(n Z 956 infants) reported that ibuprofen (oral form, initial
dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours
later) was as effective as indomethacin (intravenous form,
0.2 mg/kg every 12 hours for three doses) in closing PDA
and that ibuprofen reduces the risk of developing NEC and
transient renal insufficiency.26
Oral ibuprofen for closure of PDA in premature infants
was first used by Hariprasad14 in 13 infants in 2000. Since
then, a number of trials have been conducted to evaluate
the efficacy of oral ibuprofen for closure of PDA.17,18,21,27,28
The sample sizes in all of those studies, however, were
relatively small. In a randomized controlled study, Fakhraee
et al19 found that PDA was successfully closed in all 18
premature infants (<34 weeks of gestation) who received
oral ibuprofen and that closure of the PDA was achieved in
15 of 18 premature infants who had been given oral indomethacin
(p < 0.05).
The results from a number of clinical trials have
demonstrated that there is no significant difference in the
rate of closure of PDA in preterm infants between oral
ibuprofen and intravenous ibuprofen.15e17,22,29 However,
Chotigeat et al20 and Supapannachart et al21 found that oral
ibuprofen was more effective than intravenous indomethacin
at closing PDA. In nonrandomized open trials, oral
ibuprofen was associated with a ductal arteriosus closure
rate of 95% (38 of 40 infants) in a study by Cherif et al,15
a closure rate of 95.4% (21 of 22 infants) in a study by
Heyman et al,27 and a closure rate of 84.6% (11 of 13
infants) in a study by Hariprasad et al.14 Ohlsson et al26
reviewed a total of 7 studies (n Z 189 infants) and found
that there was no significant difference in failure rate of
PDA closure between infants who received oral ibuprofen
and infants who were treated with intravenous
indomethacin.
The endpoint of this study was the end of the initial
medical treatment. In clinical practice, if the patient was
unsuitable for medical treatment, surgical PDA ligation was
performed. According to our study, the study group who
received oral ibuprofen rarely required further surgical PDA
ligations. This phenomenon would be related to lower
complications from oral ibuprofen treatments.
Although a few studies have found that intravenous
ibuprofen was associated with a higher rate of PDA closure
than intravenous indomethacin among those VLBW infants
with higher birth body weights,30,31 our study, to the best of
our knowledge, is the first study to compare the effectiveness
of orally administered ibuprofen with that of
intravenously administered indomethacin at closing PDA
among preterm infants stratified by birth body weight. We
found that the rate of closure of PDA tended to be higher
among infants with a higher birth body weight in both
treatment groups. There was no significant difference in
closure rate between patients that received oral ibuprofen
and those that received intravenous indomethacin in each
62 PDA
closed
26 failed
3 received oral
ibuprofen
23 surgical
ligation
PDA
closed
PDA
closed
52 infants received
oral ibuprofen
32 PDA
closed
20 failed
11 received iv
indomethacin
9 surgical
ligation
PDA
closed
PDA
closed
88 infants received
intravenous
indomethacin
Figure 2 Flow chart of therapy.
Table 2 Oral ibuprofen and intravenous indomethacin for closure of PDA.
Variable Group O (N Z 52) Group I (N Z 88) p value Relative risk (95% confidence interval)
Closure of PDA, n (%)
Overall 32 (61.5) 62 (70.5) 0.342 0.872 (0.69-1.15)
Birth weight, g
<1000, n (%) 8/18 (44.4) 12/27 (44.4) 1.0 1.00 (0.51e1.95)
1000e1249, n (%) 9/13 (69.2) 25/31 (80.6) 0.456 0.858 (0.58e1.28)
1250e1499, n (%) 15/21 (71.4) 25/30 (83.3) 0.493 0.857 (0.65e1.24)
Group O: treated with oral ibuprofen. Group I: treated with intravenous indomethacin. Data are presented as mean SD (range) or
number (percent). PDA Z patent ductus arteriosus.
350 C.H. Lee et alsubgroup (Table 2). This tendency of higher rate of PDA
closure among preterm infants who received medical
treatment with higher birth body weights may be meaningful
in clinical practice. However, the relatively small
number of patients in each subgroup limited the power of
our study to detect significant differences. Large sample
and prospective randomized studies are certainly needed
to validate these findings.
Premature babies with immature organ systems are
more susceptible to pharmacological interactions. Tiker
et al32 reported that oral ibuprofen therapy was associated
with acute renal failure in extremely low birth weight
(ELBW) infants. In our analysis, five infants developed oliguria
and four infants had elevated serum Cr levels after
oral ibuprofen therapy. The majority of those patients were
ELBW infants. As can be seen from the above results, the
lower body weight premature infants are more susceptible
to pharmacologic complications. In our analysis, the incidence
of associated renal complications such as oliguria or
elevated serum Cr levels was lower in the oral ibuprofen
group than in the intravenous indomethacin group. In
addition, the incidence of oliguria was significantly lower in
the extremely low birth weight subgroup that received oral
ibuprofen. It appears that oral ibuprofen resulted in fewer
renal adverse events than intravenously administered
indomethacin. Chotigeat et al20 and Supapannachart et al21
also reported that oral ibuprofen resulted in fewer renal
adverse events than oral or intravenously administered
indomethacin. Clinicians should be vigilant for complications
of acute renal failure in treatment of PDA closure by
given oral ibuprofen, especially in ELBW infants. Even the
incidence of associated renal complications was lower in
the oral ibuprofen group than the intravenous indomethacin
group for the treatment of PDA closure.
Upper gastrointestinal hemorrhage and NEC are common
sequelae in preterm infants with PDA.33 In our study, the
incidence rates of gastrointestinal hemorrhage and NEC
were lower among infants who received oral ibuprofen,
although there was no significant difference in the development
of those sequelae between patients that received
Table 4 Incidence of upper gastrointestinal bleeding and necrotizing enterocolitis after medical PDA therapy.
Variable Group O (N Z 52) Group I (N Z 88) p value Relative risk (95% confidence interval)
UGI bleeding, n (%)
Overall 9 (17.3) 21(23.9) 0.37 0.725 (0.36-1.463)
Birth weight, g
<1000, n (%) 3/18 (16.7) 6/27 (22.2) 0.652 0.75 (0.215e2.62)
1000e1249, n (%) 2/13 (15.4) 10/31 (32.3) 0.291 0.477 (0.121e1.883)
1250e1499, n (%) 4/21 (19.0) 5/30 (16.7) 0.826 1.143 (0.347e3.759)
Necrotizing enterocolitis, n (%)
Overall 2 (3.8) 10 (11.4) 0.151 0.338 (0.077e1.485)
Birth weight, g
<1000, n (%) 0/18 (0) 4/27 (14.8) <0.001 d
1000e1249, n (%) 0/13 (0) 5/31 (16.1) <0.001 d
1250e1499, n (%) 2/21 (9.5) 1/30 (3.3) 0.378 2.857 (0.277e29.51)
Group O: treated with oral ibuprofen. Group I: treated with intravenous indomethacin. Data are presented as mean SD (range) or
number (%).
Table 3 Incidence of elevated serum creatinine and oliguria.
Variable Group O (N Z 52) Group I (N Z 88) p value Relative risk (95% confidence interval)
Elevated serum creatinine, n (%)
Overall 4 (7.7) 22 (25.0) 0.022 0.308 (0.11e0.84)
Birth weight, g
<1000, n (%) 4/18 (22.2) 11/27 (40.7) 0.224 0.55 (0.21e1.45)
1000e1249 g, n (%) 0/13 (0) 9/31 (29.0) <0.001 d
1250e1499 g, n (%) 0/21 (0) 2/30 (6.7) <0.01 d
Oliguria, n (%)
Overall 5 (9.6) 33 (37.5) 0.002 0.256 (0.107e0.616)
Birth weight, g
<1000, n (%) 2/18 (11.1) 13/27 (48.1) 0.035 0.231 (0.059e0.903)
1000e1249, n (%) 2/13 (15.4) 10/31 (32.3) 0.291 0.477 (0.121e1.883)
1250e1499, n (%) 1/21 (4.8) 10/30 (33.3) 0.054 0.143 (0.02e1.033)
Group O: treated with oral ibuprofen. Group I: treated with intravenous indomethacin. Data are presented as mean SD (range) or
number (percent).
Oral ibuprofen vs. IV indomethacin with PDA 351oral ibuprofen and infants that received intravenous indomethacin.
None of the infants who received oral ibuprofen
treatment in our study showed evidence of bowel perforation.
The rate of NEC among our infants who received
enteral ibuprofen was similar to that reported by Tulin
et al,22 but it was below the overall rate reported for
intravenous ibuprofen [27/356 (8%)] in a recent metaanalysis
of studies on preterm infants with HsPDA.34 In
our infants, the drug was given undiluted through a feeding
tube in a very small volume followed by flushing with
distilled water. The pH of the ibuprofen suspension used in
our study was 4.6, which is not associated with gastrointestinal
irritation. Toleration of the oral form of ibuprofen
was better than that of intravenously administered indomethacin
in terms of gastrointestinal complications such as
intestinal perforation or bleeding and NEC.
There are limitations in applying the results of our study
because of its retrospective design, power and sample size.
Although the infants in our study were not randomized, the
characteristics of the infants in the two groups were similar
and there were no major changes in clinical practice during
the 6-year study period. Despite these limitations, the final
result still contributes valuable information on the feasibility
of using oral ibuprofen in treatment of PDA closure in
premature infants.
5. Conclusions
In VLBW infants, oral ibuprofen is as effective as intravenous
indomethacin for closure of PDA and is associated with
significantly fewer cases of necrotizing enterocolitis among
infants with birth body weights <1250 g and significantly
lower rates of elevated creatinine levels among neonates
with birth body weights ranging from 1000 to 1500 g. Larger,
prospective randomized studies are needed to clarify the
efficacy and safety of oral ibuprofen with the efficacy and
safety of other medical treatments for closure of PDA in
infants with premature extremely low birth weight infants.
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