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Dr Fischer designed the meta-analysis, searched for relevant studies, extracted, assessed, and analyzed the data, and drafted the manuscript; Ms Reibel and
Dr Bhrer contributed to data extraction and assessment; Dr Dame conceptualized the meta-analysis, searched for relevant studies, extracted and assessed the
data, and drafted the manuscript; and all authors approved the final manuscript as submitted.
DOI: 10.1542/peds.2016-4317
Accepted for publication Feb 9, 2017
Address correspondence to Christof Dame, MD, Department of Neonatology, Charit - Universittsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
E-mail: christof.dame@charite.de
To cite: Fischer HS, Reibel NJ, Bhrer C, et al. Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis. Pediatrics. 2017;139(5):e20164317
Performance Bias
In 3 RCTs, considerable efforts were
made to blind parents and personnel
to the study intervention (low
risk).17,20,
32 By contrast, doctors and
nurses responsible for the treatment
were not blinded in the trial by Song
et al31 (high risk).
Detection Bias
Investigators performing long-term
outcome assessments were blinded
to the patients group allocation in all
studies (low risk).
Attrition Bias
The proportion of the surviving study
patients who completed follow-up
varied from 71% to 91%, according
to the particular study and group,
and the maximum difference in
follow-up between intervention and
control group was 91% versus 80%
in 1 study20 (unclear risk).
Reporting Bias
Two RCTs were registered at
ClinicalTrials.gov before or shortly FIGURE 1
PRISMA flow diagram.39
after recruitment began (low risk),20,32
and 1 RCT was not registered
asymmetries in the distribution of Prophylactic rhEPO in very preterm
(unclear risk).17 The study by Song
effect sizes around the mean, making infants significantly reduced the
et al31 was registered 6 months after
publication bias less likely. The incidence of an MDI <70 at 18 to
enrollment was completed, and the
funnel plots, detailed characteristics 24 months corrected age, with an
registered inclusion criteria and
of the included studies, and the OR (95% CI) of 0.51 (0.310.81),
primary outcomes differed from those
complete risk of bias assessment P = .005. Statistical measures did not
reported in the publication (high risk).
are available as Supplemental
indicate a heterogeneity problem
Other Bias Information (Supplemental Tables,
(2 = 4.01, P = .26, I2 = 25%). The
Supplemental Fig 4).
Two RCTs were co-funded by absolute risk of an MDI <70 was
pharmaceutical companies (low reduced from 15.7% to 8.4%,
risk).17,32
Effects of Intervention
corresponding to an NNT of 14. In a
Visual inspection of the funnel The effects of rhEPO on MDI <70 sensitivity analysis excluding the data
plots did not reveal significant and PDI <70 are shown in Fig 2. of the largest trial by Song et al31 the
IQ scores in the HamburgWechsler significant benefit of rhEPO on the recruiting 941 preterm infants
Intelligence Test for Children III, outcome measure MDI <70 in such <28 0/7 weeks gestational age to
and a subgroup analysis showed infants (Fig 2B). However, only answer this question (PENUT Trial,
a particular benefit of rhEPO stratified data from the recent Swiss NCT01378273). The PENUT Trial
in infants with intraventricular and Chinese rhEPO neuroprotection enrolls infants within 24 hours
hemorrhage. RCTs were available for the subgroup after birth to investigate an early
Because infants <28 0/7 weeks analysis, and the resulting subset of high-dose strategy of 6 doses of
gestational age are at particularly 60 rhEPO-treated and 57 placebo- intravenous Epo 1000 U/kg per
high risk of poor developmental treated infants <28 0/7 weeks dose at 48-hour intervals, followed
outcomes, the effects of rhEPO gestational age was less than the by subcutaneous Epo 400 U/kg per
in this subpopulation deserve optimal information size. We are dose 3 times per week up to 32 6/7
closer examination. In our planned aware that a multicenter RCT weeks postmenstrual age. Results
subgroup analysis, there was no in the United States is currently are expected in 2019 and will be
References
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Subspecialty Collections This article, along with others on similar topics, appears in
the following collection(s):
Developmental/Behavioral Pediatrics
/cgi/collection/development:behavioral_issues_sub
Cognition/Language/Learning Disorders
/cgi/collection/cognition:language:learning_disorders_sub
Fetus/Newborn Infant
/cgi/collection/fetus:newborn_infant_sub
Neonatology
/cgi/collection/neonatology_sub
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