Maternal PKU: Pregnancy & Child Outcomes in Relation to Dietary Control

The content in this publication was current at the time it was published, but it is not being updated. The publication is provided for historical purposes only.​

By Reuben Matalon, M.D., Ph.D.

The effects of blood phenylalanine (Phe) on the offspring of women with phenylketonuria (PKU) were recognized in the 1960s (Mabry, Denniston, Nelson, et al., 1963; Richards, 1964; Denniston, 1963; Mabry, Denniston, Coldwell, 1966; Fisch, Doeden, Lansky, et al., 1969; Stevenson, Huntley, 1967). These effects include mental retardation, cardiac defects, low birthweight, and spontaneous abortions. Lipson and colleagues (1984) showed that dysmorphic facial features were associated with the maternal PKU syndrome. Interest in the prevention of the effects of high blood Phe on offspring was prompted by the survey of Lenke and Levy (1980). The effect of high blood Phe during pregnancy raised the possibility of rebound frequency of mental retardation from PKU (Kirkman, 1982). Therefore, most metabolic clinics initiated low Phe treatment in pregnant women with PKU (Fisch, Matalon, Weisberg, et al., 1997). Treatment regimens, however, did not follow uniform guidelines about diet composition and blood levels of Phe.

Maternal PKU Collaborative Study

In 1984, a national Maternal PKU Collaborative Study was started in this country, with Canada and Germany joining subsequently. There were 574 pregnancies among 382 women with hyperphenylalaninemia (HPA), resulting in 412 live births (Koch, Hanley, Levy, et al., in press). The 350 pregnancies treated with a low Phe diet included 255 women with classical PKU, 62 with atypical PKU, and 33 with natural blood Phe of 6 to 10 mg/dL. There were 62 pregnancies with natural blood Phe of 2 to 6 mg/dL.

Offspring growth measurements were related to the length of time required to lower the blood Phe concentration to <10 mg/dL (Matalon, Michals, Azen, et al., 1991; Matalon, Michals, 1991; Matalon, Michals, Azen, et al., 1994). The longer the blood Phe was elevated, the smaller the birth measurements (Koch, Levy, Matalon, et al., 1993; Koch, Hanley, Levy, et al., in press). Other factors related to blood Phe and pregnancy outcome were the time when diet treatment began, the time when blood Phe control was achieved, mother’s intelligence quotient (IQ), weight gain, protein level, and energy intake (Matalon, Michals, Azen, et al., 1991; Michals, Acosta, Austin, et al., 1996; Waisbren, Hanley, Levy, et al., 2000).

Microcephaly and Developmental Outcomes

Growth parameters and psychological functioning were studied in a subgroup of 275 offspring from the Maternal PKU Collaborative Study. Growth measurements were obtained at birth and 2 years of age, and each child had Bayley developmental testing. The subjects were grouped by the time when blood Phe reached <10 mg/dL; 45 women achieved diet control before conception, 50 before 10 weeks gestation, 72 by 10 to 20 weeks, and 108 after 20 weeks or never. In addition, 45 offspring were born to women with mild untreated HPA, and 61 offspring were born to control women.

Of the 275 treated offspring, 53 (19 percent) were microcephalic at birth. The birth head circumference (HC) Z-score was positively correlated to the Bayley mental developmental index (MDI) and psychomotor developmental index (PDI) ( p=0.001). At 2 years of age, there was an increase in the number of microcephalic infants to 101 (37 percent). In the untreated HPA and control groups, there were three (2.8 percent) microcephalic infants at birth and five (4.7 percent) at 2 years of age. The McNemars test showed a significant increase in microcephaly at 2 years of age in groups where blood Phe control was reached before 10 weeks gestation ( p<0.05), 10 to 20 weeks ( p<0.001), and more than 20 weeks ( p<0.001). The group that did not have microcephaly at birth or at 2 years of age (n=177) had the highest mean Bayley score, 104 ±20, compared with the other groups. The group that was microcephalic at birth and remained microcephalic at 2 years of age (n=35) had the lowest mean Bayley MDI, 71 ±22 ( p=0.0001). Ten children who were microcephalic at birth but had normal HC at 2 years of age had an MDI of 93 ±29 ( p=0.0036). The group with a normal HC at birth who became microcephalic at 2 years of age (n=48) had a Bayley MDI of 88 ±21 ( p=0.0001).

The fact that there were an increased number of offspring with microcephaly at 2 years of age suggests that the effect of Phe on brain growth is carried over even after birth (Matalon, Michals, Azen, et al., 1994; Matalon, Michals-Matalon, Azen, 1997; Matalon, Michals-Matalon, Azen, et al., 1998). Repeated growth measurements are important. The size of the head and the Bayley development scores were related. Head growth is an important criterion that is affected by high blood Phe levels.

In addition to head size, blood Phe levels during pregnancy affect the facial features of the developing fetus. These facial features, which are similar to the dysmorphology seen in fetal alcohol syndrome, are usually associated with microcephaly (Rouse, Lockhart, Matalon, et al., 1990). The higher the Phe levels during the pregnancy, the more pronounced the dysmorphic features.

WISC IQ and Blood Phe Levels

The scores of offspring on the Wechsler Intelligence Scale for Children-Revised
(WISC-R) were compared between mothers who had blood Phe control before conception and those with control at 0 to10 weeks of gestation. The level of control was grouped as blood Phe <6 mg/dL or 6 to 10 mg/dL. There were 13 children with WISC-R full-scale (FS) IQ of 109 where blood Phe control was <6 mg/dL, and 11 children with IQ of 95 where blood Phe control was 6 to 10 mg/dL. In six children where blood Phe control of <6 mg/dL was achieved between 1 to 10 weeks gestation, the IQ was 99. In 15 children where blood Phe control was 6 to 10 mg/dL, the IQ was 95. In 16 children of women with untreated HPA with blood Phe control of <6 mg/dL, the IQ was 97. In four children where blood Phe control was 6 to10 mg/dL, the IQ was 107. In 67 control children, the IQ was 109. These data suggest that the level of blood Phe that affects brain development and head size is reflected in IQ (Koch, Hanley, Levy, et al., in press).

Congenital Heart Disease (CHD)

The Maternal PKU Collaborative Study found 31 (7.5 percent) infants with CHD (Rouse, Matalon, Koch, et al., 2000). There was no CHD in the group of women who achieved blood Phe control of 2 to 6 mg/dL by 8 weeks gestation. Heart development is usually completed by 10 to 12 weeks of pregnancy. The most likely etiology is related to the elevated blood Phe. However, since not all offspring develop CHD due to a certain increase in blood Phe, other factors may be involved.

p<0.0013). The low protein intake is also related to low intake of vitamins folate and B 12.


The effect of high blood Phe levels on brain growth, CHD, and IQ are still challenging problems. The data indicate that blood Phe levels need to be below 6 mg/dL for optimal pregnancy outcome. This level is not easily achieved, and education toward this goal needs to be a continued process in the treatment of PKU. Continued dietary treatment for individuals with PKU should improve the level of compliance and pregnancy outcome.


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