Paediatrics and International Child Health

ISSN: 2046-9047 (Print) 2046-9055 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch20

Oral indomethacin versus oral ibuprofen

for treatment of patent ductus arteriosus:
a randomised controlled study in very low-
birthweight infants

Varangthip Khuwuthyakorn, Chuleeporn Jatuwattana, Suchaya Silvilairat &

Watcharee Tantiprapha

To cite this article: Varangthip Khuwuthyakorn, Chuleeporn Jatuwattana, Suchaya Silvilairat &
Watcharee Tantiprapha (2018): Oral indomethacin versus oral ibuprofen for treatment of patent
ductus arteriosus: a randomised controlled study in very low-birthweight infants, Paediatrics and
International Child Health, DOI: 10.1080/20469047.2018.1483566

To link to this article: https://doi.org/10.1080/20469047.2018.1483566

Published online: 18 Jun 2018.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ypch20
Paediatrics and International Child Health, 2018
https://doi.org/10.1080/20469047.2018.1483566

Oral indomethacin versus oral ibuprofen for treatment of patent ductus

arteriosus: a randomised controlled study in very low-birthweight infants
Varangthip Khuwuthyakorna, Chuleeporn Jatuwattanab, Suchaya Silvilairatc and Watcharee Tantipraphaa
a
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; bDepartment of
Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; cDivision of Pediatric Cardiology, Department of Pediatrics,
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

ABSTRACT ARTICLE HISTORY

Background: In low- and middle-income countries (LMIC), haemodynamically significant patent Received 18 January 2017
ductus arteriosus (hsPDA) is treated with oral indomethacin (IDC) and ibuprofen (IB) instead of Accepted 28 May 2018
intravenous formulations. No significant differences in efficacy have been reported. However, KEYWORDS
previous studies had small numbers of VLBW infants (<1500 g). Indomethacin; ibuprofen;
Objective: To evaluate the efficacy of oral IDC and IB for closing PDA in VLBW infants with a patent ductus arteriosus;
gestational age of 24–32 weeks. very low-birthweight infants
Methods: This randomised controlled study enrolled 32 infants with hsPDA for treatment with
either three doses of oral IDC or oral IB. Echocardiography was performed before and after
treatment.
Results: Oral IDC was more effective than oral IB (65% vs. 27%, p = 0.03). This difference was
attributable to the subset of extremely low-birthweight infants (<1000 g) in whom an hsPDA
closed 78% of the time after oral IDC compared with 13% of those treated with oral IB (p = 0.01).
In contrast, there was no difference in hsPDA closure rates between the study groups of infants
with birthweights of 1000–1499  g. There was no significant difference between the drugs in
clinical and laboratory measures of adverse effects, nor of other clinical outcomes
Conclusion: Oral IDC was more effective than oral IB for closing PDA in VLBW infants, without
significant differences in side-effects or short-term outcomes.
Abbreviations: BPD, bronchopulmonary dysplasia; ELBW, extremely low birthweight; hsPDA,
haemodynamically significant PDA; IB, ibuprofen; IDC, indomethacin; IVH, intraventricular
haemorrhage; NEC, necrotising enterocolitis; PDA, patent ductus arteriosus; PVL, periventricular
leucomalacia; VLBW, very low birthweight

Introduction close spontaneously and treatment with indomethacin

The incidence of patent ductus arteriosus (PDA) in pre-
term infants is inversely related to gestational age. It
occurs in about 32% of preterm infants with a gestational
age (GA) of 28 weeks and increases to 55% in those with
a GA of 25 weeks [1]. Haemodynamically significant PDA
(hsPDA) results in a left-to-right shunt which causes pul-
monary congestion and left-sided heart failure. HsPDA
may decrease systemic blood flow and can result in
impaired renal, mesenteric and cerebral perfusion. VLBW
infants with hsPDA are at increased risk of adverse conse-
quences such as pulmonary haemorrhage, bronchopul-
monary dysplasia (BPD), necrotising enterocolitis (NEC),
intraventricular haemorrhage (IVH), periventricular leu-
komalacia (PVL), renal impairment, cerebral palsy and
death [2,3]. However, routine closure of a PDA in preterm
infants within the first 2 weeks does not decrease the
incidence of these major morbidities, mortality or neu-
rodevelopmental impairment [3]. Moreover, some PDAs
increases the risk of IVH [3]. Therefore, selective treat-
ment of PDA in high-risk preterm infants < 2 weeks of
age or in preterm infants > 2 weeks after birth with a
persistent PDA may be appropriate [4]. Two widely used
cyclo-oxygenase (COX) inhibitors are indomethacin (IDC)
and ibuprofen (IB). IDC has been used to close PDA in
preterm infants since the mid-1970s [5,6]. However, it
is associated with reduced blood flow to several organs
and can itself lead to renal insufficiency, NEC and gas-
trointestinal haemorrhage. Ibuprofen is as effective as
IDC for closing PDA and has fewer side-effects, including
less NEC and rarer frequency of transient renal insuffi-
ciency [7]. In many countries, intravenous medication for
PDA is not available so oral formulations of IDC are used
[8,9] and are as efficient as intravenous (IV) IDC [10,11].
Randomised clinical trials of oral IB found the efficacy to
be similar to that of IV IDC [12,13]. In three recent studies
in VLBW and ELBW infants, oral IB was more effective in
successfully closing PDA than IV IB [14–16]. When the

CONTACT  Varangthip Khuwuthyakorn  varangthip.k@cmu.ac.th

© 2018 Informa UK Limited, trading as Taylor & Francis Group
2   V. KHUWUTHYAKORN ET AL.
efficacy and safety of oral IDC and oral IB were com-
pared head-to-head for closing PDA in preterm infants,
no significant differences were found [17–19]. However,
all of these studies comparing oral IDC with oral IB were
mostly of preterm infants  <  2500  g, but few subjects
were < 1500 g. This study was undertaken to compare
the efficacy of oral IDC and oral IB in a subset of VLBW
infants with hsPDA.
Methods
The study was undertaken in the neonatal intensive care
unit of Chiang Mai University Hospital from 15 December
2013 to 31 May 2015.
After obtaining informed consent from parents,
infants were enrolled who satisfied the inclusion cri-
teria: (i) birthweight 500–1500  g, (ii) gestational age
24–32 weeks, (iii) postnatal age 1–30 days, and (iv) hsPDA
confirmed by echocardiography. Echocardiography was
undertaken in patients clinically suspected to have PDA
which included two or more of the following: (i) heart
murmur, (ii) active precordium, (iii) persistent tachy-
cardia (>160 bpm), (iv) bounding pulse, (v) wide pulse
pressure (systolic–diastolic BP ≥ 25 mm Hg) or (vi) ina-
bility to be weaned from mechanical ventilation or res-
piratory deterioration (conventional ventilation: peak
inspiratory pressure [PIP]≥18 mm Hg and FiO2 ≥ 50%;
high-frequency oscillation ventilation: mean arterial
pressure [MAP]≥12 mm Hg and FiO2 ≥ 0.5 to maintain
pH 7.25–7.35, PaCO2 45–55  mm Hg, SpO2 90–95%). If
PDA was identified and its diameter was  >  1.5  mm
(or  >  1.4  mm/kg) and/or left atrium to aorta (LA/AO)
ratio was > 1.4, with left-to-right shunting [2,20], PDA
closure with either IDC or IB was randomly initiated.
Exclusion criteria were major congenital anomalies,
life-threatening infection, hydrops fetalis, severe IVH,
severe bleeding, urine output  <  1.0  ml/kg/hr in the
previous 8  h, impaired renal function with serum
creatinine  ≥  159  μmol/L, BUN  >  40  mg/dL, platelet
count < 80,000/mm3 or a previous course of treatment
with IDC or IB for PDA. Criteria for discontinuation of the
treatment included GI perforation, severe GI bleeding
and urine output < 0.5 ml/kg/hr over a 24-h period and
serum creatinine > 159 μmol/L after receiving medica-
tion for 24 h.
On enrolment, patients were randomly assigned
by computer to receive three oral doses of either IDC
or IB. The dose of IDC was 0.2 mg/kg, followed by two
doses 12 and 24 h later or either 0.1 mg/kg if postnatal
age < 48 h or 0.2 mg/kg if PNA is 7 days or 0.25 mg/kg
if PNA > 7 days. The IB dose was 10 mg/kg, followed by
two doses at 24 and 48 h of 5 mg/kg. Oral IDC was com-
pounded into a suspension by the hospital pharmacy
using a 5-mg IDC powder from a 25-mg IDC capsule
(Indomethacin®, Greater Pharma, Bangkok, Thailand)
dissolved in 25  ml of polyethylene glycol 400 and
glycerin to achieve a final concentration of 0.2 mg/ml
[9]. Oral IB was a liquid formulation [Nurofen®, Reckitt
Benckiser (Thailand) Ltd, Samut Prakarn, Thailand] of
100  mg in 5  ml. Infants were closely monitored for
medication side-effects, including GI perforation, GI
bleeding, NEC (clinical signs and abnormal radiographic
findings including pneumatosis intestinalis, portal vein
gas or pneumoperitoneum) [21] and oliguria (urine out-
put < 1 ml/kg/hr over 24 h). Adverse drug effects were
monitored by blood chemistry for creatinine, electro-
lytes and platelets before and at 72–96 h after the first
dose. Patients were also monitored for other morbidities
such as BPD (diagnosed using published criteria) [22].
IVH was graded according to Papile’s classification [23]
if present on head ultrasound which was undertaken on
all study infants within the first week of life and again
when the infant would have been of 36 weeks of ges-
tation, or before discharge.
Echocardiography at study entry and again 24–48 h
after completion of treatment was performed by a car-
diologist or neonatologist using an Aloka Prosound
Alpha 7™ with a 3–10S transducer (Hitachi Aloka
Medical Ltd, Tokyo, Japan). If the PDA persisted after
the experimental course and remained haemodynam-
ically significant, follow-up treatment varied according
to the clinical judgement of each patient’s attending
physician who was informed of the assigned study drug
and who decided which repeat medication to give, or
to recommend PDA ligation if there were contra-indi-
cations for oral NSAIDs, e.g. necrotising enterocolitis,
severe GI haemorrhage, feeding intolerance, unstable
cardiovascular conditions. In addition, PDA ligation was
considered for patients with a persistent hsPDA after
two courses of medication.
The primary study endpoint was complete closure, or
not of the PDA regardless of any subsequent echocardi-
ography which may have been undertaken.
Statistical analysis
Power analysis for a 95% confidence interval (CI) and a
power of 80% indicated that each study group should
have at least 36 patients in order to detect a difference
of at least 35% in the PDA closure rate between the
oral indomethacin and oral ibuprofen, assuming an
expected closure rate of 70% with oral indomethacin
[16,17]. However, the introduction of IV IDC in our unit
resulted in early termination of the study. Outcomes
were analysed according to intention-to-treat, includ-
ing those who received fewer than the full three doses.
Categorical variables reported as percentages were com-
pared between the two groups by χ2 or Fisher’s Exact test.
Continuous variables such as medians were compared by
the Mann–Whitney U test. Data were analysed using the
SPSS statistical software, version 22 (IBM SPSS, Armonk,
NY, USA). Statistical significance was p < 0.05.
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   3

Figure 1. Flow chart of trial of oral indomethacin (IDC) vs oral ibuprofen (IB) for treatment of haemodynamically significant patent
ductus arteriosus (hsPDA) in infants of very low birthweight (VLBW < 1500 g).
Notes: GA, gestational age, GI, gastrointestinal, NEC, necrotising enterocolitis, NICU, neonatal intensive care unit, COX, cyclooxygenase. aOne infant of
birthweight 1090 g became asymptomatic for hsPDA after receiving one dose of oral IDC and was withdrawn from further doses after developing severe
GI bleeding; bone infant of birthweight 910 g was withdrawn after developing NEC after one dose of oral IB and underwent hsPDA surgery; cone infant re-
opened a PDA that closed during the trial but remained asymptomatic; done infant whose hsPDA became asymptomatic in response to study treatment
later developed hsPDA again and underwent surgical ligation of the PDA and another infant failed a second non-investigational course of treatment with
IDC and underwent surgical PDA ligation; eone infant developed pulmonary haemorrhage and underwent surgical ligation of PDA, and three other infants
whose hsPDA did not close during the trial observation period subsequently experienced spontaneous closure; fthree infants developed contraindications
for treatment by COX inhibitor and underwent surgical ligation of PDA and another three received a non-investigational second course of oral IDC, two of
whom did not respond and underwent surgical ligation of PDA; gone infant received two doses of IB and was found to have a closed PDA; htwo infants did not
respond to a non-investigational second course of medication by IDC and underwent surgical ligation of PDA.

Ethics contrast, there was no difference in hsPDA closure rates

The study was approved by the Research Ethics
Committee of the Faculty of Medicine, Chiang Mai
University.
Results
During the study period, 114 VLBW infants were admit-
ted to the neonatal intensive care unit (Fig. 1). Among the
51 with hsPDA, 19 did not satisfy the eligibility criteria,
leaving 32, all of whose parents signed informed consent
for their enrolment into the study. Major clinical charac-
teristics of the infants at baseline before receipt of the
study medications did not significantly differ between
the groups randomly assigned to receive oral IDC or oral
IB (Table 1). Oral IDC was more effective than oral IB in
closing the hsPDA, 65% (11/17) vs 27% (4/15), respec-
tively (p = 0.03) (Table 2). This difference was attributa-
ble to the subset of ELBW infants for whom their hsPDA
closed 78% (7/9) of the time after oral IDC, compared
to 13% (1/8) of those treated with oral IB (p = 0.01). In
between the study groups of infants of birthweights in
the range 1000–1499  g. There were no significant dif-
ferences between the two groups in the clinical signs
and biochemical measurements monitored as potential
side-effects of the drug treatments during the trial (Table
3). Among subsequent clinical outcomes, the need to
undergo surgical ligation when drug treatment failed
tended to be higher in the IB group than in the IDC group
(47% vs 18%), although not significantly different (Table
4). Similarly, there was a trend for increased frequency of
BPD in those assigned to receive oral IB (47%) compared
with oral IDC (29%), but this, too, was not significant.
Discussion
The 46.5% frequency of hsPDA in VLBW infants was
similar to previous reports from the United States [1],
suggesting that our preterm care and diagnostic criteria
are not significantly different from those used in high-in-
come countries. The finding that oral IDC had a greater
4   V. KHUWUTHYAKORN ET AL.

Table 1. Baseline characteristics of preterm infants of < 1500 g birthweight with hsPDA randomised to receive oral indomethacin
(IDC) or oral ibuprofen (IB).
Oral IDC, Oral IB, Total,
n = 17 n = 15 n = 32 p-valuea
Median gestational age, wks (range) 28 (25-30) 29 (24-32) 28 (24–32) 0.24
Median birthweight, g (range) 930 (510-1370) 950 (520-1360) 940 (510–1370) 0.93
Birthweight <1000 g (%) 9 (53) 8 (53) 17 (53) 0.98
Small for gestational age (%) 1 (6) 4(27) 5 (16) 0.09
Gestational age <28 weeks (%) 4 (24) 3 (20) 7 (22) 0.81
Male (%) 7 (41) 8 (53) 15 (47) 0.49
Received dexamethasone in utero (%) 14 (82) 12 (80) 26 (81) 0.87
Received MgSO4 in utero (%) 3 (18) 1 (7) 4 (13) 0.34
Chorioamnionitis (%) 1 (6) 4 (27) 5 (16) 0.09
Apgar score <7 at 5 min (%) 6 (35) 6 (40) 12 (38) 0.78
Respiratory distress syndrome (%) 12 (71) 9 (60) 21 (66) 0.53
Surfactant replacement (%) 8 (47) 9 (60) 17 (53) 0.46
Median age, hrs, at first dose study 60 (23-504) 64 (24-332) 63.5 (23–504) 0.64
treatment (range)
Median size, mm, pre-treatment PDA 2.7 (2-4) 2.6 (2-4) 2.7 (2-4) 0.45
(range)
Median ratio left atrium: aorta (range) 1.50 (1.2-2.0) 1.45 (0.9-1.9) 1.47 (0.9-2.0) 0.76
a
p-values for comparison of proportions/percentage between treatment groups by χ2 or Fishers Exact test, and for comparison of median by Mann–Whitney
U test. hsPDA, haemodynamically significant patent ductus arteriosus; MgSO4, magnesium sulphate.

Table 2.  Frequency of PDA closure within two days of study efficacy than oral IB differs from previous studies which
treatment, by oral indomethacin (IDC) or oral ibuprofen (IB). demonstrated a similar efficacy of the oral drugs [17–19].
Oral IDC, Oral IB Total This might be because the previous studies recruited
n = 17 (%) n = 15 (%) n = 32 (%) p-valuea infants above 1500-g birthweight, among other dif-
PDA closed/ 11/17 (65) 4/15 (27) 15/32 (47) 0.03
treated
ferences in eligibility criteria and diagnostic methods.
Birthweight 7/9 (78) 1/8 (13) 8/17 (47) 0.01 However, the success rate of 65% of oral IDC to close
<1000 g the PDA was within the same range of 65–83% in the
Birthweight 4/8 (50) 3/7 (43) 7/15 (47) 0.78
≥1000– previous studies.
<1500 g When IB was less effective it was mostly in those of
a
p-values for comparison of proportions/percentage between treatment extremely low birthweight who comprised 53% of sub-
groups by χ2 or Fisher’s Exact test and for comparison of median by
Mann–Whitney U test. jects and this is consistent with previous reports of a

Table 3. Frequency of clinical and laboratory findings that may reflect adverse effects of medication, by study groups treated with
either oral indomethacin (IDC) or oral ibuprofen (IB).
Oral IDC Oral IB Total
n = 17 (%) n = 15 (%) n = 32 (%) p-valuea
Gastro-intestinal bleeding 3 (18) 1 (7) 4 (13) 0.34
Hyponatraemia 3 (18) 3 (20) 6 (19) 0.87
Necrotising enterocolitis 3 (18) 1 (7) 4 (13) 0.34
Oliguria 3 (18) 1(7) 4 (13) 0.34
Thrombocytopenia 2 (12) 0 2 (6) 0.20

Median increase in BUN after start of treatment, mg/dL (range) 7.0 (−17 to 30) 5.0 (−14 to 19) 7.0 (−17 to 30) 0.15
Median increase in BUN as % of baseline (range) 32.1 (−65.4 to 96.8) 13.9 (−72.2 to 100) 26.5 (−72.2 to 100) 0.14
Median increase in Cr after start of treatment, μmol/dL (range) 8.8 (−88.4 to 79.6) −8.8 (−53.0 to 26.6) 0.0 (−88.4 to 79.6) 0.19
Median increase in Cr as % of baseline (range) 8.3 (−45.5 to 225) −12.5 (−66.7 to 33.3) 0 (−66.7 to 225) 0.09
a
Comparison of proportions/percentage between treatment groups by χ2 or Fisher’s Exact test and for comparison of median by Mann–Whitney U test. BUN,
serum blood urea nitrogen; Cr, serum creatinine.

Table 4. Other patient outcomes by study groups treated with oral indomethacin (IDC) or oral ibuprofen (IB).
Oral IDC n = 17 (%) Oral IB n = 15(%) Total n = 32 (%) p-valuea
Underwent surgery for PDA 3 (18) 7 (47) 10 (31) 0.08
ligation
Moderate-to-severe BPD 5 (29) 7 (47) 12 (38) 0.07
Abnormal otoacoustic emissions 8 (47) 3 (20) 11 (34) 0.48
Underwent surgery for ROP 4 (24) 1 (7) 5 (16) 0.74
Periventricular leukomalacia 2 (12) 2 (13) 4 (13) 0.84
Intraventricular haemorrhage 1 (6) 2 (13) 3 (9) 0.43
grade ≥3
Died before hospital discharge 0 1 (7) 1 (3) 0.21
Median hospital stay, days 65 (24–202) 68 (12–138) 66.5 (12–202) 0.85
(range)b
a
Comparison of proportions/percentage between treatment groups by χ2 or Fisher’s Exact test and comparison of median by Mann–Whitney U test. bDays
since admitted to NICU at time of discharge or death; BPD, bronchopulmonary dysplasia; LOS, length of stay; ROP, retinopathy of prematurity.

low rate of PDA closure after IV IB in preterm infants of
gestational ages  <  27  weeks [24]. Another hypothesis
for lower efficacy of IB is that its concentration in the
tissues is suboptimal. Hirt et al. reported that infants of
gestational ages 25–34 weeks eliminate IB more quickly
as their postnatal age increases, and thus may need a
higher dose than more mature infants [25]. In addition,
interpatient variability of plasma concentration of IV
and oral ibuprofen has been reported in many studies
[24–28]. Hypotheses for this variability included differing
CYP2C expression affecting IB metabolism, and co-ad-
ministered drugs which may alter albumin binding and
increase hepatic metabolism of IB. Unfortunately, this
study did not include any pharmacokinetic analysis to
compare with previous ones of oral IB, nor did it system-
atically collect and analyse other drugs received by these
patients to treat various conditions in order to look for
drug interference with IB pharmacokinetics. The reason
for the latter is that the IB group had a higher number
of infants who were small for gestational age (p = 0.09)
which has been shown to increase the risk of treatment
failure [29]. With regard to side-effects of oral IDC and IB,
no significant differences in clinical or laboratory findings
were observed. No patient developed the serious drug
side-effects of bowel perforation, as reported in some
studies of oral IDC and oral IB [30–32]. The one infant
in the study who died at 30 days of age succumbed to
sepsis which was unlikely to be associated with the PDA
which had already closed.
The limitation of this study was the small sample size
which was lower than intended because recruitment was
stopped prematurely when IV IDC was introduced.
Oral IDC was more effective than oral IB for closing
PDA in VLBW infants, without significant differences in
side-effects and short-term outcome. Further study with
a larger sample size concomitant with a pharmacokinetic
study should be undertaken.
Acknowledgments
The authors thank Dr Bruce Weniger for editorial assistance.
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes on contributors
Varangthip Khuwuthyakorn is an assistant professor of
Paediatrics in the Division of Neonatology, Department of
Paediatrics at Chiang Mai University, Thailand. Her research
interests include treatment of patent ductus arteriosus and
perinatal asphyxia.
Chuleeporn Jatuwattana is a paediatrician at Kasemrad
Hospital, Chiangrai, Thailand. She completed her paediat-
ric residency training at Chiang Mai university. Her research
interest includes treatment of patent ductus arteriosus and
general paediatrics.
PAEDIATRICS AND INTERNATIONAL CHILD HEALTH   5
Suchaya Silvilairat, is an associate professor of Paediatrics
in the Division of Paediatric Cardiology, Department of
Paediatrics at Chiang Mai University, Thailand. Her research
interests include paediatric echocardiography in congenital
heart disease and diastolic ventricular function in thalassemia.
Watcharee Tantiprapha is an assistant professor of Paediatrics
and Head of Division of Neonatology, Department of
Paediatrics at Chiang Mai University, Thailand. Her research
interests include neonatal hyperbilirubinemia and treatment/
outcome of preterm infants.
References
 [1] Stoll B, Hansen N, Bell E, et al. Neonatal outcomes of
extremely preterm infants from the NICHD neonatal
research network. Pediatrics. 2010;126:443–456.
  [2] Hamrick S, Hansmann G. Patent ductus arteriosus of the
preterm infant. Pediatrics. 2010;125:1020–1030.
 [3]  Benitz WE. Treatment of patent ductus arteriosus in
preterm infants: time to accept the null hypothesis? J
Perinatol. 2010;30:241–252.
 [4] Benitz WE. Committee on fetus and newborn. Patent
ductus arteriosus in preterm infants. Pediatrics.
2016;137:1–6.
  [5] Heymann MA, Rudolph AM, Silverman NH. Closure of the
ductus arteriosus in premature infants by inhibition of
prostaglandin synthesis. N Engl J Med. 1976;295:530–533.
  [6] Friedman WF, Hirschklau MJ, Printz MP, et al. Pharmacologic
closure of patent ductus arteriosus in the premature
infant. N Engl J Med. 1976;295:526–529.
  [7] Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment
of patent ductus arteriosus in preterm or low birth
weight (or both) infants. Cochrane Database Syst Rev.
2015;18:CD003481.
  [8] Thaithumyanon P, Punnahitananda S, Prasuwanna P, et al.
Treatment of PDA with oral indomethacin in very low birth
weight infants. Thai J Pediatr. 1999;38:173–179.
 [9]  Supapannachart S, Pulpeum K, Kanavong N, et al.
New solvent of oral indomethacin for PDA in preterm
infant: blood levels and clinical efficacy. Thai J Pediatr.
1999;38:180–189.
[10] Satar M, Yapicioglu H, Narli N, et al. Is oral indomethacin
effective in treatment of preterm infants with patent
ductus arteriosus? Turk J Pediatr. 2004;46:137–141.
[11] Tsao PC, Chen SJ, Yang CF, et al. Comparison of intravenous
and enteral indomethacin administration for closure of
patent ductus arteriosus in extremely-low-birth-weight
infants. J Chin Med Assoc. 2010;73:15–20.
[12] Chotigeat U, Jirapapa K, Layangkool T. A comparison of
oral ibuprofen and intravenous indomethacin for closure
of patent ductus arteriosus in preterm infants. J Med Assoc
Thai. 2003;86(Suppl 3):S563–S569.
[13] Aly H, Lotfy W, Badrawi N, et al. Oral ibuprofen and ductus
arteriosus in premature infants: a randomized pilot study.
Am J Perinatol. 2007;24:267–270.
[14] Cherif A, Khrouf N, Jabnoun S, et al. Randomized pilot
study comparing oral ibuprofen with intravenous
ibuprofen in very low birth weight infants with patent
ductus arteriosus. Pediatrics. 2008;122:e1256–e1261.
[15] Gokmen T, Erdeve O, Altug N, et al. Efficacy and safety of
oral versus intravenous ibuprofen in very low birth weight
preterm infants with patent ductus arteriosus. J Pediatr.
2011;158:549–554.
[16]  Erdeve O, Yurttutan S, Altug N, et al. Oral versus
intravenous ibuprofen for patent ductus arteriosus
6   V. KHUWUTHYAKORN ET AL.
closure: a randomized controlled trial in extremely low
birthweight infants. Arch Dis Child Fetal Neonatal Ed.
2012;97:279–283.
[17] Fakhraee SH, Badiee Z, Mojtahedzadeh S, et al. Comparison
of oral ibuprofen and indomethacin therapy for patent
ductus arteriosus in preterm infants. Zhongguo Dang Dai
Er Ke Za Zhi. (Chinese J Contemp Pediatr.). 2007;9:399–403.
[18] Pourarian S, Pishva N, Madani A, et al. Comparison of
oral ibuprofen and indomethacin on closure of patent
ductus arteriosus in preterm infants. East Mediterr Health
J. 2008;14:360–365.
[19] Yadav S, Agarwal S, Maria A, et al. Comparison of oral
ibuprofen with oral indomethacin for PDA closure in
indian preterm neonates: a randomized controlled trial.
Pediatr Cardiol. 2014;35:824–830.
[20] Skinner J. Diagnosis of patent ductus arteriosus. Semin
Neonatol. 2001;6:49–61.
[21] Kliegman RM, Walsh MC. Neonatal necrotizing
enterocolitis: pathogenesis, classification and spectrum
of illness. Curr Probl Pediatr. 1987;17:213–288.
[22] Jobe AH, Bancalari E. Bronchopulmonary dysplasia:
NICHD/NHLBI/ORD Workshop. Am J Respir Crit Care Med.
2001;163:1723–1729.
[23] Papile LA, Burstein J, Burstein R, et al. Incidence and
evolution of subependymal and intraventricular
hemorrhage: a study of infants with brain weights less
than 1,500 grams. J Pediatr. 1978;92:529–534.
[24] Desfrere L, Zohar S, Morville P, et al. Dose-finding study of
ibuprofen in patent ductus arteriosus using the continual
reassessment method. J Clin Pharm Ther. 2005;30:121–
132.
[25] Hirt D, Van Overmeire B, Treluyer JM, et al. An optimized
ibuprofen dosing scheme for preterm neonates with
patent ductus arteriosus, based on a population
pharmacokinetic and pharmacodynamic study. Br J Clin
Pharmacol. 2008;65:629–636.
[26] Van Overmeire B, Touw D, Schepens PJ, et al. Ibuprofen
pharmacokinetics in preterm infants with patent ductus
arteriosus. Clin Pharmacol Ther. 2001;70:336–343.
[27] Barzilay B, Youngster I, Batash D, et al. Pharmacokinetics
of oral ibuprofen for patent ductus arteriosus closure
in preterm infants. Arch Dis Child Fetal Neonatal Ed.
2012;97:116–119.
[28] Sharma PK, Garg SK, Narang A. Pharmacokinetics of
oral ibuprofen in premature infants. J Clin Pharmacol.
2003;43:968–973.
[29] Madeleneau D, Aubelle M, Pierron C, et al. Efficacy of
a first course of ibuprofen for patent ductus arteriosus
closure in extremely preterm newborns according to their
gestational age-specific z-score for birth weight. PLoS
One. 2015;10:e0124804.
[30] Alpan G, Eyal F, Vinograd I, et al. Localized intestinal
perforations after enteral administration of indomethacin
in premature infants. J Pediatr. 1985;106:277–281.
[31] Marshall TA, Pai S, Reddy PP. Intestinal perforation
following enteral administration of indomethacin. J
Pediatr. 1985;107:484–485.
[32] Tatli MM, Kumral A, Duman N, et al. Spontaneous intestinal
perforation after oral ibuprofen treatment of patent
ductus arteriosus in two very low-birthweight infants.
Acta Paediatr. 2004;93:999–1001.