(Replaces No. 230, January 2000)
This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.
ABSTRACT: Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by a deficiency of the hepatic enzyme, phenylalanine hydroxylase, an enzyme responsible for the conversion of phenylalanine to tyrosine, and elevated levels of Phe and Phe metabolite. All women with PKU or hyperphenylalaninemia should be strongly encouraged to receive family planning and preconception counseling. Women with PKU or hyperphenylalaninemia should begin appropriate, medically directed dietary phenylalanine restriction before conception.
Phenylketonuria is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by a deficiency of the hepatic enzyme, phenylalanine hydroxylase (PAH), an enzyme responsible for the conversion of phenylalanine to tyrosine, and elevated levels of Phe and Phe metabolite. More than 400 mutations of the PAH gene have been described, and the severity of the disorder is dependent on the type of mutation present. A deficiency of the PAH enzyme results in increased blood phenylalanine levels, which are toxic. If untreated, phenylketonuria (PKU) can result in fetal growth failure, microcephaly, seizures, and mental retardation. Two aspects of this metabolic disorder are particularly relevant to the obstetrician–gynecologist—the prevention of fetal embryopathy associated with maternal hyperphenylalaninemia and the risk of genetic transmission of PKU.
Prevention of Fetal Embryopathy Associated With Maternal Hyperphenylalaninemia
In the United States, approximately 3,000 women of reproductive age are affected with PKU. Although evidence suggests that women with PKU will benefit from remaining on a phenylalanine-free diet throughout their lives, many are not adherent to such a diet because of the unpalatable nature of many phenylalanine-free products. The failure of young women with PKU to adhere to dietary modification represents a significant public health challenge because of the significant fetal consequences of maternal hyperphen-ylalaninemia. Importantly, phenylalanine crosses the placenta by an active transport process that results in a fetal-to-maternal plasma phenylalanine ratio of 1.5. Therefore, higher levels of phenylalanine exist in fetal blood than would be expected based on the maternal blood level. The developing brain and heart are particularly vulnerable to high concentrations of blood phenylalanine. Children born to women with PKU on unrestricted diets have a 92% risk for mental retardation, a 73% risk for microcephaly, and a 12% risk for congenital heart defects (1). If phenylalanine levels are normalized (Phe levels between 120–360 micromole/L) before conception or by 8 weeks of gestation, there is evidence to suggest a reduction in the fetal sequelae of hyperphenylalaninemia (2). Reduction of the maternal blood phenylalanine level to 600 micromole/L or less, reduced the incidence of microcephaly from 73% to 8% (3). The challenge of identifying and educating women about dietary restriction before conception is highlighted by a study that found 64% of women failed to achieve blood phenylalanine control by 8 weeks of gestation (4). The crucial role played by dietary restriction should be stressed in the patient with PKU, preferably 3 months before conception, to normalize the blood phenylalanine level and optimize neural and cardiac developmental outcomes for the fetus.
Risk of Genetic Transmission of Phenylketonuria
Children of women with PKU will carry at least one abnormal gene, which is inherited from their homozygous-affected mother. The carrier frequency for PKU is approximately 1 in 60. Given an affected mother, approximately 1 in 120 children will inherit an abnormal PAH gene from both parents and will be affected with PKU. Children of women with PKU are carriers and should receive genetic counseling in the future. If the mutations are known, further consultation and screening with a genetics professional to discuss reproductive options should be recommended. Universal neonatal PKU screening in the United States has facilitated early detection of these newborns.
Conclusions and Recommendations
- All women with PKU or hyperphenylalaninemia should be strongly encouraged to receive family planning and preconception counseling.
- Women with PKU or hyperphenylalaninemia should begin appropriate, medically directed dietary phenylalanine restriction before conception (5).
- Ideally, pregnant women with PKU or hyperphenylalaninemia should be managed in consultation with practitioners from experienced PKU centers.
Maternal phenylketonuria. American Academy of Pediatrics. Pediatrics 2008;122:445–9.
- Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980; 303:1202–8.
- Widaman KF, Azen C. Relation of prenatal phenylalanine exposure to infant and childhood cognitive outcomes: results from the International Maternal PKU Collaborative Study. Pediatrics 2003;112:1537–43.
- Matalon KM, Acosta PB, Azen C. Role of nutrition in pregnancy with phenylketonuria and birth defects. Pediatrics 2003;112:1534–6.
- Brown AS, Fernhoff PM, Waisbren SE, Frazier DM, Singh R, Rohr F, et al. Barriers to successful dietary control among pregnant women with phenylketonuria. Genet Med 2002; 4:84–9.
- Levy HL, Waisbren SE, Lobbregt D, Allred E, Schuler A, Trefz FK, et al. Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. Lancet 1994; 344:1589–94.
Copyright © December 2009 by the American College of Obstetricians and Gynecologists, 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, posted on the Internet, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher. Requests for authorization to make photocopies should be directed to: Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400.
Maternal Phenylketonuria. ACOG Committee Opinion No. 449. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:1432–3.