosocial, intelligence, and behavior assessments.

Treatment Plan

To prevent the devastating effects of high blood phe levels during pregnancy, treatment in the study with a low phe diet and medical food was designed to include adequate general nutrition and supplementation with tyrosine and trace elements as needed. The diet was offered to any woman with a blood phe level over 10 mg/dl (600 µmol/L). Every effort was made to help the women keep their blood phe levels in the range of 2-10 mg/dl (120-600 µmol/L). As the study progressed, data showed that outcome for the babies was dependent on the degree of blood phe control in the mother, so the goal for metabolic control was reduced to 2-6 mg/dl (120-360 µmol/L). The ideal would be for the pregnancy to be planned and for the women to be on diet prior to conception. Only 21% of women enrolled in the study had stayed on the diet into adulthood.

Study Results

This study has clearly shown us that the major factor affecting outcome in maternal PKU is the mother's blood phe level during pregnancy. This comes as no surprise. Rather, it reaffirms our original assumption that high blood phe levels are what damage the babies of untreated mothers with PKU.

To our dismay, in only 148 of the 574 pregnancies were the mothers treated before conception. Of the total group, 206 were treated before 8 weeks of pregnancy, 109 were treated between 9 and 26 weeks, and 4 were treated between 27 and 40 weeks. Of the women with mild hyperphe, 57 were not on treatment due to blood phe levels that were already mainly within treatment range; however 9 women were on a phe-restricted diet at some time during their pregnancy.

Compared to the 1980 findings of Lenke and Levy for untreated pregnancies, in the MPKUCS we found that diet treatment during pregnancy, even when started late, resulted in dramatically improved outcome for the babies. For example, for women with classical PKU in the MPKUCS only 23% of babies had a small head, compared to 73% in the Lenke/Levy study. The rate of spon-taneous abortion (13%) was similar to the rate for normal pregnancies. Heart disease occurred in only 7% of the sample, compared to 12% in the 1980 study of untreated women (but the rates of heart defects were only improved when the mother was in good diet control before 10 weeks of pregnancy). The overall rate of mental retardation was reduced to 28%, compared to 92% in the 1980 study.

Treatment Before Pregnancy

The good news is that for women who were in optimal diet control prior to 10 weeks, their babies did not differ from normal on any tests performed at ages 4 and 7 years (see chart). Optimal control is defined as no blood phe levels above 6 mg/dl (360 µmol/L) after 10 weeks of pregnancy, and average blood phe levels throughout pregnancy of 6 mg/dl (360 µmol/L) or lower. Women in the MPKUCS who met these criteria had babies whose intelligence test (I.Q.) scores ranged from 70 to 124 at 4 and 7 years of age. This was comparable to women with mild hyperphe whose blood phe levels were in the same range during pregnancy without treatment. Only one child had heart disease (0.7%) among the pregnancies treated preconcep-tually, comparable to a 1-2% rate of defects seen in normal pregnancies.

Women in the study who started the diet before pregnancy were more likely to achieve early blood phe control and to maintain levels in the target range throughout the pregnancy. Early diet control was then associated with babies who had larger birth measurements and higher developmental and cognitive test scores. When the mother had blood phe levels in the range of 2-6 mg/dl (120-360 µmol/L), the outcome for the baby was better than when the blood phe levels were 6-10 (360-600 µmol/L).

Treatment After 10 Weeks of Pregnancy

A surprising finding is that the average measured I.Q. of children born to mothers who did not achieve good diet control until 10-20 weeks of pregnancy was 92 (range 45-124); we expected a much lower average I.Q. The relatively higher I.Q.s might be related to the fact that some of the women were actually on the phe-restricted diet before 10 weeks of pregnancy, but were not in optimal control after that.

Still, the outcome was very unpredictable for women treated late, reflected in a large range in I.Q. scores for their children, from the mentally retarded range and on up. The average measured I.Q. of the children became progressively lower with increasing delay of the mother starting the diet. Besides having mental retardation, many of these children also had small heads, poor growth, and a variety of birth defects.

Effect of Gene Mutations on Outcome

The study also found that if a woman had 2 "severe" gene mutations for PKU (resulting in zero phenylalanine hydroxylase enzyme activity) and had stopped the diet, she had an average I.Q. of only 83. Those women off the diet with one severe and one moderate mutation had an average I.Q. of 84; and those with one severe and one mild mutation had an average I.Q. of 96. The longer a woman was treated into the adolescent and teen years, the higher the average I.Q. The I.Q. differences due to mutation effects and being off the diet indirectly affected the outcome of the babies, but only when diet treatment during pregnancy was not good.

Overall Cognitive & Behavioral Development

The MPKUCS documented increasing effects from maternal PKU with each week's delay in achieving good metabolic control. Only 16% of the women were in metabolic control before conception, though more than twice that number started the diet before conceiving. Starting the diet for pregnancy clearly does not ensure good control.

The children in the lower I.Q. groups had deficits in memory, all aspects of language, and behavior (with a greater tendency toward acting out behavior, hyperactivity, and attention deficit disorder). They also had lower achievement in all academic subjects and in visual motor skills at 4, 7 and 10 years of age. The findings suggest that the problems associated with poorly treated maternal PKU are real and long-lasting. Dr. Susan Waisbren, Coordinator of Psychology for the MPKUCS, did a tremendous job of organizing data and ensuring a high rate of compliance with psychological testing (80%), enabling us to feel confident about the research findings.

Summary

The most important message of this study is that achieving good metabolic control (2-6 mg/dl or 120-360 µmol/L) before or very early in pregnancy is critically important. This will give the baby the best chance to be born free of birth defects, and to have the best chance for optimal development.