The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study.

OBJECTIVE: The purpose of this report was to update the results of the Maternal Phenylketonuria Collaborative Study, which was established to assess the efficacy of a phenylalanine-restricted diet in preventing morbidity among the offspring of women with hyperphenylalaninemia. STUDY DESIGN: During a 12-year period 576 women with hyperphenylalaninemia were enrolled in this study. Outcome measures were stratified according to classification of maternal hyperphenylalaninemia and the time at which dietary control of phenylalanine level was achieved. RESULTS: Optimal physical and cognitive fetal outcomes occurred when maternal blood phenylalanine level <600 micromol/L was achieved by 8 to 10 weeks' gestation and maintained throughout pregnancy (trimester average,

Care of the adult with phenylketonuria.

Forty-three adults with classical phenylketonuria were identified by neonatal screening and treated with a phenylalanine (Phe) restricted diet. Nineteen have remained on dietary treatment with varying levels of blood Phe control and 24 have discontinued the diet at an average age of 7.8 years. Follow up at an average age of 22 years revealed that the cohort remaining on dietary treatment have achieved substantially better social and academic achievement than the 24 who discontinued dietary treatment. Another group of 19 adults who were not diagnosed until an average age of 2.5 years have also been evaluated after an average of 22 years on a Phe restricted diet. This report is based upon Wechsler Adult Intelligence Revised Test scores, attendance at college, employment and marital status.

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 international collaborative study of maternal phenylketonuria: status report 1994.

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child-bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 mumol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings have indicated that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 mumol/l and should provide adequate energy, protein, vitamin and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated. The results of 402 pregnancies are reviewed.

Intellectual development in 12-year-old children treated for phenylketonuria.

Intelligence and achievement test scores were evaluated for 95 12-year-old children with phenylketonuria who had begun dietary therapy during the neonatal period. Dietary control of blood phenylalanine below 900 mumol/L was maintained beyond age 10 years in 23 children; 72 others had blood phenylalanine persistently above that level at ages ranging from 18 months to 10 years. Test scores at age 12 years were negatively correlated with the age at initiation of diet and with blood phenylalanine levels from ages 4 to 10 years, and positively correlated with parent IQ scores and the age at loss of dietary control. Children who maintained phenylalanine levels below 900 mumol/L beyond age 10 years showed no deficits in test scores, except for arithmetic, the scores of which declined between ages 6 and 12 years in 90% of the children in this study. These data strongly support a recommendation that dietary restriction of phenylalanine should be maintained through adolescence.

School achievement in treated PKU children.

Phenylketonuric children who were treated early and maintained a pherestricted diet through age 10 were compared with those who discontinued the diet after age 6 on a standardized test of intelligence, school achievement, language and perceptual skills. Mean IQ, reading and spelling test scores improved between ages 6 and 10 for the on-diet children in comparison to those who were off-diet. However, mean scores on arithmetic, language and perceptual skills declined at a uniform rate for both groups. Children with PKU scored significantly lower than did their non-PKU siblings on tests of visual perception and visual-motor skills. Because the school years, particularly, the early teens, pose increased stress in affected PKU individuals, it is recommended that dietary restriction at least through the high school years is prudent for their optimal physical, mental, emotional and educational growth.

Psychoeducational findings among children treated for phenylketonuria.

Early treated phenylketonuric children who maintained a phe-restricted diet through age 10 were compared with those who discontinued the diet after age 6 on standardized tests of intelligence, school achievement, language, and perceptual skills. Mean IQ, reading, and spelling test scores improved between ages 6 and 10 for the on-diet children in comparison to those who were off diet. Mean scores on arithmetic, language, and perceptual skills, however, declined at a uniform rate for both groups. Children with PKU scored significantly lower than did their non-PKU siblings on tests of visual perception and visual-motor skills. We conclude that children with PKU should be maintained on a phe-restricted diet.

Maternal phenylketonuria.

Pregnant women with untreated phenylketonuria (PKU) with blood phenylalanine levels greater than 1200 mumol/L usually give birth to offspring with congenital birth defects, including microcephaly, cardiac defects and mental retardation. According to Mabry and Levy, hyperphenylalaninaemic (HPA) women with blood phenylalanine levels between 600 and 1200 mumol/L also have an increased risk to their offspring. To study this problem further, the National Institute of Child Health and Human Development has established a collaborative study for 7 years to elucidate a proper treatment programme for these women.

Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age.

Early-treated PKU children were compared to their matched non-PKU sibling controls on Wechsler Intelligence Scale for Children (WISC) and Wide Range Achievement Test (WRAT) results at age 8. Fifty-five PKU children had mean WISC Full Scale IQ score of 100, in comparison to a mean of 107 for their matched sibling controls (p = 0.001). Treatment parameters significantly correlated with sibling-PKU IQ score differences included maximum diagnostic phe level (r = 0.244, p = 0.036) and phe levels at age 6 (r = 0.329, p = 0.007) and at age 8 (r = 0.489, p less than 0.0005). Fifty PKU subjects scored significantly lower than their matched sibling controls on standard scores of the WRAT Reading (102 vs. 107, p = 0.016) and Arithmetic (96 vs, 101, p = 0.006) subtests, and lower, but not significantly so, in Spelling (100 vs. 103, p = 0.145). When the sample was grouped according to diet status at age 8, on-diet PKUs scored at or above the level achieved by their siblings on all three scales of the WISC and all three WRAT subtests, whereas the off-diet group scored from 7 to 13 points below their siblings on all measures. These results suggest that PKU children should restrict phe intake at least through their school years.

Preliminary report on the effects of diet discontinuation in PKU.

A collaborative study of diet discontinuation in children with PKU was initiated in 1973. Children treated with the phenylalanine-restricted diet since early infancy were randomly assigned to continue or discontinue dietary therapy at age 6 years after parental consent was obtained. The 115 children participating in this study range in age from 8 to 13 years. At 6 years of age, the IQ of continuers and discontinuers was 101 and 97, respectively. At 8 years, WISC Full-Scale IQ scores adjusted for mean differences on the 6-year Stanford-Binet IQ were 101 for continuers and 98 for discontinuers (P = 0.075). School performance measured by the Wide Range Achievement Test showed significant differences on reading (3.9 vs 3.2) and spelling (3.3 vs 2.9) grade placement, although scores were above actual grade placement (2.7 vs 2.6) for both groups. Continuers and discontinuers were not different in arithmetic scores, with performance at grade placement of 2.7 and 2.6 respectively. Although these data are preliminary in nature, they suggest that subtle changes in cerebral function may occur in children with PKU in whom the phenylalanine diet has been discontinued.

EEG pattern in phenylketonuria under early initiated dietary treatment.

Nineteen of 161 infants with a confirmed diagnosis of phenylketonuria (PKU) had initially abnormal EEGs obtained within days of diagnosis. The abnormalities consisted of single repetitive or multiple spikes and/or sharp waves, focal or scattered, which rarely occurred in paroxysmal bursts. Initial maximal diagnostic serum phenylalanine (Phe) levels were significantly higher for the group with abnormal EEGs. The mean diagnostic serum Phe level was 56 mg/dL in the group with abnormal EEGs, whereas the mean diagnostic Phe level was 48 mg/dL in the group with normal tracings. The average age at initiation of restrictive dietary treatment was approximately 3 weeks. The initially abnormal EEGs became normal by 1 year of age in all but two patients who had a minimal and a mild abnormality, respectively. Hypsarrhythmic patterns were not seen. Infants with PKU detected early and treated well do not appear to need routine EEG monitoring.

Congenital and neurological abnormalities in infants with phenylketonuria.

We reported the occurrence of congenital and neurological abnormalities in 150 children with phenylketonuria (PKU) age 1 year or older, who have been treated with a restricted phenylalanine diet, according to the protocol used in a nation-wide longitudinal collaborative study of children treated for PKU. The overall occurrence (9.3%) of congenital anomalies was not significantly different from that of a general population, except for an apparent increased incidence of pyloric stenosis. None of the subjects had a persistent major neurological defect.

Intellectual performance of 36 phenylketonuria patients and their nonaffected siblings.

Thirty-six patients with a confirmed diagnosis of phenylketonuria (PKU) were identified and placed on dietary therapy before reaching 121 days of age. These children are currently between 4 and 6 years old, and have been given the Stanford-Binet Intelligence Scale. Subsequently, their normal siblings of closet age were selected as matched-pair controls and were also tested with the Stanford-Binet. The mean age of the PKU sample when tested was 50.0 months, and 50.9 months for the normal controls. The 36 index patients scored a mean IQ of 94 and their nonaffected siblings obtained a mean IQ of 99. This five-point mean difference was significant at the .02 level, and suggests the presence of a minimal intellectual impairment associated with PKU, even when treatment begins early and is rigorously monitored.