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. 2015 Jun 4;7(6):e274. doi: 10.7759/cureus.274

Ibuprofen Versus Indomethacin for Medical Closure of the Patent Arterial Duct: A Pooled Analysis by Route of Administration

Rohit Loomba 1,✉, Karan Nijhawan 2
Editors: Alexander Muacevic, John R Adler
PMCID: PMC4494534  PMID: 26180698

Abstract

Introduction:

Preterm infants are at increased risk of having a patent arterial duct (PAD). PADs may cause congestive heart failure, respiratory distress, necrotizing enterocolitis, and renal impairment. Consequently, in some infants, it becomes necessary to attempt closure of the PAD. Surgical closure can be difficult in small infants and is not without its risks; thus, medical closure offers advantages. Cyclooxygenase inhibitors have been used for medical closure of the PAD with both ibuprofen and indomethacin having been used clinically.

Methods:

We performed a systematic review of the literature to identify all studies comparing ibuprofen and indomethacin. Studies comparing ibuprofen and indomethacin for closure of the PAD in premature infants were included in the meta-analysis. A subanalysis was performed to compare the route of administration. Efficacy endpoints studied were PAD closure and surgical ligation while adverse effects studied were death in the first month of life, necrotizing enterocolitis, gastrointestinal bleeding, intestinal perforation, bronchopulmonary dysplasia in the first month of life, Grade 3 or 4 intraventricular hemorrhage, and change in the serum creatinine after treatment.

Results:

Ibuprofen and indomethacin were equally effective in closing the PAD in premature infants and demonstrated no difference in the incidence of adverse events. In respect to the route of administration, oral ibuprofen was as effective as intravenous indomethacin. When comparing both drugs via the intravenous route, the only difference noted between the ibuprofen and indomethacin was that ibuprofen was associated with a lesser increase in serum creatinine after treatment.

Conclusion:

Ibuprofen and indomethacin are equally effective in PAD closure without any difference in the incidence of adverse events. Importantly, oral ibuprofen was as effective as intravenous indomethacin.

Keywords: patent arterial duct, patent ductus arteriosus, ibuprofen, ligation, premature, indomethacin

Introduction

The arterial duct (AD) is a vascular structure that is necessary for fetal life, allowing for much of the right ventricular output to be shunted from the pulmonary artery to the descending aorta, thereby allowing for the developing lungs to receive enough blood to sustain development. Oxygenation, however, occurs at the level of the placenta during fetal life, and thus, blood does not need to pass through the pulmonary vasculature itself. The AD closes shortly after birth. In infants born at 30 to 40 weeks gestational age, the AD closes by 72 hours in 90%, and in infants born at greater than 40 weeks gestational age, the AD closes in 100% by 72 hours [1-3].

The AD is considered to be a patent ductus arteriosus (PAD) if it does not close by 72 hours of life. The prevalence of PAD is not entirely known but is present in approximately 0.06% of all live births with estimates of silent PADs having a prevalence of 0.1 to 0.2%. The prevalence of PADs is greater in those with lower birth weight and preterm gestation. For infants weighing 1,000 to 1,500 grams, 25% will have a PAD, 70% of whom will require treatment, and for infants less than 1,000 grams, 65% will have a PAD, 85% of whom will require treatment [4-7].

What justifies treatment is currently under debate with many advocating for less treatment to avoid potential adverse effects of either surgical ligation or medical therapy. Others advocate being aggressive with treatment to avoid potential adverse effects of the PAD [8-9].

If the decision is made to treat, medical therapy is an option for premature infants. Medical therapy used to consist of indomethacin; however, over the last few years, ibuprofen has become an increasingly popular alternative. Both are still used in various settings without a common practice. We present a pooled analysis of the efficacy and safety of ibuprofen and indomethacin for the closure of the PAD in preterm infants.

Materials and methods

A systematic review of the literature was performed to identify manuscripts describing comparisons between ibuprofen and indomethacin for closure of the PAD. This was a newly conducted review, and no previous review protocol has been established for the effectiveness in closing the AD and the need for surgical ligation. The following adverse events were studied: death in the first month of life, necrotizing enterocolitis, gastrointestinal bleeding, intestinal perforation, bronchopulmonary dysplasia in the first month of life, Grade 3 or 4 intraventricular hemorrhage, and change in serum creatinine after attempted treatment.

Manuscript search and identification strategy

Manuscripts were identified using electronic databases, including PubMed, EMBASE, and Ovid, which were queried using either “ibuprofen” and/or “indomethacin” in combination with “ductus arteriosus” or “arterial duct”. No specific restriction on year of publication was used. Studies in languages other than English were excluded. Resulting studies were then screened by title and abstract with manuscripts suspected of being relevant being retrieved in their entirety. References of these were hand searched for additional relevant manuscripts. No direct contact with manuscript authors was required to obtain full text manuscripts. Only studies with an ibuprofen and indomethacin group were included. Those with no data reported for any of the endpoints of interest or studies with data not deemed suitable for extraction were also excluded.

These full text manuscripts were then reviewed by two of the authors (RL, KN) and assessed for quality. Any disparities in scoring of manuscripts were then discussed and resolved. The Cochrane Handbook for Systematic Review of Interventions was used for quality evaluation. Published manuscripts available in full text were included in this review if they presented data comparing ibuprofen and indomethacin with respect to the outcomes listed above. Studies were included in this analysis if they included at least one of the outcomes identified above.

Data extraction

Data regarding baseline patient characteristics and identified outcomes were extracted from the manuscripts identified for inclusion. Trial level data were extracted independently with the use of a data collection form by two authors. The data extraction was then independently reviewed by another author to ensure the integrity of the resulting data. Authors of included studies were not contacted for additional data.

Bias analysis

Bias was assessed using the Cochrane Risk of Bias Tool. Specifically, patient eligibility, randomization and concealment of allocation, blinding, and completeness of outcome data were assessed using this scale. Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included.

Data analysis

Numeric data are presented as means with standard deviations. Categorical data are presented as frequencies with absolute numbers as well as percentages. Results are presented as pooled odds ratios (OR) with 95% confidence intervals (CI) or as mean difference (MD) where appropriate. Heterogeneity between studies was identified using chi-square and I2 tests. For outcomes with no significant heterogeneity present, a fixed effects model was used. A random effects model was used if either the p-value was significant or the I2 statistics was greater than 50%. P-values of ≤ 0.05 were considered statistically significant. The Mantel-Haenszel method was used for dichotomous endpoints while mean difference was used for continuous endpoints. Meta-analysis and forest plot creation were done using RevMan 5.0 (Cochrane Collaboration, Oxford, UK).

Analysis was done separately by route of administration. All endpoints were analyzed in the comparison of intravenous (IV) ibuprofen and IV indomethacin, oral ibuprofen versus IV indomethacin, and oral ibuprofen versus oral indomethacin. Data for all endpoints was not available for all routes of administration.

Sensitivity analyses

Sensitivity analyses were conducted to determine the effect of study size, study weight, year of publication, and study design.

Results

Search results

A total of 723 manuscripts were identified with 407 remaining after duplicates were identified and removed. Titles and abstracts of these manuscripts were reviewed, and 87 manuscripts were identified for full-text review. Of the 320 manuscripts not advancing to full-text review, 270 were excluded as there was no comparison between ibuprofen and indomethacin and 50 were excluded because they were reviews, meta-analyses, case reports, series, or letters. After a full-text review of the 87 identified manuscripts, 26 studies were identified as comparing the use of ibuprofen and indomethacin for closure of the PAD in preterm infants. Four of these studies contained data for none of the predefined endpoints of interest or had data not suitable for extraction, and thus, a total of 22 studies were included in the final pooled analysis (Figure 1) [10-31]. Of the included studies, 14 (64%) were randomized while eight (36%) were retrospective studies (Table 1).

Figure 1. Study methodology.

Figure 1

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Study methodology

Table 1. Study characteristics.

Study characteristics

Study Design Ibuprofen Indomethacin
    n Male Gestational age (wks) Birth weight (kg) Route n Male Gestational age Birth weight Route
Aly et al Randomized 12 8 (67) 32.9 ± 1.6 1.9 ± 0.5 oral 9 4 (44) 31.2 ± 2.5 1.5 ± 0.4 IV
Chan et al Retrospective 43 20 (47) 28.8 ± 2.9 1.1 ± 0.4 IV 52 28 (54) 28.4 ± 3.2 1.1 ± 0.5 IV
Fanos et al Retrospective 20 14 (70) 26.3 ± 2.4 0.9 ± 0.3 IV 20 12 (60) 26.5 ± 2.2 0.9 ±0.2 IV
Hammerman et al Randomized 32 14 (44) 27.8 ± 2.6 1.1 ± 0.4 IV 31 18 (58) 27.8 ± 2.8 1.1 ± 0.5 IV
Heo et al Retrospective 22 9 (41) 32.0 ± 4.0 1.7 ± 0.7 oral 27 13 (41) 31.0 ± 3.4 1.6 ± 0.6 IV
Katakam et al Retrospective 57 -- 26.3 ± 2.0 1.0 ± 0.3 IV 65 -- 27.3 ± 3.3 1.1 ± 0.5 IV
Lago et al Randomized 94 50 (53) 28.0 ± 2.0 1.1 ± 0.4 IV 81 44 (54) 29.0 ± 3.0 1.2 ± 0.4 IV
Lee et al Retrospective 52 29 (56) 28.8 ± 2.3 1.1 ± 0.2 oral 88 43 (49) 28.9 ± 2.2 1.1 ± 0.2 IV
Linder et al Retrospective 73 32 (44) 27.7 ± 2.5 1.0 ± 0.3 IV 46 22 (48) 27.1 ± 2.8 0.9 ± 0.3 IV
Mosca et al Randomized 8 4 (50) 29.0 ± 1.2 1.0 ± 0.3 IV 8 5 (63) 27.8 ± 1.5 0.9 ± 0.2 IV
Patel et al Randomized 12 -- -- -- IV 6 -- -- -- IV
Patel et al Randomized 18 9 (50) 27.7 ± 3.4 1.2 ± 0.7 IV 15 7 (47) 26.7 ± 2.0 0.9 ± 0.3 IV
Pezzati et al Randomized 9 -- 29.1 ± 2.1 1.2 ± 0.4 IV 8 -- 29.5 ± 2.6 1.3 ± 0.4 IV
Pourarian et al Randomized 10 7 (70) 31.3 ± 4.4 1.9 ± 0.4 oral 10 6 (60) 33.2 ± 3.1 1.7 ± 0.6 oral
Sivanandan et al Retrospective 70 44 (63) 27.0 ± 2.1 1.0 ± 0.3 oral 54 27 (50) 27.0 ± 2.3 1.0 ± 0.3 IV
Su et al Randomized 60 34 (57) 25.3 ± 1.5 0.8 ± 0.1 IV 59 33 (56) 25.3 ± 1.5 0.8 ± 0.1 IV
Su et al Randomized 32 -- -- -- IV 31 -- -- -- IV
Van Overmeire et al Randomized 20 -- 29.0 ± 2.4 1.3 ± 0.5 IV 20 -- 28.7 ± 1.9 1.2 ± 0.4 IV
Van Overmeire et al Randomized 74 -- 29.0 ± 2.3 1.2 ± 0.4 IV 74 -- 29.0 ± 2.1 1.2 ± 0.4 IV
Yadav et al Randomized 48 26 (54) 29.7 ± 3.2 1.4 ± 0.5 oral 35 17 (49) 30.3 ± 3.1 1.4 ± 0.5 oral
Yang et al Retrospective 22 9 (41) 26.7 ± 1.0 0.8 ± 0.1 oral 26 6 (23) 27.0 ± 1.3 0.9 ± 0.1 IV
Chotigeat et al Randomized 15 8 (53) 30.8 ± 2.3 1.4 ± 0.4 oral 15 7 (48) 29.9 ± 2.9 1.4 ± 0.4 IV
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Patient characteristics

A total of 1,583 patients were included in this pooled analysis. Of the 22 studies, 14 compared IV ibuprofen to IV indomethacin with 552 patients in the ibuprofen group and 516 in the indomethacin group; six studies compared oral ibuprofen to IV indomethacin with 193 patients in the ibuprofen group and 219 in the indomethacin group; and two studies compared oral ibuprofen to oral indomethacin with 58 patients in the ibuprofen group and 45 in the indomethacin group. Additional data regarding patient characteristics can be found in Table 1.

PAD closure

Fourteen studies were pooled comparing PAD closure with IV ibuprofen and IV indomethacin with a total of 552 patients having received ibuprofen and 16 having received indomethacin. Significant heterogeneity was not present (chi-squared=6.09, p=0.87, I2=0%) so a fixed-effects model was used. There was no statistically significant difference in PAD closure with IV ibuprofen when compared to IV indomethacin (odds ratio 1.07, 95% confidence interval 0.81 to 1.43) (Figure 2).

Figure 2. Forest plot.

Figure 2

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Forest plot comparing PAD closure between intravenous ibuprofen and intravenous indomethacin

Six studies were pooled comparing PAD closure with oral ibuprofen and IV indomethacin with 193 patients having received ibuprofen and 219 having received indomethacin. A fixed-effects model was used as significant heterogeneity was not present (chi-squared=0.76, p=0.51, I2=0%). There was no statistically significant difference in PAD closure with oral ibuprofen when compared to IV indomethacin (odds ratio 0.76, 95% confidence interval 0.50 to 1.18) (Figure 3).

Figure 3. Forest plot.

Figure 3

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Forest plot comparing PAD closure between oral ibuprofen and intravenous indomethacin

Two studies contained data comparing PAD closure with oral ibuprofen and oral indomethacin with 58 patients in the ibuprofen group and 45 in the indomethacin group. Significant heterogeneity was not present (chi-squared=0.45, p=0.50, I2=0%) so a fixed-effects model was used. There was no statistically significant difference between oral ibuprofen and oral indomethacin in respect to PAD closure (odds ratio 0.90, 95% confidence interval 0.40 to 2.00) (Figure 4).

Figure 4. Forest plot.

Figure 4

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Forest plot comparing PAD closure between oral ibuprofen and oral indomethacin

Need for surgical ligation

Data regarding the need for surgical ligation comparing IV ibuprofen and IV indomethacin was available from nine studies with 418 patients having received ibuprofen and 417 having received indomethacin. A fixed-effects model was used as there was no significant heterogeneity (chi-squared 3.69, p=0.88, I2=0%). No statistically significant difference was noted in the need for surgical ligation between IV ibuprofen and IV indomethacin (odds ratio 0.86, 95% confidence interval 0.58 to 1.28).

Four studies compared need for surgical ligation in 159 patients having received oral ibuprofen and 183 having received IV indomethacin. A fixed-effects model was used as there was not significant heterogeneity (chi-squared=2.47, p=0.48, I2=0%). The need for surgical ligation did not statistically significantly differ between oral ibuprofen and IV indomethacin (odds ratio 0.78, 95% confidence interval 0.45 to 1.37).

Death in first month of life

A total of nine studies compared death in the first 30 days of life between 485 patients having received IV ibuprofen and 459 having received IV indomethacin. Significant heterogeneity was not present (chi-squared=11.24, p=0.19, I2= 29%). There was no statistically significant difference between those having received IV indomethacin and those having received IV ibuprofen (odds ratio 1.03, 95% confidence interval 0.67 to 1.58).

Necrotizing enterocolitis

Eight studies compared the occurrence of necrotizing enterocolitis between IV ibuprofen and IV indomethacin with 412 and 413 patients in the two groups, respectively. No significant heterogeneity was present so a fixed-effects model was used (chi-squared=4.40, p=0.73, I2=0%). No statistically significant difference in necrotizing enterocolitis was noted between IV ibuprofen and IV indomethacin (odds ratio 0.97, 95% confidence interval 0.63 to 1.50).

Data regarding necrotizing enterocolitis comparing oral ibuprofen and IV indomethacin was available from five studies with 181 patients having received ibuprofen and 210 having received indomethacin. A fixed effects model was used as there was no significant heterogeneity (chi-squared=3.93, p=0.42, I2=0). No statistically significant difference was noted in necrotizing enterocolitis between oral ibuprofen and IV indomethacin (odds ratio 0.60, 9% confidence interval 0.30 to 1.24).

Gastrointestinal bleeding

Four studies compared the occurrence of gastrointestinal bleeding between 155 patients having received IV ibuprofen and 162 patients having received IV indomethacin. Significant heterogeneity was not present so a fixed-effects model was utilized. No statistically significant difference was noted in gastrointestinal bleeding between IV ibuprofen and IV indomethacin (odds ratio 1.40, 95% confidence interval 0.73 to 2.69).

A total of three studies compared gastrointestinal bleeding between oral ibuprofen and IV indomethacin with 144 and 169 patients in each group, respectively. A fixed-effects model was used as significant heterogeneity was not present (chi-squared=2.75, p=0.25, I2=27%). A statistically significant difference in gastrointestinal bleeding was not found between oral ibuprofen and IV indomethacin (odds ratio 0.62, 95% confidence interval 0.31 to 1.27).

Intestinal perforation

Seven studies compared intestinal perforation in 380 patients having received IV ibuprofen and 382 patients having received IV indomethacin. Significant heterogeneity was not present so a fixed-effects model was used (chi-squared=3.09, p=0.80, I2=0%). A statistically significant difference in intestinal perforation was not noted between IV ibuprofen and IV indomethacin (odds ratio 1.09, 95% confidence interval 0.54 to 2.20).

Bronchopulmonary dysplasia in the first month of life

Data regarding the frequency of bronchopulmonary dysplasia in the first month of life was pooled from six studies with 323 patients having received IV ibuprofen and 317 having received IV indomethacin. A fixed-effects model was used as there was no significant heterogeneity noted (chi-squared=5.69, p=0.34, I2=12%). No statistically significant difference was noted in bronchopulmonary dysplasia in the first month of life between IV ibuprofen and IV indomethacin (odds ratio 1.09, 95% confidence interval 0.77 to 1.54).

A total of four studies were pooled to compare the frequency of bronchopulmonary dysplasia in the first month of life between 120 patients having received oral ibuprofen and 122 having received IV indomethacin. Significant heterogeneity was not present so a fixed-effects model was used (chi-squared=3.35, p=0.34, I2=10%). No statistically significant difference in the frequency of bronchopulmonary dysplasia in the first month of life was noted between oral ibuprofen and IV indomethacin (odds ratio 0.80, 95% confidence interval 0.47 to 1.36).

Grade 3 or 4 intraventricular hemorrhage

Seven studies were pooled to compare the frequency of Grade 3 or 4 intraventricular hemorrhage between 392 patients having received IV ibuprofen and 393 patients having received IV indomethacin. A fixed-effects model was used as no significant heterogeneity was noted (chi-squared=5.66, p=0.46, I2=0%). No significant difference was noted in Grade 3 or 4 intraventricular hemorrhage between IV ibuprofen and IV indomethacin (odds ratio 0.79, 95% confidence interval 0.47 to 1.31).

Change in creatinine

A total of seven studies were pooled to compare changes in serum creatinine after attempted treatment between 345 patients having received IV ibuprofen and 310 patients having received IV indomethacin. Significant heterogeneity was present so a random-effects model was fixed (chi-squared=1244.00, p<0.001, I2=100%). A statistically significant difference in change in creatinine was present and favored ibuprofen (mean difference -0.08, 95% confidence interval -0.16 to 0.00) (Figure 5).

Figure 5. Forest plot.

Figure 5

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Forest plot comparing change in creatinine between intravenous ibuprofen and intravenous indomethacin

Five studies were pooled to compare changes in creatinine between 141 patients having received oral ibuprofen and 131 patients having received IV indomethacin. A fixed-effects model was used as no significant heterogeneity was present (chi-squared=4.09, p=0.39, I2=2%). No significant difference was noted between oral ibuprofen and IV indomethacin in regards to change in creatinine (mean difference -0.03, 95% confidence interval -0.11 to 0.05) (Figure 6).

Figure 6. Forest plot.

Figure 6

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Forest plot comparing change in creatinine between oral ibuprofen and intravenous indomethacin

Data regarding change in creatinine between oral ibuprofen and oral indomethacin was available from two studies with 58 and 45 patients in the groups, respectively. A fixed-effects model was used as there was no significant heterogeneity present (chi-squared=0.22, p=0.64, I2=0%). A statistically significant difference in change in creatinine was present, favoring oral ibuprofen (mean difference -0.10, 95% confidence interval -0.13 to -0.07) (Figure 7).

Figure 7. Forest plot.

Figure 7

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Forest plot comparing change in creatinine between oral ibuprofen and oral indomethacin

Discussion

This pooled analysis of 22 studies with 1,582 patients demonstrates that both ibuprofen and indomethacin are effective for PAD closure. Route of administration does not seem to affect efficacy and even oral ibuprofen seems to be equally effective as IV indomethacin. There was no difference in the incidence of surgical ligation between those given indomethacin and those given ibuprofen.

In regards to safety, there was no difference in the incidence of adverse outcomes, such as death in the first month of life, necrotizing enterocolitis, gastrointestinal bleeding, intestinal perforation, bronchopulmonary dysplasia in the first month of life, and Grade 3 or 4 intraventricular hemorrhage. There was a smaller increase in serum creatinine after attempted treatment associated with IV ibuprofen when compared to IV indomethacin and when oral ibuprofen was compared to IV indomethacin.

Previous studies have demonstrated a similar difference between ibuprofen and indomethacin in regards to change in creatinine [12, 18, 22]. Other studies have demonstrated that ibuprofen has less potential of adverse effects on renal function when compared to indomethacin using other endpoints, such as urine output as well as oliguria, which were not included in the current analysis due to the relatively low patient number in comparison to other endpoints. Urine output has been demonstrated to be higher in infants receiving ibuprofen rather than indomethacin for PAD closure.

The AD consists of an outer medial layer that consists of circumferential smooth muscle fibers supplied by thin-walled vasa vasorum while the inner medial layer is avascular and consists of longitudinal smooth muscle fibers. The internal elastic lamina separates this medial layer from the intima which is thin until the final end of gestation at which point it thickens. This is in contrast to the main pulmonary artery and the aorta which are comprised of circumferential elastic fibers [32].

The AD facilitates the passage of approximately 30% to 45% of the combined ventricular output in the human fetus, allowing for much of the blood to bypass the fetal lungs, which are immature and fluid filled, thus allowing them to complete development without the burden of a large amount of blood flow [33-35]. Since gas exchange occurs in the placenta, the fetal lungs require blood only for their own oxygenation and, therefore, do not require the entirety of the right ventricular output. The proportion of cardiac output that traverses the AD may presumably vary based on the amount of blood that is shunting at the atrial level via the foramen ovale, with the increased atrial level shunting leading to a decreased proportion of blood flow through the AD. It has been demonstrated that blood with a higher oxygen content in the inferior vena cava has a higher flow velocity, which facilitates streaming of this blood preferentially through the foramen ovale. This then allows for more oxygenated blood to reach the left ventricle to be pumped to the coronary arteries and head and neck vessels via the ascending aorta. While this occurs, less oxygenated blood streams preferentially into the right ventricle and into the AD or fetal lungs [36-38].

While the specific mechanisms that mediate fetal patency of the AD are not entirely elucidated, several have been proposed, which include low partial pressure of oxygen, maternal prostaglandins, adenosine, and nitric oxide production [39-46]. Since these factors promote AD patency, it thus becomes intuitive that the converse of these would result in the closure of the ductus arteriosus which in fact is seen postnatally. The AD remains open in humans for approximately 24 to 48 hours after birth and will often have bi-directional flow initially, followed by a left to right shunt before it closes. In the immediate postnatal period when pulmonary vascular resistance is still elevated, a systolic shunt from the pulmonary artery to the descending aorta is present while, in diastole, a shunt from the aorta to the pulmonary artery is present. Once pulmonary vascular resistance has decreased further, the shunt becomes purely left to right. While the AD is closing, it is still reactive to certain mediators, such as the pressure of oxygen, and this decrease in the partial pressure of oxygen will lead to potential widening of the AD and an increase in pulmonary vascular resistance with the potential return of right to left shunting. Closure of the AD is found in 44% of full-term infants by 24 hours, 88% by 48 hours, and 100% by 72 hours [47].

Thickening of the intimal layer and the resulting decrease in luminal diameter facilitates closure of the AD. While this thickening occurs throughout gestation, it is particularly marked after birth. The internal elastic lamina also begins to fragment and allow smooth muscle and endothelial cell proliferation. Eventually, the AD constricts to a point where hypoxia develops. The vasa vasorum provides blood to the adventitia while the intima and the media receive blood directly from the lumen. Thus, hypoxia ensues as the AD constricts decreases flow to the media. With this hypoxia comes apoptosis and eventual fibrous tissue deposition, which completes the AD closure. In the former phases of this process where smooth muscle constriction and intimal thickening is occurring, the process may be reversible. Once the fibrous deposition has occurred, however, the process is no longer reversible [48].

Oxygen clearly plays a role in AD closure. Studies have demonstrated that increased partial pressure of oxygen resulted in AD closure [49-50]. This, however, only appears to be the response in late gestation as even exceedingly high partial pressures of oxygen do not induce constriction of the AD at earlier gestation. The mechanism behind this is unclear as AD constriction does occur with other agents, such as calcium and acetylcholine [50]. Studies demonstrating the need for an intact cytochrome oxiADse system for oxygen to produce AD constriction have raised the possibility that perhaps oxygen directly causes smooth muscle contraction. It has been hypothesized that perhaps oxygen binding to the cytochrome p450 hemoprotein may lead to membrane depolarization with calcium influx, which then leads to muscle contraction. It has also been suggested that perhaps oxygen-sensitive potassium channels in smooth muscle may cause depolarization and activation of voltage-sensitive calcium channels with subsequent smooth muscle contraction [51-52]. Other studies have also implicated the Rho-kinase system as well as endothelin-1 release as mechanisms by which oxygen may play a role in AD closure [53-54]. Additionally, the partial pressure of oxygen required to induce constriction has also been noted to decrease with increasing gestational age [50].

Nitric oxide, a potent vasodilator, is produced by endothelial cells utilizing the nitric oxide synthase. Nitric oxide synthase has been found in the AD and its surrounding endothelial tissue. Specific nitric oxide synthase inhibitors have also been demonstrated to be ineffective in antagonism of this system in the AD at low partial pressures of oxygen, which may also explain the mechanism by which oxygen affects AD constriction. Additionally, this system thus facilitates AD closure at a later gestational age [44].

Other vasoactive agents, such as adenosine, acetylcholine, bradykinin, and norepinephrine, have also been demonstrated to lead to AD constriction and have synergistic effects to the AD’s response to oxygen. The absence of any of these agents, however, does not impair oxygen-mediated AD constriction. The precise role of these agents is not clearly defined [46, 55].

Of particular importance is the effect of prostaglandins on AD closure as both ibuprofen and indomethacin target the prostaglandin pathway. Cyclooxygenase is the enzyme responsible for synthesizing prostaglandins from arachidonic acid [56]. There are two varieties of this enzyme and both have been found to participate in prostaglandin synthesis in the wall of the AD, resulting in both prostaglandin E2 and prostaglandin I2. While prostaglandin I2 is more abundant, prostaglandin E2 is more potent with the AD being nearly 1,000 times more sensitive to prostaglandin E2, which is believed to play a vital role in maintaining the AD during fetal life [39]. In fact, prostaglandin E2 levels are higher in the fetus than in the mother with levels falling rapidly after birth, such that adult levels are reached by three hours of life [42]. What is particularly intriguing is that reductions in pulmonary blood flow, as may be seen secondary to lung disease or pulmonary vasoconstriction, can delay this fall in prostaglandin E2 levels since the lungs are the site of its metabolism. The partial pressure of oxygen does not impact the effect of prostaglandin E2 on AD constriction. Premature infants have both continued production of prostaglandin E2 but also an increased response to it [57].

These findings regarding the effect of prostaglandins on AD closure have important clinical implications. Both ibuprofen and indomethacin are nonselective cyclooxygenase inhibitors and also inhibit the synthesis of prostaglandin E2. Thus, understanding of the previously mentioned characteristics of the AD make the use of cyclooxygenase inhibitors intuitive in the setting of premature infants with PAD [58].

This study demonstrates that ibuprofen and indomethacin are equally effective in closing the PAD with ibuprofen having a renoprotective effect with some dosage routes. This current manuscript also reviews the embryology and physiology of the AD. This analysis, however, is not without its limitations. Pooled data is study-level rather than patient-level, thus limiting the opportunity for specific meta-regression. Additionally, some endpoints had significant heterogeneity. Even those endpoints without quantitative endpoints may have qualitative heterogeneity. Additionally, no cost analysis could be conducted. There was a small number of studies available to pool in regards to the comparison of the oral ibuprofen and oral indomethacin as well.

Conclusions

Ibuprofen and indomethacin are both equally effective in closure of the PAD in preterm infants. Adverse effects associated were not found to differ between the two, although ibuprofen was associated with a lower increase in creatinine.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained by all participants in this study

Animal Ethics

Animal subjects: This study did not involve animal subjects or tissue.

References

  • 1.Delayed closure of the ductus arteriosus. Auld PA. J Pediatr. 1966;69:61–66. doi: 10.1016/s0022-3476(66)80362-1. [DOI] [PubMed] [Google Scholar]
  • 2.Delayed closure of the ductus arteriosus in premature infants. Danilowicz D, Rudolph AM, Hoffman JI. Pediatrics. 1966;37:74–78. [PubMed] [Google Scholar]
  • 3.The timing of spontaneous closure of the ductus arteriosus in infants with respiratory distress syndrome. Reller MD, Colasurdo MA, Rice MJ, McDonald RW. Am J Cardiol. 1990;66:75–78. doi: 10.1016/0002-9149(90)90739-n. [DOI] [PubMed] [Google Scholar]
  • 4.Preterm patent ductus arteriosus: should we treat it? Evans N. J Paediatr Child Health. 2012;48:753–758. doi: 10.1111/j.1440-1754.2012.02542.x. [DOI] [PubMed] [Google Scholar]
  • 5.Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Clyman RI, Couto J, Murphy GM. Semin Perinatol. 2012;36:123–129. doi: 10.1053/j.semperi.2011.09.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.PDA in neonates--Please Doctor Act individually! Meyer S. Acta Paediatr. 2012;101:0. doi: 10.1111/j.1651-2227.2012.02608.x. [DOI] [PubMed] [Google Scholar]
  • 7.Patent ductus arteriosus: wait and see? Schena F, Ciarmoli E, Mosca F. J Matern Fetal Neonatal Med. 2011;24:2–4. doi: 10.3109/14767058.2011.607716. [DOI] [PubMed] [Google Scholar]
  • 8.Patent ductus arteriosus in preterm infants: do we have the right answers? Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Biomed Res Int. 2013;2013:676192. doi: 10.1155/2013/676192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Pros and cons of patent ductus arteriosus ligation: hemodynamic changes and other morbidities after patent ductus arteriosus ligation. Noori S. Semin Perinatol. 2012;36:139–145. doi: 10.1053/j.semperi.2011.09.024. [DOI] [PubMed] [Google Scholar]
  • 10.Oral Ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid IE, Hammad TA. Am J Perinatol. 2007;24:267–270. doi: 10.1055/s-2007-976550. [DOI] [PubMed] [Google Scholar]
  • 11.Ibuprofen versus indomethacin treatment of patent ductus arteriosus: comparative effectiveness and complications. Chan NM, Law CW, Kwan KF. Hong Kong Med J. 2014;20:205–212. doi: 10.12809/hkmj134080. [DOI] [PubMed] [Google Scholar]
  • 12.Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus. Fanos V, Benini D, Verlato G, Errico G, Cuzzolin L. Fundam Clin Pharmacol. 2005;19:187–193. doi: 10.1111/j.1472-8206.2004.00314.x. [DOI] [PubMed] [Google Scholar]
  • 13.Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration? Hammerman C, Shchors I, Jacobson S, Schimmel MS, Bromiker R, Kaplan M, Nir A. Pediatr Res. 2008;64:291–297. doi: 10.1203/PDR.0b013e31817d9bb0. [DOI] [PubMed] [Google Scholar]
  • 14.Comparative evaluation for the use of oral ibuprofen and intravenous indomethacin in Korean infants with patent ductus. Heo MJ, Lee OS, Lim SC. Arch Pharm Res. 2012;35:1673–1683. doi: 10.1007/s12272-012-0919-8. [DOI] [PubMed] [Google Scholar]
  • 15.Safety and effectiveness of indomethacin versus ibuprofen for treatment of patent ductus arteriosus. Katakam LI, Cotten CM, Goldberg RN, Dang CN, Smith PB. Am J Perinatol. 2010;27:425–429. doi: 10.1055/s-0029-1243371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, Saia OS. Eur J Pediatr. 2002;161:202–207. doi: 10.1007/s00431-002-0915-y. [DOI] [PubMed] [Google Scholar]
  • 17.Oral ibuprofen versus intravenous indomethacin for closure of patent ductus arteriosus in very low birth weight infants. Lee CH, Chen HN, Tsao LY, Hsiao CC, Lee ML. Pediatr Neonatol. 2012;53:346–353. doi: 10.1016/j.pedneo.2012.08.011. [DOI] [PubMed] [Google Scholar]
  • 18.Treatment of patent ductus arteriosus: indomethacin or ibuprofen? Linder N, Bello R, Hernandez A, Rosen C, Birk E, Sirota L, Pushkov Y, Klinger G. Am J Perinatol. 2010;27:399–404. doi: 10.1055/s-0029-1243315. [DOI] [PubMed] [Google Scholar]
  • 19.Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. J Pediatr. 1997;131:549–554. doi: 10.1016/s0022-3476(97)70060-x. [DOI] [PubMed] [Google Scholar]
  • 20. Ibuprofen treatment of patent ductus arteriosus. Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Lancet. 1995;346:255. doi: 10.1016/s0140-6736(95)91304-1. [DOI] [PubMed] [Google Scholar]
  • 21.Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Pediatr Res. 2000;47:36–42. doi: 10.1203/00006450-200001000-00009. [DOI] [PubMed] [Google Scholar]
  • 22.Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. J Pediatr. 1999;135:733–738. doi: 10.1016/s0022-3476(99)70093-4. [DOI] [PubMed] [Google Scholar]
  • 23.Comparison of oral ibuprofen and indomethacin on closure of patent ductus arteriosus in preterm infants. Pourarian Sh, Pishva N, Madani A, Rastegari M. East Mediterr Health J. 2008;14:360–365. [PubMed] [Google Scholar]
  • 24.Effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus in preterm infants. Sivanandan S, Bali V, Soraisham AS, Harabor A, Kamaluddeen M. Am J Perinatol. 2013;30:745–750. doi: 10.1055/s-0032-1332800. [DOI] [PubMed] [Google Scholar]
  • 25.Comparison of ibuprofen and indometacin for early-targeted treatment of patent ductus arteriosus in extremely premature infants: a randomised controlled trial. Su BH, Lin HC, Chiu HY, Hsieh HY, Chen HH, Tsai YC. Arch Dis Child Fetal Neonatal Ed. 2008;93:0–99. doi: 10.1136/adc.2007.120584. [DOI] [PubMed] [Google Scholar]
  • 26.Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Su PH, Chen JY, Su CM, Huang TC, Lee HS. Pediatr Int. 2003;45:665–670. doi: 10.1111/j.1442-200x.2003.01797.x. [DOI] [PubMed] [Google Scholar]
  • 27.Aspirin versus indomethacin treatment of patent ductus arteriosus in preterm infants with respiratory distress syndrome. van Overmeire B, Brus F, van Acker KJ, van der Auwera JC, Schasfoort M, Elzenga NJ, Okken A. Pediatr Res. 1995;38:886–891. doi: 10.1203/00006450-199512000-00010. [DOI] [PubMed] [Google Scholar]
  • 28.A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Degroote K, Langhendries JP. NEJM. 2000;343:674–681. doi: 10.1056/NEJM200009073431001. [DOI] [PubMed] [Google Scholar]
  • 29.Comparison of oral ibuprofen with oral indomethacin for PDA closure in Indian preterm neonates: a randomized controlled trial. Yadav S, Agarwal S, Maria A, Dudeja A, Dubey NK, Anand P, Yadav DK. Pediatr Cardiol. 2014;35:824–830. doi: 10.1007/s00246-014-0861-2. [DOI] [PubMed] [Google Scholar]
  • 30.A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. Chotigeat U, Jirapapa K, Layangkool Layangkool. J Med Assoc Thai. 2003;86:0–569. [PubMed] [Google Scholar]
  • 31.Comparison of oral Ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in extremely low birth weight infants. Yang EM, Song ES, Choi YY. J Pediatr (Rio J) 2013;89:33–39. doi: 10.1016/j.jped.2013.02.006. [DOI] [PubMed] [Google Scholar]
  • 32.Rudolph AM. Chichester, UK; Hoboken, NJ: Wiley-Blackwell; 2009. Congenital Diseases of the Heart: Clinical-Physiological Considerations. [Google Scholar]
  • 33.Cardiac output and central distribution of blood flow in the human fetus. Mielke G, Benda N (2001. Circulation. 2001;103:1662–1668. doi: 10.1161/01.cir.103.12.1662. [DOI] [PubMed] [Google Scholar]
  • 34.Assessment of changes in blood flow through the lungs and foramen ovale in the normal human fetus with gestational age: a prospective Doppler echocardiographic study. Sutton MS, Groves A, MacNeill A, Sharland G, Allan L. Br Heart J. 1994;71:232–237. doi: 10.1136/hrt.71.3.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta JC. Circulation. 1996;94:1068–1073. doi: 10.1161/01.cir.94.5.1068. [DOI] [PubMed] [Google Scholar]
  • 36.Bristow J, Rudolph AM, Itskovitz Itskovitz. J Dev Physiol. Vol. 3. J; 1981. A preparation for studying liver blood flow, oxygen consumption, and metabolism in the fetal lamb in utero; pp. 255–266. [PubMed] [Google Scholar]
  • 37.Preferential streaming of ductus venosus blood to the brain and heart in fetal lambs. Edelstone DI, Rudolph AM. Am J Physiol. 1979;237:0–729. doi: 10.1152/ajpheart.1979.237.6.H724. [DOI] [PubMed] [Google Scholar]
  • 38.Assessment of flow events at the ductus venosus-inferior vena cava junction and at the foramen ovale in fetal sheep by use of multimodal ultrasound. Schmidt KG, Silverman NH, Rudolph AM. Circulation. 1996;93:826–833. doi: 10.1161/01.cir.93.4.826. [DOI] [PubMed] [Google Scholar]
  • 39.PGE2 is a more potent vasodilator of the lamb ductus arteriosus than is either PGI2 or 6 keto PGF1alpha. Clyman RI, Mauray F, Roman C, Rudolph AM. Prostaglandins. 1978;16:259–264. doi: 10.1016/0090-6980(78)90028-x. [DOI] [PubMed] [Google Scholar]
  • 40.Age-dependent sensitivity of the lamb ductus arteriosus to indomethacin and prostaglandins. Clyman RI, Mauray F, Rudolph AM, Heymann MA. J Pediatr. 1980;96:94–98. doi: 10.1016/s0022-3476(80)80338-6. [DOI] [PubMed] [Google Scholar]
  • 41.Clyman RI, Brett C, Mauray Mauray. Pediatrics. Vol. 66. F; 1980. Circulating prostaglandin E2 concentrations and incidence of patent ductus arteriosus in preterm infants with respiratory distress syndrome; pp. 725–729. [PubMed] [Google Scholar]
  • 42.Circulating prostaglandin E2 concentrations and patent ductus arteriosus in fetal and neonatal lambs. Clyman RI, Mauray F, Roman C, Rudolph AM, Heymann MA. J Pediatr. 1980;97:455–461. doi: 10.1016/s0022-3476(80)80205-8. [DOI] [PubMed] [Google Scholar]
  • 43.Ductus arteriosus: developmental response to endogenous prostaglandins, oxygen, and indomethacin. Clyman RI. Adv Prostaglandin Thromboxane Res. 1980;7:887–890. [PubMed] [Google Scholar]
  • 44.Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. Clyman RI, Waleh N, Black SM, Riemer RK, Mauray F, Chen YQ. Pediatr Res. 1998;43:633–644. doi: 10.1203/00006450-199805000-00012. [DOI] [PubMed] [Google Scholar]
  • 45.The role of nitric oxide in dilating the fetal ductus arteriosus in rats. Momma K, Toyono M. Pediatr Res. 1999;46:311–315. doi: 10.1203/00006450-199909000-00010. [DOI] [PubMed] [Google Scholar]
  • 46.Hormonal role of adenosine in maintaining patency of the ductus arteriosus in fetal lambs. Mentzer RM Jr, Ely SW, Lasley RD, Mainwaring RD, Wright EM Jr, Berne RM. Ann Surg. 1985;202:223–230. doi: 10.1097/00000658-198508000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Bidirectional flow through the ductus arteriosus in normal newborns: evaluation by Doppler color flow imaging. Shiraishi H, Yanagisawa M. Pediatr Cardiol. 1991;12:201–205. doi: 10.1007/BF02310566. [DOI] [PubMed] [Google Scholar]
  • 48.Permanent anatomic closure of the ductus arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia, and gestation. Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Waleh N, Evans SM, Koch CJ. Pediatr Res. 1999;45:19–29. doi: 10.1203/00006450-199901000-00005. [DOI] [PubMed] [Google Scholar]
  • 49. The pattern and mechanisms of response to oxygen by the ductus arteriosus and umbilical artery. Oberhänsli-Weiss I, Heymann MA, Rudolph AM, Melmon KL. Pediatr Res. 1972;6:693–700. doi: 10.1203/00006450-197209000-00001. [DOI] [PubMed] [Google Scholar]
  • 50.Developmental changes in constriction of the ductus arteriosus: responses to oxygen and vasoactive agents in the isolated ductus arteriosus of the fetal lamb. McMurphy DM, Heymann MA, Rudolph AM, Melmon KL. Pediatr Res. 1972;6:231–238. doi: 10.1203/00006450-197204000-00004. [DOI] [PubMed] [Google Scholar]
  • 51.Mechanism of oxygen induced contraction of ductus arteriosus. Fay FS, Nair P, Whalen WJ. Adv Exp Med Biol. 1977;78:123–134. doi: 10.1007/978-1-4615-9035-4_9. [DOI] [PubMed] [Google Scholar]
  • 52.Cytochrome P 450-linked monooxygenase: involvement in the lamb ductus arteriosus. Coceani F, Hamilton NC, Labuc J, Olley PM. Am J Physiol. 1984;246:0–643. doi: 10.1152/ajpheart.1984.246.4.H640. [DOI] [PubMed] [Google Scholar]
  • 53.Coceani F, Kelsey L, Seidlitz Seidlitz. Can J Physiol Pharmacol. Vol. 70. E; 1992. Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth; pp. 1061–1064. [DOI] [PubMed] [Google Scholar]
  • 54. Oxygen activates the Rho/Rho-kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction. Kajimoto H, Hashimoto K, Bonnet SN, Haromy A, Harry G, Moudgil R, Nakanishi T, Rebeyka I, Thébaud B, Michelakis ED, Archer SL. Circulation. 2007;115:1777–1788. doi: 10.1161/CIRCULATIONAHA.106.649566. [DOI] [PubMed] [Google Scholar]
  • 55.Changes in plasma adenosine during simulated birth of fetal sheep. Sawa R, Asakura H, Power GG. J Appl Physiol (1985) 1991;70:1524–1528. doi: 10.1152/jappl.1991.70.4.1524. [DOI] [PubMed] [Google Scholar]
  • 56.Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo. Takahashi Y, Roman C, Chemtob S, Tse MM, Lin E, Heymann MA, Clyman RI. Am J Physiol Regul Integr Comp Physiol. 2000;278:0–1505. doi: 10.1152/ajpregu.2000.278.6.R1496. [DOI] [PubMed] [Google Scholar]
  • 57.Ductus arteriosus responses to prostaglandin E1 at high and low oxygen concentrations. Clyman RI, Heymann MA, Rudolph AM. Prostaglandins. 1977;13:219–223. doi: 10.1016/0090-6980(77)90003-x. [DOI] [PubMed] [Google Scholar]
  • 58.Ductus arteriosus: developmental response to oxygen and indomethacin. Clyman RI, Mauray F, Heymann MA, Rudolph AM. Prostaglandins. 1978;15:993–998. doi: 10.1016/0090-6980(78)90041-2. [DOI] [PubMed] [Google Scholar]

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