Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics

Abstract

Maternal phenylketonuria (MPKU) is a well-recognized complication of PKU and one of the most potent teratogenic syndromes of pregnancy. Virtually all offspring from untreated pregnancies in women with classic PKU have intellectual disabilities and microcephaly. Congenital heart disease and intrauterine growth retardation occur many times more often than expected in the general population. Control of maternal blood phenylalanine during pregnancy prevents most if not all of these complications. Previous studies demonstrated the benefits of treatment in terms of birth parameters and early development. In this study, physical examinations, a medical history, and neuropsychological evaluation were obtained in 47 children from 24 mothers with PKU who received treatment during pregnancy. Mothers were interviewed and administered an abbreviated IQ test. Associations between maternal factors and offspring outcomes were also analyzed.

The 21 male and 26 female offspring ranged in age from 1 month to 26 years with 21 (62%) over 6 years. Results indicated mean intercanthal distances above the 70th percentile. Microcephaly was present in 19% of offspring, with head circumference below the third percentile. None of the offspring had cardiac anomalies. Mean offspring IQ was 94 ± 19, with 12% performing in the range of intellectual disability (IQ < 70). Among children >5 years of age, 25% had learning disabilities, 31% had attention deficit hyperactivity disorder (ADHD), 22% were on ADHD medication, and 34% had a diagnosis of anxiety and/or depression. Among the 24 mothers, 12 reported following the diet for PKU. Only one woman on diet had a blood phenylalanine concentration <360 μmol/L (recommended range) and the majority had indications of poor nutritional status. Mean maternal Full Scale IQ was 94 ± 16 (range = 61–117), with 25% performing in the borderline intellectual range (IQ < 85). Verbal IQ was significantly lower than Performance IQ (p = 0.01, CI 2.7, 16.1). On the self-report Beck Depression Inventory, Second Edition, 25% received scores indicating mild to moderate depression, and on the Beck Anxiety Inventory, 46% reported mild to moderate anxiety. Offspring IQ correlated with maternal metabolic control during pregnancy (r = 0.51), maternal IQ (r = −0.62), and socioeconomic position (r = −0.48). Offspring with ADHD, learning disabilities, or emotional disturbances were more likely to have mothers with anxiety and/or depression. To ensure optimal offspring outcomes, healthcare providers need to assess maternal nutrition, blood phenylalanine concentrations, cognitive abilities, and socioeconomic position. Interventions can then be initiated that reduce psychosocial stressors and enhance adherence to diet and positive parenting, which in turn can lead to better cognitive functioning, behavior, and emotional well-being in their children.

Competing interests: None declared

Appendices

Compliance with Ethics Guidelines

Conflict of Interest

We wish to draw the attention of the editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work.

Dr. Susan Waisbren receives grant support from BioMarin Pharmaceuticals and has, in the past, consulted to the company with regard to psychological assessment of individuals with PKU. She also receives funds from the National Institutes of Health for the study of genomic sequencing in newborn screening.

Dr. Harvey Levy receives grant support from BioMarin Pharmaceuticals for a Phase 3 clinical trial of PEG-PAL enzyme therapy for PKU and for a PKUDOS study of outcome of Kuvan therapy in PKU. He also receives funds from the National Institute of Health for a Phase 2 crossover trial of glycomacropeptide in dietary therapy for PKU and for the study of genomic sequencing in newborn screening.

Frances Rohr, Vera Anastasoaie, Matthew Brown, Dr. David Harris, Al Ozonoff, Stephanie Petrides, and Ann Wessel have no conflicts of interest to disclose.

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki

Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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Author Contributions

Dr. Waisbren conceived and designed this study. She oversaw data collection, conducted data analyses, interpreted data and drafted the manuscript.

Frances Rohr, MS, RD, LDN assisted in data collection, analysis and interpretation. She contributed to the manuscript drafts.

Vera Anastasoaie, BA assisted in data collection, analysis and interpretation. She critically reviewed the manuscript.

Matthew Brown, BA assisted in data analysis and interpretation and critically reviewed the manuscript.

David Harris, MD assisted in data collection, analysis and interpretation and contributed to the writing and review of the manuscript.

Al Ozonoff: Assisted in data analysis and interpretation. He critically reviewed and revised the manuscript.

Stephanie Petrides, BA assisted in data collection, analysis and interpretation. She critically reviewed the manuscript

Ann Wessel, MD RD, LDN assisted in data collection, analysis and interpretation. She contributed to the manuscript drafts.

Harvey Levy, MD collected data, analyzed and interpreted the findings and contributed to the drafting of the manuscript.

This study was supported by a grant from the National PKU Alliance and the Milton Foundation from Harvard University.