Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria.

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 µmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 µmol/L planned vs. 467 µmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 µmol/L planned vs. 414 µmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy.

The first study of successful pregnancies in Chinese patients with Phenylketonuria.

BACKGROUND: Since the inception of newborn screening programs in China in the 1990s, pregnancy among patients with inherited, metabolic disorders has become more common. This study explores the management and outcomes of planned, full-term pregnancies in patients with phenylketonuria (PKU). METHOD: Married patients with PKU from 2012 to 2017 were enrolled to receive prenatal counseling and regular health assessments. Study-related assessments included the timing of Phe-restricted diets, maternal weight gain, gestational age, pregnancy complications, and blood Phe concentrations (both pre-conception and during pregnancy), obstetrical data, and offspring outcomes(e.g. anthropomorphic measurements and developmental quotients [DQs]). RESULTS: A total of six offspring were successfully delivered. The mean ± SD (range) age of the mother at delivery was 26.3 ± 4.7 (range: 21.1-32.5) years. The mean duration of Phe control before pregnancy was 5.5 ± 1.3(range: 3.1-6.5) months. During pregnancy, the proportion of blood Phe concentrations within the clinically-recommended target range (120-360 µmol/L) ranged from 63.2-83.5%. Low birth weight (< 2500 g) offspring occurred in two women who experienced suboptimal metabolic control. In addition, offspring DQ was related to the proportion of blood Phe levels per trimester that were within the recommended range (r = 0.886, p = 0.016). CONCLUSION: This is the first report of women in China with PKU who successfully gave birth to clinically healthy babies. Infant outcomes were related to maternal blood Phe management prior to and during pregnancy. In maternal PKU patients with poor compliance to dietary treatment, sapropterin dihydrochloride (6R-BH4) may be an option to improve the management of blood Phe levels.

Medical Problems in Obstetrics: Inherited Metabolic Disease.

An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Although, in general, outcomes for women and their children are good, there are a number of issues that need to be considered. Currently, limited specific guidance on the management of these conditions in pregnancy is available. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in disorders of energy metabolism or intoxication significantly reduced. Multidisciplinary management, and close liaison between obstetricians and other specialists, is required for those women in whom there is cardiac, renal, respiratory, joint or other organ involvement.

Maternal Phenylketonuria International Collaborative Study revisited: evaluation of maternal nutritional risk factors besides phenylalanine for fetal congenital heart defects.

Maternal phenylketonuria (MPKU) is known to affect fetal outcome, often being associated with microcephaly and congenital heart defects (CHD) if the maternal diet is not appropriately managed. We hypothesized that other nutrients aside from phenylalanine (Phe) may have significant effects on fetal outcome in MPKU pregnancies. The 416 pregnancies that resulted in live births reported in the Maternal PKU Collaborative Study (MPKUCS) were grouped according to whether or not the offspring were diagnosed with CHD. The groups were compared on first-trimester values of maternal data, including weight gain, plasma amino acids, protein and Phe intake, and red blood cell (RBC) folate. Patients were also grouped by first-trimester average blood Phe (≤910 µmol/L and >910 µmol/L) and then divided by total natural protein and medical food intake. The CHD group of 28 offspring had significantly higher blood Phe and lower proline, valine, methionine, isoleucine, leucine, lysine, arginine, and RBC folate. A significantly higher risk for CHD was found in the groups with lower natural protein and medical food intake, regardless of blood Phe levels. Insufficient natural protein and medical food product intake appears to be a risk factor for CHD independent of first-trimester plasma Phe levels. Low RBC folate and plasma methionine levels in the CHD group may suggest involvement of global DNA hypomethylation.

Maternal hyperphenylalaninemia: rapid achievement of metabolic control predicts overall control throughout pregnancy.

Women with hyperphenylalaninemia are at risk of having offspring affected with the maternal phenylketonuria syndrome. Here we analyze the effect of the intervention of a nutritionist on plasma phenylalanine control in Maternal Hyperphenylalaninemia. We analyzed a retrospective cohort of 35 completed pregnancies in 20 women with Maternal Hyperphenylalaninemia who visited the metabolic nutritionist during the pregnancy to achieve metabolic control. Women who promptly achieved metabolic control had lower plasma phenylalanine concentrations for the remainder of the pregnancy when compared to women who did not achieve prompt control, and this difference reached statistical significance. The achievement of plasma phenylalanine concentrations within the desired target range by the time of the second visit to the nutritionist is a strong predictor of the ability to maintain the desired target range of plasma phenylalanine for the remainder of the pregnancy. Furthermore, we demonstrate that phenylalanine tolerance increases significantly by trimester in women with classical and variant hyperphenylalaninemia.

Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies.

BACKGROUND: Untreated maternal phenylketonuria or hyperphenylalaninemia may result in nonphenylketonuric offspring with neonatal sequelae, especially intellectual disability, microcephaly, and congenital heart disease (CHD). Dietary treatment to control phenylalanine concentrations can prevent these sequelae. OBJECTIVE: We aimed to present an overview of reported pregnancy complications and neonatal sequelae of maternal phenylketonuria or hyperphenylalaninemia in untreated and treated pregnancies. DESIGN: A MEDLINE and EMBASE search was conducted for case reports and case series that assessed maternal phenylketonuria or hyperphenylalaninemia during pregnancy. Pregnancy complications (spontaneous abortion, intrauterine-fetal-death, and preterm delivery) and neonatal sequelae [small for gestational age (SGA), microcephaly, CHD, intellectual or developmental disabilities (IDDs), and facial dysmorphism (FD)] were analyzed. Fifteen unpublished pregnancies from our clinic were added. RESULTS: We retrieved 196 pregnancies, of which 126 pregnancies were untreated and 70 pregnancies were treated. The occurrence of pregnancy complications was not significantly different between untreated and treated pregnancies. Except for SGA, all neonatal sequelae were more frequent in untreated pregnancies. Moreover, the occurrence of SGA, microcephaly, and IDDs was significantly related to the mean phenylalanine concentration in each trimester, whereas the occurrence of FD was related only to the first trimester. CONCLUSIONS: We present the largest cohort of untreated pregnant women with phenylketonuria or hyperphenylalaninemia since 1980. The results follow the general pattern reported by other researchers. We underline that the treatment of pregnant women with phenylketonuria or hyperphenylalaninemia is of great importance to prevent neonatal sequelae. We strongly recommend starting treatment before conception because we showed the deleterious effect of an increased mean first-trimester phenylalanine concentration on FD.

Enhancing the quality and efficiency of newborn screening programs through the use of health information technology.

A variety of efforts are underway at national, state, regional, and local levels to enhance the performance of programs for early detection of inherited diseases and conditions of newborn infants. Newborn screening programs serve a vital purpose in identifying nonsymptomatic clinical conditions and enabling early intervention strategies that lessen morbidity and mortality. Currently, the programs of most intense focus are early hearing detection and intervention, using physiological techniques for audiology screening and use of newborn dried blood spots for detection of metabolites or proteins representing inherited disorders. One of the primary challenges to effective newborn screening programs to date has been the inability to provide information in a timely and easily accessible way to a variety of users. Other challenging communication issues being faced include the complexity introduced by the diversity of conditions for which testing is conducted and laboratory methods being used by each state's screening programs, lack of an electronic information infrastructure to facilitate information exchange, and variation in policies that enable access to information while protecting patient privacy and confidentiality. In this study, we address steps being taken to understand these challenges, outline progress made to date to overcome them, and provide examples of how electronic health information exchange will enhance the utility of newborn screening. It is likely that future advances in science and technology will bring many more opportunities to prevent and preempt disabilities among children through early detection programs. To take their advantage, effective communication strategies are needed among the public health, primary care practice, referral/specialty service, and consumer advocacy communities to provide continuity of information required for medical decision-making throughout prenatal, newborn, and early childhood periods of patient care.

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.

Tetrahydrobiopterin and maternal PKU.

A 29-year-old woman with PKU is presented, who was successfully treated with phenylalanine restriction as well as oral BH4 during this pregnancy, with a normal outcome. Her PAH mutation was R408W/F39L. Remarkably, the blood phenylalanine control was easily accomplished during this pregnancy. The lack of nausea and vomiting during the first trimester suggests that the occurrence of CHD in babies born to women with PKU may be reduced with BH4.

Normal infant by a gestational carrier for a phenylketonuria mother: alternative therapy.

The consequences of pregnancies in untreated phenylketonuria (PKU) mothers are a high incidence of spontaneous abortion, intrauterine growth retardation with microcephaly, congenital malformations, and abnormal intellectual development. PKU fathers, on the other hand, produce normal children. Obviously children of PKU women and men are at least heterozygous, proving that the abnormalities produced by the PKU mothers are not genetic but "intrauterinely environmental." Exposure to the mother's metabolic abnormalities affects the fetus during the entire pregnancy. A PKU mother can produce a healthy infant if she maintains a very restricted and controlled diet before and during pregnancy. However, even the most recent reports describe a very high incidence of congenitally abnormal children of PKU mothers, hence dietary compliance is not working in all cases. A 26-year-old PKU patient with proven fertility underwent standard ovarian stimulation in preparation for oocyte retrieval. Following conventional co-incubation of the oocytes and her husband's sperm, two embryos were transferred to the gestational carrier's uterine cavity, resulting in a single intrauterine pregnancy. Birth was induced at 39 weeks of gestation. The male infant weighed 3486 g. Head circumference was 36 cm and length 50.5 cm; there was no evidence of any abnormality and/or malformation. At 1 year of age, the child's growth measurements and development assessments were normal. This describes the first reported successful term pregnancy of an untreated PKU mother with the help of a gestational carrier (GC), producing a normal infant. This is an alternative method that should be offered to PKU women who are unable and/or unwilling to maintain a well controlled diet before and during pregnancy.

HIV in pregnancy.

The Center for Disease Control (CDC) has recommended voluntary Human Immunodeficiency Virus (HIV) screening in all pregnant patients. Is the incidence of HIV in women of child bearing age in South Dakota high enough to warrant aggressive testing? Since HIV reporting began in 1985, there have been five cases of maternal to fetal transmission (vertical transmission) of HIV in the state of South Dakota. The incidence of heterosexual transmission of HIV is increasing in South Dakota and in the year 2000, there have been seven new cases of HIV/AIDS diagnosed in women between the ages of 15-39 years of age, "According to June Snyder of the South Dakota Department of Health in April 2001."

[Dietary recommendations for pregnant women affected with phenylketonuria]. / Recommandations diététiques pour les femmes enceintes atteintes de phénylcétonurie.

Prevention of embryopathy due to maternal phenylketonuria is possible thanks to a maternal-specific low-phenylalanine diet, which has to be started before conception and followed during the whole gestation. The setup of this diet implies knowing the recommended dietary allowances for normal pregnant women as well as for women with nutritional deficiencies. Women with phenylketonuria must be considered at risk for nutritional imbalance for two main reasons. First, most adult women with phenylketonuria have been on a vegetarian diet for many years without protein substitutes or medical control. Secondly, the strict diet for pregnant women with phenylketonuria may induce anorexia or nutritional deficits if it is not well tolerated or understood. Protein, iron, calcium, selenium, vitamin B 12 and caloric intakes are the most sensitive parameters. Close cooperation with an experienced medical and dietician team is required.

Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae.

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.

Psychosocial factors in maternal phenylketonuria: women's adherence to medical recommendations.

OBJECTIVES: This study identified factors predicting adherence to medical recommendations in maternal phenylketonuria, which can result in severe fetal damage. METHODS: Sixty-nine women with phenylketonuria, 68 of their acquaintances, and 69 women with diabetes mellitus were interviewed annually for 5 years. A model in which each stage in the maternal phenylketonuria life cycle represented a treatment-related goal provided a means to assess adherence. RESULTS: At the stages of prevention of unplanned pregnancy, treatment initiation, and diet continuation throughout pregnancy, attitudes and social support were associated with adherence to medical recommendations. No specific variables were associated with outcome at reproductive decision making, but women with phenylketonuria were more likely to delay making a decision, resulting in unplanned and, hence, untreated or late-treated pregnancy. CONCLUSIONS: Women with phenylketonuria differed from their acquaintances and diabetic women in many respects, suggesting that special programs are needed. Greater emphasis on reproductive decision making is especially needed. Interventions that focus on improving social support networks and attitudes about treatment may increase adherence to recommendations.