Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU-MOMs sub-registries.

Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 µmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk-benefit ratio when used during pregnancy. Data from the maternal sub-registries-KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU-MOMs sub-registry)-were collected to assess the long-term safety and efficacy of sapropterin in pregnant women in a real-life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as 'normal' at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well-tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real-world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.

Partial hydatidiform mole in a phenylketonuria patient treated with sapropterin dihydrochloride.

Strict control of hyperphenylalaninemia is necessary in pregnant women with phenylketonuria (PKU) in order to prevent phenylalanine embryopathy in the fetus, characterized by intrauterine growth restriction, dysmorphic facies, congenital heart disease, microcephaly and intellectual disability, collectively known as maternal PKU syndrome. Sapropterin dihydrochloride (SD), an alternative or adjunct to dietary therapy in patients with tetrahydrobiopterin (BH4)-responsive PKU, has recently been used in several cases to treat PKU during pregnancy with satisfactory results. Here, we report two pregnancies treated with SD and unrestricted diet in a patient with BH4-responsive mild PKU. The first pregnancy resulted in a partial hydatidiform mole and was terminated, whereas a healthy infant was born from the second pregnancy. Phenylalanine control was optimal in both pregnancies. To the best of our knowledge, this is the first report on the development of partial hydatidiform mole associated with SD treatment and the second report on molar pregnancy in PKU. While the relation between SD and molar pregnancy is unknown, further studies may be needed to investigate the possible effects of SD on fertilization.

A new case of maternal phenylketonuria treated with sapropterin dihydrochloride (6R-BH4).

PURPOSE: A woman with phenylketonuria (PKU) was diagnosed through neonatal screening, her PAH mutation was p.V388M/p.I65T, for which she received treatment with phenylalanine restriction, and was administered oral sapropterin dihydrochloride (6R-BH(4)) from the age of thirty. The purpose of this article is to describe the treatment with BH4 during her pregnancy and to evaluate a plan for its use. METHODS: The patient had an unplanned pregnancy at 34 years of age, for which she received a phenylalanine-free supplement enriched with essential fatty acids, vitamins and trace elements. RESULTS: The dose of 6R-BH(4) was reduced from 500 mg/day to 100 mg/day until its suspension in the 28th week of gestation, and was well tolerated. Blood phenylalanine control was easily accomplished during this pregnancy, and no nutritional deficiency was seen. CONCLUSION: The pregnancy had a normal outcome, and so we consider that adaptation of the dose of 6R-BH(4) to the prenatal periods aided a greater efficiency and a lower risk in the treatment of maternal PKU.

Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases.

Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA labels. We collected data from eight pregnancies in PKU women treated with SD and we analysed the phenotypes of these patients, their tetrahydrobiopterin (BH4) responsiveness, the indications for SD treatment, the efficacy (metabolic control, phenylalanine (Phe) tolerance and offspring outcome) and the safety data. Results showed that in the seven patients known to be responsive to BH4, the use of SD during pregnancy was efficient in terms of metabolic control and Phe tolerance. The indications for giving SD included the failure of the low-Phe diet (n = 3), the fact that some of these women had never experienced the low Phe diet (n = 2), one unexpected pregnancy in a woman currently on SD and one pregnancy where the foetus was known to have PKU. The offspring of these seven pregnancies were all normal babies with normal birth measurements and outcomes. No side effect related to SD was observed in these seven cases. In the eighth case, SD was prescribed as a rescue treatment without previous knowledge of the BH4 responsiveness to a woman who was already 8 weeks pregnant without diet. The birth occurred at 33 weeks of gestational age with Potter syndrome (probably related to the absence of metabolic control during the first trimester) and the baby died in the first hours of life. In conclusion, the data presented here provides the first evidence that treatment with pharmacological doses of SD appears to be efficient and safe in women with PKU during pregnancy. Its use should, however, be restricted to those women previously identified to be clear responders to BH4.

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.

Potential role of tetrahydrobiopterin in the treatment of maternal phenylketonuria.

OBJECTIVE: To evaluate the clinical relevance of tetrahydrobiopterin (BH4) supplementation for pregnant women with phenylketonuria (PKU)/hyperphenylalaninemia (HPA) and the possibility of treating these patients with BH4 instead of a phenylalanine (Phe)-restricted diet. METHODS: Genotyping was performed on 41 patients with PKU/HPA identified by newborn screening. Evaluating the genotype according to their BH4 responsiveness is published. Follow-up of 3 patients with mild PKU treated with BH4 is evaluated. Discussion of the transfer of these experiences to the possibility of treating mothers at risk for maternal PKU is presented. RESULTS: In 41 patients with PKU/HPA, we found 17 (41%) bearing at least 1 allele with a mutation described as being responsive to BH4. In 8 of the patients, BH4 loading had been performed in the newborn period, in 6 of whom the test showed a clear decrease of blood Phe 4 and 8 hours after loading. One of the nonresponders was reinvestigated at 3 years of age, showing a clear response (genotype Y414C/R408W): BH4 supplementation resulted in a much higher Phe tolerance (500 instead of 250 mg/day) with blood Phe levels <200 micromol/L. Two children (genotype E390G/IVS10-11g>a and L48S/L48S, respectively) were treated with BH4 only (15-20 mg/kg body weight/day), one from birth, the other from 2 years of age. Blood Phe decreased from >800 micromol/L to a mean of 321.4 and 331.7 micromol/L, respectively (range: 141-718 micromol/L) under a normal diet (total observation time: 4 years). Development was normal with no adverse reactions. CONCLUSIONS: BH4 supplementation seems to be a promising alternative treatment in some patients with mild PKU. Because blood Phe levels in maternal PKU should be maintained at 120 to 360 micromol/L, clinical relevance may be even greater than for treatment of children with PKU/HPA. BH4 supplementation may also be combined with a Phe-restricted diet, allowing higher Phe intake and protecting mothers from high Phe blood peaks. However, additional studies are necessary to prove the safety and economy of such an alternative treatment in patients with PKU/HPA, especially during 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.