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By Kimberlee Michals, Ph.D., R.D., L.D.
Discontinuation of the phenylalanine (Phe)-restricted diet at the age of 6 was standard policy for patients with phenylketonuria (PKU) for many years before the National Collaborative Study for PKU began an investigation of whether that was the right approach (Williamson, Dobson, Koch, 1977). A summary report of the investigation (Holtzman, Kronmal, van Doornick, et al., 1986) then indicated that high blood Phe levels had negative effects on intelligence quotient (IQ) and learning and that the restricted diet should be continued beyond age 6. There was no specific recommendation, however, on how long the restricted diet should be continued.
A confounding issue was that when females with PKU enter the reproductive age, the fetuses become vulnerable to the effects of high blood Phe concentrations (Lenke, Levy, 1980). Reports of improved pregnancy outcomes with a low Phe diet led to new studies by Michals, Dominik, Schuett, and colleagues (1985) and Schuett and colleagues (1985) on the benefits of diet therapy. These studies were undertaken because of reports of declines in IQ and academic performance, behavior disorders, electroencephalograph (EEG) abnormalities, tremors, and eczema among children of mothers with PKU. In one study, less than half of the patients (18 of 44) were able to achieve a mean reduction of blood Phe from 29.3 mg/dL to 15 mg/dL through diet control. The studies highlighted the difficulties of patients with PKU in resuming a Phe-restricted diet and reaching acceptable levels of blood Phe (2 to 6 mg/dL).
The International Collaborative Study of Maternal PKU (MPKU) was started in 1984 to test whether restrictions on Phe intake and lowering of blood Phe would result in better pregnancy outcomes (Koch, Hanley, Levy, et al., in press). Most of the women enrolled in the study had previously discontinued the Phe-restricted diet. There were 574 pregnancies in 382 women with hyperphenylalaninemia (HPA) and 412 live births. Diet aimed at lowering blood Phe levels to <6 mg/dL was initiated before conception in 35.6 percent of the pregnancies, but only 15.9 percent of the women achieved blood Phe levels of <10 mg/dL by 10 weeks gestation. The restricted diet was initiated in the first trimester in 50 percent of the pregnancies, but only 18.4 percent of these women had blood Phe levels of <10 mg/dL by 10 weeks gestation. The remaining women started diet control in the second or third trimesters of pregnancy. The majority of subjects in this study attained diet control of blood Phe <10 mg/dL after 10 weeks gestation. Therefore, 50 percent of the fetuses were exposed to high blood Phe levels during the critical period of organ development, especially the heart.
Dietary intake of protein and maternal weight gain were found to be positively related to offspring birth measurements (Acosta, Michals-Matalon, Austin, et al., 1997; Michals, Acosta, Austin, et al., 1996; Rohr, Matalon, Acosta, et al., 1997). Furthermore, birth measurements were found to be related to the length of time required to lower the mother’s blood Phe concentration to <10 mg/dL. The longer the Phe was elevated, the smaller the birth measurements. Hence, treatment guidelines were changed to favor rapid reduction of blood Phe concentrations during pregnancy (Acosta, Austin, Castiglioni, et al., 1992; Michals-Matalon, Acosta, Castiglioni, et al., 1998).
Other investigators have also reported on the importance of dietary protein in the treatment of PKU. Pietz and colleagues (1999) studied the role of amino acids in the PKU diet and found that it was important for the diet to have adequate amounts of large neutral amino acids (LNAA), which share the same transporter to the brain as Phe.
Women in the MPKU study who had high levels of blood Phe and lower rates of congenital heart disease were found to have improved dietary intake of nutrients, especially B
12 and protein (Michals-Matalon, Matalon, Acosta, et al., 1999). Poor weight gain and inadequate intake of dietary fat were found to be predictive of microcephaly. In studies unrelated to PKU, intake of multivitamins before pregnancy has been associated with reduced risk for conotruncal heart defects (Botto, Khoury, Mulinare, et al., 1996; Czeizel, 1993), and reduced dietary intake of folate has been related to increased congenital heart disease (Scanlon, Ferencz, Loffredo, et al., 1998). Thus, adequate intake of vitamins and other nutrients needs to be considered in treating PKU during pregnancy.
The Question of Breastfeeding
Health professionals and women with PKU frequently ask whether women with PKU should nurse their babies. Although breast milk is the most appropriate food for infants, data regarding Phe content of breast milk in women with PKU and the effect on offspring blood Phe levels is limited (Fisch, Jenness, Doeden, et al., 1967). The amino acid content in breast milk is fixed. However, the amount of free amino acids present in breast milk can vary, depending on the mother’s blood Phe level. We studied free amino acids in the breast milk of two women with PKU and found differences in breast milk Phe content that reflected differences in blood Phe levels (Matalon, Michals, Gleason, et al., 1986; Sullivan, Goss, McMaster, et al., 1992). Fox-Bacon and colleagues (1997) measured total Phe in the breast milk of two sisters with PKU and elevated blood Phe levels, and compared them with blood Phe levels in controls and offspring. Although the Phe content of the breast milk was greater for the sisters than the controls, there was no significant effect on the infants’ blood Phe levels. The limited data seem to indicate that breastfeeding is safe for the infants of women with PKU.
The data from the MPKU study indicate that continued followup and treatment of PKU is needed. Long-term dietary treatment of PKU should lead to better control of blood Phe and safeguard against deficiency of nutrients.
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