Efficacy of acetaminophen compared to ibuprofen for patent ductus arteriosus in preterm neonates: A systematic review and meta-analysis

Abstract

BACKGROUND

Patent ductus arteriosus (PDA) is prevalent in preterm neonates (< 37 weeks), often leading to respiratory distress and other complications. Ibuprofen, a nonsteroidal anti-inflammatory drug, achieves PDA closure in 70%-85% of cases but poses risks of renal impairment and gastrointestinal (GI) bleeding. Acetaminophen, with analgesic and antipyretic effects, is a potentially safer alternative. This study compares their efficacy and safety for PDA closure.

AIM

To assess the efficacy and safety of acetaminophen compared to ibuprofen for the treatment of PDA in preterm neonates.

METHODS

We conducted a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in PubMed, EMBASE, Scopus, Cochrane Library, and ScienceDirect for randomized controlled trials comparing ibuprofen and acetaminophen for PDA closure in preterm infants. Screening was done on Rayyan, and data on PDA closure and adverse effects were extracted into an Excel spreadsheet. Analysis was performed on Review Manager. A random-effects meta-analysis was performed, with risk ratios and 95%CI reported.

RESULTS

Total 18 randomized controlled trials were included, involving a total of 1946 preterm neonates with PDA. Acetaminophen was found to be just as effective as ibuprofen for closing a PDA in the first course of treatment [risk ratios (RR) = 0.99; 95%CI: 0.90-1.09; P = 0.86], in the second course of treatment (RR = 0.98, 95%CI: 0.89-1.09, P = 0.73), and overall (RR = 1.01, 95%CI: 0.97-1.06, P = 0.55). Rates of surgical ligation (RR = 0.72, 95%CI: 0.44-1.17, P = 0.86) and PDA reopening (RR = 1.23, 95%CI: 0.78-1.95, P = 0.38) did not differ. Both drugs were comparable in terms of safety outcomes, including necrotizing enterocolitis (RR = 1.10, 95%CI: 0.74-1.64, P = 0.64), intraventricular hemorrhage (RR = 0.96, 95%CI: 0.66-1.40, P = 0.84), hyperbilirubinemia (RR = 0.85, 95%CI: 0.50-1.43, P = 0.53), bronchopulmonary dysplasia (RR = 1.03, 95%CI: 0.58-1.82, P = 0.92), sepsis (RR = 0.88, 95%CI: 0.65-1.18, P = 0.40), pulmonary hemorrhage (RR = 0.71, 95%CI: 0.29-1.75, P = 0.46), retinopathy of prematurity (RR = 0.91, 95%CI: 0.65-1.18, P = 0.44). However, ibuprofen was associated with a higher risk of GI bleeding (RR = 0.32, 95%CI: 0.16-0.63, P = 0.001) and renal failure (RR = 0.37, 95%CI: 0.16-0.81, P = 0.01).

CONCLUSION

Acetaminophen is as effective as ibuprofen for PDA closure in preterm neonates, with a lower risk of GI bleeding and renal failure, making it a viable alternative.

Key Words: Patent ductus arteriosus; Acetaminophen; Ibuprofen; Preterm infants; Congenital heart disease

Core Tip: Eighteen randomized controlled trials involving 1946 patients were included. Acetaminophen demonstrates comparable efficacy to ibuprofen with a more favorable safety profile, particularly regarding gastrointestinal bleeding and renal complications. This study suggests acetaminophen as first-line pharmacologic therapy in preterm infants with contraindications to nonsteroidal anti-inflammatory drugs or increased bleeding risk/renal dysfunction.

INTRODUCTION

During fetal life, the ductus arteriosus (DA) acts as a conduit between maternal and fetal circulation by shunting blood from the pulmonary artery to the descending aorta. The patency of DA during the fetal circulation is dependent on the effects of prostaglandin E2 (PGE2) on DA. Physiologically, functional closure begins spontaneously and is completed in the majority of infants by 9-12 hours after birth, with a maximum of 72 hours after birth. In preterm infants, the patent DA (PDA) often fails to close, with respiratory distress syndrome being another common risk factor[1]. Among neonates weighing between 501 g and 1500 g, PDA occurs at an incidence of 31%[2]. The hemodynamic instability caused by the left-to-right shunt results in pulmonary hypertension and systemic hypoperfusion[3]. The presence of a PDA is associated with reduced middle cerebral artery blood flow velocity[4].

Despite indomethacin still being the drug of choice for closure for PDA in the United States, ibuprofen and acetaminophen are gaining attention as newer alternatives, because use of indomethacin in preterm infants has been associated with transient or permanent derangement of renal function[5], gastrointestinal (GI) hemorrhage or perforation[6], alteration of platelet function[7], necrotizing enterocolitis (NEC)[8], and impairment of cerebral blood flow/cerebral blood flow velocity[9]. Ibuprofen lysine (NeoProfen) was approved by the Food and Drug Administration in 2006[10] for premature infants < 32 weeks’ gestation, promoting closure of the PDA by inhibiting prostaglandin synthesis, specifically PGE2, the most potent vasodilator of the ductus[11]. Ibuprofen is indicated to close a clinically significant PDA in premature infants weighing 500-1500 g when usual medical management (e.g., fluid restriction, diuretics, respiratory support) is ineffective. Ibuprofen is associated with a lower risk of NEC and transient renal insufficiency[12]. Ibuprofen effectiveness can be challenging due to variation in dosage and routes of administration[13].

Acetaminophen, hypothesized to exert its effect by inhibiting the peroxidase enzyme, leading to downregulation of PGE2, is considered a safer and equally effective agent[14]. Evidence on the safety and long-term neurodevelopment effects of acetaminophen in preterm infants is limited[9]. Its global impact has yet to be fully clarified through long-term trials, especially from a patient-based therapy perspective, given the large individual variability[15].

It has long been presumed that acetaminophen has a superior safety profile as compared to indomethacin and ibuprofen, with the suggestion of ultimately replacing it in the future, but objective data is limited. Trials conducted have had fewer infants. The objective of this meta-analysis was to thoroughly review the literature and systematically evaluate the safety profile and clinical efficacy of acetaminophen with ibuprofen in inducing closure of the PDA in premature newborns, incorporating recent randomized clinical trials published in the last 5 years (since 2021). This study will enable the filtering of current evidence to improve physicians’ informed decision-making and achieve better healthcare outcomes.

MATERIALS AND METHODS

This meta-analysis is conducted according to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement[16,17]. Our protocol is registered with PROSPERO (CRD420251061940).

Data sources and searches

A comprehensive electronic search was conducted across the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, EMBASE, ScienceDirect, and ClinicalTrials.gov, from their inception to July 2025. Additionally, the reference lists of selected studies and related systematic reviews were examined to identify additional relevant studies.

The following terms (“ductus arteriosus, patent”[MeSH Terms] OR “patent ductus arteriosus” OR “patency of the ductus arteriosus” OR “PDA”) AND (“Ibuprofen”[MeSH Terms] OR “ibuprofen”) were used as either medical subject heading terms or keywords.

Eligibility criteria

This meta-analysis included all randomized controlled trials (RCTs) evaluating the use of acetaminophen for PDA closure in preterm infants, compared with ibuprofen. Exclusion criteria included studies that did not conform to the RCT design, such as observational studies, quasi-randomized trials, and those conducted on non-human subjects.

Definition of treatment courses

The first complete pharmacological regimen given for PDA closure was referred to as the first course of treatment. For acetaminophen, this consisted of 15 mg/kg per dose every 6 hours for 3-7 days, while ibuprofen was administered according to standard protocols, most commonly a three-dose regimen (10-5-5 mg/kg).

A second course of treatment was defined as a repeat full regimen administered after echocardiographic confirmation of persistent hemodynamically significant PDA following completion of the first course. The dosing and duration of the second course were generally identical to those of the initial course, when reported.

Study selection and data extraction

To refine the search results and eliminate duplicates, Rayyan was employed. Two reviewers independently screened the titles and abstracts to discard irrelevant studies. The remaining articles were subjected to full-text screening based on the eligibility criteria. Any disagreements regarding study selection were resolved by involving a third senior reviewer.

Key data were collected using a pre-designed Excel spreadsheet, structured to capture both study-level and population-level information. The study characteristics sheet included details such as the author’s name, journal name, year of publication, country of origin, total sample size, study design, population description, inclusion and exclusion criteria, the specific regimens of acetaminophen and ibuprofen used, and the duration of follow-up. The population baseline sheet recorded clinical and demographic variables, including the sample sizes of both treatment groups, gestational age, birth weight, gender distribution, method of PDA diagnosis, presence of other baseline diseases, PDA size, and the left atrial-to-aortic root ratio.

Outcomes

The primary outcome of our study was efficacy, evaluated through a series of PDA-related endpoints: (1) Closure following the first course of treatment; (2) Closure after the second course; (3) Final total closure rate; (4) PDA reopening incidence; and (5) The need for surgical ligation. Safety and adverse events were assessed as secondary outcomes, including GI bleeding, renal failure, NEC, intraventricular hemorrhage (IVH), hyperbilirubinemia, bronchopulmonary dysplasia (BPD), sepsis, pulmonary hemorrhage, retinopathy of prematurity (ROP), mortality, and other clinically significant complications.

Risk of bias assessment

The risk of bias in the selected studies was assessed using the revised Cochrane Risk of Bias tool for randomized trials[18]. This tool evaluates bias in five domains, which comprise: (1) Bias caused by the randomized process; (2) Bias due to deviations from intended interventions; (3) Bias arising from missing outcome data; (4) Bias in the measurement of the outcome; and (5) Bias resulting from the selection of reported results. Two reviewers independently rated the risk of bias for each study as low, high, or raising concerns. Any disagreements were resolved through consultation with a senior reviewer.

Statistical analysis

The meta-analysis was performed using Review Manager (version 5.4.1) software. For dichotomous outcomes, the Mantel-Haenszel method was applied, while continuous outcomes were analyzed using the Inverse Variance method. Risk ratios (RRs) and their corresponding 95%CI were obtained for analysis. A random-effects model was employed to conduct meta-analysis. The pooled results were displayed in a forest plot, and statistical heterogeneity was assessed using the Higgins I² statistic.

RESULTS

Search results

Total of 4213 articles were found in the initial search; 2427 duplicates were eliminated, leaving 1786 articles for screening; 1702 articles were eliminated after title and abstract screening; 66 of the remaining 84 studies were eliminated after full-text screening [29 due to incorrect comparator, 11 due to abstract only, 9 due to incorrect study design, 6 due to including only term infants, 4 due to inadequate outcome data, 3 due to non-English language (Chinese), 2 due to ongoing study status, and 2 because they were study protocols only]. In the end, 18 RCTs were included in this meta-analysis. Finally, 18 RCTs were included in this meta-analysis. The detailed screening process is depicted in Figure 1.

Figure 1  Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart.

Study characteristics

Eighteen RCTs that satisfied the eligibility requirements were included in our meta-analysis. Two studies were carried out in China, two in Pakistan, and five in India, one in Italy, and the meta-analysis also involved studies from Middle Eastern nations (Iran: 4, Egypt: 2, Jordan: 1, Turkey: 1). The years of publication were 2013 through 2025. The study included 1946 patients. Table 1 presents details about the studies’ baseline characteristics[19-36].

Table 1 Baseline characteristics of the included trials, mean ± SD.

Ref.	Sample size	Gestational age (week)	Birth weight (g)	Acetaminophen regimens	Ibuprofen regimens
Balachander et al[19], 2020	110	Acetaminophen group (31.58 ± 2.9), ibuprofen group (31.54 ± 2.9)	Acetaminophen group (1534.8 ± 408.2), ibuprofen group (1513.4 ± 414.9)	15 mg/kg/6 hours via orogastric tube or paladai for 2 days	10 mg/kg stat on day 1, followed by 5 mg/kg/day later for 2 days
Dani et al[20], 2021	101	Acetaminophen group (28.2 ± 1.4), ibuprofen group (28.4 ± 2.0)	Acetaminophen group (1022 ± 266), ibuprofen group (1068 ± 278)	IV 15 mg/kg/6 hours for 3 days	IV 10 mg/kg/day initially, followed by 5 mg/kg/day
Dang et al[21], 2013	160	Acetaminophen group (31.2 ± 1.8), ibuprofen group (31.2 ± 1.8)	Acetaminophen group (1591.9 ± 348.6), ibuprofen group (1531.0 ± 453.5)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Sinol et al[22], 2020	140	Acetaminophen group (29.7 ± 1.67), ibuprofen group (29.3 ± 1.38)	Acetaminophen group (1150 ± 950), ibuprofen group (1120 ±115)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day for 3 days
Charanthimath et al[23], 2025	50	NR	NR	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day for 3 days
Bagheri et al[24], 2016	129	Acetaminophen group (31.53 ± 2.31), ibuprofen group (31.7 ± 2.24)	Acetaminophen group (1646.26 ± 59.14), ibuprofen group (1642.62 ± 58.46)	Oral 15 mg/kg/6 hours for 3 days	Oral 20 mg/kg/day initially, followed by 10 mg/kg/day
Samadi et al[25], 2022	90	Acetaminophen group (29 ± 1.5), ibuprofen group (29 ± 1.5)	Acetaminophen group (1000 ± 185), ibuprofen group (950 ± 156)	Oral 10 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day on day 1, followed by 5 mg/kg/day on days 2-3
Kumar et al[26], 2020	161	Acetaminophen group (28.7 ±1.6), ibuprofen group (28.7 ± 1.7)	Acetaminophen group (1167 ± 249), ibuprofen group (1129 ± 268)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Shah et al[27], 2025	256	Acetaminophen group (33.31 ±1.99), ibuprofen group (33.51 ± 2.10)	Acetaminophen group (1638.58 ± 140.60), ibuprofen group (1612.20 ± 141.80)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Al-Lawama et al[28], 2018	22	Acetaminophen group (28 ± 2.7), ibuprofen group (28 ± 3.37)	Acetaminophen group (1059 ± 386), ibuprofen group (1192 ± 269)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day for 3 days
Yang et al[29], 2016	87	Acetaminophen group (33.6 ± 2.1), ibuprofen group (33.4 ± 2.1)	Acetaminophen group (2219 ± 606), ibuprofen group (2091 ± 657)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Arif et al[30], 2021	150	Acetaminophen group (29.12 ± 7.44), ibuprofen group (30.09 ± 4.66)	Acetaminophen group (1487.1 ± 581.4), ibuprofen group (1501.4 ± 359.8)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Asadpour et al[31], 2018	50	NR	NR	Oral 10 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day on day 1, followed by 5 mg/kg/day on days 2-3
Jafari et al[32], 2019	30	NR	NR	IV 15 mg/kg/6 hours for 3 days	IV 10 mg/kg/day on day 1, followed by 5 mg/kg/day on days 2-3
El-Mashad et al[36], 2017	200	Acetaminophen group (26 ± 1.9), ibuprofen group (25 ± 2.1)	Acetaminophen group (1100 ± 130), ibuprofen group (1000 ± 120)	IV 15 mg/kg/6 hours for 3 days	IV 10 mg/kg/day on day 1, followed by 5 mg/kg/day on days 2-3
El-Farrash et al[33], 2019	60	Acetaminophen group (30.53 ± 1.55), ibuprofen group (31.73 ± 1.98)	Acetaminophen group (1530 ± 560), ibuprofen group (1740 ± 470)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day on day 1, followed by 5 mg/kg/day on days 2-3
Oncel et al[34], 2014	80	Acetaminophen group (27.3 ± 1.7), ibuprofen group (27.3 ± 2.1)	Acetaminophen group (931 ± 217), ibuprofen group (973 ± 224)	Oral 15 mg/kg/6 hours for 3 days	Oral 10 mg/kg/day initially, followed by 5 mg/kg/day
Meena et al[35], 2020	70	Acetaminophen group (32.14 ± 2.01), ibuprofen group (31.42 ± 1.72)	Acetaminophen group (1440 ± 340), ibuprofen group (1340 ± 220)	IV 15 mg/kg/6 hours for 3 days	IV 10 mg/kg/day initially, followed by 5 mg/kg/day

NR: Not report; IV: Intravenous.

Risk of bias assessment

The assessment of bias risk using Cochrane Risk of Bias tool identified a high risk of bias in eleven studies and some concerns in seven studies. The most common issues involved deviations from intended interventions, measurement, and selection of reported results. The summary of risk of bias assessment is summarized in Supplementary Figure 1[19-36].

Meta-analysis of primary outcomes

PDA closure after first course: Twelve studies involving 1283 patients (648 in the acetaminophen group and 635 in the ibuprofen group) documented PDA closure following the first course. Regarding PDA closure following the first course, there was no significant difference between the two groups (RR = 0.99, 95%CI: 0.90-1.09, P = 0.86, I² = 40%; Figure 2A)[19-24,26,28,33-36].

Figure 2 Patent ductus arteriosus closure. A: Patent ductus arteriosus (PDA) closure after first course; B: PDA closure after second course; C: Total PDA closure rate.

PDA closure after the second course: This result was reported in 11 studies involving 813 patients (401 in the acetaminophen group and 412 in the ibuprofen group). There was no discernible difference between the ibuprofen and paracetamol groups in the analysis (RR = 0.98, 95%CI: 0.89-1.09, P = 0.80, I² = 0%; Figure 2B)[20-24,26,28,33-36].

Total PDA closure rate: A total of 1845 patients were included in 17 studies that reported the total PDA closure rate (927 in the acetaminophen group and 918 in the ibuprofen group). The two groups did not differ significantly (RR = 1.01, 95%CI: 0.97-1.06, P = 0.55, I² = 13%; Figure 2C)[19-33,35,36].

Meta-analysis of secondary outcomes

Need for surgical ligation: This result was reported in 8 studies involving 952 patients (474 in the ibuprofen group and 478 in the acetaminophen group). Regarding this result, there was no discernible difference between the ibuprofen and acetaminophen groups (RR = 0.72, 95%CI: 0.44-1.17, P = 0.19, I² = 0%; Supplementary Figure 2)[20-23,26,33,34,36].

PDA reopening rate: The PDA reopening rate was reported in five studies comprising 580 patients (297 in the ibuprofen group and 283 in the acetaminophen group). The PDA reopening rate did not significantly differ between the two groups (RR = 1.23, 95%CI: 0.78-1.95, P = 0.38, I² = 0%; Supplementary Figure 3)[19-21,26,30].

GI bleeding: This result was reported in nine studies involving 1041 patients (519 in the ibuprofen group and 522 in the acetaminophen group). Neonates in the acetaminophen group had a significantly lower risk of GI bleeding compared to those in the ibuprofen group (RR = 0.32, 95%CI: 0.16-0.63, P = 0.001, I² = 0%; Supplementary Figure 4)[20-22,25,30,31,34-36].

Renal failure: This outcome was reported in 4 studies involving 510 patients (255 in the acetaminophen group and 255 in the ibuprofen group). Neonates in the acetaminophen group showed a significantly lower risk of renal failure than those in the ibuprofen group (RR = 0.37, 95%CI: 0.16-0.81, P = 0.01, I² = 0%; Supplementary Figure 5)[19,21,25,30].

NEC: This result was documented in 11 RCTs involving a total of 1199 patients (607 in the acetaminophen group and 592 in the ibuprofen group). No significant difference was present between the two groups (RR = 1.10, 95%CI: 0.74-1.64, P = 0.64, I² = 0%; Supplementary Figure 6)[19-22,25,26,28,29,34-36].

IVH: This result was reported in eleven studies, comprising a total of 1161 patients (586 in the acetaminophen group and 575 in the ibuprofen group). There was no significant difference between the acetaminophen and ibuprofen groups regarding IVH (RR = 0.96, 95%CI: 0.66-1.40, P = 0.84, I² = 0%; Supplementary Figure 7)[19-22,25,26,28,29,32,34,36].

Hyperbilirubinemia: This outcome was reported in 4 studies involving 560 patients (280 in the acetaminophen group and 280 in the ibuprofen group). The two groups showed no significant difference in terms of hyperbilirubinemia (RR = 0.85, 95%CI: 0.50-1.43, P = 0.53, I² = 60%; Supplementary Figure 8)[19,21,22,30].

BPD: Six studies reported cases of BPD, involving a total of 600 patients (303 in the acetaminophen group and 297 in the ibuprofen group). There was no significant difference between the two groups (RR = 1.03, 95%CI: 0.58-1.82, P = 0.92, I² = 0%; Supplementary Figure 9)[19,21,26,29,32,33].

Sepsis: Five studies mentioned sepsis as an outcome, involving a total of 631 patients (317 in the acetaminophen group and 314 in the ibuprofen group). The analysis revealed no significant difference between the acetaminophen and ibuprofen groups (RR = 0.88, 95%CI: 0.65-1.18, P = 0.40, I² = 0%; Supplementary Figure 10)[20,21,25,34,36].

Pulmonary hemorrhage: Pulmonary hemorrhage was reported in 5 studies, including a total of 462 patients (233 in the acetaminophen group and 229 in the ibuprofen group). No significant difference was observed between the two groups (RR = 0.71, 95%CI: 0.29-1.75, P = 0.46, I² = 0%; Supplementary Figure 11)[25,28,34-36].

ROP: ROP was reported in 8 studies involving 924 patients (464 in the acetaminophen group and 460 in the ibuprofen group). There was no significant difference between the acetaminophen and ibuprofen groups (RR = 0.91, 95%CI: 0.65-1.26, P = 0.56, I² = 0%; Supplementary Figure 12)[19-21,25,26,32,34,36].

Mortality: Eleven studies reported mortality as an outcome, including a total of 1104 patients (557 in the acetaminophen group and 547 in the ibuprofen group). The analysis showed no significant difference between the two groups in terms of mortality (RR = 0.90, 95%CI: 0.68-1.18, P = 0.44, I² = 0%; Supplementary Figure 13)[19-22,25,26,28,30,32-34].

DISCUSSION

Our meta-analysis, comprising 18 RCTs and 1946 patients, conducted between 2013 and 25 across various regions of the globe, including Europe, the Middle East, and Southeast Asia, found that acetaminophen and ibuprofen had comparable efficacy for PDA closure. PDA closure, both first and second courses, as well as the total closure rate, was uniform across results, with low-to-moderate heterogeneity and non-significant risk ratios. There was no significant difference in mortality, need for surgical ligation, PDA reopening rate, NEC, IVH, hyperbilirubinemia, BPD, pulmonary hemorrhage, sepsis, and ROP between the paracetamol and ibuprofen groups. There was a significant difference between the two groups regarding GI bleeding and renal failure. Acetaminophen demonstrated a superior safety profile compared with ibuprofen, with lower rates of both GI bleeding and renal impairment.

Our meta-analysis aligns with a previous study by Pranata et al[37], which demonstrated comparable efficacy of oral acetaminophen and ibuprofen. Our study is also in line with Ohlsson and Shah[38], a pooled meta-analysis of 5 studies that compared oral and intravenous forms of acetaminophen and ibuprofen with respect to primary closure and mortality. Both studies reported significantly lower risks of renal dysfunction and GI bleeding in the paracetamol groups, which support our findings. da Silva et al[39] demonstrated that the equivalence of acetaminophen and ibuprofen extends beyond oral formulations, with both having comparable efficacy for PDA closure and no significant differences in adverse effects. Kumar et al[26] reported that oral acetaminophen may be needed at a higher dose and/or for a longer time to achieve PDA closure compared with oral ibuprofen. Furthermore, a recent network meta-analysis by Al-Shaibi et al[40] continues to report that ibuprofen is superior for effective PDA closure, particularly at higher doses. Of note is Lu et al[41], which investigates high-dose oral ibuprofen (10 mg/kg/day for 3 days) and Bagheri et al[24] (an initial dose of 20 mg/kg, followed by 10 mg/kg at 24 hours and 48 hours). Both reported paradoxical results: Lu et al[41] showed a high rate of ductal closure at a high dose, while Bagheri et al[24] reported comparable results and recommended paracetamol due to minimal complications. Oncel et al[34] reported that the mathematically calculated reopening rate may be higher in the ibuprofen group and so the need for second course, but the difference was not statistically significant [24.1% (7 of 29) vs 16.1% (5 of 31); P = 0.43]. The latest retrospective study by Caruggi et al[42] reported that a second pharmacological course was required in 20% infants in the acetaminophen group, and 25% cases required a second course for PDA closure in the ibuprofen group.

Although our study found no significant differences in most adverse effects between the two groups, paracetamol showed a safer profile with respect to GI bleeding and renal impairment. These safety signals are consistent with previous reports by Pranata et al[37] and Ohlsson and Shah[38] and Balachander et al[19] reported a significantly higher incidence of acute kidney injury (all stages) in the ibuprofen group compared with paracetamol (P = 0.024). However, most cases were transient, with creatinine levels normalizing within 48 hours. A high dose of ibuprofen was shown to be associated with an increase in bilirubin; however, this was reported to have little clinical significance. A recent Cochrane review of 138 RCTs involving 11856 preterm infants corroborates previous findings with moderate-certainty evidence that oral ibuprofen was more effective than intravenous ibuprofen for PDA, and that high-dose ibuprofen was more effective than the standard dose[41]. Dang et al[21] found significantly lower rates of GI bleeding and hyperbilirubinemia in newborns with PDA treated with acetaminophen than in those receiving ibuprofen (P < 0.05). As far as safety is concerned, both Yang et al[29] and El-Farrash et al[33] found that there was no difference in the incidence of adverse effects (IVH, NEC, BPD, thrombocytopenia, liver and kidney dysfunction), which supports our findings except in respect to kidney dysfunction.

General observations are consistent with recent trends toward ibuprofen as first-line therapy for PDA in neonates, compared with the older standard, indomethacin, due to prior reports of enhanced efficacy and reduced toxicity[2,43]. Ibuprofen has a more selective effect on COX-1 than indomethacin, which could account for a less protracted course and fewer side effects[44]. Although ibuprofen has a good success rate in PDA closure, its use has been linked to a number of adverse effects, such as nephrotoxicity and the potential for acute kidney injury. When given at a dose of 15 mg/kg every 6 hours for 3-7 days, acetaminophen is a very promising alternative to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of PDA, with comparable success rates and a good safety profile compared to traditional NSAIDs. Only a small number of patients have shown a transient increase in liver transaminases with acetaminophen[15].

According to El-Mashad et al[36], there was no significant difference in PDA closure or treatment failure between paracetamol, ibuprofen, and indomethacin (P > 0.05), with similar closure rates following the first course of treatment (80%, 77%, and 81%, respectively) and a further boost after a second course (88%, 83%, and 87%, respectively). Additionally, the percentage of newborns in each group who needed surgical ductal ligation was comparable. Importantly, secondary outcomes were similar, except for GI bleeding, which was more common in the ibuprofen and indomethacin groups than in the paracetamol group (P < 0.05), indicating a better safety profile for paracetamol. In clinical practice, oral or orogastric administration of paracetamol at 15 mg/kg every 6 hours for 3 days is the most common route; intravenous formulations have been reserved for infants who cannot tolerate enteral therapy. During treatment, it is still essential to regularly monitor renal function and any indications of GI bleeding. Acetaminophen provides PDA closure rates comparable to ibuprofen while offering a more favorable GI and renal safety profile. This makes acetaminophen a safe and effective alternative, and a reasonable option for initial medical therapy. All of these results point to the use of paracetamol as an efficient and possibly safer substitute for PDA closure, especially in preterm infants who are more likely to experience NSAID-related problems, those who are contraindicated for ibuprofen or indomethacin, or in situations where NSAIDs are not available[36,45].

The majority of randomized controlled trials and meta-analyses that compare ibuprofen and paracetamol for PDA closure in the current literature focus more on the incidence of GI bleeding and renal dysfunction than on specific clinical severity or management outcomes. RCTs and observational cohorts rarely report granular data such as the need for blood transfusions, dialysis, reversibility of renal injury, or long-term renal sequelae. As a result, rather than severity grading or treatment course of these adverse events, the current body of evidence primarily concentrates on relative risk and incidence comparisons between treatment groups. The absence of standardised reporting of clinically significant severity endpoints is a significant limitation of pooled analyses, despite the fact that the available data consistently indicate a lower incidence of both GI bleeding and renal injury with paracetamol compared with ibuprofen. In order to better inform clinical decision-making in preterm infants with PDA, this gap highlights the need for future high-quality studies with standardised, comprehensive definitions of adverse events[37,45-48].

The results of this meta-analysis demonstrate a significant shift in the therapeutic approach to treating PDA in premature infants. As acetaminophen demonstrates comparable efficacy to ibuprofen with a more favorable safety profile, particularly regarding GI bleeding and renal complications, it opens the door for broader adoption as a first-line or alternative therapy. Future research should focus on long-term neurodevelopmental and cardiopulmonary outcomes associated with acetaminophen use, as evidence in these domains remains limited. Additionally, well-designed trials evaluating optimal dosing strategies, timing of therapy initiation, and pharmacogenomic differences among preterm infants may further refine treatment guidelines.

Further comparative cost-effectiveness analyses and real-world implementation studies are also required to inform policy development in resource-limited neonatal units, where safety and accessibility are paramount. Overall, these results support a move toward more individualized, safety-oriented strategies for the management of PDA and set the stage for revising clinical guidelines that balance efficacy with organ protection.

Our meta-analysis followed a comprehensive search strategy, included a broad geographical representation, conducted a thorough risk-of-bias assessment, and was consistent across multiple clinical outcomes. Our study is unique as it suggests paracetamol as first-line pharmacologic therapy in preterm infants with contraindications to NSAIDs or increased bleeding risk/renal dysfunction. Large, multicenter, RCTs are needed to address all these aspects and establish the safety and efficacy of oral acetaminophen vs ibuprofen.

Limitations

A limitation of this systematic review and meta-analysis is the potential for publication bias, as indicated by the asymmetry of the funnel plot. Some studies had an unclear risk of bias, which may have confounded some results. There was also inter-study variability in drug dosing regimens and administration routes, which could have altered the significance for some clinically relevant outcomes. Some of our RCTs had smaller sample sizes, and long-term follow-up data were not accounted for in most. In addition, aspects such as real efficacy in extremely low birth weight newborns, the best route of administration and dosage, timing of the first dose, and long-lasting effects remain largely unexplored.

CONCLUSION

This systematic review and meta-analysis establish that acetaminophen is as effective as ibuprofen for the medical closure of PDA in preterm neonates but carries a significantly safer profile with regard to GI and renal adverse effects. Such findings add to the growing body of evidence that positions acetaminophen as a reliable therapeutic option and point toward its possible role as a safer first-line agent, especially in vulnerable infants at higher risk of NSAID-related complications. This study has provided clinicians with a less toxic alternative that is comparable in efficacy, thus underlining the importance of revisiting existing treatment algorithms and incorporating emerging evidence into neonatal practice. Further research to investigate long-term outcomes and to home in the optimal treatment strategies will continue to shape and improve care for this high-risk population.