Neurodevelopment of Hypoglycemic Neonates

Neonatal hypoglycemia is the most common metabolic problem in neonates and a preventable cause of brain injury in infancy. Key risk factors for neonatal hypoglycemia include being born preterm, small for gestational age (SGA), large for gestational age (LGA), and being an infant of a diabetic mother (IDM) (1). Approximately 30% of all neonates are considered at risk, of whom approximately 50% develop hypoglycemia (2). Neonatal hypoglycemia is tightly related to adverse neurodevelopmental and brain injury outcomes, particularly among preterm infants who are SGA (3). Screening is recommended for babies with known risk factors (4). Glucose is an essential molecule that supplies energy for brain consumption. Neurons and glial cells in the brain are sensitive to hypoglycemia. Neonatal hypoglycemia has been recognized as a cause of long-term severe neurologic and neurodevelopmental morbidity due to damage to these cells (5). Neonatal hypoglycemia is a common finding associated with brain injury, neurodevelopmental delay, visual impairment, and behavioral problems.

Management of hypoglycemia in the newborn period is highly variable among institutions, and recommendations from different professional societies vary. In 2011, the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn published a clinical report suggesting management guidelines for late-preterm and term infants with associated risk factors, targeting infants of IDM, LGA and SGA neonates (2). Of note, AAP clinical report provides guidelines only for the initial 24 hours of life and recommends screening of IDM and LGA infants for 12 hours and screening of SGA and late preterm infants for 24 hours. Canadian Paediatric Society in their updated position statement recommends a similar screening algorithm based on risk factors, stressing the importance of adequate feeding in SGA and late preterm infants. The Pediatric Endocrine Society (PES) issued the recommendations for evaluation and management of persistent hypoglycemia in neonates, infants and children beyond the initial 24 hours of life. The 2011 AAP guidelines define neonatal hypoglycemia as blood glucose \<47 mg/dL and recommend maintaining blood glucose \>40 mg/dL in the first 4 hours and \>45 mg/dl between hours 4-24 (6). The PES has an even stricter threshold of \>50 mg/dL. The AAP guidance, however, applies only to the first 24 hours of life, and the PES strategy focuses on infants beyond 48 hours of life with persistent hypoglycemia (7).

Due to poor correlation between blood glucose concentrations, clinical manifestations and controversial treatment thresholds, it is difficult to define a safe blood glucose level. Several studies have analyzed the effects of various ranges of hypoglycemia on neurodevelopmental outcome. However, variable results regarding the effect of hypoglycemia on the neurodevelopmental outcome have been reported without any clear conclusion (5,8-12).

In this study investigators propose to prospectively conduct a neurodevelopmental evaluation of SGA and late preterm neonates who underwent risk-based screening for hypoglycemia at newborn nursery during the first 24 hours of life based on AAP hypoglycemia guidelines at 18 to 24 months of age. As per neonatal unit protocol (reflecting AAP guidelines), all neonates at risk of hypoglycemia (all preterm infants, term infants who are SGA or LGA and IDM) are routinely screened for hypoglycemia during the first 24 hours of life via bedside point of care glucose devices (see attached Weiler NICU hypoglycemia screening protocol).

Aims:

1. To compare cognitive and motor development assessed with the Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk SGA/late preterm neonates
2. To assess language development, social-emotional and adaptive behavior in the normoglycemic and hypoglycemic at-risk neonates
3. To compare Bayley-4 scores between the cohort of neonates needing intravenous (IV) dextrose administration/neonatal intensive care admission to those with hypoglycemia managed in the newborn nursery as well as to those neonates who remained normoglycemic

Hypothesis:

The investigators hypothesize that SGA and late preterm hypoglycemic neonates admitted to newborn nursery will have inferior neurodevelopmental outcome at 18 to 24 months age when compared to SGA and late preterm infants with normoglycemia.