OBJECTIVE. Our goal was to assess the effect of episodes of neonatal hypoglycemia on subsequent neurodevelopment.METHODS. We searched Medline and Embase for cohort studies on subsequent neurodevelopment after episodes of hypoglycemia in the first week of life. Reference lists of available studies were reviewed, and content experts were contacted for additional studies. Included studies were selected and appraised for methodologic quality by 2 reviewers. Methodologic quality was assessed according to well-accepted criteria for prognostic studies. Eventually, all studies were given an overall quality score: poor, moderate, or high quality. Studies in the latter 2 categories were considered for quantitative data analysis.RESULTS. Eighteen eligible studies were identified. The overall methodologic quality of the included studies was considered poor in 16 studies and high in 2 studies. Pooling of results of the 2 high-quality studies was deemed inappropriate because of major clinical and methodologic heterogeneity. None of the studies provided a valid estimate of the effect of neonatal hypoglycemia on neurodevelopment. Building on the strengths and weaknesses of existing studies, we developed a proposal for an “optimal” future study design.CONCLUSIONS. Recommendations for clinical practice cannot be based on valid scientific evidence in this field. To assess the effect of neonatal hypoglycemia on subsequent neurodevelopment, a well-designed prospective study should be undertaken. We submit a design for a study that may answer the still-open questions.