10.1576/toag.7.1.028.

27039

www.rcog.org.uk/togonline

REVIEW The Obstetrician & Gynaecologist 2005;7:2833

Maternal phenylketonuria in pregnancy

Uma Krishnamoorthy, Malcolm Dickson
The treatment of phenylketonuria, an inherited metabolic disorder, is one of the great success stories of the past 40 years. Prior to 1963, virtually all women with the disease who were of childbearing age suffered brain damage and bore few, if any, children. The success of newborn screening has resulted in a large number of women with phenylketonuria worldwide who are now of childbearing age. The offspring of women with phenylketonuria who remain untreated during pregnancy face a poor outcome. Optimising the care of these women prior to conception and throughout the pregnancy is therefore imperative to prevent significant fetal damage and is essential if the benefits to one generation attained by the universal screening programme are not to be lost to the next generation.

Keywords
maternal phenylketonuria, antenatal screening, neonatal screening

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 up largely 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 activity of the enzyme phenylalanine hydroxylase (PAH) that catalyses the conversion of phenylalanine (Phe) to tyrosine, leading to elevated levels of

Author details

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 hyperphenylalaninaemia with significant residual PAH activity. Rare variants can be because of deficiency of dihydrobiopterin reductase or defects in biopterin 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).

Uma Krishnamoorthy MRCOG, Specialist Registrar, Rochdale Infirmary, Whitehall Street, Rochdale, OL12 0NB, UK. email: ukrishnamoorthy@hotmail.com (corresponding author)

Extent
The success of newborn screening has resulted in a 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

Malcolm Dickson MRCOG, Consultant Obstetrician and Gynaecologist, Rochdale Infirmary, Rochdale, UK.

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Table 1. Incidence of phenylketonuria from the PKU Register at Great Ormond Street Hospital, London
Year span 196473 197483 198493 Men (n) 371 397 421 Women (n) 288 327 361 Unknown (n) 10 27 57

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lifelong Phe-restricted diet, since it was discontinued 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 risk of having children with maternal PKU syndrome.11 The 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 112 obstetricians 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 an excess 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

Figure 1. Oxidation of phenylalanine to tyrosine

Table 2. Maternal PKU in North West (Manchester) region

Year span 196574 197584 198594 19952003 Cases (n) 13 9 14 42

Fetal effects
Abnormalities in the children of women with uncontrolled PKU during pregnancy were first reported in 1957 and subsequently in 1963.The adverse fetal features from uncontrolled maternal
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Table 3. Fetal effects of uncontrolled maternal PKU24

Fetal effect Psychomotor impairment Microcephaly Intrauterine growth restriction Spontaneous miscarriage Congenital heart defects Craniofacial dysmorphic featuresa Abnormal neurological findingsa Postnatal growth restrictiona Major bowel anomalies
a

Incidence (%) 92 73 40 24 10 12

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

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 be unusual 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 at preconception 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 (60-240 mol/l). Contraception should be recommended until Phe levels stay in the desired ranges for at least a minimum of 4 consecutive weeks.1

PKU are termed the maternal PKU syndrome and shown in Table 3. There are as yet insufficient data relating to several areas of longterm 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 described.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 dietary compliance 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.

Risk of inheritance
PKU is an autosomal recessive disorder. The PAH locus of the PKU gene is defined on chromosome 12. 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 gene mapping 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

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% 30

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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 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

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Care and monitoring in pregnancy 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 Once pregnant, 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 intake increases; 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 of microcephaly and CHD may be reduced if nutrient intake is optimal while attempting to control blood phe levels.
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Prepregnancy care
The frequency of abnormalities is directly related to maternal Phe levels in pregnancy and the 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 are included in Table 4. The Phe allowance in the
Table 4. Food items that can be included and to be avoided in PKU diet1
Avoid Meat Eggs Chicken Fish Milk Cheese Other dairy products Nuts Bread Biscuits Cakes Pasta Aspartame (Nutra Sweet) Include Most fruit Some vegetables Sugar Butter Boiled sweets Some squashes Low-protein flour Low-protein bread Low-protein pasta Low-protein biscuits Low-protein energy bars Egg replacer

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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 a previous 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 prenatal scanning 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.

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 the infant 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 tetrahydrobiopterin 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 in molecular 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 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 32 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 wide front and highlights of this progress include an appreciation of the fetal risk in uncontrolled or poorly controlled maternal PKU. Intensive case

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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, we could 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.

Acknowledgements
Dr 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 Metabolic Dietician, Willink Biochemical Genetics Unit, Central Manchester and Manchester Childrens University Hospitals (for dietary information).

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References
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