# The First 1000 Days of PKU: A Narrative Review of Maternal PKU and Early Life Management After Positive Newborn Screening

## TL;DR

This review discusses how early nutrition and metabolic control in PKU during the first 1000 days of life can prevent neurological issues and support healthy development.

## Contribution

The paper provides a comprehensive narrative review of maternal and early life PKU management, emphasizing the importance of the first 1000 days.

## Key findings

- Optimized metabolic control in pregnant women with PKU reduces risks of miscarriage and congenital defects.
- Early dietary treatment in PKU infants helps maintain safe phenylalanine levels and supports neurodevelopment.
- Breastfeeding combined with Phe-free substitutes is feasible, but gut microbiota data remain limited.

## Abstract

Background/Objectives: The first 1000 days of life represent a critical window for growth and neurodevelopment, during which nutrition strongly influences brain development and metabolic programming. In phenylketonuria (PKU), dietary management is essential to prevent neurological impairment and later-life risk of non-communicable diseases (NCDs). This review examines current evidence on PKU from pregnancy through complementary feeding, highlighting the impact of nutritional strategies on neurodevelopmental and metabolic outcomes. Methods: This narrative review, following PRISMA guidelines, used a systematic search of PubMed and Scopus with defined PICO questions. Original research, reviews, and guidelines on PKU nutrition during the first 1000 days were included, emphasizing neurological and metabolic outcomes. Results: Articles addressed prenatal and postnatal factors in PKU. Optimised metabolic control in women with PKU is critical to prevent maternal PKU syndrome, reducing risks of miscarriage, congenital heart defects, microcephaly, and neurocognitive impairment. Pre-conception dietary management, frequent blood Phe monitoring, supplementation with Phe-free protein substitutes (PSs), micronutrients, and emerging pharmacological therapies support maternal and foetal health. Following newborn screening, early dietary treatment in infants with PKU maintains plasma Phe within safe ranges, promoting growth and neurodevelopment. Breastfeeding, combined with Phe-free infant PSs, is feasible, and complementary feeding should be introduced carefully. Frequent monitoring and tailored dietary adjustments, including second-stage PSs, support metabolic control, while data on gut microbiota remain limited. Conclusions: Early multidisciplinary interventions are crucial to optimise metabolic and neurodevelopmental outcomes during this window of opportunity. Further research is needed to address remaining gaps and optimise PKU management across the first 1000 days.