The Journal of Maternal-Fetal & Neonatal Medicine

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Comparison of efficacy of oral paracetamol

versus ibuprofen for PDA closure in preterms – a
prospective randomized clinical trial

Bharathi Balachander, Nivedita Mondal, Vishnu Bhat, Bethou Adhisivam,

Mahesh Kumar, Santhosh Satheesh & Mahalakshmi Thulasingam

To cite this article: Bharathi Balachander, Nivedita Mondal, Vishnu Bhat, Bethou Adhisivam,
Mahesh Kumar, Santhosh Satheesh & Mahalakshmi Thulasingam (2018): Comparison of
efficacy of oral paracetamol versus ibuprofen for PDA closure in preterms – a prospective
randomized clinical trial, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2018.1525354

To link to this article: https://doi.org/10.1080/14767058.2018.1525354

Accepted author version posted online: 19

Sep 2018.
Published online: 29 Oct 2018.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2018.1525354

ORIGINAL ARTICLE

Comparison of efficacy of oral paracetamol versus ibuprofen for PDA

closure in preterms – a prospective randomized clinical trial
Bharathi Balachandera, Nivedita Mondala, Vishnu Bhata, Bethou Adhisivamb, Mahesh Kumarc,
Santhosh Satheeshc and Mahalakshmi Thulasingamc
a
Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India;
b
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India;
c
Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India

ABSTRACT ARTICLE HISTORY

Background: Currently nonselective cyclooxygenase (COX) inhibitors, ibuprofen and indometh- Received 21 January 2018
acin, are approved drugs for closure of patent ductus arteriosus but have potential toxicities. Accepted 14 September 2018
There are reports of the effectiveness of paracetamol in ductal closure. However, there is paucity
KEYWORDS
of data comparing paracetamol to ibuprofen or indomethacin in relation to the efficacy and
Ductus; ibuprofen;
safety profile. paracetamol; PDA; preterm
Methods: This randomized clinical trial was done in our tertiary care neonatal unit from
October 2014 to January 2016 after clearance from ethical committee. It was registered with
clinical trial registry of India (CTRI/2016/09/007261) and drug controller general of India (CT/
Drugs/56/2014). Preterm neonates with clinical suspicion of hemodynamically significant PDA
after echo confirmation were included in the study. Randomization was done by stratified ran-
domization through sealed opaque envelopes. A sample size of 150 was estimated with an
expected difference in success of closure as 20% between the treatment groups at level of 5%
significance and 80% power. The echocardiography was done 24 hours after completion of treat-
ment by a cardiologist blinded to treatment.
Results: The baseline parameters were comparable between two groups. One hundred and
forty-six babies had hs-PDA, out of which 110 babies were randomized. No significant difference
was found between the two groups with respect to PDA closure (RR 0.97, 95%CI 0.78–1.20,
p ¼ 1), mortality or cardio-respiratory morbidity. The babies who received ibuprofen had a
higher occurrence of acute kidney injury (RR 0.33, 95%CI 0.13-0.85, p ¼ 0.024).
Conclusions: Paracetamol is as effective as ibuprofen for PDA closure in preterm neonates.
Ibuprofen used for PDA closure in preterms poses an increased risk for acute kidney injury com-
pared to paracetamol.

Introduction 70–85% but without short-term benefits like reduction

The transition of the neonate to extrauterine life is
characterized by the occurrence of several events,
among which a crucial one is the closure of ductus
arteriosus [1]. Failure of the ductus arteriosus to close
is a maladaptation that occurs more commonly in pre-
term neonates, contributing significantly to their mor-
bidity, with increased risks of necrotizing enterocolitis
(NEC), broncho-pulmonary dysplasia and neurodeve-
lopmental impairment [2,3]. Ductal closure can be
achieved in preterms by pharmacological modification
of the prostaglandin pathway or transcatheter closure
or surgical ligation. Currently, nonselective COX (cyclo-
oxygenase) inhibitors, ibuprofen and indomethacin,
are approved for this use with success rates of
in mortality [4] and potential toxicities namely nephro-
toxicity, NEC, intraventricular hemorrhage (IVH) and
thrombocytopenia [1,2]. Ultrasound guided closure of
PDA is proven to reduce the adverse effects [5]. There
are reports of the effectiveness of paracetamol in duc-
tal closure, which may be considered a safer option
with potentially fewer side effects [6–8]. The Cochrane
review concludes that paracetamol is as effective as
ibuprofen. However, data-comparing paracetamol with
ibuprofen in relation to efficacy and safety profile is
inadequate [9]. The primary objective of this study
was to compare the success of echocardiographic duc-
tal closure and clinical response in preterms following
administration of oral paracetamol as compared to

CONTACT Vishnu Bhat drvishnubhat@yahoo.com Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education & Research
(JIPMER), Pondicherry, India
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 B. BALACHANDER ET AL.
oral ibuprofen. The secondary objective was to com-
pare the mortality, cardio-respiratory morbidity and
side effects of the two drugs.
Materials and methods
This study was a randomized clinical trial conducted in
our tertiary care neonatal unit from October 2014 to
January 2016. The JIPMER scientific advisory commit-
tee and ethics committee approved the study. This
study was approved by the drug controller general of
India (CT/Drugs/56/2014). Neonates, who were 37
weeks gestational age and 2500 g birth weight, were
examined for the presence of a hemodynamically sig-
nificant patent ductus arteriosus (hs-PDA) by a cardi-
ologist if they had clinical features suggestive of PDA,
hyper-dynamic precordium, systolic or continuous
murmur, bounding pulses, wide pulse pressure, com-
pensated or hypotensive shock, on mechanical ventila-
tion for >24 hours, on CPAP with FiO2 requirement of
>30% for >24 hours, unexplained metabolic acidosis,
feed intolerance, unexplained clinical deterioration,
tachycardia/tachypnea, hepatomegaly.
Preterm neonates with PDA of size 1.5 mm and
left to right shunt after 24 hours of life up to day 28,
confirmed by echocardiography and any one of the
following: (1) features of cardiac failure, (2) on mech-
anical ventilation, and (3) left atrial to aortic root ratio
>1.5 were included. Neonates with other cardiac
anomalies or duct dependent lesions, major congenital
malformations, oliguria (urine output <1 ml/kg/hour
during the preceding 24 hours), serum creatinine
>1.6 mg/dl, intra ventricular hemorrhage within the
last 24 hours, NEC, jaundice requiring exchange trans-
fusion, platelet counts <50,000/mm3 or overt bleeding
were excluded.
A sample size of 150 (75 in paracetamol group; 75
in ibuprofen group) was estimated considering
expected difference in success of closure as 25%
between the treatment groups at level of 5% signifi-
cance and 80% power. However, the trial was stopped
at 110 as interim analysis revealed significant stage 1
and 2 AKI in the ibuprofen group.
The neonates were randomized to a treatment
branch after written informed consent from the
parents. Randomization was done as stratified block
random sampling for two groups, namely <34 weeks
and 34–37 weeks in varying block sizes for both strata,
through the website www.sealedenvelopes.com the
allocation was done through sequentially numbered
opaque sealed envelopes, opened by the resident on
duty in the NICU. The trial was a parallel design with
equal chance of allocation to two groups with ratio of
1:1. The patients falling under group A were given
paracetamol 15 mg/kg/dose Q6h by oro-gastric tube
or by paladai for two days. The patients falling under
group B were given ibuprofen 10 mg/kg stat on day 1
followed by 5 mg/kg 24 hours after first dose for two
days. A person blinded to the treatment allocation did
echocardiography 24 hours after treatment completion
to reassess the above parameters. The evaluation was
done by the same cardiologist. If treatment with ibu-
profen failed, a second course of ibuprofen was given
as rescue therapy and reassessed. If the second course
of ibuprofen failed, the neonate was referred for coil
closure or surgery or managed symptomatically
depending on the cardiologist’s opinion. If treatment
with paracetamol failed, the neonate was switched
over to ibuprofen as rescue therapy.
Statistical analysis was done using SPSS ver22 (SPSS
Inc., Chicago, IL). Intention to treat analysis was done.
Clinical outcomes like success of ductal closure and
mortality were expressed as frequency and percen-
tages. The comparison of these variables was carried
out by using chi square or Fisher’s exact test.
Continuous variables such as birth weight, gestational
age, number of days of hospital stay, duration of ven-
tilation, or time taken to reach full enteral feeds were
expressed as mean with SD or median with range. The
comparison of these variables was carried out using
independent Student’s t test or Mann–Whitney’s U
test. The statistical analysis was carried out at 5% level
of significance.
Results
During the study period from October 2014 to January
2016, there were a total of 3309 preterm neonates
37 weeks admitted to the NICU. Of them PDA was
clinically suspected in 320 babies and were subjected
to echocardiography. One hundred and forty-six
babies were found to have hemodynamically signifi-
cant PDA. Of them, 36 babies had contra-indication to
medical therapy and hence were excluded. One hun-
dred and ten babies were randomized by stratified
randomization (Figure 1).
The baseline parameters were comparable between
the two groups (Table 1). The commonest clinical fea-
tures to diagnose PDA were hyperdynamic circulation,
tachycardia and increased oxygen requirement. The
primary objective was to compare the efficacy of PDA
closure between the two groups (Table 2). PDA clos-
ure in our study was found to be 74.5% in the para-
cetamol group and 76.4% in the ibuprofen group.
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

Clinically suspected PDA and echocardiographic done =

320

Number detected to have hs-PDA = 146

Excluded n= 36
Thrombocytopenia – 14
Duct dependent lesion – 2
NEC – 12
Oliguria – 4
IVH – 2
Major congenital anomalies – 2

Recruited into study aer informed consent = 110

Randomizaon

Paracetamol Ibuprofen
(n=55) (n =55)

Expired
Expired
(n=11)
(n= 12)

Discharged
Discharged
(n= 44)
(n=43)

Figure 1. CONSORT diagram.

Table 1. Baseline characteristics of the study population.

Parameter Paracetamol (n ¼ 55) Ibuprofen (n ¼ 55) p Value
Birth weight (g) (mean ± SD) 1534.8 ± 408.2 1513.4 ± 414.9 .8
Gestational age (weeks) (mean ± SD) 31.58 ± 2.9 31.54 ± 2.9 .9
Male infants (n) 24 (43.6%) 24 (43.6%) 1.0
Maternal preeclampsia (n (%)) 17 (30.9%) 12 (21.8%) .3
Maternal GDM (n (%)) 9 (16.3%) 10 (18.2%) 1
IUGR (n (%)) 7 (12.7%) 11 (20.0%) .4
Abnormal Doppler studies (AEDF/REDF) (n (%)) 6 (10.9%) 6 (10.9%) 1
APH (n (%)) 4 (7.3%) 4 (7.3%) 1
Antenatal steroids (complete course) (n (%)) 12 (21.8%) 9 (16.3%) .8
LSCS (n (%)) 13 (23.6%) 12 (21.8%) .74
5th min APGAR (median (IQR)) 9 (6–8) 8.5 (7–9) 1
Ventilated (n (%)) 32 (58.2%) 28 (50.9%) .56
Received surfactant (n (%)) 15 (26%) 17 (31%) .9
Culture positive sepsis (n (%)) 10 (18.2%) 11 (20.0%) .81
ELBW (n (%)) 7 (12.7%) 5 (9.1%) .28
IUGR: intrauterine growth restriction; GDM: gestational diabetes mellitus; AEDF/REDF: absent end diastolic
flow/reverse diastolic flow; ELBW: extremely low birth weight.

Among the babies who had received paracetamol and
required rescue therapy (n ¼ 51), 92.2% closed after
medical rescue therapy. Ninety percent PDA closed in
the ibuprofen after medical rescue therapy. However,
the difference between the two groups was not
statistically significant (RR 1.01, 95%CI 0.9–1.13, p ¼ 1).
There was no significant difference in the mortality
and cardio-respiratory morbidity between the two
groups. The occurrence of AKI (all stages) was signifi-
cantly higher in the ibuprofen group (p ¼ .024)
4 B. BALACHANDER ET AL.

Table 2. Clinical and echocardiographic characteristics of PDA in both groups.

Parameter Paracetamol (n ¼ 55) Ibuprofen (n ¼ 55) RR (CI) p Value
Hyperdynamic precordium 35 (63.6%) 33 (60.0%) 1.0 (0.7–1.4) .8
Increased oxygen requirement 31 (56.3%) 32 (58.2%) 0.96 (0.7–1.3) 1
Tachycardia 34 (61.8%) 36 (65.4%) 0.94 (0.7–1.2) .8
Systolic murmur 23 (41.8%) 32 (58.2%) 0.7 (0.4–1.05) .1
Shock 10 (18.2%) 7 (12.7%) 1.4 (0.5–3.4) .6
Acidosis 12 (21.8%) 13 (23.6%) 0.9 (0.8–1.2) 1
Wide pulse pressure 3 (5.4%) 4 (7.3%) 1.0 (0.9–1.1) 1
Bounding pulses 5 (9.1%) 10 (18.2%) 0.5 (0.1–1.3) .2
Day of life PDA was diagnosed (mean ± SD) 3.3 ± 1.6 3.3 ± 1.6 – .7
PDA size (mm) (mean ± SD) 2.4 ± 0.75 2.38 ± 0.75 – .59
LA/Ao ratio (mean ± SD) 1.69 ± 0.26 1.72 ± 0.16 – .51

Table 3. Comparison of PDA closure, mortality and adverse effects between paracetamol and ibuprofen.
Paracetamol (n ¼ 55) Ibuprofen (n ¼ 55) RR (95%CI) p Value
PDA closed after first course of either drug 41 (71.5%) 42 (76.4%) 0.97 (0.78–1.2) 1
Required rescue therapy 10 (18.2%) 13 (23.6%) 0.76 (0.36–1.6) .64
Total no. of PDA s closed (first course and rescue therapy combined) 47/51 (92.2%) 50/55 (90.2%) 1.01 (0.9–1.13) 1
No. of PDAs reopened 4 (8.5%) 4 (8%) 1.01 (0.29–3.5) 1
Expired 12 (21.8%) 11 (20%) 1.09 (0.52–2.2) 1
Number of days on ventilator 3.25 ± 3.3 2.5 ± 3.0 – .25
Evidence of CCF after medical therapy 14 (25.5%) 15 (27.3%) 0.93 (0.5–1.79) 1
Number of days requiring respiratory support (CPAP/HFNC) 7.52 ± 5.68 10.52 ± 10.9 – .07
BPD 0 (0%) 3 (5.24%) – .24
NEC (all stages) 15 (27.3%) 12 (21.8%) 1.25 (0.6–2.4) .65
Feed intolerance 9 (16.3%) 8 (14.5%) 1.12 (0.48–2.6) 1
Jaundice requiring phototherapy 32 (58.2%) 25 (45.5%) 1.28 (0.88–1.84) .25
Cholestasis 2 (3.6%) 2 (3.6%) 1 (0.14–6.84) 1
IVH (all stages) 5 (9.1%) 5 (9.1%) 1 (0.30–3.26) 1
Bleeding manifestations 12 (21.8%) 11 (20.0%) 1.09 (0.52–2.25) 1
Thrombocytopenia 17 (30.9%) 16 (29.6%) 1.0 (0.5–1.8) 1
AKI (all stages) 5 (9.1%) 15 (27.3%) 0.33 (0.13–0.85) .024
AKI (stage 3) 0 4 (7.3%) – .11
IVH: intraventricular hemorrhage; NEC: necrotizing enterocolitis; BPD: bronchopulmonary dysplasia; CCF: congestive cardiac failure.

Table 4. Comparison of parameters at discharge between paracetamol and ibuprofen.

Paracetamol (n ¼ 55) Ibuprofen (n ¼ 55) RR (CI) p Value
Duration of hospital stay (days) (mean ± SD) 21.4 ± 11.8 25.7 ± 15.1 .14
Number of days to regain birth weight (mean ± SD) 18.62 ± 9.48 18.62 ± 7.2 .8
Gestational age at discharge (weeks) (mean ± SD) 35.3 ± 2.8 35.3 ± 2.9 .9
Number of days to full enteral nutrition (mean ± SD) 8.488 ± 5.5 9.023 ± 4.53 .63
Screening OAE fail 3 (6.9%) 3 (6.8%) 1
ROP (all stages) 22 (55.1%) 21 (56.7%) 0.94 (0.63–1.42) .82
ROP requiring LASER 5 (12.5%) 3 (8.1%) 1.66 (0.4–6.13) .69
ROP: retinopathy of prematurity.

compared to paracetamol. However, most of them

were transient and returned to baseline by 48 hours. PDA closure
Four neonates had stage 3 AKI out of which two neo- Mortality
nates required peritoneal dialysis. The other adverse Bleeding

events were not different between the two groups AKI

IVH
(Table 3). The duration of hospital stay, retinopathy of
Thrombocytopenia
prematurity (ROP), time taken to full enteral feeds
Cholestasis
were similar between the two groups (Table 4). The Hyperbilirubinemia
summary of relative risks is depicted in Figure 2. NEC
Feed intolerance
CCF
Discussion BPD

One of the significant contributors to mortality "ROP requiring LASER "

and morbidity in a premature neonate is the presence 0.1 0.4 1.6 6.4
of a hemodynamically significant PDA. Medical Favors paracetamol Relave risk (CI) Favors Ibuprofen

management currently comprises of the use of Figure 2. Summary of relative risks of all outcomes.

cyclo-oxygenase inhibitors, namely indomethacin and
ibuprofen. Currently, there are two published random-
ized clinical trials comparing paracetamol to ibuprofen
[10,11], there is one RCT comparing paracetamol to
indomethacin [12].
We conducted an RCT to compare the percentage
of closure of PDA in neonates who received paraceta-
mol versus ibuprofen. Our study did not reveal any
difference in the percentage of PDA closure between
the two groups. Our closure rates were 74.5% in the
paracetamol group and 76.4% in the ibuprofen group
(RR 0.9, 95%CI 0.78–1.2, p ¼ 1). Dang et al. had an
overall closure rate of 81.2% in the paracetamol group
and 78.8% in the ibuprofen group (p¼.69). There was
no difference between the two groups [6]. Oncel et al.
also demonstrated similar closure rates between ibu-
profen and paracetamol. However, Dang et al. found
that the time to closure of PDA was faster with para-
cetamol when compared to ibuprofen. In a meta-ana-
lysis of two studies comprising 250 infants, there was
no difference in the PDA closure between the two
groups (RR 0.95, 95%CI 0.67–1.22) [9].
There was no difference in mortality between ibu-
profen (20%) and paracetamol (21.8%) in our study.
Oncel et al. reported mortality of 5% in the ibuprofen
group and 7.5% in the paracetamol group (p¼.64).
Dang et al. found no significant difference in mortality
[10]. The meta-analysis of two studies revealed no dif-
ference in the in-hospital mortality between the two
groups [9].
The incidence of reopening of PDA was similar in
both the groups in our study (RR 1.01, 95%CI
¼0.29–3.5, p ¼ 1). Dang et al. found similar reopening
rate in the paracetamol group (7.5%) and the ibupro-
fen group (9.9%). However, Oncel et al. found a higher
reopening rate with paracetamol (24.1%) than with
ibuprofen (16.1%) which was not statistically signifi-
cant [11]. The meta-analysis also showed no significant
difference in the reopening rates between the two
groups [9].
We found no difference between ibuprofen and
paracetamol concerning cardio-respiratory morbidity
in our study. The number of days on mechanical venti-
lation, the requirement of CPAP, evidence of congest-
ive cardiac failure after therapy and incidence of BPD
were similar between the two groups. Oncel et al.
reported no difference in the number of days of
mechanical ventilation, pneumothorax and pulmonary
hemorrhage between the two groups. In the meta-
analysis, the mean difference in the duration of venti-
lator requirement between the two groups was found
to be 4.15 days [9].
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
We found that the neonates who received para-
cetamol had a higher incidence of jaundice requiring
phototherapy, although it was not statistically signifi-
cant. Our finding was in contrast to that of Dang et al.
who found a significantly lower incidence of jaundice
with paracetamol. It is known that ibuprofen displaces
bilirubin from albumin and which may lead to hyper-
bilirubinemia. However, none of our neonates required
an exchange transfusion. Oncel et al. showed that
there was no difference in the mean bilirubin levels
before and after treatment [11]. The meta-analysis
revealed that in neonates with hyperbilirubinemia,
paracetamol may be a better option.
The occurrence of AKI (all stages) as classified by
the AKIN staging was significantly higher in neonates
who received ibuprofen. However, most of them
returned to baseline within 48 hours. In the study by
Oncel et al., there was a transient rise in post-treat-
ment creatinine by 0.06 mg/dl in the ibuprofen group,
although not statistically significant. In the paraceta-
mol group, posttreatment creatinine was lower than
the pretreatment values. However, urine output was
similar in both the groups. It is known that ibuprofen
affects nephrogenic cell rests [13]. Although ibuprofen
has a lesser degree of nephrotoxicity when compared
to indomethacin, Fanos et al. reported that 19 out of
29 infants had AKI during ibuprofen therapy [13].
There are also two case reports of severe forms of AKI
after ibuprofen therapy [14,15]. The mean difference
in creatinine, post treatment between the two groups
in the meta-analysis was 1.05 mmol/L and it was not
statistically significant.
When thrombocytopenia and bleeding were com-
pared, there was no significant difference between the
two groups in our study. Oncel et al. reported no dif-
ference in the occurrence of IVH and gastrointestinal
bleeding between paracetamol and ibuprofen [11].
There was no difference in the occurrence of ROP
between the two groups. The need for laser therapy
was higher in the paracetamol group (12.5%) com-
pared to ibuprofen group (8.1%), but the numbers
were small, and the difference was not statistically sig-
nificant. Dang et al. found that there was no differ-
ence between the drugs with regards to the
occurrence of ROP [10]. The findings were similar to
that seen in the Cochrane meta-analysis as well [10].
The neonates treated with paracetamol had a mean
duration of hospital stay of 21.4 days and those
treated with ibuprofen had a mean duration of hos-
pital stay of 25.7 days. However, the difference was
not statistically significant. No difference was found in
the number of days to regain birth weight, and
6 B. BALACHANDER ET AL.
number of days to reach full feeds between neonates
in paracetamol and ibuprofen group. The duration of
hospital stay was similar in both groups in the study
by Oncel et al. [8]. The follow up of these infants is
ongoing and we intend to follow them up till 18
months of age.
The strengths of the study are adequate sample
size and study design. To the best of our knowledge,
this is one of the first RCT in India. The limitation of
the study is that was blinding of drug administration
could not be done.
Conclusions
Paracetamol is as effective as ibuprofen for PDA clos-
ure in preterm neonates. Incidence of AKI is signifi-
cantly lower with paracetamol as compared
to ibuprofen.
Disclosure statement
No potential conflict of interest was reported by the authors.
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