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Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates — an updated meta-analysis

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Abstract

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes.

Conclusion: There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings.

What is Known:

• Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects.

• Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants.

What is New:

• Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation.

• EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs.

How might it impact clinical practice in the foreseeable future?

• Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

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Availability of data and material

Yes.

Code availability

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Abbreviations

CI:

Confidence interval

CNRG:

Cochrane neonatal review group

DARIS:

Diversity adjusted required information size

EPO:

Erythropoietin

FEM:

Fixed effect model

GRADE:

Grading of recommendations, assessment, development, and evaluation

LOS:

Late onset sepsis

MD:

Mean difference

NEC:

Necrotizing enterocolitis

PRISMA:

Preferred reporting items for systematic review

RCT:

Randomized controlled trial

REM:

Random effects model

ROB:

Risk of bias

RR:

Relative risk

TSA:

Trial sequential analysis

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Authors and Affiliations

  1. Department of Neonatology, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India

    Anitha Ananthan

  2. Department of Neonatology, Surya Hospitals, Mumbai, India

    Haribalakrishna Balasubramanian

  3. Department of International Health, Global Disease Epidemiology & Control Program, John Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA

    Diwakar Mohan

  4. Neonatal Directorate, Perth Children’s Hospital, Nedlands, Western Australia, Australia

    Shripada Rao

  5. School of Medicine, University of Western Australia, Perth, WA, Australia

    Shripada Rao & Sanjay Patole

  6. Neonatal Directorate, King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia

    Sanjay Patole

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  1. Anitha Ananthan
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  2. Haribalakrishna Balasubramanian
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  3. Diwakar Mohan
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  4. Shripada Rao
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  5. Sanjay Patole
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Contributions

All authors made substantial contributions to the study conception and design, data acquisition, analysis and interpretation of data, drafting the manuscript, and revising the manuscript critically for important intellectual content. Conceptualization: SP; methodology: AA, HB, DM, SR; data curation: AA, HB, DM, SR, SP; writing: all authors.

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Correspondence to Haribalakrishna Balasubramanian.

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Communicated by Daniele De Luca

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Ananthan, A., Balasubramanian, H., Mohan, D. et al. Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates — an updated meta-analysis. Eur J Pediatr 181, 1821–1833 (2022). https://doi.org/10.1007/s00431-022-04394-y

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