DOI: 10.1111/tog.

12517
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Phenylketonuria in pregnancy
Carol R Munyame MD MRCOG PgCert (MedEd),a,* Nirmala Vaithilingam MBBS FSLCOG FRCOG,b
Yusof Rahman MRCP FRCPath,c Roshni Vara MBBS MRCPCH MSc,d Amanda Freeman FRCP FRCPCHe
a
Consultant Obstetrician and Gynaecologist, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth PO6 3LY, UK
b
Diploma in Obstetric and Gynaecological Ultrasound, Consultant Obstetrician and Gynaecologist, Queen Alexandra Hospital, Portsmouth
Hospitals NHS Trust, Portsmouth PO6 3LY, UK
c
Consultant in Inherited Metabolic Disease, Centre for Metabolic Disorders, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, UK
d
Consultant in Paediatric Inherited Metabolic Disease, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London
SE1 7EH, UK
e
Consultant Paediatrician, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth PO6 3LY, UK
*Correspondence: Carol R Munyame. Email: carolmunyame@gmail.com

Accepted on 1 May 2017.

Key content  To understand the implications of hyperphenylalaninaemia on

 Phenylketonuria (PKU) is a rare, autosomal recessive metabolic disorder pregnancy and fetal outcomes.
characterised by the body’s inability to utilise the essential amino acid  To understand the importance of involving a multidisciplinary
phenylalanine. There are three different subgroups of this disorder. team in the management of patients with PKU.
 Untreated or poorly controlled phenylalanine levels are associated
Ethical issues
with intrauterine growth restriction and other fetal abnormalities. 
 Fetuses born to mothers with PKU exhibit clinical similarities to
Women with poor compliance to PKU management in the
prepregnancy period are at significant risk of fetal abnormalities.
those born with fetal alcohol syndrome.
Should we recommend alternative reproductive options?
 Management of pregnant women with PKU is best performed
under a multidisciplinary team with close monitoring of Keywords: fetal abnormalities / hyperphenylalaninaemia / maternal
phenylalanine blood levels. phenylketonuria / phenylketonuria
Learning objectives
 To understand the importance of pre-conception counselling in
women born with PKU.

Please cite this paper as: Munyame CR, Vaithilingam N, Rahman Y, Vara R, Freeman A. Phenylketonuria in pregnancy. The Obstetrician & Gynaecologist 2018;
https://doi.org/10.1111/tog.12517

a maternal Phe-restricted diet during pregnancy.2 This was a

Introduction
Caused by deficiency of the liver enzyme phenylalanine
hydroxylase (PAH), phenylketonuria (PKU) is one of the
most common inborn errors of metabolism. PAH converts
the amino acid phenylalanine (Phe) into tyrosine (Tyr).
Before 1969, when the Newborn Screening Programme was
introduced by the UK’s National Health Service (NHS), all
affected children sustained irreversible brain damage before a
diagnosis could be made.1 Few affected infants reached
reproductive age and went on to have children of their own.
The screening programme has been such a success for
affected children that many women who were treated in early
childhood are now having children of their own. We know
now that early treatment is successful.
In 1994, the North American Maternal Phenylketonuria
Collaborative Study (MPKUCS) was initiated in the USA.
This aimed to evaluate the outcomes among maternal PKU
pregnancies, and the effects on the offspring of implementing
prospective, longitudinal, multicentre study involving
researchers from the USA, Canada and Germany. The
findings suggested that a dose–response relationship existed
between negative cognitive effects in offspring and the
achievement of metabolic control in late pregnancy.2–4
The primary treatment for PKU is a low Phe-restricted diet
requiring specialised medical foods to supplement sufficient
amino acids and energy.5 Patients treated with this diet are
now in their mid-40s and have already had (or are about to
have) children. Input is required from members of a
multidisciplinary team, including the paediatric/adult
dietitian, biochemist/chemical pathologist, clinical nurse
specialist, paediatrician/adult physician with experience
in metabolic diseases, an obstetrician and the general
practitioner (GP), and sometimes a social worker and/or
clinical psychologist.1
Untreated maternal PKU or hyperphenylalaninaemia
(HPA) during pregnancy can cause maternal PKU

ª 2018 Royal College of Obstetricians and Gynaecologists 1

 Phenylketonuria in pregnancy

syndrome in the neonate. This consists of intrauterine growth
restriction (IUGR), low birthweight, microcephaly,
congenital heart disease,6 intellectual or developmental
disabilities, facial dysmorphism7 and eczematous rash.8
What is phenylketonuria?
PKU is an autosomal recessive inherited metabolic disease.
PAH is required to convert Phe to Tyr (Figure 1). PAH
deficiency results in toxic levels of Phe in the blood and a
potential Tyr deficiency. Tyr is a proteinogenic amino acid,
which is involved in signal transduction processes in the
body. Tyr can be found in several high protein foods, such as
dairy, chicken, fish, eggs, beans, oats, wheat and nuts. The
build-up of Phe is toxic to the brain; it alters myelin
synthesis, which accounts for the complications of untreated
PKU. It has long been recommended that afflicted
individuals follow dietary restrictions during the first
5–6 years of life, when brain growth is most rapid.9
The incidence of PKU is 1:10 000 births in Caucasians and
East Asians.10 Some ethnic groups have a higher incidence
(e.g. Turks, 1:2600; Irish, 1:4500) and some have lower rates (e.g.
Japanese, 1:143 000; Finnish, 1:200 000).11–13 PKU is rare in
Africans. In the USA, 14 988 individuals were diagnosed with
PKU between 1965 and 2010. The PKU register was
discontinued in 1997, but it is estimated that the number of
people living with PKU is between 3000 and 4000.
Classification of phenylketonuria
PKU can be classified depending on residual enzyme activity
or serum Phe levels. Normal Phe levels should be below
120 lmol/l. Reference levels may vary between units. In the
UK we use two categories:
 Classical PKU, which is when Phe levels are typically above
1200 lmol/l or there is a complete/profound absence of
PAH activity; or
 Non-classical PKU, which includes mild-to-moderate and
HPA. Mild PKU occurs when Phe levels are between 600
and 900 lmol/l; moderate is when Phe levels are between
900 and 1200 lmol/l; and HPA is when Phe levels are less
than 600 lmol/l.14
Patients with HPA have a less severe accumulation of
Phe. This is often managed through monitoring and
little dietary restriction.15
Pathogenesis
Untreated or suboptimally treated women with PKU have
elevated Phe levels that are teratogenic to the unborn fetus.
Phe is actively transported across the placenta, reaching fetal
concentrations that are 1.25–2.5 times greater than maternal
concentrations.16 Common clinical manifestations of PKU
are IUGR, microcephaly, congenital heart disease and facial
dysmorphism,7 which are very similar to those found in fetal
alcohol syndrome (FAS). On clinical examination, it is often
difficult to distinguish the difference between FAS and PKU.
Older, untreated children with PKU present with the
following: microcephaly, epilepsy, a musty body odour
(caused by the build-up of phenylactic acid in the urine17),
decreased skin and hair pigmentation, eczema, severe
intellectual disability and behavioural problems
(hyperactivity, and problems with language, memory, and
attention). Magnetic resonance imaging scans also reveal
visible structural brain changes.18 In both maternal PKU and
FAS infants, a dose–response relationship exists: the greater
the exposure, the poorer the outcome. However, for both

O2 H2O Dopamine

Dietary protein
Phenylalanine Tyrosine Melanin
(especially plant proteins)

Phenylalanine
hydroxylase
Body proteins

Phenylatic acid Tetrahydrobiopterin Dihydrobiopterin

Dihydropteridine
reductase

Figure 1. The oxidation reaction of the phenylalanine to tyrosine pathway.

2 ª 2018 Royal College of Obstetricians and Gynaecologists


syndromes, the microcephaly, facial dysmorphisms and
growth delays generally improve over time.19
Tyr is also required for melanin production. Therefore,
children with PKU and lacking Tyr tend to have blue eyes,
and are fair haired and fair skinned.17
In PKU, developmental neurotoxicity can be ascribed to in
utero fetal exposure to high Phe levels.20 The mechanism by
which elevated levels of Phe or its other metabolites cause
intellectual disability remains largely unknown. Although it is
believed that Phe interferes with brain growth, myelination
and neurotransmitter synthesis, there are several other
hypotheses. While a child born with PKU can be treated by
early dietary intervention, the damage caused to the fetus by
the mother’s high Phe values is irreversible.4 Studies in
children with maternal PKU revealed a loss of neurons, and
animal studies have suggested an increase in cell death in
the developing brain.21
Treatment of phenylketonuria
PKU is treated with a Phe-restricted diet. This requires
restricting intake of protein-rich foods, particularly those of
animal origin. Achieving the recommended intake of amino
acids in the diet, without ingesting excessive levels of Phe,
often necessitates the addition (and/or supplementation) of a
liquid formula containing protein hydrolysates, or free amino
acids. However, this is often perceived as being unpleasant in
taste,1 and has been the main reason for low compliance
with this treatment. Several types of protein hydrolysate
preparation are now available, including powders and tablets.
Steps have been taken to improve the tolerance of protein
substitutes (i.e. to improve the flavour of the substitutes and
disguise the odour). Phe restriction can be especially
challenging for adolescents and young adults who have left
the family home, and they often choose to stop complying
with the diet. This is currently acceptable, albeit controversial.
Discontinuing dietary therapy after adolescence has no
reported serious adverse effects on the nervous system and,
as a result, strict dietary control is often not maintained after
the age of 17 years. Conversely, continuing the diet after this
time appears to be beneficial: in some studies,22,23 loss of IQ
and/or behavioural changes have been reported in older
children and adolescents who did not adhere to the diet. This
is reversible with resumption of the diet. Once the diet has
been stopped, resumption is more difficult, and this is a
dilemma that pregnant women may face.
Management in pregnancy
Pre-conception
Outcome is improved substantially when treatment results in
low maternal Phe concentrations, ideally before conception,
or less optimally before 10 weeks of gestation.24–27 By the time
ª 2018 Royal College of Obstetricians and Gynaecologists
Munyame et al.
they reach reproductive age, many women who would have
grown up with PKU have discontinued their Phe-restricted
diet. Most commonly, this is because they may have left the
family home, thereby isolating them from support and help.
The Phe-restricted diet often requires good forward planning
and organisational skills; it can be time consuming for an
individual to plan meals for themselves. For this reason, pre-
conception counselling is critical so that pregnancies can be
planned and the proper diet commenced before conception.
Family planning advice is crucial. Contraceptive choice is
essentially unrestricted, and that choice should conform to
the UK Medical Eligibility Criteria for Contraceptive Use
(UKMEC).28 The combined oral contraceptive pill has an
advantage over the mini-pill because the presence of regular
periods which, if missed, would indicate the possibility of an
unplanned undiagnosed pregnancy. Further advice can be
sought from family planning centres. It is strongly
recommended that women with PAH deficiency use reliable
methods of contraception to prevent unplanned pregnancies,
and continue until such time that their serum Phe
levels are controlled.
When the decision to conceive has been made, women
taking the oral contraceptive pill (OCP) should switch to a
barrier method of contraception at least 3 months (and
ideally 6 months) before conceiving. This allows the
menstrual cycle – which may have been altered by the
OCP – to revert to normal. Folic acid supplements should
be commenced. The target blood Phe level should be kept
low, ideally between 120 and 300 lmol/l (NSPKU guideline
2014)1 as if following a low Phe diet (though this can vary
according to local guidelines). The European PKU
guideline 2017 has recently recommended a blood Phe level
of 120–360 lmol/l.29 In order to achieve this degree of
control, significant commitment is required by the woman
and the support of the multidisciplinary team must
be unwavering.
Women with PKU wanting to have children are put on a
pre-conception Maternal PKU Programme, which entails
reduced natural protein intake or protein exchanges, plus
extra Phe-free protein supplements to lower Phe levels. This
can be particularly difficult in classical PKU. These women
are also required to undergo twice-weekly blood spot
monitoring. Dried blood spot specimens are collected by
carefully applying a few drops of blood, freshly drawn by
finger stick with a lancet from adults, or by heel stick with a
lancet from infants, onto specially manufactured absorbent
specimen collection (filter) paper. The blood is allowed to
thoroughly saturate the paper and is air-dried for a minimum
of 3 hours before analysis.30
Once women with PKU have achieved three to four blood
Phe readings below 350 lmol/l, it is considered safe for them
to have unprotected sexual intercourse to start trying to
conceive. Some patients may take longer than others to
3
 Phenylketonuria in pregnancy
conceive. If they fail to fall pregnant after 12 months, some
may consider consulting fertility specialists, especially since
having to wait an additional 12 months after already
maintaining the strict Phe-diet for 12 months may feel like
too great a challenge.
Antenatal care
The antenatal care of women with PKU is best managed by a
multidisciplinary team involving a dietitian, an obstetrician
with an interest or experience in maternal PKU, a metabolic
consultant, and a midwife. Partners, family members, or
other members of the woman’s support group should also be
included in her care as they provide essential support with
regard to dietary changes. Women should be offered
continued nutritional guidance. It is recommended that
they continue to undergo dried blood spot Phe level testing
three times per week, because dietary Phe levels and protein
requirements can change considerably during pregnancy.18
The first trimester of pregnancy is often complicated by
nausea and vomiting, or worse, hyperemesis. During these
episodes it is important to observe an adequate and balanced
macronutritional diet. Admission to hospital maybe necessary
to ensure that Phe levels are controlled and the diet adjusted
accordingly. The help and support of the dietitian is
paramount in this stage. Care should be centred on dietary
input and maintenance of blood Phe levels. Ideally, blood Phe
levels should be measured two to three times per week during
the pregnancy1, and the profiles of amino acids, vitamins,
minerals and trace elements, and a full blood count, measured
before the dating scan and at 20–22 weeks of gestation. As
an essential amino acid, Tyr is required in supplementary
form after 16 weeks of gestation. Most fortified supplements
come with various vitamins and minerals caution must be
taken to ensure excess vitamins such as vitamin A are not
administered. When blood Phe levels cannot be brought
to within normal levels, especially in early pregnancy or
unplanned pregnancies, an additional Phe-free protein
supplement (without additional minerals and vitamins) can
be introduced that will reduce the blood Phe level.
Energy requirements remain unchanged in pregnancy, so
expectant mothers should gain no more weight than is
appropriate for normal pregnancy. One study31 found that
the highest occurrence of microcephaly (58%) was found in
women who failed to gain more than 70% of the
recommended weight during pregnancy, suggesting a link
between weight gain in pregnancy and microcephaly.
Routine antenatal care with additional ultrasound
surveillance can be offered in local units, following a
multidisciplinary management plan.
Ultrasound surveillance
Ultrasonography is also key to adequate management of
women with PKU in pregnancy. First trimester screening can
4 ª 2018 Royal College of Obstetricians and Gynaecologists
identify non-viability, which in turn prevents needless
continuation of the restrictive diet and the associated costly
metabolic serum monitoring during the pregnancy.32
An advantage of second trimester ultrasound is that
congenital abnormalities (e.g. congenital heart disease,
microcephaly, IUGR) can be identified. A fetal medicine
scan with a fetal echocardiogram is recommended between
20 and 22 weeks of gestation. Identification of any anomalies
provides the early option of termination. Another benefit of
second trimester ultrasound is that it aids full antenatal
counselling, and helps to plan for the place and timing of
delivery, as well as the postnatal care the infant will receive.
The risk of congenital heart defects is quoted at 7–10%
(MPKUCS).33 Serial growth scans are beneficial in these
women as their fetuses are at an increased risk of
IUGR and microcephaly.
It is difficult to detect microcephaly in the antenatal
period, as the majority of fetuses have a normal head
circumference (HC) in early gestation. Diagnosis is made, on
average, at 28 weeks of gestation.34 The definition of
microcephaly is controversial as there is no consensus on
the definition of an abnormally small HC.34 Microcephaly
should be suspected if the HC falls 2 standard deviations
below the mean for gestational age. A definitive diagnosis can
be made when the measurement is 5 or more standard
deviations below the mean.35 The overall prognosis of the
fetus with an HC below 3 standard deviations from the
mean is guarded.35
Delivery and intrapartum
The timing and mode of delivery should be guided by
obstetric indications and are not influenced by PKU.
Breastfeeding is safe and is encouraged. Breast milk
contains lower Phe concentrations than most infant
formulas; therefore children can ingest larger quantities of
breast milk without exceeding the recommended Phe limit.36
Reduced Phe formula milk is available if desired.
Postnatal
The metabolic consultant usually reviews PKU mothers at
approximately 3 months postpartum. A neonatologist should
perform a neonatal examination to assess the clinical features
of PKU. Neonates born to mothers with PKU should be
offered PKU screening on day 5, as per the routine national
screening programme. It is recommended that a clinical
psychologist conducts assessments at 18 months, and 4, 8 and
14 years to identify any developmental or cognitive problems
and suggest additional educational support if required.1
Unplanned pregnancies
Unplanned pregnancies can mean that the fetus is exposed to
higher Phe levels, which can therefore lead to teratogenicity.
This inadvertently causes women anxiety. Serum Phe levels

should be attained and the low Phe diet commenced under the
supervision of the dietitian and physician. Gestation should be
confirmed with a detailed ultrasound scan. An anomaly scan
(preferably with the fetal medicine unit) is also indicated.
Psychological impact
Education and psychological input is vital in the management
of pregnant women with PKU. Access to a clinical psychologist
provides the patient with the support needed to maintain a
low Phe diet as an adult, ensures the woman’s emotional
wellbeing, and offers support for her family as well.1 The
general practitioner is important to provide an essential link
between members of the multidisciplinary team and much-
needed support and reassurance to the whole family.
Conclusion
The Newborn Screening Programme has been a great success in
the management and diagnosis of women and children with
PKU. Extensive research has improved our understanding of
PKU, and its effects on the fetus and the mother. Affected
women now have access to expert advice and psychological
counselling during childhood, adolescence and their
reproductive years, all of which will optimise their outcomes
and allow them to have healthy babies. With the advent of gene
therapy, we may one day be able to cure this condition, but up
until now, prevention and management of PKU is sufficient
that our PKU mothers are now becoming grandmothers.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
CRM made substantial contributions to the study concept
and design, data acquisition, analysis and interpretation of
data. NV, YR and RV drafted the article and critically revised
it for important intellectual content. All authors approved
the final version.
Acknowledgements
The authors acknowledge the contribution of Paula Hallam
RD, Dietitian Advisor for the National Society for
Phenylketonuria (UK) Ltd.
References
1 National Society for Phenylketonuria (UK) Ltd. Management of
phenylketonuria: a consensus document for the diagnosis and management
of children, adolescents and adults with phenylketonuria (PKU). London:
National Society of Phenylketonuria (UK) Ltd; 2014 [http://www.nspku.org/
sites/default/files/publications/Mgt_of_PKU_18pp_2_Web.pdf].
2 Waisbren SE, Hanley W, Levy HL, Shifrin H, Allred E, Azen C, et al. Outcome
at age 4 years in offspring of women with maternal phenylketonuria: the
Maternal PKU Collaborative Study. JAMA 2000;283:756–62.
ª 2018 Royal College of Obstetricians and Gynaecologists
Munyame et al.
3 Cipcic-Schmidt S, Trefz F, F€unders B, Seidlitz G, Ullrich K. German maternal
phenylketonuria study. Eur J Pediatr 1996;155:S173–6.
4 Drogari E, Beasley M, Smith I, Lloyd J. Timing of strict diet in relation to
fetal damage in maternal phenylketonuria: an international collaborative
study by the MRC/DHSS Phenylketonuria Register. Lancet 1987;330:
927–30.
5 Harding CO, Blau N. Advances and challenges in phenylketonuria. J Inherit
Metab Dis 2010;33:645–8.
6 van Spronsen FJ, van Rijn M, Bekhof J, Koch R, Smit PG. Phenylketonuria:
tyrosine supplementation in phenylalanine-restricted diets. Am J Clin Nutr
2001;73:153–7.
7 Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and
hyperphenylalaninemia in pregnancy: pregnancy complications and
neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr
2012;95:374–82.
8 van Spronsen FJ, van Wegberg AM, Ahring K, Belanger-Quintana A, Blau N,
Bosch AM, et al. Key European guidelines for the diagnosis and
management of patients with phenylketonuria. The Lancet Diabetes &
Endocrinology 2017;5:743–56.
9 Sheard NF. Importance of diet in maternal phenylketonuria. Nutr Rev
2000;58:236–9.
10 Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase
deficiency. In: Scriver C, Beaudet AL, Sly WS, Valle D, Vogelstein B, Childs B,
editors. The Metabolic and Molecular Basis of Inherited Disease, 8th ed.
New York: McGraw-Hill; 2001: p. 1667–724.
€
11 Ozalp I, Cosßkun T, Ceyhan M, Tokol S, Oran O, Erdem G, et al. Incidence of
phenylketonuria and hyperphenylalaninaemia in a sample of the Turkish
newborn population. In: Addison GM, Harkness RA, Isherwood DM, Pollitt
RJ, editors. Practical Developments in Inherited Metabolic Disease: DNA
Analysis, Phenylketonuria and Screening for Congenital Adrenal
Hyperplasia. Lancaster: Springer; 1986. p. 237–9.
12 DiLella AG, Kwok SC, Ledley FD, Marvit J, Woo SL. Molecular structure and
polymorphic map of the human phenylalanine hydroxylase gene.
Biochemistry 1986;25:743–9.
13 Aoki K, Wada Y. Outcome of the patients detected by newborn screening in
Japan. Acta Paediatr Jpn 1988;30:429–34.
14 G€uttler F, Guldberg P. Genotype/phenotype correlations in phenylalanine
hydroxylase deficiency. In: Blau N, editor. PKU and BH4: advances in
phenylketonuria and tetrahydrobiopterin. Heilbronn: SPS Publications;
2006. p. 311–20.
15 Guldberg P, Rey F, Zschocke J, Romano V, Francßois B, Michiels L, et al. A
European multicenter study of phenylalanine hydroxylase deficiency:
classification of 105 mutations and a general system for
genotype-based prediction of metabolic phenotype. Am J Hum Genet
1998;63:71–9.
16 Hanley W, Clarke J, Schoonheyt W. Maternal phenylketonuria (PKU) — a
review. Clin Biochem 1987;20:149–56.
17 Kirby RB. Maternal phenylketonuria: a new cause for concern. J Obstet
Gynecol Neonatal Nurs 1999;28:227–34.
18 Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency.
Genet Med 2011;13:697–707.
19 Koch R, Trefz F, Waisbren S. Psychosocial issues and outcomes in maternal
PKU. Mol Genet Metab 2010;99 Suppl 1:S68–74.
20 Costa L, Guizzetti M, Burry M, Oberdoerster J. Developmental neurotoxicity:
do similar phenotypes indicate a common mode of action? A comparison
of fetal alcohol syndrome, toluene embryopathy and maternal
phenylketonuria. Toxicol Lett 2002;127:197–205.
21 Reynolds R, Burri R, Herschkowitz N. Retarded development of neurons and
oligodendroglia in rat forebrain produced by hyperphenylalaninemia results
in permanent deficits in myelin despite long recovery periods. Exp Neurol
1993;124:357–67.
22 Holtzman NA, Kronmal RA, van Doorninck W, Azen C, Koch R. Effect of age
at loss of dietary control on intellectual performance and behavior of
children with phenylketonuria. N Engl J Med 1986;314:593–8.
23 Seashore MR, Friedman E, Novelly RA, Bapat V. Loss of intellectual function
in children with phenylketonuria after relaxation of dietary phenylalanine
restriction. Pediatrics 1985;75:226–32.
24 Lee PJP. Maternal phenylketonuria: report from the United Kingdom
Registry 1978–97. Arch Dis Child 2005;90:143–6.
5
 Phenylketonuria in pregnancy
25 Rouse B, Azen C. Effect of high maternal blood
phenylalanine on offspring congenital anomalies and
developmental outcome at ages 4 and 6 years: the importance of strict
dietary control preconception and throughout pregnancy. J Pediatr
2004;144:235–9.
26 Levy HL, Lobbregt D, Barnes PD, Poussaint TY. Maternal phenylketonuria:
magnetic resonance imaging of the brain in offspring. J Pediatr
1996;128:770–5.
27 Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and
hyperphenylalaninemia in pregnancy: pregnancy complications and
neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr
2012;95:374–82.
28 Faculty of Sexual and Reproductive Healthcare. UK Medical Eligibility Criteria
for Contraceptive Use (UKMEC). 2016. [https://www.fsrh.org/standards-
and-guidance/uk-medical-eligibility-criteria-for-contraceptive-use-ukmec/].
29 Van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau
N, Bosch AM, et al. The complete European guidelines on
phenylketonuria: diagnosis and treatment. Orphanet Journal of Rare
Diseases 2017;12:162.
30 Knudsen RC, Slazyk WE, Richmond JY, Hannon WH. Guidelines for the
shipment of dried blood spot specimens. Infant Screening 1993;16:1–3.
6 ª 2018 Royal College of Obstetricians and Gynaecologists
31 Bryce F, Lilford R, Rodeck C. Antenatal diagnosis of craniospinal defects. In:
Lifford R, editor. Prenatal diagnosis and prognosis. London: Butterworths;
1990. p. 5–29.
32 Levy H, Waisbren S, Lobbregt D, Allred E, Leviton A, Schuler A, et al.
Maternal mild hyperphenylalaninaemia: an international survey of offspring
outcome. Lancet 1994;344:1589–94.
33 Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia:
an international survey of treated and untreated pregnancies. N Engl J Med
1980;303:1202–8.
34 Den Hollander N, Wessels M, Los F, Ursem N, Niermeijer M, Wladimiroff
J. Congenital microcephaly detected by prenatal ultrasound: genetic
aspects and clinical significance. Ultrasound Obstet Gynecol
2000;15:282–7.
35 Malinger G, Pilu G. Sonography of the fetal central nervous system. In:
Rodeck CH, Whittle MJ, editors. Fetal medicine: basic science and clinical
practice. London: Elsevier; 2009. p. 379.
36 Duncan LL, Elder SB. Breastfeeding the infant with PKU. J Hum Lact
1997;13:231–5.