Interventions to Reduce Severe Brain Injury Risk in Preterm Neonates: A Systematic Review and Meta-analysis

IMPORTANCE: Interventions to reduce severe brain injury risk are the prime focus in neonatal clinical trials. OBJECTIVE: To evaluate multiple perinatal interventions across clinical settings for reducing the risk of severe intraventricular hemorrhage (sIVH) and cystic periventricular leukomalacia (cPVL) in preterm neonates. DATA SOURCES: MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases were searched from inception until September 8, 2022, using prespecified search terms and no language restrictions. STUDY SELECTION: Randomized clinical trials (RCTs) that evaluated perinatal interventions, chosen a priori, and reported 1 or more outcomes (sIVH, cPVL, and severe brain injury) were included. DATA EXTRACTION AND SYNTHESIS: Two co-authors independently extracted the data, assessed the quality of the trials, and evaluated the certainty of the evidence using the Cochrane GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Fixed-effects pairwise meta-analysis was used for data synthesis. MAIN OUTCOMES AND MEASURES: The 3 prespecified outcomes were sIVH, cPVL, and severe brain injury. RESULTS: A total of 221 RCTs that assessed 44 perinatal interventions (6 antenatal, 6 delivery room, and 32 neonatal) were included. Meta-analysis showed with moderate certainty that antenatal corticosteroids were associated with small reduction in sIVH risk (risk ratio [RR], 0.54 [95% CI, 0.35-0.82]; absolute risk difference [ARD], −1% [95% CI, −2% to 0%]; number needed to treat [NNT], 80 [95% CI, 48-232]), whereas indomethacin prophylaxis was associated with moderate reduction in sIVH risk (RR, 0.64 [95% CI, 0.52-0.79]; ARD, −5% [95% CI, −8% to −3%]; NNT, 20 [95% CI, 13-39]). Similarly, the meta-analysis showed with low certainty that volume-targeted ventilation was associated with large reduction in risk of sIVH (RR, 0.51 [95% CI, 0.36-0.72]; ARD, −9% [95% CI, −13% to −5%]; NNT, 11 [95% CI, 7-23]). Additionally, early erythropoiesis-stimulating agents (RR, 0.68 [95% CI, 0.57-0.83]; ARD, −3% [95% CI, −4% to −1%]; NNT, 34 [95% CI, 22-67]) and prophylactic ethamsylate (RR, 0.68 [95% CI, 0.48-0.97]; ARD, −4% [95% CI, −7% to 0%]; NNT, 26 [95% CI, 13-372]) were associated with moderate reduction in sIVH risk (low certainty). The meta-analysis also showed with low certainty that compared with delayed cord clamping, umbilical cord milking was associated with a moderate increase in sIVH risk (RR, 1.82 [95% CI, 1.03-3.21]; ARD, 3% [95% CI, 0%-6%]; NNT, −30 [95% CI, −368 to −16]). CONCLUSIONS AND RELEVANCE: Results of this study suggest that a few interventions, including antenatal corticosteroids and indomethacin prophylaxis, were associated with reduction in sIVH risk (moderate certainty), and volume-targeted ventilation, early erythropoiesis-stimulating agents, and prophylactic ethamsylate were associated with reduction in sIVH risk (low certainty) in preterm neonates. However, clinicians should carefully consider all of the critical factors that may affect applicability in these interventions, including certainty of the evidence, before applying them to clinical practice.