Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy, according to genetic background.

BACKGROUND AND AIMS: Phenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. METHODS AND RESULTS: A total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype. Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. CONCLUSIONS: Several factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.

Maternal phenylketonuria syndrome: studies in mice suggest a potential approach to a continuing problem.

BackgroundUntreated phenylketonuria (PKU), one of the most common human genetic disorders, usually results in mental retardation. Although a protein-restricted artificial diet can prevent retardation, dietary compliance in adults is often poor. In pregnant PKU women, noncompliance can result in maternal PKU syndrome, where high phenylalanine (Phe) levels cause severe fetal complications. Enzyme substitution therapy using Phe ammonia lyase (PAL) corrects PKU in BTBR Phe hydroxylase (Pahenu2) mutant mice, suggesting a potential for maternal PKU syndrome treatment in humans.MethodsWe reviewed clinical data to assess maternal PKU syndrome incidence in pregnant PKU women. We treated female PKU mice (on normal diet) with PAL, stabilizing Phe at physiological levels, and mated them to assess pregnancy outcomes.ResultsPatient records show that, unfortunately, the efficacy of diet to prevent maternal PKU syndrome has not significantly improved since the problem was first noted 40 years ago. PAL treatment of pregnant PKU mice shows that offspring of PAL-treated dams survive to adulthood, in contrast to the complete lethality seen in untreated mice, or limited survival seen in mice on a PKU diet.ConclusionPAL treatment reduced maternal PKU syndrome severity in mice and may have potential for human PKU therapy.

[Singleton and twin pregnancies of PKU patients - individual variability of phenylalanine tolerance: experience of a single treatment center (Preliminary report)].

Phenylketonuria (PKU) is the autosomal recessive deficiency of phenylalanine hydroxylase resulting in the accumulation of phenylalanine (Phe) in blood and in the brain. Phe restriction in a patient's diet is determined depending on the amount of Phe intake which allows for stable blood Phe levels within the therapeutic range of 120-360µmol/L. In clinical practice the empirical determination of Phe tolerance relies on frequent assessment of blood Phe concentrations in relation to Phe intake from food records. Untreated maternal PKU may lead to maternal PKU syndrome in offspring. The objective of the study was to compare Phe tolerance during the course of singleton and multiple pregnancies of PKU patients. Case subjects and methods: The cases reviewed included three sets of classical PKU-affected Polish women on a low-phenylalanine diet during the course of singleton and twin pregnancies and their PKU-unaffected newborns. All the patients were under regular supervision of a metabolic dietitian to stabilize blood Phe levels and determine Phe tolerance. Data on pregnancy weight gain, the gestational age when the diet initiated, the percent of Phe assessments < 120 µmol/L and > 360 µmol/L, as well as offspring birth measurements were analyzed. RESULTS: The total increase in Phe tolerance and its pattern during the course of singleton and twin pregnancies differed remarkably in each patient. Three PKU women (Q383X/R408W, EX3DEL/EX3DEL, R281L/R408W) increased their Phe tolerance in singleton and twin pregnancies by 579%/468%, 674%/261%, and 427%/236%, respectively. During the last 10 weeks of singleton and twin pregnancy Phe tolerance showed an increase by 62%/149%, 33%/64%, and 37%/40%, respectively. The analysis of predictors for Phe tolerance showed that an individual's weight gain and the fetal weight gain as estimated from liveborn birth-weight data had no predictive capacity. CONCLUSIONS: Individual Phe tolerance in singleton pregnancies of PKU patients does not predict tolerance in twin pregnancy. Further research on the growing population of multiple pregnancy PKU patients is necessary to provide evidence-based guidelines to optimize the treatment of PKU in females of childbearing age.

Sapropterin dihydrochloride use in pregnant women with phenylketonuria: an interim report of the PKU MOMS sub-registry.

For pregnant women with phenylketonuria (PKU), maintaining blood phenylalanine (Phe)<360µmol/L is critical due to the toxicity of elevated Phe to the fetus. Sapropterin dihydrochloride (sapropterin) lowers blood Phe in tetrahydrobiopterin (BH4) responsive patients with PKU, in conjunction with a Phe-restricted diet, but clinical evidence supporting its use during pregnancy is limited. As of June 3, 2013, the Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry contained data from 21 pregnancies - in women with PKU who were treated with sapropterin either before (N=5) or during (N=16) pregnancy. Excluding data for spontaneous abortions (N=4), the data show that the mean of median blood Phe [204.7±126.6µmol/L (n=14)] for women exposed to sapropterin during pregnancy was 23% lower, and had a 58% smaller standard deviation, compared to blood Phe [267.4±300.7µmol/L (n=3)] for women exposed to sapropterin prior to pregnancy. Women on sapropterin during pregnancy experienced fewer blood Phe values above the recommended 360µmol/L threshold. When median blood Phe concentration was <360µmol/L throughout pregnancy, 75% (12/16) of pregnancy outcomes were normal compared to 40% (2/5) when median blood Phe was >360µmol/L. Severe adverse events identified by the investigators as possibly related to sapropterin use were premature labor (N=1) and spontaneous abortion (N=1) for the women and hypophagia for the offspring [premature birth (35w4d), N=1]. One congenital malformation (cleft palate) of unknown etiology was reported as unrelated to sapropterin. Although there is limited information regarding the use of sapropterin during pregnancy, these sub-registry data show that sapropterin was generally well-tolerated and its use during pregnancy was associated with lower mean blood Phe. Because the teratogenicity of elevated maternal blood Phe is without question, sapropterin should be considered as a treatment option in pregnant women with PKU who cannot achieve recommended ranges of blood Phe with dietary therapy alone.

Importancia del diagnóstico precoz de fenilcetonuria en la mujer y del control de los niveles de fenilalanina en la gestación / Importance of early diagnosis of phenylketonuria in women and control of phenylalanine levels during pregnancy

La Fenilalanina Hidroxilasa (PAH) hidroxila a nivel hepático la fenilalanina proveniente de la dieta. Los fetos dependen para la hidroxilación de fenilalanina de la función materna, ya que por inmadurez fetal esta función no se adquiere hasta la semana 26. Los pacientes con deficiencia de PAH (Fenilcetonuria, PKU) no hidroxilan adecuadamente la fenilalanina de la dieta por lo que sus niveles en sangre estan elevados. Los niveles de fenilalaninemia se consideran teratogénicos y neurotóxicos por encima de 360 umol/L (N < 120). Las mujeres PKU embarazadas deberán seguir estrictamente un tratamiento dietético y/o farmacológico para mantener niveles de fenilalaninemia < 180 umol/L y evitar las posibles complicaciones teratogénicas en el feto (Sindrome Fetal de Hiperfenilalaninemia Materna), como el caso que presentamos. Recomendamos descartar Fenilcetonuria en mujeres en quienes no se haya realizado un despistaje neonatal y/o tengan abortos, hijos con microcefalia, cardiopatía o malformaciones renales (AU)

The phenylalanine hydroxylase (PAH) in the liver hydroxylates phenylalanine from the diet. Fetuses depend for the hydroxylation of phenylalanine the maternal metabolism , fetal maturity does not come until week 26. Though the women with PAH deficiency (phenylketonuria, PKU) not adequately hydroxylate phenylalanine diet so their blood levels are high. Fenilalaninemia levels are considered neurotoxic teratogenic and above 360 umol/L (N < 120). Pregnant women should strictly follow PKU dietary treatment and/or drug to maintain levels of fenilalaninemia < 180 umol/L and avoid the teratogenic complications in the fetus (Hyperphenylalaninaemias Maternal Fetal Syndrome), as the case presented. We recommend discarding Phenylketonuria in women who have not been done a neonatal screening and/or have abortions, children with microcephaly, cardiac or renal malformations (AU)

Maternal phenylketonuria: low phenylalaninemia might increase the risk of intra uterine growth retardation.

BACKGROUND: Malformations and mental retardation in the offspring of women with Phenylketonuria (PKU) can be prevented by maintaining maternal blood Phenylalanine (PHE) within a target range (120-300 µmol/L) through a PHE-restricted diet. In a former French study, a high and unexpected proportion of intra uterine growth retardation (IUGR) has been reported. Guidelines have been proposed to all French centres caring for maternal PKU since 2002. OBJECTIVE: To confirm IUGR and investigate its causes. The other goals were to assess the follow-up of these pregnancies based on the new guidelines and the pertinence of these recommendations. DESIGN: Clinical, biological and ultrasound data of all pregnancies in PKU women in France, from 2002 to 2007 were retrospectively analyzed. RESULTS: Data from 115 pregnancies in 86 women with PKU were collected. Ninety percent of women had been informed of the risk of maternal PKU in the absence of a strict diet during pregnancy, 88 % of women had started a diet before conception, and 45 % of infants were born small for gestational age (birth length and/or weight ≤-2 SD). PHE intakes were lower in the group with IUGR from the fifth to the eighth month of pregnancy and duration of time spent at <120 µmol/L during pregnancy was associated with a higher risk of IUGR. CONCLUSION: Hyperphenylalaninemia (HPA) is not the only risk factor for IUGR; PHE lower than 120 µmol/L could also be associated with the IUGR occurrence. Even if the monitoring of these pregnancies has been improved since the initiation of guidelines, we would like to stress on the importance of the dietary aspect of the disease.

Dietary treatment of phenylketonuria: the effect of phenylalanine on reaction time.

There is no evidence that high phenylalanine (Phe) levels have irreversible effects on the adult brain. Many adults with phenylketonuria (PKU) no longer follow a protein-restricted diet. Neuropsychological studies have shown that reaction time in adults with PKU is slower than controls. There are no data to show that this is directly related to Phe levels. Another way to assess reaction time is to measure saccadic latency. We have used a portable, head-mounted saccadometer to measure latency in the outpatient setting. Patients with PKU were split into three groups: off-diet (Phe >1,200 µmol/l), on-diet (Phe < 800 µmol/l) and maternal diet (Phe 100-400 µmol/l ). Reciprocal median latency (RML) was compared between groups. Latency was significantly slower in patients who were off-diet than in patients on-diet, on a maternal diet or in normal controls. Reaction times in both diet-treated groups were not significantly different from normal controls. In 16 women planning pregnancy we obtained values before and after they commenced the maternal diet. Stricter control of Phe levels resulted in a significant improvement in reaction times. We conclude that saccadometry is useful in monitoring PKU patients. Adult patients with PKU not on a protein-restricted diet have significantly slower reaction times than controls. In addition, off-diet patients have significantly slower reaction times than on-diet. Paired data show that effects of Phe levels on reaction time are reversible.

Síndrome de fenilquetonuria materna, un nuevo desafío para Chile / Maternal phenylketonuria syndrome, a new challenge for Chile

Phenylquetonuria (PKU) is a hereditary disease, caused by the deficiency or absence of the enzyme phenylalanine hydroxylase, which produces an abnormal conversion of phenylalanine (Phe) to tyrosine. If PKU is not diagnosed and treated during the neonatal period, blood accumulation of Phe causes neurological damage. Chile has a neonatal screening program for PKU and congenital hypothyroidism since 1992; this program has diagnosed 162 PKU patients in Chile, which are being followed-up in INTA, Universidad de Chile. Nowadays, there are 20 PKU patients in adolescence, so we face a new challenge such as maternal PKU syndrome. This syndrome refers to the teratogenic effect of Phe in a pregnant PKU female. The most frequent anomalies are intrauterine growth retardation, microcephaly, global development retardation and congenital heart defects. Their occurrence is directly related to maternal Phe during pregnancy. In order to assure a normal pregnancy and to prevent this syndrome, levels of Phe in blood should be kept between 2 and 6 mgldl prior to conception and throughout pregnancy. Considering this challenge, INTA has proposed a strict protocol of follow-up to improve the compliance to nutritional therapy and prevent maternal PKU syndrome.

La fenilquetonuria (PKU) es una patología hereditaria, producida por la deficiencia o ausencia de la enzima fenilalanina hidroxilasa, lo que impide la metabolización normal de la fenilalanina (FA) a tirosina. La acumulación de fenilalanina en la sangre ocasiona daño neurológico si no es diagnosticada y tratada desde el periodo neonatal. Desde 1992 Chile tiene un programa de pesquisa neonatal de PKU e hipotiroidismo congénito, lo que ha permitido diagnosticar 162 casos con PKU, los que mantienen un seguimiento integral en el INTA, de la Universidad de Chile. Actualmente hay 20 PKU en etapa de adolescencia, por lo que nos enfrentamos a un nuevo desafío, el síndrome de PKU materna. Este síndrome se refiere al efecto teratogénico de la FA en una embarazada con PKU. Las alteraciones más características son el retraso del crecimiento intrauterino, la microcefalia, el retraso global del desarrollo y los defectos cardiacos congénitos. La presencia de estas alteraciones está directamente relacionada con los niveles de FA de la madre durante el embarazo. Para asegurar un embarazo normal y prevenir este síndrome se recomienda la mantención de niveles de FA entre 2 y 6 mg/dl, desde el período preconcepcional y durante todo el embarazo. El INTA considerando este desafío, ha propuesto un protocolo de seguimiento estricto preconcepcional y durante el embarazo con el objetivo de favorecer la adherencia al tratamiento nutricional y prevenir el síndrome de PKU materna.

[The maternal phenylketonuria syndrom--still current problem]. / Zespól fenyloketonurii matczynej--problem nadal aktualny.

UNLABELLED: Phenylketonuria (OMIM 261600) is a congenital genetically conditioned error of metabolism phenylalanine to tyrosine. Being untreated or insufficiently treated phenylketonuria (PKU) sometimes leads to irreversible damage of mielin. Similarly, high phenylalanine concentration in the blood of pregnant woman with PKU exert the teratogenic effect on growing and developing foetus (in the majority of cases being the carrier of PKU), which leads to appearance of maternal phenylketonuria syndrom (MPKU syndrom). The features of MPKU syndrome consist: low weight at birth, the congenital heart defects, digestive tract defects, osseous arrangements, microcephaly, handicap of intellectual development. Spontaneous miscarriages at pregnant women with PKU are more often. THE AIM OF WORK: the evaluation of influence hyperphenylalaninemia of pregnant woman with PKU on her foetus, depending on the metabolic control in the pre- and postconception period. MATERIAL AND METHOD: under the care of Outpatient Metabolic Clinic of University Children's Hospital in Cracow remain 430 patients aged from 0 to 56 years with hyperphenylalaninemia. In the register of Outpatient Metabolic Clinic there are the data about 50 pregnancies of 21 women with hyperphylalaninemia (from mild hyperphenylalaninemia to classic PKU). Only 10 pregnancies were planned - the low-phenylalanine diet was obligatory introduced 3 months before conception and was applied throughout the whole period of pregnancy in order to maintain the levels of phenylalanine in the range of 2 to 6 mg/dl. One pregnancy finished with spontaneous miscarriage, the other 9- the birth of healthy offspring. By contrast, out of 40 unplanned pregnancies 8 ended in spontaneous miscarriage, and of the remaining 32 unplanned pregnancies 33 children were born: 24 (75%) newborns with the maternal PKU features, 1 child died during thel-st year of life, 3 have the lack of any data, and only 5 (15.6%) children were born clinically healthy (1 twin birth). Among the children with maternal PKU syndrome: microcephaly was diagnosed in 17 cases, congenital heart defect and microcephaly in 6 children, and microcephaly and the anal atresia in 1 child. Among the children, born from unplanned pregnancies, there are two (twins), whose mother from the 6 week of gestation had returned to applying diet (average phe levels 6.37 mg/dl); two children of mothers who were conducting the therapeutic implemented since 18-th and 32-th weeks of gestation (average phe 7.5 mg/dl) (there is the lack of detailed data about these children, because the women are never reported to our Outpatient Clinic), and one child, whose mother raised and began the therapy from 12-th week of gestation (average phe levels 10.37 mg/dl), who presents the features of ADHD syndrome. CONCLUSIONS: 1. All pregnancies of women with hyperphenylalaninemia should be planned to avoid the complications in the form of maternal PKU syndrom. 2. It is essential to educate the women with PKU and their families about the problems concerning maternal PKU. 3. It is also necessary to inform pediatricians, family physicians and gynaecologists-obstetricians about the features of maternal PKU syndrom.

Phenylalanine tolerance in three phenylketonuric women pregnant with fetuses of different genetic PKU status.

Pregnancy management in phenylketonuric women includes continuous dietary control starting before conception, aiming to maintain blood phenylalanine concentrations in a desirable range, irrespective of the fetal genetic PKU status. While the maternal phenylalanine hydroxylase (PAH) genotype will influence metabolic control, an effect of the fetal genetic PKU status on maternal metabolic control during pregnancy has not been described. We monitored three pregnancies of women with classical PKU by dietary protocols of daily phenylalanine intake, phenylalanine blood concentrations, and obstetric care. Patients 1 and 2 carried a heterozygous (not PKU-affected) fetus, while patient 3 was pregnant with a PKU-affected fetus (PAH p.R408W and p.R408W). The expected increase in phenylalanine tolerance during the course of pregnancy was observed in patients 1 and 2 in whom phenylalanine intake could be steadily increased from 400 to 1700 mg/day while phenylalanine blood concentrations remained in the desired range. Gain of body weight was 13.0 and 17.7 kg, respectively. In patient 3, the phenylalanine tolerance did not rise above 600 mg/day, and phenylalanine blood concentrations were above the desired range on several occasions. Caloric intake was therefore encouraged, which led to a weight gain of 20.0 kg. The course of pregnancy was otherwise normal in all three cases, and infants with normal birth weight and head circumference were born. The different phenylalanine tolerance in pregnancies with PKU-affected and non-affected fetuses suggests that PAH genotype and metabolic situation of the fetus influence maternal metabolic control. A phenylalanine tolerance remaining low in the third trimester of pregnancy may indicate fetal PKU.

ACOG Committee Opinion No. 449: Maternal phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by a deficiency of the hepatic enzyme, phenylalanine hydroxylase, an enzyme responsible for the conversion of phenylalanine to tyrosine, and elevated levels of Phe and Phe metabolite. All women with PKU or hyperphenylalaninemia should be strongly encouraged to receive family planning and preconception counseling. Women with PKU or hyperphenylalaninemia should begin appropriate, medically directed dietary phenylalanine restriction before conception.

A practical approach to maternal phenylketonuria management.

More women with phenylketonuria are becoming pregnant and need appropriate management to avoid the effects of raised phenylalanine on the fetus: facial dysmorphism, microcephaly, growth retardation, developmental delay and congenital heart disease. Here we describe our experiences from a single centre gained over almost three decades. A series of six cases is presented to illustrate key points in management. Ideally, phenylalanine-restricted diet is started before conception in a planned fashion, but some women present pregnant and blood phenylalanine must be lowered rapidly. The aims of management are to maintain blood phenylalanine concentration in the target range (100-250 micromol/L) before and throughout the pregnancy, and to ensure adequate maternal nutrition and appropriate weight gain. Blood phenylalanine is monitored twice, three times a week, before and after conception respectively. Weight is monitored on a weekly basis and key micronutrients are monitored every 6-8 weeks in clinic. From the second trimester onwards, dietary phenylalanine intake has to be promptly increased, as phenylalanine tolerance increases rapidly. Postnatal management includes a neurological assessment of the infant at 4-8 weeks and an echocardiogram for infants conceived off diet. Subsequently, offspring are seen at 1 year, 4 years, 8 years and 14 years for neuropsychometric evaluations. Regular follow-up of the mother remains important whether on or off a phenylalanine-restricted diet.

Maternal phenylketonuria: report from the United Kingdom Registry 1978-97.

BACKGROUND: The effects of maternal phenylalanine on the fetus include facial dysmorphism, microcephaly, intrauterine growth retardation, developmental delay, and congenital heart disease. AIMS: To evaluate the impact of phenylalanine restricted diet in pregnant women with phenylketonuria (PKU) on their offspring. METHODS: Data on virtually all pregnancies of women with PKU in the United Kingdom between 1978 and 1997 were reported to the United Kingdom PKU Registry. The effect of the use and timing in relation to pregnancy of a phenylalanine restricted diet on birth weight, birth head circumference, the presence or absence of congenital heart disease (CHD), 4 year developmental quotient, and 8 year intelligence quotient were examined. RESULTS: A total of 228 pregnancies resulted in live births (seven twin pregnancies were excluded). In 110 (50%), diet started before conception. For this group mean (SD) birth weight was 3160 (612) g, birth head circumference 33.6 (1.9) cm, 4 year DQ 108.9 (13.2), 8 year IQ 103.4 (15.6), and incidence of CHD was 2.4%. In comparison, for those born where treatment was started during pregnancy (n = 91), birth weight was 2818 (711) g, birth head circumference 32.7 (2.0) cm, 4 year DQ 96.8 (15.0), 8 year IQ 86.5 (13.0), and incidence of CHD was 17%. Month-by-month regression analyses suggested that metabolic control by 12-16 weeks gestation had most influence on outcome. CONCLUSIONS: Many features of the maternal PKU syndrome are preventable by starting a phenylalanine restricted diet. Women with PKU and their carers must be aware of the risks and should start the diet before conception, or as soon after as possible.

Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy.

OBJECTIVES: The Maternal Phenylketonuria Study was designed to determine the effect of a phenylalanine (Phe)-restricted diet in reducing the morbidity on the fetus. Congenital abnormalities were noted, with the focus on the effect of congenital heart defects (CHDs) and microcephaly (MICRO) on developmental outcome at 4 and 6 years of age. STUDY DESIGN: Women with blood Phe levels >240 micromol/L (n=526; to convert micromol/L to mg/dL, divide by 60) were enrolled; 382 contributed 572 pregnancies. The women had 413 offspring examined at birth and annually. At 4 years, the McCarthy General Cognitive Index was administered, and at 6 years, the Wechsler Intelligence Scale for Children Revised was administered. RESULTS: Microcephaly was noted in 137 (33%) of the offspring, and 32 (7.7%) had CHD. Maternal blood Phe levels were higher for infants with CHD and MICRO than for infants with CHD only (P=.02). Mean Phe levels at 4 to 8 weeks gestation predicted CHD (P<.0001). The McCarthy General Cognitive Index score was lower with CHD (P=.005) and MICRO (P=.0017), as was the Wechsler Intelligence Scale for Children Revised full-scale IQ score (P=.0002 for CHD and P=.0001 for MICRO). None of the subjects who had offspring with CHD had Phe control between 120 and 360 micromol/L during the first 8 to 10 weeks of gestation. CONCLUSIONS: Women with phenylketonuria need to be educated regarding diet for life. This should help improve diet control before conception and throughout pregnancy.

The Maternal Phenylketonuria Project: a summary of progress and challenges for the future.

The results of the International Collaborative Study of Maternal phenylketonuria have shown that dietary phenylalanine restriction of women with hyperphenylalaninemia during pregnancy decreases the incidence of mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation in their offspring. The best results are achieved when treatment is initiated before conception. Psychosocial problems are the most pervasive obstacle to the achievement of optimum dietary treatment. Novel, nondietary approaches to the treatment of maternal phenylketonuria are under development.

The National Institute of Child Health and Human Development and phenylketonuria.

The National Institute of Child Health and Human Development (NICHD) was established shortly after the Guthrie test for screening newborn infants for phenylketonuria (PKU) was introduced. The NICHD supported the study demonstrating the long-term efficacy of screening and a low-phenylalanine diet in preventing mental retardation. With the identification of the adverse impact on fetal development of high intrauterine phenylalanine exposure from a mother with PKU, the NICHD organized and supported the study reported here, demonstrating the protective effect of phenylalanine restriction of the mother's diet during pregnancy. The study provides clear guidance for the management of pregnancy in women with PKU.

Historical background for the maternal PKU syndrome.

OBJECTIVE: To provide information on the history of maternal phenylketonuria. METHODS: A review of the literature and personal observations were conducted. RESULTS: Compilation of sequential information about the development of our understanding of maternal PKU was produced. CONCLUSIONS: The history of maternal PKU reflects continuous additions to our understanding of this teratogenic syndrome.

Research design, organization, and sample characteristics of the Maternal PKU Collaborative Study.

OBJECTIVE: The Maternal PKU Collaborative Study (MPKUCS) was initiated in 1984 by the National Institute of Child Health and Human Development (NICHD). The purpose was to assess the efficacy of dietary restriction of phenylalanine in reducing morbidity in offspring of women with hyperphenylalaninemia (HPA). A contract was awarded to Childrens Hospital Los Angeles as the Coordinating Center to provide implementation of the research protocol, data collection, and analysis. METHODS: The Study included four regional contributing centers: Childrens Hospital Los Angeles (Western Region), Boston Children's Hospital (Northeast Region), University of Illinois (Midwest Region), and University of Texas Medical Branch, Galveston (Southeast Region). Within each region, many participating clinics were responsible for obstetric care, treatment, and monitoring protocols. In 1985, Canada joined the MPKUCS, and in 1992, Germany entered. They were selected because they provided dietary supplies and strong professional services. Acquisition began in 1984 and ended in October 1995. The study included 574 pregnancies in women with HPA and 100 control subjects matched on age, race, parity, and weeks of gestation. The sample included women with blood phenylalanine values >240 micromol/L, 66% of whom had classical PKU, 22% had atypical PKU, and 12% had mild HPA. Informed consents were obtained on all participants. The women ranged in age from 15 to 36 years of age, with a mean age at conception of 23 years. Teenage pregnancies accounted for 19%. Seventy-five percent graduated from high school. Offspring included 416 newborns, 317 of whom were evaluated at 4 years of age and 289 at 6 to 7 years. Follow-up involved medical, nutritional, psychosocial, and psychological assessments. CONCLUSION: Women with PKU treated before conception and in control of their blood phenylalanine levels between 120 and 360 micromol/L (2-6 mg) exhibited normal pregnancies and neonatal outcome. Surprisingly, women who achieved control in the recommended range by 8 weeks of pregnancy also had a normal fetal outcome.

The Maternal Phenylketonuria International Study: 1984-2002.

OBJECTIVE: The purpose of this report is to review the obstetric medical, psychological, and nutritional aspects and outcome of the women and offspring enrolled in the Maternal Phenylketonuria Study, which was established to assess the efficacy of a phenylalanine (Phe)-restricted diet in preventing the morbidity associated with this disorder. METHODS: A total of 382 women with hyperphenylalaninemia (HPA) were enrolled in the study and completed 572 pregnancies. Outcome measures were analyzed with chi2, Fisher exact text, analysis of variance, t test, Wilcoxon nonparametric test, and multiple logistic regression. Outcome measures were stratified according to maternal HPA classification and the time when dietary control was achieved. RESULTS: Optimal birth outcomes occurred when maternal blood Phe levels between 120 and 360 micromol/L were achieved by 8 to 10 weeks of gestation and maintained throughout pregnancy (trimester averages of 600 micromol/L). Mothers with mild HPA achieved similar birth outcomes as mothers who were in control preconceptually and those in control by 8 to 10 weeks of pregnancy. CONCLUSIONS: Before conception, counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with HPA. The achievement of pre- and periconceptional dietary control with a Phe-restricted diet significantly decreased morbidity in the offspring of women with HPA.