Untreated maternal phenylketonuria (PKU) results in a significant occurrence of microcephaly and congenital heart disease in the offspring. Before the documentation of this fact by Lenke and Levy1 in 1980, there was confusion as to the occurrence of these abnormalities. In fact, a chapter by Knox in the 1966 book The Metabolic Basis of Inherited Disease2 concluded: “Births of normal children from phenylketonuric mothers establish the fact that no intrauterine damage need be done to the fetus by the metabolic abnormalities of the mother.” This conclusion served to strengthen the opinion of physicians who were opposed to continuation of a phenylalanine-restricted diet beyond early childhood.
For these reasons, in 1984 the National Institute of Child Health and Development launched an 18-year study to evaluate the value of treatment of maternal PKU pregnancies.3,4 Despite the dedicated participation of clinics serving more than 400 pregnancies and financial resources of the granting agency, microcephaly occurred in slightly more than 24% and congenital heart disease in 7% of the offspring. In mothers with blood phenylalanine levels of 120 to 360 μmol/L throughout pregnancy, outcome approached that of non-PKU pregnancies.3 Although it was true that women with normal intellect had significantly better outcome in general, there was a significant number of women who were not able to maintain the recommended treatment guidelines.
With the development of sapropterin dihydrochloride (Kuvan [BioMarin Pharmaceutical, Inc, Novato, CA],5 a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin [also known as BH4 or 6R-BH4]) and its approval by the US Food and Drug Administration, its use in pregnancy has been authorized and includes the proviso that a pregnancy registry for women with maternal PKU using sapropterin dihydrochloride alone or in combination with a standard phenylalanine-restricted diet during pregnancy be developed.
To date, only 1 such pregnancy has been reported.6 This offspring is now 4 years old and has an IQ of 132. Sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin and is well tolerated. There have been minimal adverse reactions to its use. The recommended dose by the manufacturer is 10 mg/kg per day orally for a person who is sensitive to biopterin. However, I have administered small doses of sapropterin dihydrochloride for these early cases of maternal pregnancy. Because the fetal brain does not develop cortical tissue until the second trimester, only 50 to 100 mg/day has been prescribed during the first trimester. The dose is then increased to 200 mg/day during the second trimester and 300 to 400 mg/day in the third trimester.
European guidelines for maternal PKU pregnancies are more stringent than those in the United States. The Maternal PKU International Study3 recommended blood phenylalanine levels of 120 to 360 μmol/L and advocated that treatment be initiated before pregnancy. In practice, however, most women do not realize they are pregnant until they have missed a period. They seek help from the PKU clinic at about the second month of pregnancy. The data gathered in the Maternal PKU Study did not indicate a detrimental effect in offspring in which control was established by 6 to 8 weeks of pregnancy and maintained thereafter. Despite this published experience, most European centers recommend phenylalanine levels of 60 to 240 μmol/L during pregnancy. These levels are often difficult to maintain during the first trimester because of nausea and vomiting.
There is no reason to withhold sapropterin dihydrochloride therapy during pregnancy. Because tetrahydrobiopterin is also a cofactor for nitric-oxide synthase,7 it may actually improve outcome. Initial experience suggests that sapropterin dihydrochloride improves control of blood phenylalanine, which in turn seems to enhance outcome.
In conclusion, Hanley8 recently pointed out that pediatricians need to be alert to the recognizable characteristics of post-PKU syndrome, in which the child has a typical clinical appearance with mild-to-moderate microcephaly, congenital heart disease, and dysmorphic features in which the philtrum is longer than usual. This syndrome suggests that the mother may have PKU.
I acknowledge the editorial assistance provided by Joanne Lee, BSc, and Trish Rawn, BScPhm, PharmD, of MediResource Inc. BioMarin Pharmaceutical Inc funded the editorial assistance provided by MediResource Inc.
- Accepted September 10, 2008.
- Address correspondence to Richard Koch, MD, University of Southern California/Keck School of Medicine, Genetics Division, Department of Pediatrics, 2125 Ames St, Los Angeles, CA 90027. E-mail:
Financial Disclosure: Dr Koch was a member of and received honoraria as part of the BioMarin PKU advisory board from 2003 to 2005.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
- ↵Knox EW. Phenylketonuria. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, et al, eds. The Metabolic Basis of Inherited Disease. 2nd ed. New York, NY: McGraw-Hill; 1966
- ↵American Academy of Pediatrics, Committee on Genetics. Maternal phenylketonuria. Pediatrics.2008;122 (2):445– 449
- ↵Bredt D. In: Scriver CR, William SS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2002
- Copyright © 2008 by the American Academy of Pediatrics