The Journal of Maternal-Fetal & Neonatal Medicine

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Paracetamol versus ibuprofen for the treatment

of patent ductus arteriosus in preterm neonates: a
meta-analysis of randomized controlled trials

Xintao Huang, Fang Wang & Kai Wang

To cite this article: Xintao Huang, Fang Wang & Kai Wang (2017): Paracetamol versus
ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: a meta-analysis
of randomized controlled trials, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2017.1338263

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1338263

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017
https://doi.org/10.1080/14767058.2017.1338263

REVIEW ARTICLE

Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus

in preterm neonates: a meta-analysis of randomized controlled trials
Xintao Huanga
, Fang Wangb
and Kai Wangb
a
Department of Cardiology, Zhumadian Central Hospital, Zhumadian, China; bDepartment of Pediatrics, Zhengzhou Central Hospital,
Zhengzhou, China

ABSTRACT ARTICLE HISTORY

Background: Paracetamol has been suggested as an effective treatment for patent ductus arte- Received 11 May 2017
riosus (PDA). However, the comparative efficacy and safety between paracetamol and ibuprofen Revised 29 May 2017
were not determined. Accepted 31 May 2017
Methods: A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant studies
were identified via database searching. A fixed or random effect model was applied depending KEYWORDS
on the extent of heterogeneity. Ibuprofen; meta-analysis;
Results: Five RCTs with 677 neonates were included. The efficacies for the primary (risk ratio paracetamol; patent ductus
[RR]: 1.03, p ¼ .56) and overall PDA closure were comparable between the two medications (RR: arteriosus; randomized
1.02, p ¼ .62). Neonates of the two groups were comparable for the incidence of PDA complica- controlled trials
tions, including necrotizing enterocolitis (RR: 0.86, p ¼ .70), intraventricular hemorrhage (RR: 0.84,
p ¼ .55), bronchopulmonary dysplasia (RR: 0.69, p ¼ .16), and retinopathy of prematurity (RR: 0.58,
p ¼ .15), and the risks of sepsis (RR ¼ 0.88, p ¼ .48) and death (RR: 1.45, p ¼ .45) within hospitaliza-
tion. However, treatment with paracetamol was associated with a trend of reduced risk of renal
failure (RR: 0.20, p ¼ .07), and a significantly reduced risk of gastrointestinal bleeding (RR: 0.28,
p ¼ .009).
Conclusions: Paracetamol may confer comparable treatment efficacy for the closure of PDA as
ibuprofen, although paracetamol is associated with lower risk of adverse events.

Introduction
Patent ductus arteriosus (PDA) is a common congenital
cardiac defect, which mainly affects the preterm neo-
nates of gestational age (GA) < 28 weeks [1]. The inci-
dence of PDA is reported to be between 30 and 70%,
depending on the GA of the preterm neonates investi-
gated [2]. Neonates with PDA often suffer from the
left-to-right shunt, which causes the increment of the
pulmonary blood flow [3]. Moreover, patients with
hemodynamically significant PDA are associated with
increased risk for long-term complications, including
chronic lung disorders, retinopathy, cardiac failure, or
even death [2]. Therefore, closure of PDA is indicated
in neonates with significant hemodynamic disorders
for the prevention of the above complications and
improvement of prognosis.
Currently, closure of PDA could be achieved via
medications or surgical interventions [2].
Pharmacologically closure of PDA is considered to be
the first-line treatment, because it is noninvasive and
without the risk of potential morbidities related to the
surgical procedures, including vocal cord palsy, pul-
monary dysplasia, and neurosensory dysfunction [4].
Pathophysiologically, prostaglandins (Pg) have been
recognized to be a key mediator for the patency of
the ductus arteriosus [5]. Accordingly, nonsteroidal
anti-inflammatory drugs (NSAIDs), particularly of ibu-
profen, are conventionally used as the pharmacologic-
ally treatment for neonates with PDA [6]. By
competitively inhibition of cyclooxygenase (COX), ibu-
profen reduces the endogenous level of Pg, resulting
in the successful closure of PDA in about 70% of the
cases [7]. However, ibuprofen is contradicted in
patients with renal dysfunction or those at higher risk
for bleeding, because administration of ibuprofen is
associated with the increased incidence of renal failure
and gastrointestinal bleeding (GIB), probably related to
its effect of peripheral vasoconstriction [8]. Therefore,
development of alternative medications for the closure
of PDA is of important significance in clinical practice.

CONTACT Kai Wang kaiwang2017@sina.com Department of Pediatrics, Zhengzhou Central Hospital, Zhengzhou, China

These authors contributed equally to the work
Supplemental data for this article can be accessed here.
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 X. HUANG ET AL.
Paracetamol is recently proposed as an alternative
medication for the closure of PDA since it functions as
an inhibitor to the prostaglandin synthetase, and
causes reduced endogenous Pg [9,10]. Besides, para-
cetamol may be superior to other NSAIDs regarding
the safety because it is proved to have no effect of
peripheral vasoconstriction [11]. Indeed, accumulating
evidence from case series and cohort studies con-
firmed the efficacy of paracetamol as an effective
treatment for neonates with PDA [12]. However, the
efficacy and safety of paracetamol as compared with
ibuprofen for the treatment of PDA in preterm neo-
nates have not been fully determined. Although some
related randomized controlled trials (RCTs) have been
published to compare the therapeutic effects of para-
cetamol and ibuprofen for PDA [13–17], most of these
studies retrieved insignificant results, possibly due to
the limited sample sizes of the studies. Therefore, in
this study, we aimed to combine the results of the
RCTs via a meta-analysis to systematically compare the
efficacy of safety between paracetamol and ibuprofen
in neonates with PDA.
Materials and methods
This systematic review and meta-analysis was con-
ducted in accordance with the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-
Analyses) statement and the Cochrane Handbook
guidelines [18].
Search strategy
PubMed, Embase, and the Cochrane Library (Cochrane
Center Register of Controlled Trials) were systematic-
ally searched for relevant studies, using the term
“patent ductus arteriosus” or “PDA”, paired with
“paracetamol” or “acetaminophen”, “ibuprofen”, and
“randomly”, “randomized” or “random”. The search was
limited to studies in humans. We also analyzed refer-
ence lists of the original and review articles using a
manual approach. The final searching was performed
on 25 February 2017.
Study selection
Studies were included if they met the following crite-
ria: (a) published as full-length articles in English; (b)
reported as RCTs with a parallel design; (c) included
preterm neonates with echocardiography confirmed
PDA who were assigned to either a paracetamol treat-
ment group or an ibuprofen treatment group (regard-
less of the administrative routes or the dosages
of the medications); (d) reported at least one of the
following efficacy or safety outcomes: incidence of
primary PDA closure (defined as echocardiography
confirmed closure of PDA after the first course of the
treatment); incidence of overall PDA closure (defined
as echocardiography confirmed closure of PDA after
one or more courses of the treatment); incidences of
complications, including necrotizing enterocolitis (NEC,
defined in accordance with the modified Bell’s classifi-
cation [19]), intraventricular hemorrhage (IVH, defined
in accordance with the Volpe’s classification [20]),
bronchopulmonary dysplasia (BPD, defined in accord-
ance with the National Institutes of Health consensus
definition [21]), and retinopathy of prematurity (ROP,
defined in accordance with the international classifica-
tion [22]); incidences of adverse events, including renal
failure, GIB, and sepsis, which were defined in consist-
ence with the definitions from the original studies;
and all-cause mortality within hospitalization. Reviews,
nonhuman studies, observational studies without lon-
gitudinal follow-up, cross-sectional studies, duplicate
publications, and studies in which the outcomes of
interest were not reported or unavailable were
excluded from the current study.
Data extraction and quality assessment
Two authors independently performed the literature
searching, data extraction, and quality assessment
according to inclusion criteria. Discrepancies were
resolved by consensus. Extracted data included the
country where the study was performed, study design
characteristics (blind or open-label), characteristics of
the neonates (number of participants, gender, mean
GA, mean birth weight [BW], and the postnatal ages),
mean diameters of the PDA, administrative routes and
dosages of the medications, and treatment durations.
We used the seven domains of the Cochrane risk of
bias tool to evaluate the quality of the included stud-
ies [18], which include criteria concerning sequence
generation, allocation concealment, blinding of partici-
pants and personnel, blinding of outcome assessors,
incomplete outcome data, selective outcome report-
ing, and other potential threats to validity.
Statistical analysis
Dichotomous data were analyzed using risk ratios
(RRs) with 95% confidence intervals (CIs). Cochrane’s Q
test was applied to evaluate the heterogeneity among
the included studies, and significant heterogeneity was
considered for p < .10 [23]. Also, determined was the I2
statistic, which describes the percentage of total
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

variation across studies that is due to heterogeneity
rather than chance [24]. I2 > 50% indicated significant
heterogeneity among the trials. Pooled analyses were
calculated using fixed-effect models if no significant
heterogeneity was detected by Cochrane’s Q test,
whereas random-effect models were applied in cases
of significant heterogeneity across studies [18].
Predefined subgroup analyses were used to evaluate
whether the treatment efficacy for PDA closure were
different between studies in which the medications
were administered orally and those in which the medi-
cations were applied intravenously. Sensitivity analyses
by omitting one study at a time were used to evaluate
the robustness of the results [18]. Potential publication
bias was assessed with Egger’s regression asymmetry
test [25] and visual inspection of funnel plots; p values
were two-tailed and statistical significance was set at
0.05. We used RevMan software for the meta-analysis
and statistical study (Version 5.1; Cochrane, Oxford,
UK) and Stata software (Version 12.0; Stata, College
Station, TX).
Iran [15], and Egypt [16], respectively. The number of
the neonates included in each study varied from 80 to
200, with the proportions of males ranging from 51.9
to 70.0%. The mean GA of the included neonates var-
ied between 25.5 and 33.5 weeks, and the mean BW
varied between 952 and 2155 grams. All of the
included neonates were at a postnatal age of
14 days. The mean diameters of PDA varied from 2.0
to 2.8 mm. As for the characteristics of the interven-
tions, oral paracetamol of 60 mg daily for 3 days or
oral ibuprofen of 10, 5, and 5 mg for day 1 to day 3
were applied in three RCTs [13,14,17]; oral paracetamol
of 60 mg daily for 3 days or oral ibuprofen of 20, 10,
and 10 mg for day 1 to day 3 were applied in one
RCTs [15]; while intravenous paracetamol of 60 mg
daily for 3 days or intravenous ibuprofen of 10, 5, and
5 mg for day 1 to day 3 were applied in the other one
study [16]. The course of the medication was main-
tained for 3 days in each of the included studies and
all the medications were treated as the first-line ther-
apy for the PDA of the included neonates.

Results Data quality

Search results The details of risks of biases of the included studies

A total of 126 articles were identified through the
database searching, and 112 were excluded based on
titles and abstracts screening, mainly because they
were not relevant studies. Of the 14 potentially rele-
vant articles, five studies met the inclusion criteria for
the current meta-analysis [13–17] (Supplemental
Figure 1). Nine articles were excluded because two of
them were not relevant studies, five were not RCTs,
one was duplicated publications, and the other one
did not report data interested outcomes.
Study characteristics
Overall, five RCTs [13–17] with a total of 677 neonates
were included in the current meta-analysis, all of
which were published after year 2013. The characteris-
tics of the included RCTs were summarized in Table 1.
Two [13,17] of the included studies were performed in
China, and the other three were performed in Turkey [14],
according to the Cochrane assessment tool are listed
in Supplemental Table 1. Briefly, one of the included
RCTs were double-blinded studies [16], two were sin-
gle-blinded [14,15], while the other two [13,17] were
open label. Details of random sequence generation
were reported in two studies [16,17], and the strat-
egies of allocation concealment were reported in three
studies [13,14,16]. Details of withdrawals and dropouts
were reported in all studies.
Efficacy of paracetamol versus ibuprofen for PDA
closure in preterm neonates
Pooled results of the five RCTs with a fixed-effect
model showed that the efficacies for the primary
(RR: 1.03, 95%CI: 0.93–1.13, p ¼ .56; Figure 1(A)) and
overall PDA closure were comparable between
paracetamol and Ibuprofen (RR: 1.02, 95%CI:
0.95–1.09, p ¼ .62; Figure 1(B)) with no significant het-
erogeneity among included studies (both I2 ¼ 0%).

Table 1. Characteristics of included studies.

Study No. of GA BW PA Ductal Route Dose (P/I) Durations Timing
Author, year Location design infants Male % weeks grams days diameter mm (P/I) mg/kg/d (P/I) (P/I)
Dang, 2013 China R, OL 160 51.9 31.1 1562  14 2.4 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Oncel, 2014 Turkey R, SB 80 52.5 27.3 952 24 2.3 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Yang, 2016 China R, OL 87 59.8 33.5 2155  10 2 Oral/Oral 60-60-60/10-5-5 3 days First-line therapy
Bagheri, 2016 Iran R, SB 150 53.5 31.6 1644  14 NR Oral/Oral 60-60-60/20-10-10 3 days First-line therapy
El-Mashad, 2017 Egypt R, DB 200 70 25.5 1050  14 2.8 IV/IV 60-60-60/10-5-5 3 days First-line therapy
R: Random; OL: open label; SB: single blinded; DB: double blinded; GA: gestational age; BW: birth weight; PA: postnatal age; P: paracetamol; I: ibuprofen.
4 X. HUANG ET AL.

Figure 1. Forest plots comparing the efficacies of paracetamol and ibuprofen on PDA closure in preterm neonates. (A) The out-
come of primary PDA closure with one course of medication; (B) The outcome of overall PDA closure with multiple courses of
medications.

Subsequent subgroup analyses showed that these
results were consistent for studies in which the medi-
cations were administered orally, and for those in
which the medications were administered intraven-
ously (p for the subgroup interaction ¼ .86 and .38,
respectively, for the outcomes of primary and overall
PDA closure; Figure 1(A,B)). Subgroup analyses by
omitting one study at a time did not significantly
change the results, suggesting that these results were
not driven by a single study.
Complication risks of paracetamol versus
ibuprofen for preterm neonates with PDA
The comparative risks for the incidences of the compli-
cations of PDA in neonates assigned to a paracetamol

or an ibuprofen treatment group were shown in
Supplemental Figure 2. Pooled results showed that the
preterm neonates with PDA allocated to the two
groups were comparable as for the risk of NEC (RR: 0.
86, 95%CI: 0.41–1.81, p ¼ .70; Supplemental Figure
2(A)), IVH (RR: 0.84, 95%CI: 0.49–1.46, p ¼ .55;
Supplemental Figure 2(B)), BPD (RR: 0.69, 95%CI: 0.
41–1.16, p ¼ .16; Supplemental Figure 2(C)), and ROP
(RR: 0.58, 95%CI: 0.28–1.21, p ¼ .15; Supplemental
Figure 2(D)), with no evidence of significant
heterogeneities.
Risks of adverse events in neonates receiving
paracetamol versus ibuprofen
Pooled results showed that PDA neonates that
received paracetamol were associated with a trend of
reduced risk of renal failure (RR: 0.20, 95%CI: 0.04–1.15,
p ¼ .07; Figure 2(A)), and a significantly reduced risk of
GIB (RR: 0.28, 95%CI: 0.11–0.73, p ¼ .009; Figure 2(B)) as
compared with those received ibuprofen. However,
the two groups were not significantly different for the
incidences of sepsis (RR: 0.88, 95%CI: 0.62–1.25,
p ¼ .48; Figure 2(C)). No significant heterogeneities
were detected for the above analyses (all I2 ¼ 0%). In
addition, meta-analyses with a random-effect model
showed that the two groups were not significantly dif-
ferent for the incidence of death within hospitalization
(RR: 1.45, 95%CI: 0.55–3.81, p ¼ .45; Figure 2(D)),
although considerable heterogeneity was detected
among the included studies (I2 ¼ 42%).
Publication bias
The publication bias for the current meta-analysis was
difficult to estimate because only five studies were
included. The funnel plots seemed to be symmetrical
on visual inspection for both the meta-analyses com-
paring the primary and overall closure of the PDA after
paracetamol or ibuprofen treatment (Supplemental
Figure 3(A,B)). These were consistent with the results
of the Egger’s regression tests which suggested no sig-
nificant publication bias for the above meta-analyses
(p ¼ .81 and .28, respectively).
Discussion
In this meta-analysis, by pooling the results of five
available RCTs, we found that there was no significant
difference between paracetamol and ibuprofen for the
closure of PDA in preterm neonates. Moreover, treat-
ment with paracetamol or ibuprofen did not signifi-
cantly affect the risk of PDA associated complications,
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
the risk of renal failure, or the mortality risk within
hospitalization. However, treatment with paracetamol
was associated with reduced risk of adverse events,
including renal failure and GIB, as compared with ibu-
profen. Taken together, these results suggested that
paracetamol may confer comparable treatment efficacy
as ibuprofen for the closure of PDA. Moreover, para-
cetamol may be optimal in this clinical condition since
it was associated with lower risk of adverse events of
renal failure and GIB as compared with ibuprofen.
A previous meta-analysis [26] including only two
RCTs [13,14] investigated the safety and efficacy of
paracetamol as compared with ibuprofen for the treat-
ment of PDA. However, it included only 240 neonates
in total, and suggested that no confirmed conclusion
could be drawn regarding the relative efficacy of para-
cetamol as compared with ibuprofen for the closure of
PDA since limited evidence was available. Our study
updated the previous meta-analysis by including 5
available RCTs with a total of 677 neonates, found that
treatment of paracetamol and ibuprofen have no sig-
nificant differences regarding the closure rate of PDA.
The insignificant result was not likely to be caused by
the inadequate of the statistical power due to limited
participants included, because over 300 neonates were
included in each group. Although these results need
to be confirmed in further studies, our study did not
support that there is significant difference regarding
the efficacy between paracetamol and ibuprofen for
the closure of PDA in preterm neonates. These results
were further reflected by the findings that no signifi-
cant differences were detected between the two treat-
ment groups for the incidences of PDA related
complications, including NEC, IVH, BPD, and ROP.
Interestingly, as for the incidence of adverse events,
we found that neonates receiving paracetamol were
associated with lower incidences of renal failure and
GIB as compared with ibuprofen. Both of these events
were considered to be related to the potential periph-
eral vasoconstrictive effect of ibuprofen [27], and para-
cetamol did not have this effect [28]. Besides, the
potential antiplatelet aggregative effect of ibuprofen
may also contribute to the pathogenesis of GIB related
to the use of ibuprofen [29]. These results suggested
that although conferring comparative efficacy towards
the closure of PDA, administration of paracetamol may
be safer as compared with ibuprofen, particularly in
those at risk for the development of renal dysfunction
or GIB.
Our study has limitations which should be consid-
ered when interpreting the results. First, since limited
RCTs were available and individual patient-based data
was unavailable, we could not determine whether
6 X. HUANG ET AL.

Figure 2. Forest plots comparing the influences of paracetamol and ibuprofen on the incidences of adverse events in preterm
neonates with PDA within hospitalization. (A) The incidence of renal failure; (B) The incidence of gastrointestinal bleeding; (C) The
incidence of sepsis; (D) The incidence of death.

characteristics of the treatment (such as the dosages,
administrative routes, and the timing) may affect the
therapeutic efficacy of paracetamol or ibuprofen on
PDA closure by performing a metaregression analysis.
Future RCTs with adequate sample sized are warranted
to evaluate the potential influence of above factors on
the therapeutic efficacies of the medications. Second,
the follow-up durations of the included studies were
relatively short and limited to the hospitalization.
Further studies are needed to evaluate whether the
therapeutic efficacies of paracetamol or ibuprofen for
PDA remained after these neonates were discharged.
Moreover, long-term safety of these medications in
preterm neonates with PDA also deserves investiga-
tion. Third, some of the included RCTs were open-label
and of low quality, which may introduce potential
bias. Our results need to be confirmed in high-quality
RCTs in the future. Finally, since PDA is prevalent in

extreme preterm neonates, whether paracetamol and
ibuprofen confer comparable therapeutic efficacy in
these subgroups of the patients deserve further
investigation.
In conclusion, paracetamol may confer comparable
treatment efficacy for the closure of PDA as ibuprofen,
although paracetamol is associated with lower risk of
adverse events including renal failure and GIB.
Disclosure statement
The authors report no declarations of interest.
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