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Maternal phenylketonuria (PKU) has adverse effects on the offspring including microcephaly, mental retardation, congenital heart disease, and intrauterine growth retardation. Maternal non-PKU mild hyperphenylalaninaemia (MHP) is believed to be benign, but whether there may be long-term consequences to offspring is unclear. In an international survey we have obtained information about 86 mothers with MHP (blood phenylalanine 167-715 mumol/L), their 219 untreated pregnancies, and 173 offspring. Spontaneous fetal loss (13% of pregnancies), congenital heart disease (2.3% of offspring), and severe non-cardiac anomalies (2.9% of offspring) occurred at frequencies within expected limits for the general population. For weight and length at birth the median percentile was the 50th but that for birth head circumference was the 25th. Median z-scores for birth length and head circumference were significantly lower for offspring of mothers with phenylalanine concentrations above 400 mumol/L than for those whose mothers had lower values (p = 0.05 and p = 0.005, respectively). The median intelligence quotient (IQ) of the offspring (3-27 years) was 100 for those whose mothers had higher phenylalanine concentrations and 108 for those of the lower phenylalaninaemia group. However, offspring IQ correlated slightly more closely with maternal IQ (r = 0.53, p < 0.001) than with maternal phenylalanine concentration (r = 0.45, p = 0.02). Maternal MHP does not seem to have serious consequences for the fetus. A maternal phenylalanine concentration of less than 400 mumol/L does not warrant intervention. Nevertheless, maternal blood phenylalanine above this value is associated with slightly lower birth measurements and offspring IQ than lower maternal blood phenylalanine concentrations.
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PMID:Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. 784 32

Maternal phenylketonuria (PKU) is associated with significant complications such as mental retardation, microcephaly and congenital heart defects in nonphenylketonuric offspring. Dietary control with a low phenylalanine diet during the gestation period is effective in improving perinatal outcome in these cases. We present the case of a 27-year-old woman with classical features of PKU who had previously given birth to three babies, all of whom died of congenital heart disease. A low phenylalanine diet was started one month prior to the pregnancy and satisfactory fetal outcome was achieved.
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PMID:Successful management of a pregnancy with maternal phenylketonuria: report of a case. 810 49

The maternal phenylketonuria (PKU) syndrome refers to the teratogenic effects of PKU during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation. In untreated pregnancies wherein the mother has classic PKU with a blood phenylalanine level > or = 1,200 microM (20 mg/dl), the frequencies of these abnormalities in offspring are exceedingly high, approaching 75-90% for microcephaly and mental retardation and 15% for congenital heart disease. There is a dose response relationship with progressively lower frequencies of these abnormalities at lower phenylalanine levels, both in the pregnancies of women with variants of PKU and in treated classic PKU pregnancies. The pathogenesis of this syndrome is unknown; it may be related to inhibition by phenylalanine of large neutral amino acid transport across the placenta or to direct toxicity of phenylalanine and/or a phenylalanine metabolite in certain fetal organs. A mouse model for PKU now exists, and studies of maternal PKU in this model are in progress. The treatment of maternal PKU consists of biochemical control through a phenylalanine restricted diet during pregnancy. The best results are obtained with diet initiation before conception or no later than the earliest weeks of pregnancy. Women with PKU and their families require much psychosocial support to meet the strict requirements of a maternal PKU pregnancy, including compliance with a difficult diet. With such compliance, however, it seems that bearing normal or near normal offspring is possible.
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PMID:Maternal phenylketonuria: a metabolic teratogen. 876 85

The reproductive effects of metabolic disorders in women can be divided into four categories. The first of these is infertility. Galactosemia with its complication of ovarian failure is the disorder in this category. This complication may be prenatal in origin but whether this is so and its cause are unknown. The second category includes pregnancy effects of maternal metabolic disorders. The urea cycle disorder ornithine transcarbamylase (OTC) deficiency, maternal maple syrup urine disease and maternal homocystinuria are in this category. In the first two disorders, postpartum life-threatening illness due to metabolic crisis has occurred. Maternal homocystinuria is associated with a high risk for postpartum thromboembolic complications. The third category is the pregnancy effect of a fetal metabolic disorder. Pregnancies in which the fetus had long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) have been complicated by the life-threatening (HELLP) syndrome during the third trimester. Rapid recovery of the mothers followed delivery, on occasion by emergency cesarean section. The fourth category is the fetal effects (teratogenicity) from a maternal metabolic disorder. The best-known example of this is maternal phenylketonuria (PKU), which produces microcephaly, mental retardation, congenital heart disease and intrauterine growth retardation. Treatment with a low phenylalanine diet begun before conception or no later than the earliest weeks of the first trimester markedly reduces the risk to the fetus and can result in normal offspring. Other examples of teratogenicity may include maternal homocystinuria and maternal hypothyroidism.
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PMID:Reproductive effects of maternal metabolic disorders: implications for pediatrics and obstetrics. 882 3

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 mumol/l 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.
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PMID:Outcome implications of the International Maternal Phenylketonuria Collaborative Study (MPKUCS): 1994. 882 36

By November 1994, 39 pregnancies had been completed in phenylketonuric mothers. Dietary control was post-conception in 6 and 2 of these offspring died of congenital heart disease and 1 other needed surgery for coarctation. There were no heart defects in the 34 offspring of the 33 pregnancies following preconception diet controlled by Guthrie assays of maternal phenylalanine three (Phe) weekly. These Phe results were analysed by trimester for the means, the number of days over 300 mumol/l or below 60 mumol/l. Generally good control was achieved suggesting the UK guidelines drawn up by the MRC Working Party are broadly achievable but excessively high and low values occur intermittently in many pregnancies both of which may adversely affect the fetus. Though developmental assessment scores at 1 year were over 100 in all but five, early outcome results suggest that intellectual development may still be impaired at 4 years. Until much more information is available caution is still needed in discussing outcome with phenylketonuria patients who wish to conceive.
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PMID:Maternal phenylketonuria. A study from the United Kingdom. 882 40

Maternal phenylketonuria (PKU) is teratogenic and results in birth defects that include microcephaly, mental retardation, congenital heart disease, and intrauterine growth retardation. Treatment with a low phenylalanine diet can prevent or reduce the severity of the complications. Optimal benefit, however, requires frequent monitoring with fetal ultrasonography as a critical element. We have studied ultrasonography in 39 pregnancies enrolled in the Maternal PKU Collaborative Study and followed at our centre. First-trimester examinations in 24 pregnancies resulted in the discovery of non-viability in five. In each, this led to discontinuation of the difficult and expensive diet. Among the 33 pregnancies with second-trimester evaluation, congenital heart disease was identified in five. Two of these pregnancies were terminated. Microcephaly as determined by biparietal diameter (BPD) was identified in the second trimester in only one of nine fetuses who had microcephaly at birth. Among 20 pregnancies with third-trimester ultrasound, fetal microcephaly was identified by BPD in three of seven who had birth microcephaly. We conclude that fetal ultrasonography in maternal PKU is valuable during the first trimester in identifying non-viable pregnancies and determining gestational age and is also valuable during the second trimester in identifying congenital heart disease and perhaps other major anomalies, but not in identifying fetal microcephaly. Third-trimester ultrasound seems to be of limited usefulness.
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PMID:Fetal ultrasonography in maternal PKU. 884 68

Maternal phenylketonuria (PKU) in untreated women has resulted in offspring with microcephaly, mental retardation, congenital heart disease (CHD), and intrauterine growth retardation. The Maternal Phenylketonuria Collaborative Study (MPKUCS) was designed to determine the effect of dietary control of blood phenylalanine (Phe) during pregnancy in preventing damage to the fetus associated with untreated Maternal PKU. A cohort of offspring from MPKUS pregnancies was ascertained and examined to evaluate malformations, including CHD, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal neurological signs. For analysis, the women were grouped according to their mean Phe levels in mumol/liter, < or = 360, 361-600, 601-900, or > 900, during critical gestational weeks of 0-8 (N = 203) and 8-12 (N = 190), and average for Phe exposure throughout pregnancy (N = 183). Frequencies of congenital abnormalities increased with increasing maternal Phe levels. Significant relationships included average Phe 0-8 weeks and CHD (P = 0.001); average Phe 8-12 weeks and brain, fetal, and postnatal growth retardation (P < 0.0005 for all), wide nasal bridge (P < 0.0005), and anteverted nares (P = 0.001); and average Phe exposure during the entire pregnancy and neurological signs (P < 0.0005). Although 14% of infants had CHD, none of the CHD occurred at 120-360 mumol/liter and only one (3%) at 361-600 mumol/liter. At levels of 120-360 mumol/liter, there were three infants (6%) with microcephaly, two (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with Phe above 900 mumol/liter. These data support the concept that women with PKU should begin a low-phenylalanine diet to achieve Phe levels of < 360 mumol/liter prior to conception and should maintain this throughout pregnancy.
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PMID:Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. 906 90

Screening programmes in child health have evolved on the basis of individual enthusiasm and professional consensus, rather than being based on objective evidence of benefit. Three reviews have been carried out in the UK over the past 10 years. The only programmes which show robust evidence of effectiveness are those for PKU and hypothyroidism. The value of screening for hearing loss and vision defects is widely accepted, but there are many unresolved issues. Programmes for detection of congenital dislocation of the hip, congenital heart disease and growth disturbances are of doubtful value. Early identification of developmental problems is stressed by parents, but screening may not be the best way to achieve this. The UK programme of well-child care places increasing emphasis on promotion of physical and emotional health; screening tests should either be subjected to quality monitoring, or removed from the programme if they cannot fulfil the classic criteria of Wilson and Jungner.
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PMID:Screening in child health. 1036 24

Phenylketonuria in pregnancy carries with it an increased risk of spontaneous abortion and development of a fetus that is affected by the maternal phenylketonuria syndrome. This syndrome is characterized by low birthweight, congenital heart disease, microcephaly, childhood growth failure, and cognitive impairment. It is the result of the hyperphenylalaninemia that accompanies the phenylketonuric state, and may therefore be avoided by maintaining maternal serum phenylalanine levels within the normal range. Phenylalanine is an essential amino acid and may be controlled by dietary manipulation. Presented here is a case history of a woman with phenylketonuria who was unable to satisfactorily control her serum phenylalanine levels in each of her three pregnancies. All three children were adversely affected by the fetopathy of the maternal phenylketonuria syndrome, each with evidence of growth failure and impaired neurodevelopment. This patient illustrates the difficulties that may be encountered when providing obstetric care to the woman with phenylketonuria who is not able or not willing to restrict her dietary intake of phenylalanine. The discussion includes consideration of management strategies, including dietary therapy and legal intervention.
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PMID:Repeated adverse fetal outcome in pregnancy complicated by uncontrolled maternal phenylketonuria. 1057 68


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