Placental Transfusion Strategies in Preterm Infants in Low- and Middle-Income Countries: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Placental transfusion strategies in preterm newborns have not been evaluated in low- and middle-income countries (LMICs). The objective of this systematic review was to compare placental transfusion strategies in preterm newborns in LMICs, including delayed cord clamping (DCC) for various time intervals, DCC until cord pulsations stop, umbilical cord milking, and immediate cord clamping (ICC). METHODS: Medline, Embase, CINAHL, and CENTRAL were searched from inception. Observational studies and randomized controlled trials (RCTs) were included. Two authors independently extracted data for Bayesian random-effects network meta-analysis (NMA) if more than 3 interventions reported an outcome or a pairwise meta-analysis was utilized. RESULTS: Among newborns <34 weeks of gestation, NMA of 9 RCTs could not rule out benefit or harm for survival from DCC 30-60 s compared to ICC: relative risk (RR) (95% credible interval) 0.96 (0.78-1.12), moderate certainty, or any included strategy compared to each other (low to very low certainty). Among late preterm newborns, DCC 120 s might be associated with improved survival: RR (95% confidence interval) 1.11 (1.01-1.22), very low certainty. We could not detect differences in the risk of intraventricular hemorrhage grade > II and bronchopulmonary dysplasia for any included intervention (low to very low certainty). DCC 60 s and 120 s might improve the hematocrit level among all preterm newborns (very low certainty), and DCC 45 s may decrease the risk of receipt of inotropes among newborns <34 weeks of gestation (low certainty). CONCLUSIONS: In LMICs, DCC for 60 s and 120 s might improve hematocrit level in preterm newborns, and DCC for 45 s may decrease the risk of receipt of inotropes in newborns <34 weeks, with no conclusive effect on survival.

Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses.

IMPORTANCE: Bronchopulmonary dysplasia (BPD) has multifactorial etiology and long-term adverse consequences. An umbrella review enables the evaluation of multiple proposed interventions for the prevention of BPD. OBJECTIVE: To summarize and assess the certainty of evidence of interventions proposed to decrease the risk of BPD from published systematic reviews. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science were searched from inception until November 9, 2020. STUDY SELECTION: Meta-analyses of randomized clinical trials comparing interventions in preterm neonates that included BPD as an outcome. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed in duplicate. Quality of systematic reviews was evaluated using Assessment of Multiple Systematic Reviews version 2, and certainty of evidence was assessed using Grading of Recommendation, Assessment, Development, and Evaluation. MAIN OUTCOMES AND MEASURES: (1) BPD or mortality at 36 weeks' postmenstrual age (PMA) and (2) BPD at 36 weeks' PMA. RESULTS: A total of 154 systematic reviews evaluating 251 comparisons were included, of which 110 (71.4%) were high-quality systematic reviews. High certainty of evidence from high-quality systematic reviews indicated that delivery room continuous positive airway pressure compared with intubation with or without routine surfactant (relative risk [RR], 0.80 [95% CI, 0.68-0.94]), early selective surfactant compared with delayed selective surfactant (RR, 0.83 [95% CI, 0.75-0.91]), early inhaled corticosteroids (RR, 0.86 [95% CI, 0.75-0.99]), early systemic hydrocortisone (RR, 0.90 [95% CI, 0.82-0.99]), avoiding endotracheal tube placement with delivery room continuous positive airway pressure and use of less invasive surfactant administration (RR, 0.90 [95% CI, 0.82-0.99]), and volume-targeted compared with pressure-limited ventilation (RR, 0.73 [95% CI, 0.59-0.89]) were associated with decreased risk of BPD or mortality at 36 weeks' PMA. Moderate to high certainty of evidence showed that inhaled nitric oxide, lower saturation targets (85%-89%), and vitamin A supplementation are associated with decreased risk of BPD at 36 weeks' PMA but not the competing outcome of BPD or mortality, indicating they may be associated with increased mortality. CONCLUSIONS AND RELEVANCE: A multipronged approach of delivery room continuous positive airway pressure, early selective surfactant administration with less invasive surfactant administration, early hydrocortisone prophylaxis in high-risk neonates, inhaled corticosteroids, and volume-targeted ventilation for preterm neonates requiring invasive ventilation may decrease the combined risk of BPD or mortality at 36 weeks' PMA.

Delivery room CPAP in improving outcomes of preterm neonates in low-and middle-income countries: A systematic review and network meta-analysis.

AIM: To study the impact of delivery room continuous positive airway pressure (DRCPAP) on outcomes of preterm neonates in low- and middle- income countries (LMICs) by comparing with interventions: oxygen supplementation, late DRCPAP, DRCPAP with sustained inflation, DRCPAP with surfactant and invasive mechanical ventilation (IMV). METHODS: Medline, Embase, CENTRAL, WOS and CINAHL searched. Observational studies and randomized controlled trials (RCTs) were included. Pair-wise meta-analysis and Bayesian network meta-analysis (NMA) were utilized. Primary outcome was receipt of IMV. RESULTS: Data from 11 of the 18 included studies (4 observational studies, 7 RCTs) enrolling 4210 preterm infants was synthesized. Moderate certainty of evidence (CoE) from NMA of RCTs comparing DRCPAP with surfactant administration versus DRCPAP alone suggested no decrease in subsequent receipt of IMV [Risk ratio (RR); 95% Credible Interval (CrI): 0.73; (0.34, 1.40)]. Very low CoE from observational studies comparing use of DRCPAP versus oxygen supplementation indicated a trend towards decreased IMV [RR; 95% Confidence Interval (CI): 0.75; (0.56-1.00)]. Although moderate CoE from NMA evaluating DRCPAP versus oxygen supplementation showed a trend towards decreased receipt of surfactant, it did not reach statistical significance [RR; 95% CrI: 0.69; (0.44, 1.06)]. Moderate CoE from NMA indicated that none of the interventions, when compared with use of supplemental oxygen alone or with each other decreased mortality or bronchopulmonary dysplasia. LIMITATIONS: CoE was very low for primary outcome. CONCLUSIONS: Present evidence is not sufficient for use of DRCPAP, but also did not show harm. Since it seems unlikely that there are marked variations in patient physiology to explain the difference in efficacy between high income countries and LMICs, we suggest future research evaluating other barriers in improving the effectiveness of DRCPAP in LMICs.

Risk Factors for Periventricular Leukomalacia in Preterm Infants: A Systematic Review, Meta-analysis, and GRADE-Based Assessment of Certainty of Evidence.

BACKGROUND: We analyzed the certainty of evidence (CoE) for risk factors of periventricular leukomalacia (PVL) in preterm neonates, a common morbidity of prematurity. METHODS: 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. RESULTS: 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, PPROM >48 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. CONCLUSION: 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.

ELBW and ELGAN outcomes in developing nations-Systematic review and meta-analysis.

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).