Supplementary Material for: Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

Background: Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. Objective: To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. Methods: We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). Results: 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86–1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13–10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20–5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05–12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20–3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21–3.44). No data were available for adolescents. Conclusions: Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age.