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We analyzed the certainty of evidence (CoE) for risk factors of periventricular leukomalacia (PVL) in preterm neonates, a common morbidity of prematurity.Medline, CENTRAL, Embase, and CINAHL were searched. Cohort and case-control studies and randomised randomized controlled trials were included. Data extraction was performed in duplicate. A random random-effects meta-analysis was utilizedused. CoE was evaluated as per Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines.One hundred eighty-six studies evaluating 95 risk factors for PVL were included. Of the 2,509,507 neonates assessed, 16,569 were diagnosed with PVL. Intraventricular hemorrhage [adjusted odds ratio: 3.22 (2.52-4.12)] had moderate CoE for its association with PVL. Other factors such as hypocarbia, chorioamnionitis, PPROM48 hour, multifetal pregnancy reduction, antenatal indomethacin, lack of antenatal steroids, perinatal asphyxia, ventilation, shock/hypotension, patent ductus arteriosus requiring surgical ligation, late-onset circulatory collapse, sepsis, necrotizing enterocolitis, and neonatal surgery showed significant association with PVL after adjustment for confounders (CoE: very low to low). Amongst the risk factors associated with mother placental fetal (MPF) triad, there was paucity of literature related to genetic predisposition and defective placentation. Sensitivity analysis revealed that the strength of association between invasive ventilation and PVL decreased over time (P 0.01), suggesting progress in ventilation strategies. Limited studies had evaluated diffuse PVL.Despite decades of research, our findings indicate that the CoE is low to very low for most of the commonly attributed risk factors of PVL. Future studies should evaluate genetic predisposition and defective placentation in the MPF triad contributing to PVL. Studies evaluating exclusively diffuse PVL are warranted.

Context Morbidity and mortality amongst extremely low birth weight (ELBW) and extremely low gestational age neonates (ELGANs) in developing nations has not been well studied. Objectives Evaluate survival until discharge, short- and long-term morbidities of ELBW and ELGANs in LMICs. Data sources CENTRAL, EMBASE, MEDLINE and Web of Science. Study selection Prospective and retrospective observational studies were included. Data extraction and synthesis Four authors extracted data independently. Random-effects meta-analysis of proportions was used to synthesize data, modified QUIPS scale to evaluate quality of studies and GRADE approach to ascertain the certainty of evidence (CoE). Results 192 studies enrolling 22,278 ELBW and 18,338 ELGANs were included. Survival was 34% (95% CI: 31% - 37%) (CoE–low) for ELBW and 39% (34% - 44%) (CoE—moderate) for ELGANs. For ELBW neonates, the survival for low-income (LI), lower middle-income (LMI) and upper middle income (UMI) countries was 18% (11% - 28%), 28% (21% - 35%) and 39% (36% - 42%), respectively. For ELGANs, it was 13% (8% - 20%) for LI, 28% (21% - 36%) for LMI and 48% (42% - 53%) for UMI countries. There was no difference in survival between two epochs: 2000–2009 and 2010–2020. Except for necrotising enterocolitis [ELBW and ELGANs—8% (7% - 10%)] and periventricular leukomalacia [ELBW—7% (4% - 11%); ELGANs—6% (5%-7%)], rates of all other morbidities were higher compared to developed nations. Rates of neurodevelopmental impairment was 17% (7% - 34%) in ELBW neonates and 29% (23% - 37%) in ELGANs. Limitations CoE was very low to low for all secondary outcomes. Conclusions Mortality and morbidity amongst ELBW and ELGANs is still a significant burden in LMICs. CoE was very low to low for all the secondary outcomes, emphasizing the need for high quality prospective cohort studies. Trial registration PROSPERO (CRD42020222873).