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

REVIEWED BY

Elizabeth Sewell, MD, MPH

Children’s Healthcare of Atlanta and Emory University School of Medicine

elizabeth.sewell@emory.edu

Susan Cohen, MD

Medical College of Wisconsin, Children’s Wisconsin

scohen@mcw.edu

FUNDING

ES receives funding from Patient-Centered Outcomes Research Institute for research related to mild hypoxic-ischemic encephalopathy.

SC receives funding from Ceribell® for neonatal point of care EEG clinical research.

MANUSCRIPT CITATION

TYPE OF INVESTIGATION

Meta-analysis

QUESTION

(P) Among infants born less than 37 weeks gestation, (I) which perinatal interventions (C) compared to standard care (O) result in reduced risk of severe brain injury (T) before discharge?

METHODS

• Design: Systematic review and fixed-effects pairwise meta-analysis was used for data synthesis.
• Participants: Preterm infants with a gestational age <37 weeks or in term and preterm neonates for whom data could be extracted
• Data Sources: MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases searched through September 8, 2022 using prespecified search terms and no language restriction.
• Study Selection: Randomized clinical trials (RTC) that evaluated perinatal interventions, chosen a priori, and reported for one or more of the primary outcomes.
• Data Extraction and Synthesis: Two independent authors searched databases, evaluated the quality of the studies, and assigned a score for the certainty of evidence based on Cochrane GRADE approach.
• Outcome Measures: Three pre-specified outcomes were severe intraventricular hemorrhage (sIVH), cystic periventricular leukomalacia (cPVL), and severe brain injury that were identified on any cranial ultrasound prior to discharge. sIVH was defined as grade 3 or 4 using Papille Classification. cPVL was defined as necrosis of white matter near the lateral ventricles (must include cystic changes). Severe brain injury was defined as either sIVH or cPVL.

MAIN RESULTS

Analysis and Sample Size:

• Fixed-effects pairwise meta-analysis of 221 RCTs evaluating 44 perinatal interventions
  • 6 antenatal, 6 delivery room, 32 neonatal

CONCLUSION

Several interventions are associated with reduced sIVH in preterm infants, but clinicians should carefully consider interventions in the context of the certainty of evidence, the effect size, and the clinical context of specific neonatal units. Additional studies that evaluate currently in use interventions and include neurodevelopmental outcome are needed.

COMMENTARY

The aim of this meta-analysis was to evaluate the impact of perinatal interventions on severe intraventricular hemorrhage (sIVH) and cystic periventricular leukomalacia (cPVL).¹  Razak and colleagues included randomized trials that evaluated chosen interventions and reported sIVH, cPVL, or severe brain injury.  Two authors independently assessed the level of evidence and evaluated the certainty of evidence using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. GRADE has four levels of evidence- also known as certainty in evidence- or quality of evidence: very low, low, moderate, and high. This meta-analysis identifies only six perinatal interventions that were associated with decreased risk of sIVH and the certainty of the evidence was low to moderate.

 

Severe brain injury including sIVH and cPVL has been independently associated with worse outcomes in preterm infants.² This meta-analysis by Razak and colleagues is the first to summarize evidence on the impact of specific perinatal interventions on severe brain injury.  Interestingly, the effect size of antenatal corticosteroids was small whereas prophylaxis indomethacin was moderate.  While antenatal corticosteroid administration is standard of care,³ postnatal indomethacin prophylaxis varies significantly by institution.⁴Many clinicians have concerns about adverse effects of indomethacin, including spontaneous intestinal perforation.  Additionally, while postnatal indomethacin prophylaxis reduces the risk for sIVH, meta-analyses have not demonstrated a corresponding improvement in neurodevelopmental outcome.⁵

 

Razak and colleagues give clinicians and decision-makers an important tool to better understand the impact of specific perinatal interventions on sIVH and cPVL in preterm infants.  Parent values may differ from clinicians, so it is important to incorporate their preferences into decision-making.⁶ A reduction in brain injury may be a clinically important outcome for families, even without evidence demonstrating improved neurodevelopmental outcomes.⁷   The GRADE framework aids communication and shared-decision-making around perinatal interventions.

 

Neonatal providers must consider factors that affect clinical applicability of these results before bringing these interventions to the bedside. Use of absolute risk difference in addition to relative risk facilitates clinicians translating results for specific patients.⁸ An infant at high risk for sIVH may benefit from postnatal indomethacin prophylaxis, even without clear benefits to neurodevelopmental outcome.  Additionally, the context of the specific unit environment in which the patient is being cared for could affect baseline utilization rates for each intervention and may not reach the number needed to treat or harm.  Lastly, some perinatal interventions were not evaluated due to lack of randomized trials or were not shown to significantly reduce the risk of severe brain injury on meta-analysis but have been shown to reduce the risk for severe brain injury as part of quality improvement bundles.⁹ Further studies are needed to confirm safety and efficacy of many interventions to prevent severe brain injury before clinical implementation.

 

Razak and colleagues presented a novel meta-analysis evaluating the impact of specific perinatal interventions on severe brain injury.  Ultimately, clinicians will need to consider the certainty of evidence and effect size in the context of patient risk factors, parental preferences, and unit environment when applying them in clinical practice.

REFERENCES

1. Razak A, Patel W, Durrani NUR, Pullattayil AK. Interventions to Reduce Severe Brain Injury Risk in Preterm Neonates: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023;6(4):e237473.

2. Gotardo JW, Volkmer NFV, Stangler GP, Dornelles AD, Bohrer BBA, Carvalho CG. Impact of peri-intraventricular haemorrhage and periventricular leukomalacia in the neurodevelopment of preterms: A systematic review and meta-analysis. PLoS One. 2019;14(10):e0223427.

3. Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstet Gynecol. 2017;130(2):e102-e109.

4. Curtis SF, Cotten CM, Laughon M, et al. Indomethacin Prophylaxis in Preterm Infants: Changes over Time. Am J Perinatol. 2022.2000;343(10):674-681. indomethacin exposure. J Perinatol. 2006;26(2):93-99.

5. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;2010(7):Cd000174.

6. Soltys F, Philpott-Streiff SE, Fuzzell L, Politi MC. The importance of shared decision-making in the neonatal intensive care unit. J Perinatol. 2020;40(3):504-509.

7. AlFaleh K, Alluwaimi E, AlOsaimi A, et al. A prospective study of maternal preference for indomethacin prophylaxis versus symptomatic treatment of a patent ductus arteriosus in preterm infants. BMC Pediatr. 2015;15:47.

8. Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Absolute risk reduction, relative risk reduction, and number needed to treat. Perspect Clin Res. 2016;7(1):51-53.

9. de Bijl-Marcus K, Brouwer AJ, De Vries LS, Groenendaal F, van Wezel-Meijler G. Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2020;105(4):419-424.