W. Hanley

Congenital Heart Disease in Maternal Phenylketonuria: Report from the Maternal PKU Collaborative Study

The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI, 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level ≥ 900 μM (15 mg/dL) [normal blood phenylalanine < 120 μM (2 mg/dL)] and not in metabolic control [phenylalanine level ≤ 600 μM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 μM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 μM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.

Calcium Ion Activity in the Sick Neonate: Effect of Bicarbonate Administration and Exchange Transfusion

Extract: Calcium ion activity was measured in plasma obtained by venous or arterial puncture using a calcium-selective flow-through electrode. Mean level of ionized calcium in umbilical venous plasma was 2.48 ± 0.04 mEq/liter. Within 30 hr after birth, the values decreased in sick infants to 1.35 ± 0.11 mEq/liter. Total calcium concentra tions were in the normal adult range at birth (5.20 ± 0.08 mEq/liter), showing a subsequent decline to subnormal values (3.47 ± 0.28 mEq/liter at age 30–40 hr). A calcium ion activity of less than 1.4 mEq/liter was associated with total calcium level at or below 3 mEq/liter in 80% of patients. Symptoms and signs attributable to hypocalcemia (ionized fraction) or hypomagnesemia, or both, were found only in infants in whom plasma levels of both divalent cations were below the lower limit of normal. Administration of NaHGO3 for acidosis caused a slight rise in pH (from 7.20 to 7.28 mEq/liter) and a decrease in plasma calcium ion activity (from 1.68 to 1.51 mEq/liter). During exchange transfusion with acid-citrate-dextrosc (ACD)-Tham buffered blood, calcium ion activity decreased significantly from 1.90 ± 0.08 to 1.20 ± 0.09 mEq/liter, whereas total calcium levels increased consistently (from 4.22 ± 0.13 to 5.33 ± 0.15 mEq/liter).Speculation: The temporary hypocalcemia, observed in sick newborn infants, may also occur in healthy newborns. It is thought to initiate normal calcium homeostasis by stimulating parathormone secretion and by bringing into play the two feedback mechanisms for calcitonin and parathormone secretion.

The international collaborative study on maternal phenylketonuria: organization, study design and description of the sample

The International Maternal Phenylketonuria (PKU) Collaborative Study commenced in 1984 to evaluate the efficacy of the low-phenylalanine diet in reducing the morbidity associated with maternal PKU syndrome. Four hundred and sixty eight (468) pregnancies resulted in 331 live births, 3 stillbirths, 61 spontaneous abortions, 2 ectopic pregnancies and 71 elective terminations. Since its inception, the study has steadily progressed toward its goal of diet initiation preconception or early in pregnancy. By 1994, 51% of the sample began the diet preconceptionally, with an additional 41% doing so by 8 weeks gestation. The number of adolescent pregnancies has decreased from 31% to 9%, college attendance has increased from 5% to 16%, number of women in the lowest socioeconomic classes has decreased from 95% to 59% and average IQ has increased from 78 to 88. The organization of the network of 130 referral centers and clinics within the U.S.A., Canada and Germany and the objectives of the scientific research investigation have served to provide a derived benefit of outreach, education, reproductive counseling and early diet intervention in a large cohort of PKU women.

The North American Maternal Phenylketonuria Collaborative Study, developmental assessment of the offspring: preliminary report

Preliminary results of 2-year Bay ley and 4-year McCarthy test scores are presented. To date numbers are too small to statistically correlate: — offspring from pregnancies in which diet was started prior to conception, offspring from pregnancies with phenylalanine (Phe) levels of 120–360 µmol/l versus 360–600 µmol/l, influence of home environment, influence of maternal nutrition, language development, behaviour/hyperactivity, Revised Wechsler Intelligence Score, school performance and learning disabilities. Two-year Bayley scores (mental and motor) revealed a median developmental quotient of 113 in 58 offspring from control pregnancies, 104 in 19 offspring from untreated “non-phenylketonuria (PKU) mild hyper-phenylalaninaemia” (natural Phe levels <600 µmol/1) pregnancies, 104 in 32 offspring from pregnancies whose Phe levels decreased on treatment to <600 µmol/1 by 10 weeks gestation and remained in that range for the remainder of the pregnancy, 98 in offspring from 32 pregnancies where permanent control was not achieved until 10–20 weeks and 72 in offspring from 51 pregnancies where control was not attained until after 20 weeks gestation. IQ scores determined by the McCarthy test at age 4–5 years revealed a mean of 112 in 43 offspring of control mothers, 99 in 12 offspring of “non PKU mild hyperphenylalaninaemia” women, 93 in 14 offspring whose mother’s Phe levels were continuously under 600 µmol/1 by 10 weeks gestation, 88 in 24 offspring from pregnancies in metabolic control by 10–20 weeks and 73 in 28 offspring of pregnancies not in metabolic control until after 20 weeks gestation. These preliminary results suggest that early and adequate dietary treatment during pregnancy in maternal PKU may provide some protection to the fetus for later intellectual development but much more data is required before definitive statements about cognition can be made.

Maternal non-phenylketonuric mild hyperphenylalaninemia

Unlike maternal phenylketonuria (PKU) which produces severe birth defects when untreated during pregancy, maternal non-PKU mild hyperphenylalaninemia (MHP) has a less severe impact but whether it is benign or may have long-term consequences for offspring has been unclear. From an international survey of maternal MHP we obtained information about 86 mothers (blood phenylalanine (Phe) 150–720 µmol/1), their 219 untreated pregnancies and 173 offspring. Spontaneous fetal loss and congenital anomalies were no more frequent than normally expected. Median Z-scores for birth length and birth head circumference and offspring IQ (100), however, were significantly lower for maternal Phe > 400 µjnol/1 than for maternal Phe <400 µmol/1, in which the median offspring IQ was 108. Data on maternal MHP from the prospective Maternal PKU Collaborative Study (MPKUCS) are as yet incomplete but seem to be conforming to the general pattern of the international survey. We conclude that maternal blood Phe levels above 400 µmol/1 in maternal MHP are associated with lower birth measurements and slightly lower offspring IQ. It would seem that dietary intervention to lower the maternal Phe levels to below 400 µmol/l might be indicated in maternal MHP pregnancies with the higher blood Phe levels.

Outcome implications of the International Maternal Phenylketonuria Collaborative Study (MPKUCS): 1994

It is well established that women with phenylketonuria who remain untreated during pregnancy face serious problems in offspring outcome. Surveys have documented that maternal phenylalanine (Phe) blood concentrations above 1200 µmol/1 are associated with microcephaly, congenital heart disease and intrauterine growth retardation among their offspring. To investigate the efficacy of the Phe restricted diet, the National Institute of Child Health and Human Development in Bethesda Maryland developed an international study to evaluate fetal outcome in pregnancies treated with the Phe restricted diet. The study involves over 100 metabolic clinics in the United States, Canada and Germany, and is now in its 10th year. The results included in this report are still preliminary in nature and the actual risk for such pregnancies remains to be determined.

Maternal PKU collaborative study: the effect of nutrient intake on pregnancy outcome

R. MATALON 1, K. MICHALS 1, C. AZEN 2, E. G. FRIEDMAN 2, R. KOCH z, E. WZNZ 2, H. LEVY 3, F. ROHR 3, B. R o u s e 4, L. CASTIGLIONI 4, W. HANLEY 5, V. AUSTIN 5 and F. DE LA CRUZ 6 1Department of Nutrition and Medical Dietetics, University of Illinois at Chicago and the Research Institute, Miami Childrens Hospital, 6125 S.W. 31st St., Miami, Florida 33155, USA; 2Childrens Hospital of Los Angeles, USA; 3Boston Childrens Hospital, USA; 4University of Texas Medical Branch, Galveston, Texas, USA; 5Hospital for Sick Children, Toronto, Canada; 6NICHD, Canada

The International Collaborative Study of Maternal Phenylketonuria status report 1998

The Maternal PKU Study began in 1984 and during the intervening years, 572 pregnancies in women with hyperphenylalaninemia (HPA) and 99 controls and their outcomes have been evaluated. Among Women with HPA who delivered a live infant, only 15.9% were treated and in metabolic control preconceptionally; however, another 18.4% were in control by 10 weeks. Compared to the results reported by Lenke and Levy in 1980, there is a marked improvement in outcome with treatment. Microcephaly was unusual in preconceptionally treated pregnancies with well-controlled phenylalanine-restricted diets. Even in pregnancies that established control after conception but before the 8th week, congenital heart disease did not occur in the offspring; however, it did occur in 12% of pregnancies not achieving control until after 10 weeks of pregnancy. The recommended level of blood phenylalanine during pregnancy is 120–360 μmol/L. Best results were obtained by close cooperation between the attending obstetrician and a metabolic team experienced in the care of persons with phenylketonuria. MRDD Research Reviews 1999;5:117–121.

Maternal PKU Collaborative Study: Pregnancy outcome and postnatal head growth

Pregnant women who have phenylketonuria (PKU; McKusick 261600) are at risk of having children with microcephaly, cardiac defects and mental retardation (Dent 1957; Mabry et al 1963; Lenke and Levy 1980). The results of a 7-year longitudinal, prospective, observational investigation on maternal PKU in the United States and Canada are reported. The goal of the study is to enroll all women of child-bearing age whose blood phenylalanine level on an unrestricted diet is greater than 240 μmol/L (4 mg/dl). Those planning pregnancy are treated with a phenylalanine-restricted diet and adequate nutrition is maintained while keeping the blood phenylalanine level between 120 and 360 μmol/L (2 and 6 mg/dl). The outcome of 318 pregnancies is presented and compared to 52 control pregnancies