pku-role of pre-natal diagnosis

7/28/2019 PKU-Role of Pre-natal Diagnosis

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2004 Royal College of Obstetricians and Gynaecologists28

REVIEW

The Obstetrician& Gynaecologist

2005;7:2833

Keywords

maternalphenylketonuria,

antenatal screening,neonatal screening

2005 Royal College of Obstetricians and Gynaecologists

Introduction

Phenylketonuria (PKU) is the most common

inborn error of protein metabolism.Prior to the

introduction of an effective national screening

programme in the 1960s, most affected children

sustained irreversible brain damage before

diagnosis. Today, babies born with the disorder

can expect to have the same career and social

ambitions as normal unaffected people.1 We are

just beginning to understand the later effects of

PKU on the adult and adolescent brain and,

consequently, their continuing care is important

and has to be provided within the adult service.

Prior to the introduction of newborn screening

for PKU, women with PKU rarely reproduced as

they were confined to institutions.2 The success

of treatment means that there is now a generation

of responsible young women who have grown uplargely unaffected by the disorder.The needs of

women are of particular importance because of

the potential risks of inevitable miscarriage or

severe fetal damage associated with untreated

maternal PKU.3 Improvements can be achieved

through better multidisciplinary management

commenced prior to pregnancy and continued

throughout to reach the aspiration of outcomes

similar to those of uncomplicated pregnancies.

PKU is an autosomal recessive inborn error of

metabolism. It is characterised by deficient activityof the enzyme phenylalanine hydroxylase (PAH)

that catalyses the conversion of phenylalanine

(Phe) to tyrosine, leading to elevated levels of

phenylalanine and its metabolites and low plasma

tyrosine levels. Phe is an essential amino acid

required for normal growth and development.

Classical PKU is associated with Phe levels greater

than 1.2 mmol/l where there is little or no PAH

activity. There are variants of PKU associated with

lower levels of Phe, termed as hyperphenyl-alaninaemia with significant residual PAH activity.

Rare variants can be because of deficiency of

dihydrobiopterin reductase or defects in biopter in

synthesis.4 Enzymes involved with the

interconversion of Phe and tyrosine, and whose

deficiencies can produce hyperphenylalaninemia,

are shown in Figure 1.

If untreated, PKU leads to mental restriction,

seizures, psychomotor impairment, psychosis,

autistic behaviour, microcephaly, eczema, rashes

and unusual body odours.5,6 Neonatal screening

and early dietary intervention are so efficient today

that it is unusual to see children with severe mental

handicap from PKU.7 The overall incidence

of PKU in the UK is 7-11/100 000 or 1 in

10-15 000 live births.8,9 A universal screening

programme for PKU was introduced in the 1960s.

Data available in the UK over a 30-year period

(1964-93) revealed 2259 infants with PKU, of

whom 976 (43.2%) were females (Table 1).

Extent

The success of newborn screening has resulted ina large number of women with PKU worldwide

who are now of childbearing age. Until the

1980s, most of these women had not been on a

Maternal phenylketonuriain pregnancy

Uma Krishnamoorthy, Malcolm Dickson

The treatment of phenylketonuria, an inherited metabolic disorder, isone of the great success stories of the past 40 years. Prior to 1963,virtually all women with the disease who were of childbearing agesuffered brain damage and bore few, if any, children. The success ofnewborn screening has resulted in a large number of women withphenylketonuria worldwide who are now of childbearing age. Theoffspring of women with phenylketonuria who remain untreatedduring pregnancy face a poor outcome. Optimising the care of thesewomen prior to conception and throughout the pregnancy is

therefore imperative to prevent significant fetal damage and isessential if the benefits to one generation attained by the universalscreening programme are not to be lost to the next generation.

10.1576/toag.7.1.028.27039 www.rcog.org.uk/togonline

Author details

Uma Krishnamoorthy MRCOG,

Specialist Registrar, Rochdale

Infirmary, Whitehall Street,

Rochdale, OL12 0NB, UK. email:

[email protected]

(corresponding author)

Malcolm Dickson MRCOG,

Consultant Obstetrician and

Gynaecologist, Rochdale Infirmary,

Rochdale, UK.


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2004 Royal College of Obstetricians and

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lifelong Phe-restricted diet, since it wasdiscontinued in childhood.Therefore an increased

potential risk exists for their offspring.10 There is

a difference in the outcome of children born with

PKU and those damaged by the maternal PKU

syndrome. The child born with PKU can be

protected by early treatment but the damage

caused to the fetus by the mothers high Phe

values is irreversible.2

There are more than 3000 women of reproductive

age in the USA with PKU and in excess of 6000

women who, including variants of PKU, are at riskof having children with maternal PKU

syndrome.11The International Collaborative Study

on Maternal PKU commenced in the USA in

1984 evaluated the efficacy of a restricted Phe diet

in reducing the morbidity associated with maternal

PKU.This study included over 400 women with

PKU and evaluated 575 pregnancies from 130

referral centres and metabolic clinics within the

USA, Canada and Germany.9 Case series from

various parts of Australia have reported 61 cases of

maternal PKU.12,13

Based on the national figures available from the

PKU register in the UK, the average number of

women identified with PKU per year was 32.5.

It was predicted that there would be more than

500 women in the reproductive age group in

UK by the year 2000.14 The national figures

revealed that this number would more than

double over the next decade, based on the

current trend in prevalence. Figures from the

Manchester Metabolic Unit Register on maternal

PKU in the North West region over the last 39

years from 1965 to 2003 revealed a total of 78

mothers (Table 2).An opportunistic survey of 112obstetricians in the North West region, which

included consultants and trainees, revealed that

only three had ever encountered a case of

maternal PKU. This highlights the existent

inexperience of many obstetricians in caring for a

mother with PKU while the figures are rising.

Pathogenesis

Women with PKU who remain untreated during

pregnancy face serious adverse pregnancy

outcomes.3 Elevated Phe levels in pregnancy are

teratogenic and the effects are analogous to those

seen with fetal alcohol exposure and occur

regardless of the genetic PKU status of the

fetus.18 While a child born with PKU can be

treated by early dietary intervention, the damage

caused to the fetus by the mothers high Phe

values is irreversible.14

The exact mechanism of fetal damage is not

known but the ability of the placenta to

concentrate Phe on the fetal side may be a major

factor.Although the fetus is heterozygous for the

gene coding for PAH, its immature hepatic

enzyme system may be the reason for its inability

to deal adequately with transplacental Phe

uptake.15 Because of placental concentration of

amino acids the fetus is exposed to a higher

concentration of phenylalanine than that in the

mother.

16

It has not been determined whether anexcess of Phe and its metabolites, a deficiency of

tyrosine owing to absence or inactivity of PAH,

an amino acid imbalance or a combination effect

causes the disruption of normal development and

fetal growth throughout pregnancy.17 The

frequency of abnormalities seems to be directly

related to the degree of elevation of maternal Phe

levels during critical periods of embryogenesis

and organogenesis early in pregnancy.3

Fetal effects

Abnormalities in the children of women withuncontrolled PKU during pregnancy were first

reported in 1957 and subsequently in 1963.The

adverse fetal features from uncontrolled maternal

Figure 1. Oxidation of

phenylalanine to tyrosine

Table 1. Incidence of phenylketonuria from the PKU Register at Great Ormond Street

Hospital, London

Year span Men (n) Women (n) Unknown (n)

196473 371 288 10197483 397 327 27198493 421 361 57

Table 2. Maternal PKU in North West

(Manchester) region

Year span Cases (n)

196574 13197584 9198594 1419952003 42


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30

PKU are termed the maternal PKU syndrome

and shown in Table 3. There are as yet

insufficient data relating to several areas of long-

term follow-up assessment in the offspring of

PKU women, notably of mental ability. The

available data have established that these infants

have poorer cognitive outcomes and increased

behavioural difficulties.13

Uncontrolled maternal PKU has a quoted

incidence of congenital heart disease (CHD) of

10%, microcephaly of 73%, and major bowel

anomalies of 2%. Other craniofacial dysmorphic

features have been descr ibed.2-4

Maternal effects

The features of underlying PKU in mothers are

similar to those in the general population with

PKU, depending on the severity and dietarycompliance adhered to since childhood.

Although dietary control is recommended for

life, by late adolescence many affected persons

stop using special medical foods and are lost from

follow up.3 Subjects with PKU are more prone

to depression, anxiety, phobic tendencies and

isolation from their peers.19 They also have mean

IQs that are significantly below population

norms, which is attributed to high phenylalanine

levels.20 These factors adversely affect dietary

compliance and preconceptual treatment.

The emotional strain put on the mother by

worrying about the fetal outcome and by having

to follow an unpleasant diet may be considerable.

Thus, great care needs to be taken to provide

these mothers with appropriate support and

understanding during the pregnancy and to ensure

continuity of this support to prevent postpartum

depression. Although there has been no research

on this particular aspect of the disease, it has been

identified as an area with scope for future research.

Preconception counselling

Counselling of mothers before pregnancy about

the fetal risks associated with a high plasma Phe

concentration is essential. In the UK,nearly 50%

of PKU children are managed in nonspecialist

centres and the provision of services for the

treatment of PKU varies widely from centralised

clinics and specialist teams to patient

management by a local family practitioner

working in isolation.1 It is often the responsibility

of the GP in this circumstance to ensure

appropriate referral. As a result, it will not beunusual for an obstetrician in a district general

hospital to be faced with the task of offering pre

conceptual counselling to these women.

Ideally, preconception treatment and family

planning advice should be given by the

paediatrician and clinical nurse specialist before

transfer to an adult clinic.This advice needs to be

reinforced throughout adolescence and the

provision of written information is necessary.

Specific risks related to the maternal PKU

syndrome should be fully explained atpreconception counselling.

The emphasis of counselling should be on the

currently recommended Phe levels prior to and

during pregnancy (60-240 mol/l).7 Women

need to be aware that these levels are stricter

than those recommended for treatment during

early childhood. To ensure optimal outcome and

to prevent the effects of maternal PKU

syndrome, the diet needs to be initiated before

conception.21 Achieving this degree of control

requires a major commitment by the woman and

support by the treating professionals.

Women should be advised to refrain from

pregnancy until levels of phenylalanine are

consistently optimised to recommended ranges

(60-240mol/l). Contraception should be recom-

mended until Phe levels stay in the desired ranges

for at least a minimum of 4 consecutive weeks.1

Risk of inheritance

PKU is an autosomal recessive disorder.The PAH

locus of the PKU gene is defined on chromosome12. Depending upon the PKU carrier status of the

father, approximately 1 in 120 children of a PKU

affected mother will inherit an abnormal PKU

gene from both parents and will also have PKU.21

For the child to have PKU, the father must be a

carrier: 1 in 60 of the population of the UK are

carriers. If a woman with PKU does marry a carrier

then at each pregnancy there is a 50% chance of

having a child with PKU.1

Theoretically, there is a potential for prenatal

diagnosis for families at risk of PKU using genemapping and DNA probe analysis.22 However, it

should be borne in mind that the presence of the

PKU gene in the fetus seems unlikely to affect

Table 3. Fetal effects of uncontrolled maternal

PKU24

Fetal effect Incidence (%)

Psychomotor impairment 92Microcephaly 73Intrauterine growth restriction 40Spontaneous miscarriage 24Congenital heart defects 10

Craniofacial dysmorphic featuresa Abnormal neurological findingsa Postnatal growth restrictiona Major bowel anomalies 12

aExact figures are unknown;only case reports have been documented.


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the fetal outcome, at least in a comparison of

PKU and non-PKU siblings from a woman with

untreated PKU in pregnancy.23 Despite the

interesting genetics, there is no place for invasive

prenatal testing as PKU is identifiable and

entirely treatable at birth.

Screening for maternal PKU

Some children with PKU may be lost to follow

up and, because of the evidence that moderate

elevations of Phe in the blood do not cause PKU

but are still harmful to the fetus,24 there is a case

for routine screening test in pregnancy.25 It is also

reasonable to consider this in areas with a

significant immigrant population from developing

countries where neonatal screening for PKU is

not routine and hence the mothers PKU status is

unknown. Since the efficacy of the treatment is

maximised if instituted before conception, such a

screen should ideally be part of a prepregnancy

service.26 Nevertheless, the yield of such tests is

low at 1 in 10 000 Guthrie tests. Screening may

therefore be more worthwhile in populations

where the risk of PKU is greater. Screening for

maternal PKU should be part of the investigation

of any microcephalic infant or fetus with features

of maternal PKU syndrome.27

Prepregnancy care

The frequency of abnormalities is directly

related to maternal Phe levels in pregnancy andthe lack of control during critical periods of

embryogenesis and organogenesis. Therefore,

control of Phe levels within strict limits of

60-240 mol/l is essential both preconceptually

and throughout pregnancy to prevent damage to

the developing fetus.14 The best pregnancy

outcomes from maternal PKU occur when strict

control of Phe level is instituted before conception

and continued throughout pregnancy.21

A list of food products that can be included in

the PKU diet and those to be avoided areincluded in Table 4. The Phe allowance in the

prepregnancy diet includes daily Phe exchanges

and Phe free protein supplement,with additional

vitamin and mineral supplements as required.

Phe levels should be monitored weekly and

intake adjusted consistently with desired ranges.

These levels should be maintained for a

minimum of 4 consecutive weeks before

advising that contraceptives can be stopped.1

Care and monitoring inpregnancy

Dietary care

Ideally, measures should be taken to initiate a strict

dietary regimen before and throughout pregnancy,

with at least weekly measurement of blood Phe

levels during pregnancy.Antenatal admissions may

be necessary for dietary stabilisation.7

Oncepregnant,a womans diet needs to be tailored with

an increase of Phe free protein supplement to give

total protein intake (natural protein plus Phe free

protein supplement) of approximately 70 g daily.

In the early stages of pregnancy nausea may affect

appetite and energy supplements may be required

to maintain an adequate energy intake to prevent

weight loss. Studies on women with PKU have

found that up to 65% of them discontinued the

special diet because of its unpleasant taste.28

There is some suggestion that low maternal

tyrosine levels may harm the fetus.Tyrosine levels

may fall below the normal range during

pregnancy, necessitating the addition of

supplements of L-tyrosine to the Phe free protein

supplement.30 During the second half of

pregnancy, Phe tolerance usually increases as the

fetus grows rapidly and metabolises Phe. The

Phe levels should be monitored weekly and the

diet altered as necessary to maintain levels within

the accepted range of 60-240 mol/l.7 Phe

intake should be increased on the basis of blood

Phe levels and the amount of Phe protein

supplement may be reduced as Phe intakeincreases; management should be undertaken by

a dietician.An elective termination of pregnancy

may need to be considered as an option if the

maternal Phe levels in the preconception and

early pregnancy phase are unacceptably high.3

Normal pregnancy weight gain should be

encouraged to reduce microcephaly. Matalon

et al.35 have confirmed that the highest

occurrence of microcephaly (58%) was found in

pregnant women who gained less than 70%

of recommended weight gain. The rate ofmicrocephaly and CHD may be reduced if

nutrient intake is optimal while attempting to

control blood phe levels.

Table 4. Food items that can be included and

to be avoided in PKU diet1

Avoid Include

Meat Most fruitEggs Some vegetablesChicken Sugar Fish Butter Milk Boiled sweetsCheese Some squashesOther dairy products Low-protein flour Nuts Low-protein breadBread Low-protein pasta

Biscuits Low-protein biscuitsCakes Low-protein energy barsPasta Egg replacer Aspartame (Nutra Sweet)


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Ultrasound surveillance

The rates of malformation suggest that medical

specialists in obstetric ultrasound who have

access to specialist fetal echocardiography should

undertake fetal surveillance in these women.The

risk of CHD in maternal PKU (10%) is

considerably higher than if a woman had aprevious child with CHD (2%).The purpose of

prenatal detection of CHD is two-fold. First,

where a major structural cardiac malformation is

detected in early pregnancy, the option of

termination of pregnancy can be considered.

Second, the prediction of an abnormality can

allow antenatal care and delivery in a unit where

paediatric cardiac facilities are available. This

avoids delay in diagnosis and treatment, which is

often an important contribution to infant

mortality.34 Full specialist echocardiography is

therefore recommended.

Antenatal diagnosis of microcephaly is difficult,

with debate on definitions in the prenatal period

even in high-risk women.The head size should

be more than three standard deviations below

expected values before the diagnosis can be

considered and serial scanning is necessary for

this diagnosis. As a consequence, microcephaly

may not sometimes be obvious until the late

second or even the third trimester.35,36 In view

of this, it is suggested that pregnant women with

PKU should be referred to appropriate fetal

medicine specialist consultants for prenatalscanning and the counselling needed in these

challenging diagnoses.

Referral to a specialist in fetal medicine for

expert ultrasound scanning and fetal

echocardiography is recommended for the

prenatal diagnosis of associated abnormalities

and appropriate counselling. Serial scans for

growth are mandatory in view of the high

potential for intrauterine growth retardation and

to aid diagnosis of microcephaly.

Multidisciplinary care

A tailored multidisciplinary care involving the

consultant obstetrician, fetal and maternal

specialist, consultant geneticist, consultant

paediatrician, metabolic dietician and clinical

nurse specialist, clinical psychologist, social

worker and biochemist with close liaison with

community staff is recommended, with added

understanding and support towards underlying

maternal PKU status.

The mode and timing of delivery should be

guided by the obstetric indications and the fetal

wellbeing encountered during pregnancy and

not by the mothers PKU status. Breastfeeding

should be encouraged as the increased dietary

load of Phe in breast milk will not cause

hyperphenylalaninaemia in the newborn.30

The children of mothers with PKU should be

assessed for PKU during their routine neonatal

screening at 6-14 days. Initial examination of theinfant should be by a neonatologist aware of the

clinical features of infants born to PKU mothers.

Long-term assessment of development is

recommended by psychologists at 1, 4 and

8 years of age. The birth and follow-up

assessment details should be notified to the PKU

Register. Clinical follow up should be by a

paediatrician with an interest in PKU and

metabolic disease.1,7

Future prospects for the

treatment of PKU

Novel non-dietary approaches to treatment

have been proposed, which include tetra-

hydrobiopterin supplementation, Phe ammonium

lyase, recombinant human PAH enzyme

replacement therapy and the administration of

large neutral aminoacids. However, the safety of

these alternative therapies, especially during

pregnancy, has yet to be established effectively.36

The search for a preventive treatment for the

disease has been greatly aided by advances inmolecular genetics.Modified liver cells have been

implanted in mice,which have not only corrected

the PAH defect but have remained healthy for a

normal life span of the animal. Overall, however,

prevention and treatment have not progressed as

quickly as had been hoped and research and

development must be pursued vigorously to take

account of contemporary perceptions of the

disease. In the future, transfer of normal genes for

PAH to liver cells may allow women to maintain

normal Phe levels without dietary therapy.31

Conclusions

The beneficial effects of newborn screening for

PKU may be overshadowed by the mental

restriction and birth defects associated with

maternal PKU syndrome. Identification of

women with PKU, tracking them over the period

of their reproductive years, providing expert

nutritional, metabolic and obstetric care during

pregnancy and documenting their course is

important and could serve as a model of care for

future generations. Progress in medical disorders

of pregnancy has inevitably occurred over a widefront and highlights of this progress include an

appreciation of the fetal risk in uncontrolled or

poorly controlled maternal PKU. Intensive case

32


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2004 Royal College of Obstetricians and Gynaecologists33

management of PKU-related psycho-educational

and psychosocial issues can impact on

reproductive decision making and the ability to

comply with strict dietary regimen prior to and in

pregnancy. Thus, by adopting this preventive

approach to the management of maternal PKU

and by collaborating with the multidisciplinary

team to optimise the care of these women, wecould ensure that the benefits to one generation

attained by the universal PKU screening

programme are not lost to the next generation

the children of mothers with PKU.

AcknowledgementsDr Jill Pepper, Programme Manager, UK

Newborn Screening Programme Centre, Great

Ormond Centre, London; Ms Christine

Caven, Willink Biochemical Genetics Unit,

Pendlebury Hospital, Manchester (for

providing national and regional data on

PKU); and Fiona White, Chief MetabolicDietician, Willink Biochemical Genetics

Unit, Central Manchester and Manchester

Childrens University Hospitals (for dietary

information).

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References

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