Nutrition 416

Pregnancy &
PKU
Denielle Saitta

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Denielle Saitta
Nutrition 416
April 14, 2014
Pregnancy & PKU
Abstract:
Phenylketonuria (PKU) is an inherited autosomal-recessive disorder of amino acid
metabolism in which the bodys normal processing of the essential amino acid, phenylalanine is
disrupted (1). Long-term management of PKU involves dietary therapy with the restriction of
dietary phenylalanine (PHE), which requires a decrease in the intake of natural protein and
replacing it with a protein source barren of PHE. If the diet of a patient with PKU is not
restricted, then the blood phenylalanine levels are elevated, which can lead to irreversible brain
damage and severe mental retardation. PKU was the first inborn error of metabolism ever
identified through population-based screening which created a new era in the diagnosis and
management of genetic disorders. Pregnancy presents a particular challenge for women with
PKU, because high levels of PHE are toxic to the emerging fetuss brain as well as other
teratogenic effects. Those with PKU should retain a PHE-restricted diet during conception and
every trimester.
Introduction:
Phenylketonuria (PKU) is an inborn error of metabolism caused by an alteration of the
phenylalanine hydroxylase (PAH) gene, which decreases the rate of translation of phenylalanine
to tyrosine (2). PKU is characterized by elevated blood phenylalanine levels, which are toxic for
the brain. Although phenylketonuria is rare, identifying phenylketonuria right away can help
prevent serious health problems. Untreated PKU can lead to mental retardation or delayed
cognitive development, growth abnormalities, and behavioral difficulties, among other adverse
clinical disorders. Treatment of patients with PKU includes following a strict diet that eliminates

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foods high in protein including all meat, milk, eggs, cheese and nuts. Protein is provided with a
special formula that does not contain PHE and from measured amounts of fruits, vegetables,
breads and cereals (3). A PKU diet should be maintained and followed for life. For women with
PKU, it is essential for the health of their children to maintain low PHE levels before and during
pregnancy. If the mother fails to maintain proper PHE levels then the child may develop
congenital heart disease, growth retardation, microcephaly and intellectual disability as a result.
However, PKU affected women themselves are not at risk of additional complications during
pregnancy. The purpose of this review is to analyze the guidelines and limitations of a woman
with PKU during pregnancy.
Phenylketonuria (PKU):
PKU was the first inborn error of metabolism identified through population screening,
initiating a new era in the diagnosis and treatment of genetic disorders. The Norwegian physician
Asbjorn Folling first described PKU in 1934, however it was not until the mid-1950s that a
patient with PKU deficiency was treated with a low PHE diet (4). The most severe form of this
disorder is known as classic PKU. Less severe forms of the condition PKU are sometimes called
variant PKU and non-PKU hyperphenylalaninemia. People with very mild cases may not require
treatment with a low-phenylalanine diet.
In the United States, PKU occurs in 1 in 10,000 newborns. Most cases of PKU are
detected shortly after birth by newborn screening (NBS), and treatment is started immediately.
Newborn screening is the practice of testing every newborn for certain harmful or potentially
fatal disorders that are not otherwise apparent at birth (4). Newborn screening tests are most
commonly done from whole blood samples collected on specially designed filter paper. Samples
are collected from infants between 24 hours and 7 days after birth, with the requirement that the

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baby has been fed at least once. Screening is mandatory, but parents do have an option to opt out
if they wish. NBS for PKU became widespread in North America by the mid- to late-1960s.
Since the initiation of NBS, almost all cases of PKU are diagnosed following a positive newborn
screening test.
Treatment and maintenance of PKU should be started earlier in life. If PKU is diagnosed
early enough, an affected newborn can grow up with normal brain development, but only by
managing and controlling PHE levels through diet, or a combination of diet and medication.
Patients with late-treated PKU and severe cognitive impairment also represent a special
challenge. It is unlikely that a patient diagnosed with PKU will improve in cognitive abilities
even if dietary treatment successfully reduces blood PHE (4). However, there is evidence that
with dietary modifications patients may experience improvements in behavior, psychiatric
symptomatology, and seizure control (4).
Everyone has a pair of genes that make the PAH enzyme. In children with PKU, neither
of these genes works correctly. These children inherit one non-working gene for the condition
from each parent. Though parents of children with PKU rarely have the condition themselves,
each parent has a single non-working gene. When both parents are carriers, there is a 25%
chance in each pregnancy for the child to have the metabolic disorder. PKU is inherited in an
autosomal recessive fashion (4).
PKU is monitored through blood PHE levels in which all patients should be maintained
in the range of 120-360 micromole/L. Blood levels should be measured at least once weekly until
age 1 with increased surveillance during periods of rapid growth and transitions of diet, such as
introduction of solid foods (4). Biweekly to monthly sampling is often adequate for children 1 to

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12 years of age. In adolescents and adults who have a stable and well controlled diet, monthly
testing may be sufficient.
PKU is treated throughout life and managed through a low PHE diet. While intellectual
disability does not occur in patients who are well controlled in infancy and childhood, a variety
of adverse neurocognitive and psychiatric outcomes can develop later in life. All PKU patients
must follow a special diet low in PHE for optimal brain development. A PKU diet requires
severely restricting foods high in PHE like meat, chicken, fish, eggs, nuts, cheese, legumes, milk
and other dairy products (4). Supplementary formulas are used for patients to provide the amino
acids and other necessary nutrients that would otherwise be lacking. Since PHE is needed for the
synthesis of many proteins, it is required for appropriate growth.
There have also been a number of drug therapies used in place of the formula. The first
pharmacologic agent used for PKU, called Kuvan, was approved in 2007 but the United States
Food and Drug Administration (FDA) (4). Tetrahydrobiopterin or BH4 acts as a pharmacologic
chaperon leading to improved folding and stability of the mutant protein (4). Approximately 2550% of PKU patients are responsive to Kuvan. The medication is taken once or twice a day at a
dose of 5-20mg/kg. No serious side effects of the drug have been detected. It is currently the only
FDA-approved medication used for the treatment of PKU and may be useful in reducing levels
of PHE in responsive patients. However, formal testing should be done before being put on
Kuvan.
Management during Pregnancy:
For women with PKU who are pregnant or planning to become pregnant, there are
important recommendations and guidelines that they should follow to ensure a safe and healthy 9
months for themselves as well as the baby. High maternal PHE concentrations are associated

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with facial dysmorphism, microcephaly, development delay, learning difficulties, and congenital
heart disease (CHD) in the offspring of women with PKU (5). Developmental delay in the
offspring of women with PKU can be prevented however by maintaining maternal blood PHE
within a target range (5). Eating the correct foods as well as supplementing needed nutrients is
crucial in having a healthy baby and achieving a good health status. Many women who are
pregnant with PKU are required to supplement many vitamins and minerals to assist with proper
growth and development for the child and to help assure a safe delivery. It is also important for
the mother to continue drinking the low PHE formula or taking the necessary dietary pills.
Studies have shown that if PHE levels were within the target range before conception,
children had higher IQ scores as well as less health risks. When maternal metabolic control is not
reached until after pregnancy begins, neuropsychological functions are differentially weakened.
The developmental profile of maternal PKU offspring shows a distinct trend toward lower scores
on tests of language, memory, and quantitative abilities, while motor skills and behavior are
relatively less affected (6). Women with PKU and uncontrolled phenylalanine levels also have an
increased risk of pregnancy loss. Though there are some recommendations that do not follow a
strict low PHE diet, these are not safe for the unborn baby and will produce unhealthy side
effects. Infants may still be breastfed to provide all of the benefits of breast milk, but the quantity
must be monitored and supplementation for missing nutrients will be required.
Effects in Offspring:
When women with PKU do not adhere to their diet before and during pregnancy, infants
will have a risk for mental retardation and other neurological disorders, microcephaly, and
congenital heart disease. These risks result from the toxic effects of high maternal blood PHE
levels during pregnancy. By 7 years of age, 18% of children who were born to mothers with

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PKU performed in the range of mental retardation, 18% attained scores in the borderline range,
and 64% could be considered average or above in terms of their intellectual abilities (7). All DQ
and IQ scores were significantly higher when the diet began before conception. Several different
study measures have been conducted to assess development standards such as the Bayley Scales
of Infant Development, the McCarthy Scales of Childrens Abilities, and the Wechsler
Intelligence Scale for Children.
Neurodevelopment and the occurrence of CHD, metabolic PKU control is critical early in
pregnancy, and it must be maintained throughout pregnancy to ensure satisfactory cognitive
development (5). A CHD means a child is born with an abnormally structured heart and/or large
vessels. Beginning the PHE restricted diet before conception and achieving metabolic control no
later than the 8th week of gestation can significantly reduce the incidence of CHD (5). A study
that looked at 251 pregnant women diagnosed with PKU, 22 offspring had major cardiac
malformations while none of the women who had blood PHE levels less than 600 micromole/L
by 8 weeks gestation had offspring with CHD (8).
Another possible side effect that children could inherit due to mothers not following a
low PHE diet is microcephaly. Microcephaly is a neurodevelopment disorder in which a childs
head is significantly smaller than the head of other children of the same age and sex. Detected at
birth, microcephaly usually is caused from the brain developing uncharacteristically in womb or
not growing as it should after birth. It has been noted that lessening of the maternal blood
phenylalanine level to 600 micromole/L or less, reduces the incidence of microcephaly from
73% to 8% (8). Though there is still disagreement over safe PHE levels, it is strongly suggested
that those with PKU stay, and for those who are pregnant should stay between, 360-760
micromole/L to produce the safest health conditions.

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Conclusion:
It can be concluded that the potential for normal cognitive development is existent and
will be shown if dietary action is well controlled by the mother; they will have children with IQ
scores not influenced by their disorder (9). If mothers choose to not follow their low PHE diet
then there are serious health consequences that will effect both the mother and child. It should be
stressed about 3 months before conception to the patient diagnosed with PKU the fundamental
role played by dietary restriction. All women with PKU should be strongly encouraged to receive
family planning and preconception counseling.

References

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