Neonatal Hypoglycemia and Neurodevelopmental Outcomes—An Updated Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVE: The effects of neonatal hypoglycemia on the developing brain are well known, resulting in poor neurological outcomes. We aimed to perform an updated meta-analysis on neonatal hypoglycemia, the severity of hypoglycemia, and the associated neurodevelopmental outcomes from infancy to adulthood. METHODS: A systematic literature search was conducted from inception until March 2024, using the PubMed, CINAHL, Embase, and the CENTRAL databases. Randomized/quasi-randomized trials and observational studies that evaluated at least one of the pre-specified outcomes were included. A random-effects model meta-analysis was performed to yield the pooled OR and its 95% CI for each outcome due to the expected heterogeneity in the studies. The study findings were reported as per the PRISMA guidelines. Neurodevelopmental impairment (NDI), cognitive impairment, and visual-motor or visual impairment were the primary outcomes. RESULTS: A total of 17 studies (19 publications) were included in the final analysis. NDI, as defined by authors, was significantly higher in early- (OR = 1.16; 95% CI = 1.11-1.43) and mid-childhood (OR = 3.67; 95%CI = 1.07-12.2) in infants with neonatal hypoglycemia. 'Any cognitive impairment' was significantly more common in infants with neonatal hypoglycemia (OR = 2.12; 95%CI = 1.79-2.52). Visual-motor impairment (OR = 3.33; 95%CI = 1.14-9.72) and executive dysfunction (OR = 1.99; 95%CI = 1.36-2.91) were also more common in the hypoglycemic group. No difference in the incidence of epilepsy, motor impairment, emotional-behavioral problems, or hearing impairment were noted. Certainty of evidence was adjudged as 'low' to 'very low' for most outcomes. The severity of hypoglycemia was studied at different intervals, with NDI more common with a blood glucose interval between 20 and 34 mg/dL (1.1-1.9 mmol/L). CONCLUSIONS: Low-quality evidence from large observational studies finds a significant association with hypoglycemia in the early neonatal period and long-term neurodevelopmental problems. Additional studies with long enough follow-up are paramount to determine the cut-off concentration and to quantify the impact beyond the infancy period.