Glycemic Variability as a Temporal Dimension of Intrauterine Glucose Exposure in Addition to Glycated Hemoglobin: Associations with Fetal Neurometabolic Outcomes – A Systematic Review

Abstract Although glycated hemoglobin (HbA1c) remains the principal marker of glycemic control in pregnancy, adverse fetal and neonatal outcomes are still observed in pregnancies considered well controlled by conventional thresholds. This observation has prompted reconsideration of whether averaged glycemia sufficiently characterizes intrauterine glucose dynamics. The present systematic review, conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses 2020 guidance, examined glycemic variability as a temporal dimension of maternal glucose exposure evaluated alongside HbA1c rather than as a replacement for it. Electronic databases and trial registries were searched through 2025. Studies were eligible if they quantified variability metrics, derived primarily from continuous glucose monitoring, and reported maternal or offspring outcomes. Given substantial heterogeneity in metric definitions, gestational timing, analytic thresholds, and outcome ascertainment, a structured qualitative synthesis was prespecified in place of meta-analysis to avoid artificial precision across noncomparable constructs. Thirty-six studies met the inclusion criteria following duplicate screening and domain-based risk-of-bias assessment. Across diverse populations, indices of temporal glucose instability were recurrently associated with fetal overgrowth, neonatal dysglycemia, hypertensive disorders of pregnancy, and markers suggestive of neurometabolic vulnerability, including in settings where HbA1c showed limited discriminatory capacity. However, the predominance of observational designs, variable confounder adjustment, and differences in variability definitions limit causal inference. The evidence base, therefore, supports interpretation of glycemic variability as a complementary exposure dimension whose clinical relevance remains hypothesis-generating. Whether deliberate reduction of temporal glucose instability improves perinatal outcomes requires prospective interventional evaluation.