Hypoxic-Ischaemic Encephalopathy in Maternal Diabetes: Mirror of a Chronic Antepartum Process or an Acute Intrapartum Event? A Systematic Review

Background: Maternal diabetes is associated with several adverse perinatal outcomes, but its relationship with hypoxic-ischaemic perinatal injury remains poorly defined. Fetal compromise may reflect an acute intrapartum event, a chronic antepartum process, or both. Objective: To systematically review the evidence linking gestational diabetes mellitus (GDM) and pregestational diabetes to hypoxic-ischaemic perinatal injury, assessing diagnosed or coded neonatal brain injury, acid–base status at birth, and chronic antepartum markers separately. Methods: PubMed, Embase, and Scopus were searched from inception to 16 October 2026. Observational studies comparing pregnancies with and without diabetes and reporting diagnosed or coded hypoxic-ischaemic encephalopathy, neonatal encephalopathy or neonatal seizures, umbilical acid–base status, or a chronic marker of fetal hypoxia were eligible; studies reporting only Apgar-based or other non-specific outcomes were excluded. Risk of bias was assessed with the Newcastle–Ottawa Scale together with a separate judgement of outcome-definition adequacy, certainty of evidence was rated with GRADE, and synthesis followed the SWiM guideline, with vote counting by direction of effect. The protocol was registered in PROSPERO (CRD420261435362). Results: Seventy-four studies were included (30 GDM only, 12 pregestational diabetes only, 32 both or unspecified). Pregestational diabetes was associated with hypoxic-ischaemic encephalopathy, neonatal encephalopathy, or neonatal seizures in all five studies with sufficient events (adjusted odds or risk ratios 1.5–5.1; very low certainty). In GDM, estimates pointed in an adverse direction in six of seven informative comparisons but were mostly small and imprecise; statistically significant associations came only from a large registry (adjusted relative risk 1.24–1.25) and a study restricted to small-for-gestational-age infants (very low certainty). Umbilical acid–base status was less favourable in pregestational diabetes in 9 of 10 studies. In GDM, differences were small (less favourable in 13 of 17 comparisons; pooled mean difference in umbilical arterial pH −0.025, 95% CI −0.041 to −0.010, prediction interval −0.10 to 0.05, three studies; very low certainty for clinically relevant acidaemia). Chronic markers pointed in an adverse direction in 33 of 37 independent evidence sources, most consistently erythropoietin, nucleated red cells, and polycythaemia, but certainty was very low for every marker. No study documented a chronic marker, an identified acute event, and diagnosed or coded brain injury in the same fetus. Conclusions: Pregestational diabetes is associated with diagnosed or coded hypoxic-ischaemic encephalopathy, neonatal encephalopathy, or seizures and with markers of chronic fetal hypoxic stress, but the certainty of this evidence is very low. In GDM, estimates for these outcomes mostly point in an adverse direction but are small and imprecise (very low certainty), and acid–base differences at birth are small. Whether a chronic process and an acute event combine to cause injury in an individual fetus has not been studied.