Prophylactic Early Erythropoietin

for Neuroprotection in Preterm

Infants: A Meta-analysis
Hendrik S. Fischer, MD, Nora J. Reibel, MSc, Christoph Bhrer, MD, Christof Dame, MD

CONTEXT: Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent abstract

for neuroprotection in neonates.
OBJECTIVE: To investigate whether prophylactic rhEPO administration in very preterm infants
improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials
(RCTs).
DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials were
searched in December 2016 and complemented by other sources.
STUDY SELECTION: RCTs investigating the use of rhEPO in preterm infants versus a control
group were selected if they were published in a peer-reviewed journal and reported
neurodevelopmental outcomes at 18 to 24 months corrected age.
DATA EXTRACTION: Data extraction and analysis followed the standard methods of the Cochrane
Neonatal Review Group. The primary outcome was the number of infants with a Mental
Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary
outcomes included a Psychomotor Development Index <70, cerebral palsy, visual
impairment, and hearing impairment.
RESULTS: Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic
rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio
(95% confidence interval) of 0.51 (0.310.81), P < .005. The number needed to treat was 14.
There was no statistically significant effect on any secondary outcome.
CONCLUSIONS: Prophylactic rhEPO improved the cognitive development of very preterm infants,
as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other
neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing
and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.

Department of Neonatology, Charit University Medical Center, Berlin, Germany

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

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PEDIATRICS Volume 139, number 5, May 2017:e20164317 REVIEW ARTICLE
Improving neurodevelopmental
outcomes is a major goal in
neonatology, especially with regard
to the increasing survival rate of
the most immature infants.1 3 In
particular, extremely low birth
weight (ELBW) infants may develop
cognitive delay or cerebral palsy later
in life, even if the cranial ultrasound
examination at discharge is normal.4
Recombinant human erythropoietin
(rhEPO) is 1 of the most promising
pharmacological substances for
neuroprotection in newborn
infants and may be beneficial for
regeneration and repair after
neonatal brain injury.5,6
Interestingly, the endogenous
erythropoietin receptor system
activates in response to hypoxic
ischemic injury. This means that
rhEPO may be particularly potent
for neuroprotection and neuronal
regeneration if administered timely
after an acute brain injury.7 9
Conversely, if rhEPO is administered
prophylactically, higher doses may
be needed to cross the bloodbrain
barrier.10,11 Numerous in vitro and
in vivo experiments (including
models of the fetal or immature
brain) have shown that rhEPO has
antioxidant, antiexcitotoxic, and anti-
inflammatory properties, prevents
neuronal apoptosis,12 and promotes
neurogenesis and angiogenesis.7,13 15
Debate continues over whether
premature infants at high risk of
neurodevelopmental impairment
may benefit from prophylactic
rhEPO.16 Most clinical follow-up
studies on preterm infants primarily
treated with rhEPO (or its higher-
glycosylated derivate darbepoetin)
for anemia of prematurity indicated
improved neurodevelopmental
outcomes,17 21
whereas only a few
studies have shown no effect.22,23
In 2005, the first phase I and II
trials were initiated to establish the
safety of early high-dose rhEPO for
neuroprotection.24,25 So far, only
a limited number of randomized
controlled trials (RCTs) have
2 Fischer et al
reported data on the neuroprotective
effects of rhEPO in preterm infants.
This limitation was reflected in 2
previous meta-analyses26,27
that
included several quasi-RCTs25,28
30
19
and a cohort study. Recently,
neurodevelopmental outcomes
at a corrected age of 18 to 24
months from 2 prospective RCTs,
intended primarily to evaluate the
neuroprotective effects of rhEPO
in a total of 978 very preterm
infants, were published almost
simultaneously.31,32
Therefore, the
present meta-analysis aimed to
study whether prophylactic rhEPO
improves the neurodevelopmental
outcomes of very preterm infants
at 18 to 24 months corrected age,
solely including data from previous
and recent RCTs.
Methods
Criteria for Considering Studies for
This Review
All RCTs that investigated the effect
of prophylactic rhEPO in preterm
infants were eligible for the meta-
analysis. Included trials had to
compare an rhEPO-treated group
with a control group that received
no treatment or placebo, and they
had to report neurodevelopmental
outcomes. Only studies published in
full in peer-reviewed journals were
accepted. No language restrictions
were applied.
Types of Outcome Measures
Outcome measures were specified
beforehand in a review protocol,
considering the outcomes reported
by recently published RCTs.31,32
The primary outcome of the meta-
analysis was the number of infants
with a Mental Developmental
Index (MDI) <70 on the Bayley
Scales of Infant Development,
Second Edition (BSID-II), at 18
to 24 months corrected age.33 If
infants were assessed according to
the Third Edition (BSID-III),34 we
used cognitive scores <85 as the
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primary outcome, because a recent
study showed that a cognitive score
<85 (BSID-III) predicts an MDI <70
(BSID-II), with an overall agreement
of 97.3%.35 A planned subgroup
analysis assessed the incidence of
an MDI <70 (BSID-II) or cognitive
score <85 (BSID-III) in infants
<28 weeks gestational age. Other
predetermined secondary outcomes
were the number of infants with a
Psychomotor Development Index
(PDI) <70 (BSID-II), cerebral palsy,
severe visual impairment, and severe
hearing impairment, respectively.
After the literature search, we
added the secondary outcome any
neurodevelopmental impairment at
18 to 24 months corrected age.
Search Methods for Identification of
Studies
For the literature search, we followed
the standard search methods of
the Cochrane Collaboration.36 Two
authors independently searched
the databases Medline, Embase, and
the Cochrane Central Register of
Controlled Trials (CENTRAL). The
results were combined with cross-
referencing of previous reviews
and trials and with the use of expert
information. Additional information
about ongoing trials was sought
through the search portal of the
International Clinical Trials Registry
Platform.37 Medline, Embase, and
CENTRAL were searched on May
31, 2016. The search was updated
on December 18, 2016. A highly
sensitive search strategy was
applied, as outlined in the Cochrane
Handbook for Systematic Reviews
of Interventions, and complied
with specific recommendations for
identifying RCTs in Medline and
Embase.36,38
A variety of search
terms were applied to identify
RCTs concerned with rhEPO use in
premature infants (search concept:
premature infant AND erythropoietin
AND randomized controlled trial)
or with follow-up studies on
children of all ages that reported
neurodevelopmental outcomes
after rhEPO treatment (search
concept: child AND erythropoietin
AND [RCT OR follow-up study]
AND [neurodevelopmental testing
OR neurodevelopmental outcomes
OR neuroprotection]). Altogether,
we used >60 free-text and indexed
search terms, including many from
the Medical Subject Headings (MeSH)
and Excerpta Medica Tree indexing
systems. The detailed search strategy
is available in the Supplemental
Information. We followed the
Preferred Reporting Items for
Systematic Reviews and Meta-
analyses (PRISMA) Statement.39,40
(log[OR]) in funnel plots.36,41
Assessment of Methodological
Quality
The methodological quality of
the selected studies was assessed
according to Cochranes guidelines.36
The risks of selection bias (quality
of randomization, allocation
concealment), performance
bias (blinding of intervention),
detection bias (blinding of
outcome assessment), attrition
bias (completeness of follow-up),
selective reporting (reporting
bias), and other potential biases
were independently examined by
2 study authors (H.S.F., N.J.R.) and
categorized as low risk, high risk, or
unclear risk. Any discrepancies were
resolved by a third author (C.D.).
Data Collection and Analysis
Trial searching, study selection, and
data extraction were performed
independently by 2 study authors
(H.S.F., C.D.). At each stage,
differences were discussed and
resolved by consensus or by a
third author (C.B.). We planned to
contact the corresponding authors
of the included RCTs up to 3 times
via e-mail to request stratified data
or additional information about
their trials, allowing 2 months for
their response. RevMan version 5.3
(Cochrane Collaboration, Nordic
Cochrane Centre, Copenhagen)
was used for data analysis. The
impacts of rhEPO on primary and
PEDIATRICS Volume 139, number 5, May 2017
secondary outcomes were calculated
via the MantelHaenszel method
for dichotomous outcomes in a
random effects model. Results for
all studies and for the pooled data
were reported as odds ratios (ORs)
and 95% confidence intervals (CIs).
Statistical significance was defined
as P < .05. For pooled outcomes with
significant effects, a number needed
to treat (NNT) was calculated. To
estimate heterogeneity, we applied
the 2 test and I2 value. To assess for
publication bias, the treatment effects
of rhEPO were plotted against SE
Results
A total of 576 records were identified,
564 through database searches and
12 through other sources (Fig 1).
From them, 114 potentially met the
inclusion criteria and were assessed
as full-text articles. A subset of 21
articles were published in languages
other than English: 4 in Bulgarian, 1
in Chinese, 2 in French, 3 in Italian, 2
in Japanese, 2 in Polish, 6 in Spanish,
and 1 in Turkish.
Excluded Studies
After the full-text assessment, 110
articles had to be excluded. As shown
in Fig 1, 19 articles did not report
RCTs, 2 reported RCTs that compared
different schemes of rhEPO
administration but lacked a control
group,42,43
and 86 RCTs had rhEPO
and control groups but did not report
neurodevelopmental outcomes.
Three studies were excluded for
other reasons: Newton et al22
presented neurodevelopmental
outcomes of 40 infants enrolled in
2 small pilot RCTs (n = 28) and 1
multicenter trial (n = 22) conducted
between 1988 and 1993.44 46
However, these studies were
excluded because the follow-up
article presented only pooled
follow-up data and did not allow any
outcome analysis at the level of the
original RCTs. Bierer et al18
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correlated neonatal peak serum
erythropoietin concentrations with
neurodevelopmental outcomes at
18 to 22 months corrected age in
a single-center follow-up study on
an RCT of rhEPO versus placebo,
but the study was excluded because
the population was a subset of the
Eunice Kennedy Shriver National
Institute of Child Health and
Human Development Neonatal
Research Network Trial included
in our meta-analysis.17 A third RCT
(NCT01207778), recently published
by Ohls et al,21 was excluded because
it reported neurodevelopmental
outcomes at 3.5 to 4 years.
Included Studies
Four RCTs, which assessed a total of
1133 patients at 18 to 24 months'
corrected age, were included in
the meta-analysis; their main
characteristics are summarized
in Table 1. All studies included
preterm infants of 32 0/7 weeks
gestational age, but only 2 used the
infants birth weight to define the
inclusion criteria.17,20
Notably, the
timing, dosing, and duration of rhEPO
administration varied. Whereas 1
RCT applied early high-dose rhEPO
only (first dose within 3 hours after
birth, cumulative dose of 9000 IU/kg
within the first 42 hours),32 the other
3 RCTs started rhEPO later (within
the first 4896 hours), applied lower
doses (12001750 IU/kg per week),
and prescribed sustained treatment
of several weeks.17,20,
31 One RCT was
designed primarily to prevent red
blood cell transfusions by reducing
the anemia of prematurity.17 Another
RCT targeted both hematologic and
neurodevelopmental outcomes,
comparing rhEPO, placebo, and a
third intervention group receiving
darbepoetin.20 For methodological
reasons, however, the latter was not
included in the meta-analysis.
To obtain additional data or
information, we contacted the first or
senior authors of all included RCTs.
We highly appreciate the cooperation
3
of 1 author who provided us with
previously unpublished data for
infants <28 0/7 weeks gestational
age.32

Risk of Bias in the Included Studies

Selection Bias
Random sequence generation
and allocation concealment were
adequate in all studies (low risk).

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
after recruitment began (low risk),20,32
and 1 RCT was not registered
(unclear risk).17 The study by Song
et al31 was registered 6 months after
enrollment was completed, and the
registered inclusion criteria and
primary outcomes differed from those
reported in the publication (high risk).
Other Bias
Two RCTs were co-funded by
pharmaceutical companies (low
risk).17,32
Effects of Intervention
Visual inspection of the funnel
plots did not reveal significant
FIGURE 1
PRISMA flow diagram.39
asymmetries in the distribution of
effect sizes around the mean, making
publication bias less likely. The
funnel plots, detailed characteristics
of the included studies, and the
complete risk of bias assessment
are available as Supplemental
Information (Supplemental Tables,
Supplemental Fig 4).
The effects of rhEPO on MDI <70
and PDI <70 are shown in Fig 2.
Prophylactic rhEPO in very preterm
infants significantly reduced the
incidence of an MDI <70 at 18 to
24 months corrected age, with an
OR (95% CI) of 0.51 (0.310.81),
P = .005. Statistical measures did not
indicate a heterogeneity problem
(2 = 4.01, P = .26, I2 = 25%). The
absolute risk of an MDI <70 was
reduced from 15.7% to 8.4%,
corresponding to an NNT of 14. In a
sensitivity analysis excluding the data
of the largest trial by Song et al31 the

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4 Fischer et al
calculated effect size of rhEPO on MDI
<70 remained in favor of rhEPO but
was no longer statistically significant,
with an OR (95% CI) of 0.68 (0.4
1.18), P = .17 (data not shown).
RhEPO had no significant impact
on MDI <70 in infants <28 weeks
gestational age (Fig 2B) or on PDI
<70 (Fig 2C). The definitions of the
other secondary outcomes (cerebral
palsy, severe visual impairment,
severe hearing impairment, and any
neurodevelopmental impairment) all
showed some variation between the
included studies (see Supplemental
Tables for details). As shown in Fig
3, there was no significant effect of
rhEPO on any of these outcomes in
the meta-analysis. The combined OR
(95% CI) of any neurodevelopmental
impairment was 0.55 (0.281.08),
P = .08, with substantial statistical
heterogeneity between the included
studies (2 = 10.38, P = .02, I2 = 71%).
Discussion
This is the largest meta-
analysis to date to investigate
the neuroprotective effects of
prophylactic rhEPO in very preterm
infants of 18 to 24 months corrected
age and the first to include only RCTs.
Our analysis is highly topical, because
2 of the 4 RCTs, which included
978 of the 1133 patients studied, had
only been reported recently.31,32
The meta-analyzed data showed
that rhEPO reduced the number
of patients with an MDI <70 at 18
to 24 months corrected age but
had no significant effect on motor
development, hearing, or vision.
Quality of Evidence
The included RCTs were mostly of
high methodological quality, with
a low risk of bias (Supplemental
Tables). The only major problems
related to the RCT by Song et al31
were the lack of blinding of personnel
and indications of selective reporting.
Incomplete outcome data were
considered as a minor point in all
PEDIATRICS Volume 139, number 5, May 2017
TABLE 1 Characteristics of Included Studies
Author Year N Gestational
Age, Birth Wt
Ohls et al17 2004 102 32 0/7,
1000 g
Ohls et al20 2014 53a Any GA,b
5001250 g
Natalucci et 2016 365 26 0/731 6/7,
al32 any BW
Song et al31 2016 613 32 0/7, any
BW
BW, birth wt; GA, gestational age; IV, intravenously; SC, subcutaneously.
a This study had 3 groups: rhEPO (n = 29) versus placebo (n = 24) versus darbepoetin (n = 27). The darbepoetin group was
not included in the meta-analysis.
b Median (interquartile range) GA of included infants 28 (2629) wk; study entry criteria: preterm infants with a birth wt
of 5001250 g.
studies. However, the reported
follow-up rates at 18 to 24 months
corrected age were satisfactory
from a practical point of view. In
accordance with Cochrane methods,
we used funnel plots to assess
for publication bias,36 but we did
not identify major asymmetries
(Supplemental Fig 4). However, we
were aware that this method had
low power to detect bias, because
only 4 RCTs were included in the
meta-analysis. More importantly,
there remains a possibility of
unpublished data, in that 86 RCTs of
rhEPO were excluded from the meta-
analysis because they did not report
neurodevelopmental outcomes
(Fig 1).
Effect on Cognitive Outcome
The beneficial effect of prophylactic
rhEPO on the incidence of MDI <70
at 18 to 24 months corrected age
was consistent across all included
RCTs (Fig 2A), although timing and
dosing of rhEPO administration
varied between trials. With an
absolute risk reduction from
15.7% to 8.4% and an NNT of 14
patients, the estimated effect is
clinically relevant. The observed
benefits of rhEPO are robust,
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Time Point of Intervention Recruitment
Intervention
2496 h of age rhEPO 400 IU/kg IV 19971998
or SC, 3 times per
wk until 35 0/7
wk gestation
48 h of age rhEPO 400 IU/kg SC, 20062010
3 times per wk
until 35 0/7 wk
gestation
<3 h of age rhEPO 3000 IU/kg 20052012
IV at <3 h, 1218
h and 3642 h
of age
<72 h of age rhEPO 500 IU/kg IV 20092013
every other day
for 2 wk
because they are in agreement with
available evidence from longer-
term follow-up studies, which
also reported improved cognitive
outcomes. In the second follow-up
on the previously mentioned RCT
of rhEPO, darbepoetin, or placebo,
Ohls et al21,47
assessed 53 children
via the Wechsler Preschool and
Primary Scale of Intelligence, Third
Edition at the age of 3.5 to 4 years.
The study compared the pooled
data of the rhEPO group (n = 24)
and darbepoetin group (n = 15)
with the placebo group (n = 14) and
showed that the children treated by
erythropoiesis-stimulating agents
scored significantly better for full-
scale IQ, performance IQ, overall
executive function, and working
memory. When cognitive function
was analyzed, results at 18 to 22
months and 4 years correlated
significantly between BSID-II
composite score and full-scale
IQ.20,21 Neubauer et al19 analyzed
neurodevelopmental outcomes at
the age of 10 to 13 years in a cohort
study of 89 ELBW infants who
received rhEPO from the first
week of life to near-term and 57
untreated ELBW infants. rhEPO-
treated infants attained higher
verbal, nonverbal, and composite
5
FIGURE 2
Effects of rhEPO on neurodevelopment, as assessed by BSID-II or BSID-III at 18 to 24 months corrected age. Forest plots show the effects on the number
of infants with an MDI <70 (BSID-II) or cognitive score <85 (BSID-III) in all infants (primary outcome, A), in infants <28 0/7 weeks gestational age (planned
subgroup analysis, B), and on the number of infants with a PDI <70 as assessed by BSID-II (secondary outcome, C). M-H, MantelHaenszel.

IQ scores in the HamburgWechsler
Intelligence Test for Children III,
and a subgroup analysis showed
a particular benefit of rhEPO
in infants with intraventricular
hemorrhage.
Because infants <28 0/7 weeks
gestational age are at particularly
high risk of poor developmental
outcomes, the effects of rhEPO
in this subpopulation deserve
closer examination. In our planned
subgroup analysis, there was no
significant benefit of rhEPO on the
outcome measure MDI <70 in such
infants (Fig 2B). However, only
stratified data from the recent Swiss
and Chinese rhEPO neuroprotection
RCTs were available for the subgroup
analysis, and the resulting subset of
60 rhEPO-treated and 57 placebo-
treated infants <28 0/7 weeks
gestational age was less than the
optimal information size. We are
aware that a multicenter RCT
in the United States is currently
recruiting 941 preterm infants
<28 0/7 weeks gestational age to
answer this question (PENUT Trial,
NCT01378273). The PENUT Trial
enrolls infants within 24 hours
after birth to investigate an early
high-dose strategy of 6 doses of
intravenous Epo 1000 U/kg per
dose at 48-hour intervals, followed
by subcutaneous Epo 400 U/kg per
dose 3 times per week up to 32 6/7
weeks postmenstrual age. Results
are expected in 2019 and will be

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6 Fischer et al
FIGURE 3
Effects of rhEPO on secondary outcomes at 18 to 24 months corrected age. Forest plots show the effects on cerebral palsy (A), severe visual impairment
(B), severe hearing impairment (C), and any neurodevelopmental impairment (D). M-H, MantelHaenszel.

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PEDIATRICS Volume 139, number 5, May 2017 7
stratified by gestational age at birth
(<26 or 2627 6/7 weeks).48
Effect on Motor Outcomes, Vision,
and Hearing
In the meta-analysis, prophylactic
rhEPO had no significant effect on
the incidence of PDI <70, cerebral
palsy, severe visual impairment, or
severe hearing impairment at 18
to 24 months corrected age (Figs
2C and 3 AC). Admittedly, these
adverse outcomes are rare, and the
meta-analysis may not be sufficiently
powered to detect minor effects.
The latter also applies to longer-
term follow-up studies that did not
detect prophylactic rhEPO to have
any impact on gross and fine motor
activity, cerebral palsy, vision, or
hearing.19,21
Reassuringly, the lack
of effect on visual outcome in the
meta-analysis is consistent with
previous meta-analyses showing
that early rhEPO did not increase the
risk of retinopathy of prematurity
(ROP)49,50
and with experimental
data suggesting that rhEPO may
even protect the neuronal cells of
the retina.51 Most recently, a meta-
analysis by Fang et al52 evaluated the
influence of rhEPO (independent of
early or late treatment initiation) on
ROP and found no impact on the rates
of any stage ROP, severe ROP, or ROP
necessitating intervention.
Effect on Any Neurodevelopmental
Impairment
Despite the robust beneficial effect
of rhEPO on cognitive development,
this meta-analysis showed only a
trend toward lowering the combined
outcome of any neurodevelopmental
impairment (OR 0.55; 95% CI, 0.28
1.08; P = .08; Fig 3D). One possible
explanation is that rhEPO targets
only a subset of cells or certain
areas of the brain responsible for
cognitive development. Alternatively,
the aforementioned discrepancy
may result from the fact that data
on the incidence of PDI <70 were
not available for 2 RCTs.20,31
In the
meta-analysis, this limitation may
8 Fischer et al
have biased the calculated effect
of rhEPO on PDI <70 and on any
neurodevelopmental impairment
in favor of the placebo (Figs 2C
and 3D). Notably, Song et al31
reported absolute PDIs, which were
significantly higher in their rhEPO
group compared with placebo
(median PDI 99 vs 90; P < .001).
Future Directions
The results of the present meta-
analysis clearly indicate that more
clinical trials are warranted to
investigate open questions about
prophylactic rhEPO administration
in preterm infants. Most importantly,
major variations in the study
protocols of the 4 RCTs included
in the meta-analysis indicate that
the optimal timing and dosing
of rhEPO for neuroprotection in
preterm infants are still unknown.
It is therefore interesting that the
follow-up on a previous phase I
and II dose escalation trial of early
high-dose rhEPO showed that rhEPO
improved cognitive and motor
outcome measures at 4 to 36 months
corrected age.53 The protocol of
the Swiss RCT (first dose within 3
hours after birth, cumulative dose
of 9000 IU/kg within the first 42
hours)32 was the only RCT that
closely followed experimental data,
arguing for early high-dose rhEPO
to achieve therapeutic levels in the
brain within the most vulnerable
early postnatal period.54,55
Because
a subset of the study patients who
were examined by cranial MRI
scans at term-corrected age showed
significantly lower white and gray
matter injury scores after rhEPO
treatment,56 it was disappointing
that BSID-II scores at 18 to 24
months were not improved, neither
in the subset nor in the entire study
population.32 However, benefits in
neurodevelopmental outcome may
not be ascertainable until school
age or even later.19,57,
58 Looking at
the encouraging outcome data of
preterm rhEPO-treated infants in
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the retrospective study of Neubauer
et al19 which extend the follow-up
examinations from 2 to 13 years of
age, the 2-year time point was the
only one that showed no effects of
rhEPO. Therefore, patients from the
4 analyzed RCTs need long-term
neurodevelopmental follow-up
examinations at 5 to 6 and 10 to
13 years of age, and additional
funding should be provided for this
purpose.
The fact that in the other 3
RCTs, repeated low-dose rhEPO
treatment (started between 24
and 96 hours after birth, in doses
of 12001750 IU/kg per week,
sustained for 2 weeks31 or longer17,20
)
significantly improved neurologic
outcomes provides an indication
that continued treatment may
be essential. So far, it is unclear
whether this effect is caused by
a direct impact of rhEPO on the
premature brain or by stimulated
erythropoiesis and reduced red
blood cell transfusions. However,
the question deserves more
research, particularly considering
pharmacodynamically optimized
rhEPO treatment to prevent
transfusions.59 To date, clinical
data from meta-analyses and
studies of early high-dose rhEPO
indicate no increased risk for
typical disorders in very preterm
infants such as necrotizing
enterocolitis, bronchopulmonary
dysplasia, and other adverse
outcomes.24,25,
27,
32,
49,
50,53
Two
cohort studies even found a lower
incidence of bronchopulmonary
dysplasia in infants treated with
rhEPO to prevent red blood cell
transfusions.60,61
However, more
skin hemangiomas were reported in
2 other cohort studies.25,62
Future RCTs of prophylactic
rhEPO in preterm infants should
investigate treatment protocols
that combine an early high-dose
strategy with continued treatment.
The aforementioned PENUT trial in
the United States (NCT01378273)48
and another ongoing trial in China
(NCT02601872, NCT02550054)
apply such strategies. Moreover,
the EPO REPAIR trial in Switzerland
currently investigates a similar
dosing protocol for the rescue
treatment of preterm infants with
intraventricular hemorrhage
(NCT02076373).6 However, the
results of these studies will not be
available before the end of 2018.
Limitations
The limitations of the available
evidence are discussed above.
Importantly, the RCT by Song et al31
had a substantial impact on the
primary outcome but involved a high
risk of bias in 2 domains. In addition,
there were limitations at the meta-
analysis level; as a primary outcome,
we accepted a cognitive score <85
(BSID-III) as equivalent to an MDI
<70 (BSID-II), as recommended by
Johnson et al.35 However, authors of
other studies found slightly different
cutoff levels.63,64
With regard to
the secondary outcomes, visual
impairment, hearing impairment,
and any neurodevelopmental
impairment, we deliberately accepted
minor deviations of the respective
outcome definitions between the
included studies (Supplemental
Tables).
Conclusions and Drs Makoto Kashiwabara,
The current meta-analysis of 4 RCTs, Paulina Aleksander, and Banu Orak
including 574 rhEPO-treated and for translating articles published in
547 placebo-treated premature Bulgarian, Chinese, Italian, Japanese,
infants, indicates that prophylactic Polish, and Turkish, respectively.
rhEPO improves neurocognition,
as assessed by the MDI at 18 to 24 Abbreviations
months corrected age. By contrast,
BSID-II:Bayley Scales of Infant
rhEPO had no significant effects on
Development, Second
other neurodevelopmental outcomes.
Edition
These findings demonstrate the
BSID-III:Bayley Scales of Infant
promising potential of rhEPO for
Development, Third
neuroprotection in very preterm
Edition
infants. New data from current and
CENTRAL:Cochrane Central
future RCTs are needed to identify
Register of Controlled
the optimal timing and dosing of
Trials
prophylactic rhEPO administration
CI:confidence interval
in this age group. Ongoing RCTs
ELBW:extremely low birth
and those already completed
weight
should be funded for long-term
MDI:Mental Developmental
neurodevelopmental follow-up.
Index
MeSH:Medical Subject Headings
Acknowledgments NNT:number needed to treat
OR:odds ratio
We thank Dr Giancarlo Natalucci for
PDI:Psychomotor Development
providing previously unpublished
Index
data and additional information
PRISMA:Preferred Reporting
on his study.32 We appreciate the
Items for Systematic
expert neuropediatric advice of Drs
Reviews and
Elisabeth Walch and Gitta Reuner
Meta-analyses
regarding the comparison of the
RCT:randomized controlled trial
different editions of the Bayley Scales
rhEPO:recombinant human
of Infant Development. In addition,
erythropoietin
we thank Lukas Bomke, Judith
ROP:retinopathy of prematurity
Hollnagel, Christina Dame-Paasch,

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2017 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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11
Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A
Meta-analysis
Hendrik S. Fischer, Nora J. Reibel, Christoph Bhrer and Christof Dame
Pediatrics; originally published online April 7, 2017;
DOI: 10.1542/peds.2016-4317
Updated Information & including high resolution figures, can be found at:
Services /content/early/2017/04/05/peds.2016-4317.full.html
Supplementary Material Supplementary material can be found at:
/content/suppl/2017/04/05/peds.2016-4317.DCSupplemental.
html
References This article cites 60 articles, 21 of which can be accessed free
at:
/content/early/2017/04/05/peds.2016-4317.full.html#ref-list-1

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A
Meta-analysis
Hendrik S. Fischer, Nora J. Reibel, Christoph Bhrer and Christof Dame
Pediatrics; originally published online April 7, 2017;
DOI: 10.1542/peds.2016-4317

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2017/04/05/peds.2016-4317.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2017 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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