Maternal phenylketonuria: dietary treatment during pregnancy L. ANNE ZALESKI,* MB, FRCP[C]; ROBIN E. CASEY,t M Sc; WITOLD ZALESKI4 MD, MRC PSYCH, FRCP[C]

There has been growing concern about the harmful effects on the fetus of high blood levels of phenylalanine in pregnant women who have phenylketonuria. The clinical manifestations of classic phenylketonuria are variable, and even before the advent of dietary treatment some women homozygous for the condition, having escaped severe brain damage, were able to reproduce. Documented pregnancies in women with phenylketonuria indicate a high frequency of prenatal and postnatal growth retardation, microcephaly, mental retardation and congenital anomalies (cardiac, skeletal, neurologic, ocular etc) in their heterozygous, metabolically normal children, as well as an above-average incidence of spontaneous abortion and stillbirth.'-9 In the late I 950s dietary treatment of phenylketonuria was introduced and, as a result, mental retardation due to this condition is waning. Some girls who have been treated for phenylketonuria have now reached reproductive age and are no longer on the diet. They have normal intelligence but their metabolic disorder threatens their offspring during intrauterine life. Whether the control of blood phenylalanine levels by diet can protect the fetus remains unclear, though there are indications that this might be the case.'0" We report the results of treatment during pregnancy in a woman with phenylketonuria whose blood phenylalanine level was controlled by diet starting at 18 weeks in the first pregnancy and at 12 weeks in the second. From the Alvin Buckwold Centre, department of pediatrics, University Hospital, Saskatoon * Research associate, Alvin Buckwold Centre tBiochemist, Alvin Buckwold Centre tDirector, Alvin Buckwold Centre and professor of pediatrics, University of Saskatchewan Reprint requests to: Dr. L. Anne Zaleski, Alvin Buckwold Centre, University Hospital, Saskatoon, Sask. S7N 0W8

Case report The mother A 22-year-old woman with phenylketonuria was referred to the Alvin Buckwold Centre, University Hospital, Saskatoon, for the first time at 18 weeks' gestation because her blood phenylalanine level was uncontrolled. Phenylketonuria had been diagnosed through a routine premarital Guthrie test done by the provincial laboratory. The diagnosis had been confirmed when a plasma phenylalanine level of 26 mg/dl had been determined by spectrofluorometry. An older brother with an intelligence quotient (10) of 69 had also been found to have phenylketonuria. The family physician had informed the young couple of the risk to their future children because of the woman's metabolic disorder, but they decided to have a child. A low-protein diet had been started by the family physician 4 weeks before the woman's last menstrual period. The diet had consisted of 12 scoops of Lofenalac. (Mead Johnson Can.ida) per day, which provided 17 g of protein and 90 mg of phenylalanine. In addition she had been allowed one egg per week, one glass of milk per week, six slices of bread per day, an occasional wiener and unrestricted amounts of vegetables and fruit. Meat, fish and cheese had been excluded. Plasma phenylalanine levels, measured four times during the first 4 months of pregnancy, had ranged from 18 to 27 mg/dl. She had not taken the Lofenalac® regularly as it made her nauseated. The woman was a stable person with common sense. She had attended school to grade 10 and then had completed a secretarial course and worked as a secretary prior to her marriage. Her height was 150 cm, her weight 50 kg and her head circumference 53.5 cm. She was blonde and blue-eyed, and had mild eczema on her arms. The uterus was 2 cm below the umbilicus. There were no abnormal physical

findings, apart from hyperactive tendon reflexes and downgoing plantar reflexes. The electroencephalogram was within normal limits. The Wechsler Adult Intelligence Scale gave a full-scale 10 of 93 and verbal and performance lOs of 91 and 98 respectively. Laboratory findings were within the normal range apart from a fasting plasma phenylalanine level of 13.2 mg/dl and a tyrosine level of 0.5 mg/dl. Phenylketones were not detected in her urine by the ferric chloride test. Dietary treatment The diet was revised to provide 11.7 to 12.6 MJ (2800 to 3000 Cal) and 70 g of protein per day, as specified by the Dietary Standard for Canada.'4 Lofenalac®, 400 g/d, supplemented with natural foods, including 60 to 100 ml of cow's milk per day and double cream, as well as iron, calcium and Parmettc® vitamins (Ayerst Laboratories Ltd., Saint-Laurent, P0), was prescribed. The total daily phenylalanine intake was 500 mg or 9 mg/kg. The Lofenalac® was most easily accepted when given doublestrength and mixed with chocolate syrup. Because of difficulty in maintaining the diet at home the patient was admitted to the hospital hostel for the remainder of her pregnancy, with weekend passes. Albumaid-XP® (Scientific Hospital Supplies Ltd., Liverpool) was substituted at 24 weeks' gestation because it contains no phenylalanine and therefore permits a greater variety of natural foods to be included in the diet. It was supplemented with Ketovite® syrup and tablets (Paines & Byrne Ltd., Greenford, Middlesex, England) and a metabolic mineral mixture prepared by the University Hospital pharmacy; the composition was that used by Allen and Brown.'0 The Albumaid.XP® was best tolerated when given five times a day in grapefruit juice. The course of the dietary management is shown in Fig. 1.

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The plasma phenylalanine concentration was determined with the use of a Technicon TSM-1 amino acid analyser (Technicon Instruments Corp., Tarrytown, New York). The plasma phenylalanine level remained between 3 and 8 mg/dl except at 34 weeks' gestation, when it fell to less than 2 mg/dl; the dietary phenylalanine intake was then increased to 800 mg. At 24 weeks' gestation the phenylalanine level was 5.2 mg/dl in the amniotic fluid and 7.0 mg/dl in the maternal plasma. Following delivery the low phenylalanine diet was discontinued. The plasma phenylalanine level promptly rose to 27 mg/dl and phenylketones appeared in the urine. The first child A girl was born 1 week post term, by vaginal vertex delivery. The Apgar score at 1 minute was 9. The infant's birth weight was 2600 g, head circumference 32 cm, chest circumference 31 cm and length 45 cm. At the time of delivery the phenylalanine levels were 5.5 mg/dl in the mother's plasma and 12.9 mg/dl in the cord blood. The infant's phenylalanine level declined rapidly to normal in the first 48 hours of life (Table I). Formula feeding xvas started and the postnatal course was uneventful. How-

ever, mild coarctation of the aorta was diagnosed clinically when the infant was 7 weeks of age. The child's progress was reviewed at the ages of 9 months, 14 months and 24 months. All milestones were reached at the appropriate time. Both linear growth and head circumference increased at a normal rate but remained below the third percentile. The coarctation remained asymptomatic. At 4 years and 8 months of age the child was 96 cm tall (below the third percentile for her age; average for 36 months), weighed 16 kg (10th percentile) and had a head circumference of 46.2 cm (more than two standard deviations below the mean for her age; average for 14 months). The blood pressure was 150/90 mm Hg in the

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arms and the systolic pressure was 60 mm Hg in the legs. She was a vivacious child and was small but well developed. The deep tendon reflexes were hyperactive and she tended to walk on her toes. The plantar reflexes were equivocal. Isolated mild coarctation of the aorta distal to the origin of the left subclavian artery was confirmed by cardiac catheterization. Skeletal roentgenography showed interruption of the posterolateral aspect of the left first rib, and fusion of the spinous processes of C2 and C3. The sacrum was abnormal with a very wide neural canal. There were abnormalities of segmentation of the sacral vertebrae and a small spina bifida was present at 51 to S3. Skull roentgenography r..vealed no abnormalities. At 5½ years the child underwent surgical correction of the coarctation because of rising blood pressure. At 6 years of age (Fig. 2) she was attending grade one and progressing normally; the Wechsler Preschool and Primary Scale of Intelligence showed a full-scale 10

of 108. Her rate of growth was normal, but height and head circumference remained below the 3rd percentile. The second child Following the birth of the first child the mother was advised to resume her diet if she wished to have another pregnancy. The family left Saskatchewan at this time and the woman was referred to Dr. E.E. McCoy at the University of Alberta in Edmonton. The diet was resumed for the next two pregnancies, which resulted in spontaneous abortions. With the fourth pregnancy the mother resumed the diet herself at 12 weeks' gestation, taking both Lofenalac® and Albumaid.X P®, but she did not cooperate with regular monitoring of the plasma phenylalanine level. A boy was born at term by cesarean section because of breech presentation. The infant's birth weight was 3050 g. At 12 months of age (Fig. 2) the boy was 72 cm long (at the 10th percentile), weighed 10.8 kg (between the 50th and the 75th percentile) and had a head circumference of 44 cm (two standard deviations below the mean for his age). He had begun walking at 11 months of age and his psychomotor development was normal. Epicanthic folds were present. Bilateral syndactyly of the third and fourth toes and dorsal misplacement of the right small toe were noted in both mother and son. Discussion Although the first child functions with a normal range of intelligence she does have small stature, microcephaly, congenital heart disease and skeletal anomalies. Since these physical findings have been noted in children of women with phenylketonuria who received no treatment during pregnancy one can presume that the damage occurred because of the teratogenic effect of the high phenylalanine level in the mother's blood during early gestation. The second child is only mildly affected; he has microcephaly but normal development. In three of the four similar cases described in the literature10'11"3 phenylketonuria was detected in the mother during the second trimester

of pregnancy, at which time treatment was initiated and successful lowering of the plasma phenylalanine concentration achieved. Two of the offspring had normal psychomotor development in spite of microcephaly, and one had normal head size and psychomotor development. In the fourth case'2 treatment was started at 10 weeks' gestation; the infant was normocephalic but died at 14 days of age of severe congenital heart disease. At this time our limited experience with dietary treatment suggests that severe brain damage may be prevented by introduction of dietary control in the second half of pregnancy. This is a period of active myelination as well as cellular proliferation in the central nervous system. A study of the composition of cerebral lipids in the heterozygous offspring of a phenylketonuric woman demonstrated biochemical abnormalities similar to those seen in the brain of untreated persons with phenylketonuria.'5 This proves that exposure of the fetus to high concentrations of phenylalanine or its metabolites produces irreversible neurochemical alterations. Therefore, considerable benefit may be derived from controlling the mother's blood phenylalanine level during this active period of fetal brain growth. However, the variety of congenital anomalies in the offspring of women with phenylketonuria must result from an abnormal metabolic environment during early gestation.'6 In all probability these anomalies develop during organogenesis through a combination of factors: the toxic influence of elevated concentrations of phenylalanine and its metabolites, a low tyrosine concentration and a familial genetic predisposition. In addition, the same metabolic aberration produces a hypoplastic fetus with resultant postnatal growth deficiency. Experience in the treatment of children with phenylketonuria tells us that caution must be exercised, however, as overenthusiastic treatment may be harmful by leading to hypophenylalaninemia and possibly hypotyrosinemia. Frequent monitoring to maintain the blood phenylalanine level between 4 and 10 mg/dl should prevent that prob-

lem if, in addition, prolonged periods of fasting are avoided and adequate phenylalanine and protein intake, tailored to the individual patient's needs, is ensured. Treatment should be initiated and monitored by a centre with a team of medical, dietary and biochemical laboratory personnel experienced in the treatment of phenylketonuria. Prior to referral of the woman in our case report to the Alvin Buckwold Centre her treatment had been haphazard and the use of a poorly controlled low protein diet had placed the fetus at increased risk. From his epidemiologic study of maternal phenylketonuria Hansen'7 suggested that maternal intelligence appears to be a stronger predictor of reproductive outcome than the degree of hyperphenylalaninemia, and that the risk of damage to the fetus is concentrated in women who have been affected by their metabolic disorder. He based his recommendations for treatment on the maternal plasma phenylalanine level, maternal intelligence and "prior reproductive casualty". We find Hansen's recommendations unacceptable on several points. First, the plasma phenylalanine level can vary with maternal age, diet, time of sample collection and test used. The effects of these variables are not discussed in his report. Second, our case was identified through unselected screening; the mother was of normal intelligence and had a plasma phenylalanine level of less than 30 mg/dl, but congenital anomalies were present in her children, most likely because dietary treatment was not started early enough. Third, we would not recommend waiting for "prior reproductive casualty" before prescribing the diet. We conclude that much remains to be learned about the effectiveness of a low phenylalanine diet in preventing the high rate of mental retardation, congenital anomalies, microcephaly and failure to grow resulting from maternal phenylketonuria. Every girl with phenylketonuria should be counselled accordingly, with the possibility of adoption offered as an alternative to bearing her own child. If she opts to bear a child, with a clear understanding of all the risks involved, the diet should be given a

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The Royal College of Physicians

and Surgeons of Canada

Examinations The examinations of the Royal College are held In September of each year. Candidates wishing to sit for the examinations should note the following: 1. Every candidate for admission to the examinations must submit an application for assessment of training. 2. Candidates in training in Canada should apply for preliminary assessment of training at least one year before the; date on which they expect to sit for the examinations, that Is to say not later than September 1st of the preceding year. Candidates who have had training outside of Canada should submit their initial application for assessment at least eighteen months before they expect to sit for the examinations, that is by March 1st of the preceding year. Only candidates whose assessment of credentials is complete will be accepted to sit for the examinations. 3. Candidates who desire to sit for an examination, having complied with the above requirement of preliminary assessment of training, must notify the College in writing of their intent before February 1st of the year of the examination. Upon receipt of this notice of intent, the evaluation of the candidate's performance during training will be added to the previously completed assessment of credentials. Each candidate will then receive notification as to eligibility together with an application formfor admission to the examination which he will complete and return. 4. The following documents may be obtained from the College office: (a) Application forms for assessment oftraining. (b) General Information booklet on training requirements and examinations. (c) Specific requirements for training and regulations relating to the examinations of each specialty. Requests should indicate the specialty or specialties of interest to the applicant. (d) Listing of specialty training programmes in Canada accredited by the College.

5. Address all enquiries to: Division of Training and Evaluation ROYAL COLLEGE OF PHYSICIANS AND SURGEONS OF CANADA 74 Stanley Avenue Ottawa, Ontario KIM 1P4 Tel.: (613) 746-8177

trial before conception; if the diet is not tolerated, adoption remains an alternative. Since some girls treated for phenylketonuria may be lost to followup once their diet has been discontinUed, screening for the condition may be advisable as part of a premarital check-up. We also advise that girls with phenylketonuria continue to include Lofenalac® or another low phenylalanine preparation in their, diet so that the unusual taste will be better tolerated. Thanks are due to Mrs. Wendy Stockan, dietitian, for painstaking attention to the patient's dietary management; to Mrs. J0 Nanson, psychologist, who did the evaluations of development and intellectual function; to the Alvin Buckwold Centre laboratory staff; to Dr. T.B. MacLachlan, who provided the obstetric care for the patient and performed the amniocentesis; and to Dr. E.E. McCoy, for information regarding the woman's follow-up in Edmonton. This study was partly supported by a grant from the Department 6f Social Services, Province of Saskatchewan to the laboratory of the Alvin Buckwold Centre. References 1. FRANKENBURO WK, DUNCAN BR, COFFELT RW, et al: Maternal phenylketonuria: implications for growth and development. J Pedjair 73: 560, 1968 2. MACCREADY RA, LEVY HL: The problem of maternal phenylketonu-

na. Am J Obstet Gynecol 113: 121, 1972 3. DENT DE: Relation of biochemical abnormality to development of mental defect in phenylketonunia, in

Etiologic Factors in Mental Retardation; Report of XXIII Ross Pediatric Research Con ference, Ross Laboratories, Winston-Salem, NC. Nov 1956, p 32 4. Fisci-i RO, DOEDEN D, LAN5KY LL, et al: Maternal phenylketonuria. Detrimental effects on embryogenesis and fetal development. Am J Dis Child 118: 847, 1969 5. MABRY CC, DENIsTON JC, NELSON

TL, et al: Maternal phenylketonunia. A cause of mental retardation in children without the metabolic defect. N Engi J Med 269: 1404, 1963 6. STEVENSON RE, HUNTLEY CC: Con-

genital malformations in offspring of phenylketonunic mothers. Pediatrics 40: 33, 1967 7. ANGELI

E,

DENMAN

AR,

HARRIS

RF, et al: Maternal phenylketonuna: a family with seven mentally retarded children. Dev Med Child Neurol 16: 800, 1974

1594 CMA JOURNAL/DECEMBER 22, 1979/VOL. 121

8. GOLDSTEIN

AD,

AUERBACK

VH,

GROVER WD: Normal development in an infant of a mother with phenylketonuria. J Pediatr 82: 489, 1973 9. ZALESKI A, ZALESKI WA: Maternal

phenylketonuria. Report of four families (abstr 9). Presented at the Canadian Paediatric Society annual meeting, Quebec, June 27, 1973 10. ALLEN JD, BROWN JK: Maternal phenylketonuria and fetal brain damage, in Some Recent Advances in Inborn Errors of Metabolism, HOLT KS, COFFEY VP (eds), Williams & Wilkins, Baltimore, Md, 1968, p 14 11. ARTHUR LJH, HULME JD:

Intel-

ligent, small for dates baby born to oligophrenic phenylketonuric mother after low phenylalanine diet during pregnancy. Pediatrics 46: 235, 1970 12. BUSH RT, DUKES PC: Progeny, pregnancy and phenylketonuria. NZ Med J 82: 226, 1975 13. FARQUHAR JW: Baby of a phenylketonuric mother: inferences drawn from a single case. Arch Dis Child 49: 205, 1974 14. Dietary Standard for Canada, rev ed, suppl 1968, DNH&W, Ottawa, 1964 15. MENKES JH, AEBERHARD E: Maternal phenylketonuria. The composi-

tion of cerebral lipids in an affected offspring. I Pediatr 74: 924, 1969 16. SMITH I, ERDOHAZI M, MACARTNEY

FJ, et al: Fetal damage despite lowphenylalanine diet after conception in a phenylketonuric woman. Lancet 1: 17, 1979 17. HANSEN H: Variability of reproductive casualty in maternal phenylalaninemia. Early Hum Dev 2: 51, 1978

BOOKS I continued from page 1588 GENETIC DISEASES OF THE SKIN. V.M. Der Kaloustian and AK. Kurban. 339 pp. IlIust. Springer-Verlag New York, Inc., New York, 1979. $97.90. ISBN 3-540-09151-3 THE HYPERLIPOPROTEINAEMIAS AND ATHEROSCLEROSIS. Current Understanding of their Inter-relationships. Volume I. W. Fraser Bremner and Jane L.H.C. Third. 257 pp. Eden Press Inc., Westmount, P0, 1979. $26. ISBN 088831-056-0 "LET ME INTRODUCE MYSELF". The First 30 Months of Life. A Guide for Parents of Infant Children. Ernest Mayfield Ligon, Lucie W. Barber, Herman J. Williams and the staff of the Union College Character Research Project. 128 pp. Illust. Girling/Wade Marketing Inc., Mississauga, Ont., 1976. $7.95, paperbound; $11.95, clothbound; Si 4.95, deluxe album. ISBN 0-9690946-0-4 paperbound; ISBN 0-9690946-1-2, clothbound; ISBN 0-9690946-2-0, deluxe album

continued on page 1596

Maternal phenylketonuria: dietary treatment during pregnancy.

Maternal phenylketonuria: dietary treatment during pregnancy L. ANNE ZALESKI,* MB, FRCP[C]; ROBIN E. CASEY,t M Sc; WITOLD ZALESKI4 MD, MRC PSYCH, FRCP...
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