Oral Paracetamol versus Oral Ibuprofen in the Management of Patent

Ductus Arteriosus in Preterm Infants: A Randomized Controlled Trial

Mehmet Yekta Oncel, MD1, Sadik Yurttutan, MD1, Omer Erdeve, MD2, Nurdan Uras, MD1, Nahide Altug, MD3,
Serife Suna Oguz, MD1, Fuat Emre Canpolat, MD1, and Ugur Dilmen, MD1,4

Objective To compare the efficacy and safety of oral paracetamol and oral ibuprofen for the pharmacological
closure of patent ductus arteriosus (PDA) in preterm infants.
Study design This prospective, randomized, controlled study enrolled 90 preterm infants with gestational age
#30 weeks, birthweight #1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed sig-
nificant PDA. Each enrolled patient received either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral
ibuprofen (initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours).
Results Spontaneous closure rate for the entire study group was 54%. After the first course of treatment, the PDA
closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the oral
paracetamol group (P = .6). The reopening rate was higher in the paracetamol group than in the ibuprofen group, but
the reopening rates were not statistically different (24.1% [7 of 29] vs 16.1% [5 of 31]; P = .43). The cumulative
closure rates after the second course of drugs were high in both groups. Only 2 patient (2.5%) in the paracetamol
group and 3 patients (5%) in the ibuprofen group required surgical ligation.
Conclusion This randomized, controlled clinical study compared oral paracetamol with ibuprofen in preterm
infants and demonstrated that paracetamol may be a medical alternative in the management of PDA. (J Pediatr
2014;164:510-4).

H
emodynamically significant patent ductus arteriosus (hsPDA) is a common cause of morbidity and mortality among
preterm infants, affecting more than 40% of preterm infants.
Several comorbidities such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), pulmonary edema/
hemorrhage, chronic lung disease (CLD), and retinopathy of prematurity (ROP) are associated with a patent ductus arteriosus
(PDA), but whether or not a PDA is responsible for their development is still unclear.1,2 Treatment options for the closure of
hsPDA include medical therapy and surgical ligation. The most commonly used drugs for this purpose are cyclooxygenase in-
hibitors, predominantly indomethacin and ibuprofen, which block the conversion of arachidonic acid to prostaglandins.3,4 The
reported treatment success with ibuprofen for the management of hsPDA is between 70%-85%.5-8 Several adverse effects have
been reported with such medications, including peripheral vasoconstriction, gastrointestinal bleeding and perforation,
decreased platelet aggregation, hyperbilirubinemia, and renal failure.9,10
Paracetamol (also known as acetaminophen) acts by directly inhibiting the activity of prostaglandin synthase.11
Unlike ibuprofen, paracetamol is thought to act on prostaglandin synthase at the peroxidase region of the enzyme.
Paracetamol inhibition is facilitated by a decreased local concentration of hydroperoxides.12 The role of paracetamol
as an alternative treatment for the closure of hsPDA has gained attention in recent years because of the potential
side-effects of cyclooxygenase inhibitors.13-15 In our previously reported case series, we showed that intravenous para-
cetamol could be an alternative treatment in patients in whom feeding was contraindicated or who had feeding intol-
erance.15 Recently, we reported that paracetamol in oral form could be used successfully as the primary choice in
PDA closure.16
Based on our earlier reports, we planned to test the hypothesis of whether paracetamol is as effective as ibuprofen in
treatment of hsPDA. Therefore, we conducted this prospective, randomized, controlled trial in preterm infants with birth-
weights #1250 g to compare the efficacy and safety of oral paracetamol with ibuprofen for the pharmacologic closure
of PDA.

From the 1Division of Neonatology, Zekai Tahir Burak

Maternity Teaching Hospital; 2Division of Neonatology,
Department of Pediatrics, Ankara University School of
ALT Alanine amino transferase Medicine; 3Division of Pediatric Cardiology, Zekai Tahir
CLD Chronic lung disease Burak Maternity Teaching Hospital; and 4Department of
hsPDA Hemodynamically significant patent ductus arteriosus Pediatrics, Yildirim Beyazit University School of
Medicine, Ankara, Turkey
IVH Intraventricular hemorrhage
The authors declare no conflicts of interest.
NEC Necrotizing enterocolitis
Registered with ClinicalTrials.gov: NCT01536158.
PDA Patent ductus arteriosus
ROP Retinopathy of prematurity 0022-3476/$ - see front matter. Copyright 2014 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.11.008

510
 Vol. 164, No. 3  March 2014

a second course via the same route. Patients with minimal

Methods
ductal shunting were followed up regularly by a neonatolo-
gist and a pediatric cardiologist. Patients who achieved
The study was conducted in the neonatal intensive care unit
PDA closure but had signs and symptoms of reopening later
of Zekai Tahir Burak Maternity Teaching Hospital, Ankara,
during hospitalization were reevaluated by echocardiography
Turkey between February and December 2012. This trial
and were treated according to their echocardiographic find-
was approved by the local ethics committee, and infants
ings and clinical condition.
were enrolled in the study after written parental consent
For all patients enrolled in the study, fluid intake was
was obtained.
started at 70-80 mL/kg per day and was increased by incre-
The study enrolled preterm infants with a gestational age
ments of 10-20 mL/kg each day, to a maximum of 150 mL/
#30 weeks, birthweight #1250 g, postnatal age 48-96
kg per day. Hypotension was treated with dopamine for cases
hours, and 1 of the following echocardiographic criteria:
in which fluid treatment had failed. Ventilation was sup-
a duct size >1.5 mm, a left atrium-to-aorta ratio >1.5,
ported according to the severity of respiratory distress, using
end diastolic reversal of blood flow in the aorta, or poor
nasal continuous positive airway pressure or mechanical
cardiac function in addition to clinical signs of a PDA.5,6
ventilation. The patients were given penicillin G and genta-
Two-dimensional color Doppler echocardiography was
micin or netilmicin on admission, if required.
performed using a GE Vivid 7 Pro, 10S transducer (GE
The success rate, defined as a closed duct on echocardiog-
Healthcare, Salt Lake City, Utah). Exclusion criteria were
raphy after the completed course and the safety of the drugs
the presence of major congenital abnormalities, right-to-
in preterm infants with birthweight #1250 g were the major
left ductal shunting, life-threatening infection, grade III
outcomes of the study. Secondary outcomes included the
or grade IV IVH, urine output of less than 1 mL/kg/h dur-
need for retreatment or surgical ligation of the PDA (per-
ing the preceding 8 hours, serum creatinine level >1.6 mg/
formed for patients who had hsPDA after 2 completed
dL, platelet count <60 000/mm3, liver failure, hyperbiliru-
courses of medical treatment), mode and duration of venti-
binemia requiring exchange transfusion, and persistent
lation; increase in blood urea nitrogen, serum creatinine, bili-
pulmonary hypertension.
rubin, aspartate amino transferase, or ALT levels after
Before and 24 hours after treatment, all patients were evalu-
treatment, rates of ductal reopening, surfactant treatment,
ated with a complete blood count; renal function tests (serum
pneumothorax, pulmonary hemorrhage, CLD, IVH, NEC
creatinine, blood urea nitrogen, and urine output), aspartate
(any stage, according to Bell classification), gastrointestinal
amino transferase, alanine amino transferase (ALT) and bili-
bleeding, ROP (according to the International Classifica-
rubin levels, cranial ultrasonography, and echocardiography.
tion), definite sepsis (clinical symptoms and signs of sepsis
During the study period, 247 preterm infants with gesta-
and a positive blood bacterial culture), and death. CLD was
tional age #30 weeks and birthweight #1250 g were
defined as a persistent oxygen requirement at 36 weeks post-
admitted to our neonatal intensive care unit. Fifteen of the
menstrual age. A physiological test was used to confirm the
105 preterm infants with hsPDA were excluded before enroll-
need for oxygen at the time of CLD diagnosis. Patients who
ment for exclusion criteria listed above (Figure 1). The
demonstrated $30% oxygen requirement and/or positive
patients were randomly assigned to a treatment group by
pressure at 36 weeks postmenstrual age (severe CLD) were
cards in sequentially numbered sealed opaque envelopes,
treated with dexamethasone.
and 80 patients completed the study protocol. Each
enrolled patient received either oral paracetamol (Calpol;
GlaxoSmithKline, Istanbul, Turkey) at a dose of 15 mg/kg Statistical Analyses
every 6 hours for 3 days or oral ibuprofen (Pedifen; Power analysis revealed that a study group of at least 78 pa-
Atafarm, Istanbul, Turkey) at an initial dose of 10 mg/kg tients was necessary for the study to be able to detect a differ-
followed by 5 mg/kg at 24 and 48 hours. ence of at least 25 percentage points in the closure rate
Both paracetamol and ibuprofen were administered via an between the oral ibuprofen and the oral paracetamol groups,
orogastric tube, which was flushed with 1-2 mL of sterile wa- assuming a closure rate of 83.3% with oral ibuprofen, with a
ter to ensure delivery of the drug. An exclusive breast milk P value of .05, and a power of 80%.5
diet was attempted for all infants from the first day of life, Statistical analyses were performed using the statistical
and all infants continued their current enteral feeding package SPSS for Windows v. 17.0 (SPSS Inc, Chicago, Ili-
regimen during the study. At the beginning of the study, daily nois). The paired samples t test and independent samples t
oral intake ranged between 20 and 40 mL/kg for patients in test were used for continuous variables. The c2 test was used
both groups. The osmolarity for oral ibuprofen was 312 for categorical variables. Continuous variables are presented
mosm/L. We also evaluated dilution of paracetamol that re- as the mean
SD, and categorical variables are given as fre-
sulted in osmolarity of approximately 500 mosm/L, which quencies and percentages. In addition to the P value of the pri-
was higher for ibuprofen. One day after the treatment, an mary outcomes, results were given as relative risk and 95% CI
echocardiographic evaluation was performed by a pediatric by using Stata 9.1 program (StataCorp, College Station,
cardiologist who was blinded to the treatment group Texas). A P value of <.05 was considered statistically
to determine the success of the treatment and the need for significant.

511
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Figure 1. Study assignment and follow-up.
Results
Patients completed the entire study protocol (n = 80) and the
other patients were excluded for various reasons (Figure 1).
The clinical characteristics and echocardiographic findings of
the preterm infants are summarized (Table I; available at
www.jpeds.com). Flow chart of the study according to
gestational weeks is demonstrated (Figure 2; available at
www.jpeds.com).
Spontaneous closure rate for the entire study group was
54%. After the first course of treatment, the PDA was
completely closed in 31 (77.5%) of the patients assigned to
the oral ibuprofen group and 29 (72.5%) of those enrolled
in the oral paracetamol group (P = .6; Table II). Nine
patients (22.5%) in the oral ibuprofen group required a
second course of drug therapy, compared with 11 (27.5%)
in the oral paracetamol group (P = .6). The reopening rate
was higher in the paracetamol group than in the ibuprofen
group, but the reopening rates were not statistically
different (24.1% [7 of 29] vs 16.1% [5 of 31]; P = .43). The
cumulative closure rates were high after the second course
of the drugs in both groups, and only 1 patient (2.5%) in
the paracetamol group and 2 patients (5%) in the
ibuprofen group required surgical ligation.
In the evaluation of renal tolerance, none of the patients
had oliguria. Bilirubin levels and renal and liver function
test results before and after the first and second course of
512
Vol. 164, No. 3
each drug did not differ significantly within or between the
groups (Table III). There was no statistically significant
difference between the 2 groups for secondary outcomes
(Table IV).
Discussion
Our study was designed with sufficient power to determine if
oral paracetamol and ibuprofen are equally efficacious and
safe for PDA closure. The results demonstrated that oral
paracetamol and ibuprofen were similarly effective for the
closure of PDA with 1 course of treatment. In addition,
both oral medications were well-tolerated and deemed safe
in terms of renal and liver variables, as well as a lack of statis-
tically significant difference in major complications (renal
tolerance, hypertransaminasemia, hyperbilirubinemia,
gastrointestinal bleeding, NEC, IVH, CLD, and ROP).
In the first case series by Hammerman et al,13 oral paracet-
amol was effective in 5 patients who did not respond to
ibuprofen. In our previous case series with a median gesta-
tional age of 28.5 weeks and a median birthweight of 995 g,
paracetamol was administered after a median of 9.5 days
(5-27) from birth.14 We performed an observational study
to evaluate the efficacy of paracetamol in 8 preterm infants
with hsPDA who did not respond to 2 sequential courses of
ibuprofen and/or for whom treatment with ibuprofen was
contraindicated. The hsPDA closed in 7 of the infants.14 In
Oncel et al
March 2014 ORIGINAL ARTICLES

ibuprofen in comparison with intravenous ibuprofen after

Table II. Primary outcomes according to gestational the first course of treatment in very low birth weight preterm
weeks* infants. Our current study demonstrated that the closure rate
Characteristics Ibuprofen Paracetamol RR 95% CI P value with oral paracetamol was comparable with oral ibuprofen.
Total (<30 wk) n = 40 n = 40 It should be noted that the infants treated were #30 weeks
PDA closure rate 31 (77.5) 29 (72.5) 0.818 0.381-1.757 .6 gestation and treated before 96 hours after birth. Because
(after the first
course) most infants born >27 weeks gestation will spontaneously
Reopening and 5 (16.1) 7 (24.1) 0.668 0.239-1.871 .43 close their PDA by the time they are 7 days old, and those
closure with who do not close their PDA by 7 days will most likely close
second cure
Surgical ligation 2 (5) 1 (2.5) 0.5 0.047-5.296 .55 their PDA spontaneously before discharge, one would as-
rate sume that many of the infants in the study who were born af-
<28 wk n = 19 n = 23 ter 27 weeks might have closed their PDA without
PDA closure rate 11 (57.9) 17 (73.9) 0.783 0.498-1.233 .27
(after the first treatment.18-20 However, 52.5% of the enrolled preterms
course) were <28 weeks and our study extended the data also in
Reopening and 4 (36.4) 7 (41.2) 0.883 0.336-2.321 .79 this group of patients. Data on stratified patients based on
closure with
second cure gestational age <28 and 26 weeks gestation (Table II)
Surgical ligation 2 (10.5) 1 (4.3) 2.42 0.237-24.69 .43 reveal a higher (albeit not significant) rate of closure in
rate those who received paracetamol compared with those given
#26 wk n = 16 n = 13
PDA closure rate 9 (56.2) 10 (76.9) 0.731 0.433-1.236 .24 ibuprofen. In this context, we can surmise that paracetamol
(after the first administration enhances closure of PDA in even very early
course) gestational age infants.
Reopening and 4 (44.4) 6 (60) 0.741 0.305-1.801 .49
closure with Safety measurements for both drugs should be interpreted
second cure cautiously because the study was not large enough to evaluate
Surgical ligation 2 (12.5) 1 (7.7) 1.625 0.165-15.98 .67 safety. For example, although not significant, ROP rate was
rate
higher in ibuprofen-treated groups. In an experimental
RR, relative risk. study, Sharma et al21 concluded that ibuprofen improved
*Values are given as percentage.
oxygen-induced retinopathy when administered concur-
rently during the injury phase without affecting the normal
our other case series, we used intravenous paracetamol in 10 retinal development. However, a recent meta-analysis by
preterm infants with hsPDA in whom feeding was either not Ohlsson et al22 demonstrated that there was no significant
tolerated or contraindicated, and the PDA closure was suc- difference in ROP according to treatment regimen. Although
cessful in all patients.15 In a case series by Yurttutan et al,16 there was no difference in ALT, this should be carefully inter-
which was conducted to investigate the efficacy of paraceta- preted because the dose of paracetamol that was used in this
mol as the first choice for the treatment of PDA in 6 preterm trial is designed for fullterm infants rather than preterm in-
infants, 5 infants were successfully treated.16 fants, and there have already been 2 reports of altered liver
In the current study, we observed that the PDA closure rate function tests in preterm infants when higher doses of para-
was similar for ibuprofen (77.5%) and paracetamol (72.5%) cetamol were administered.23,24 Our current study increases
after the first course of the treatment. Although closure rates the number of infants randomized and expands the informa-
were similar, the broad CI observed does not allow the tion about the safety and efficacy of oral paracetamol in pre-
conclusion that the drugs are equally effective. In the litera- term infants #30 weeks.
ture, few randomized controlled studies have determined Our study had several limitations. First, the intervention
the efficacy and safety of oral ibuprofen in preterm infants was not completely blinded because of the different number
with PDA.5,6,17 Gokmen et al6 and Erdeve et al5 found that of doses per day of the drugs. However, the most important
the PDA closure rate was significantly higher with oral outcomePDA closurewas made by a cardiologist who

Table III. Evaluation of bilirubin levels, hepatic, and renal function tests after the first course of treatment
Oral ibuprofen Oral paracetamol
Measurement Pre-treatment Post-treatment P value Pre-treatment Post-treatment P value P value*
BUN (mg/dL) 60.3
21.5 60.9
29.6 .88 62.1
25.7 55.1
22.8 .13 .46
Serum creatinine (mg/dL) 0.66
0.22 0.72
0.24 .19 0.77
0.21 0.75
0.23 .68 .52
Urine output (mL/kg/h) 2.4
0.87 2.3
0.93 .91 2.72
0.76 2.31
0.68 .86 .32
Serum bilirubin (mg/dL) 3.9
1.5 4
1.7 .71 4.3
1.7 3.8
1.5 .18 .58
Serum AST (U/L) 39.5
13.8 38.4
16.3 .52 41
13.5 42.5
11.9 .6 .21
Serum ALT (U/L) 28.3
18.2 22.4
18 .15 22
18.7 27.7
18.3 .2 .19

AST, aspartate amino transferase; BUN, blood urea nitrogen.

*P value for post-treatment measurements between groups.

Oral Paracetamol versus Oral Ibuprofen in the Management of Patent Ductus Arteriosus in Preterm Infants: 513
A Randomized Controlled Trial
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 164, No. 3

4. Demirel G, Erdeve O, Dilmen U. Pharmacological management of

Table IV. Safety outcomes and adverse events after oral PDA: oral vs intravenous medications. Curr Clin Pharmacol 2012;7:
ibuprofen and paracetamol treatment 263-70.
5. Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al.
Ibuprofen Paracetamol P
Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a
(n = 40) (n = 40) value
randomized controlled trial in extremely low birthweight infants. Arch
Sepsis* 10 (25) 12 (30) .61 Dis Child Fetal Neonatal Ed 2012;97:279-83.
NEC* 2 (5) 3 (7.5) .64 6. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy
Gastrointestinal bleeding* 1 (2.5) - .31 and safety of oral versus intravenous ibuprofen in very low birth
Increase in the grade of IVH* 3 (7.5) 2 (5) .64
weight preterm infants with patent ductus arteriosus. J Pediatr 2011;
Pulmonary hemorrhage* 2 (5) 1 (2.5) .55
Pneumothorax* 2 (5) 4 (10) .39 158:549-54.
Duration of n-CPAP, d
6 (1-47) 7 (1-25) .66 7. Erdeve O, Yurttutan S, Ozdemir R, Dilmen U. Oral ibuprofen for treat-
Duration of mechanical ventilation, d 3 (1-80) 3 (1-22) .11 ment of patent ductus arteriosus: more than a cheap alternative? Neona-
Postnatal steroid use for severe CLD*x 16 (40) 10 (25) .15 tology 2012;102:96.
ROP requiring laser treatment*{ 7 (17.5) 3 (7.5) .17 8. Erdeve O, Gokmen T, Altug N, Dilmen U. Oral versus intravenous
Duration of hospitalization, daysz 73.9
28.4 67
32.9 .33 ibuprofen: which is better in closure of patent ductus arteriosus? Pediat-
Death* 2 (5) 3 (7.5) .64 rics 2009;123:763.
n-CPAP, nasal continuous positive airway pressure.
9. Zecca E, Romagnoli C, De Carolis M, Costa S, Marra R, De Luca D. Does
*Values are given as percentages. ibuprofen increase neonatal hyperbilirubinemia? Pediatrics 2009;124:
Values are given as the median (minimum-maximum). 480-4.
zValues are given as the mean
SD. 10. Erdeve O, Sarici SU, Sari E, Gok F. Oral ibuprofen-induced acute renal
xPatients with severe (oxygen requirement $30%
positive pressure support) CLD at post-
menstrual wk 36 or discharge, whichever comes first.
failure in a preterm infant. Pediatr Nephrol 2008;23:1565-7.
{Patients with pre-threshold type I ROP or who progressed to threshold disease received laser 11. Green K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo
photocoagulation treatment. prostacyclin synthesis in humans by paracetamol. Prostaglandins 1989;
37:311-5.
was blinded to the treatment groups. Second, safety out- 12. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of
acetaminophen: role of cyclo-oxygenase. FASEB J 2005;19:635-7.
comes should have been defined more clearly before the 13. Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M,
study started to prevent overestimation in evaluation. Third, Fink D. Ductal closure with paracetamol: a surprising new approach
we did not investigate the possible side-effects of osmolarity to patent ductus arteriosus treatment. Pediatrics 2011;128:1618-21.
of drugs, which are different because of their preservative- 14. Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, et al. An
and sugar contents. However, oral ibuprofen and paraceta- alternative drug (paracetamol) in the management of patent ductus ar-
teriosus in ibuprofen-resistant or contraindicated preterm infants. Arch
mol are used commonly in some parts of the world, and no Dis Child Fetal Neonatal Ed 2013;98:F94.
harm has been reported related to osmolarity of drugs in 15. Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O,
newborns. We also suggest that to continue feeding during et al. Intravenous paracetamol treatment in the management of patent
the application of drug and to flush with sterile water to ductus arteriosus in extremely low birthweight infants. Neonatology
ensure delivery might have diluted the osmolarity and pre- 2013;103:166-9.
16. Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O, et al. A
vented possible gastrointestinal side effects. Fourth, this different first choice drug in the medical management of patent ductus
study only enrolled preterm infants #30 weeks who needed arteriosus: Oral paracetamol. J Matern Fetal Neonatal Med 2013;26:
a treatment for the significant PDA. We suggest that further 825-7.
studies need to address a comparison of treatments in a 17. Cherif A, Khrouf N, Jabnoun S, Mokrani C, Amara MB, Guellouze N,
group of infants who are more likely to have a PDA (<1000 et al. Randomized pilot study comparing oral ibuprofen with intrave-
nous ibuprofen in very low birth weight infants with patent ductus arte-
g) that is unlikely to close spontaneously for several weeks riosus. Pediatrics 2008;122:1256-61.
and who are most likely to benefit from these treatments. n 18. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prev-
alence of spontaneous closure of the ductus arteriosus in neonates at a
We thank Ronald Clyman, MD (University of California San Francisco, birth weight of 1000 grams or less. Pediatrics 2006;117:1113-21.
School of Medicine), for his suggestions and critisms during editing of the 19. Thankavel PP, Rosenfeld CR, Christie L, Ramaciotti C. Early echocardio-
manuscript, and Sevilay Karahan, PhD (Department of Biostatistics, graphic prediction of ductal closure in neonates #30 weeks gestation. J
Hacettepe University), for her help in the statistical analysis. Perinatol 2013;33:45-51.
20. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA,
Lorenz JM. The ductus arteriosus rarely requires treatment in infants
Submitted for publication May 23, 2013; last revision received Oct 11, 2013;
accepted Nov 5, 2013.
>1000 grams. Am J Perinatol 2008;25:661-6.
21. Sharma J, Barr SM, Geng Y, Yun Y, Higgins RD. Ibuprofen improves
Reprint requests: Mehmet Yekta Oncel, MD, Division of Neonatology, Zekai
oxygen-induced retinopathy in a mouse model. Curr Eye Res 2003;27:
Tahir Burak Maternity Teaching Hospital, 06230, Altndag, Ankara, Turkey.
E-mail: dryekta@gmail.com
309-14.
22. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent duc-
tus arteriosus in preterm and/or low birth weight infants. Cochrane
References Database Syst Rev 2013;4:CD003481. http://dx.doi.org/10.1002/1465
1858.CD003481.pub5.
1. Hermes-De Santis ER, Clyman RI. Patent ductus arteriosus: pathophys- 23. Tekgunduz KS, Ceviz N, Demirelli Y, Olgun H, Caner I, Sahin IO, et al.
iology and management. J Perinatol 2006;26:14-8. Intravenous paracetamol for patent ductus arteriosus in premature in-
2. Van Overmeire B, Chemtob S. The pharmacological closure of the patent fants - a lower dose is also effective. Neonatology 2013;104:6-7.
ductus arteriosus. Semin Fetal Neonatal Med 2005;10:177-84. 24. Alan S, Kahvecioglu D, Erdeve O, Atasay B, Arsan S. Is paracetamol a
3. Noori S. Patent ductus arteriosus in the preterm infant: to treat or not to useful treatment for ibuprofen-resistant patent ductus arteriosus?
treat? J Perinatol 2010;30:31-7. Neonatology 2013;104:168-9.

514 Oncel et al
March 2014 ORIGINAL ARTICLES

Figure 2. Flow chart of the study according to gestational weeks.

Table I. Clinical characteristics and echocardiographic findings of both groups

Ibuprofen (n = 40) Paracetamol (n = 40) P value
Gestational age, wk* 27.3
2.1 27.3
1.7 .87
Birthweight, g* 973
224 931
217 .39
Cesarean delivery 29 (72.5) 33 (82.5) .28
Male sex 19 (47.5) 23 (57.5) .37
Antenatal steroids 30 (75) 30 (75) 1
Premature rupture of membrane >18 h 7 (17.5) 8 (20) .77
APGAR 1 minz 5 (1-7) 5 (2-7) .41
APGAR 5 minz 7 (5-9) 8 (5-9) .37
Surfactant for respiratory distress syndrome 39 (97.5) 36 (90) .16
Caffeine treatment 35 (87.5) 34 (85) .74
PDA diameter, mm* 2.19
0.49 2.37
0.55 .13
LA:Ao* 1.92
0.34 2.02
0.36 .21

APGAR, American Pediatric Gross Assessment Record; LA:Ao, left atrium-to-aorta ratio.
*Values are given as the mean
SD.
Values are given as percentages.
zValues are given as the median (minimum-maximum).

Oral Paracetamol versus Oral Ibuprofen in the Management of Patent Ductus Arteriosus in Preterm Infants: 514.e1
A Randomized Controlled Trial