Patent ductus arteriosus (PDA) is a persistent communication between the descending aorta and the pulmonary artery that normally exists during fetal life but typically closes shortly after birth. The ductus arteriosus functions as a critical fetal circulatory shunt that allows oxygenated blood from the placenta to bypass the non-functional fetal lungs and enter the systemic circulation [1,2]. Following birth, physiological changes including increased oxygen tension and decreased circulating prostaglandins stimulate ductal constriction and eventual anatomical closure. In full-term infants, this process usually occurs within the first 72 hours of life [3]. However, in premature infants the ductus arteriosus frequently remains patent due to immaturity of the ductal smooth   muscle   and increased prostaglandin activity [4]. 

The incidence of PDA is inversely proportional to gestational age. It occurs in approximately 10% of infants born at 30–37 weeks of gestation, but the prevalence may reach 80% among infants born between 25 and 28 weeks and nearly 90% among those born before 24 weeks of gestation [5–7]. Persistent ductal patency may result in significant hemodynamic consequences including pulmonary overcirculation, systemic hypoperfusion, pulmonary edema, and congestive heart failure [8,9]. If left untreated, PDA can contribute to complications such as bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and impaired growth [10]. Management strategies include conservative monitoring, pharmacological closure, and surgical ligation when medical therapy fails [11]. Pharmacological closure is usually achieved using cyclooxygenase inhibitors such as indomethacin or ibuprofen, which inhibit prostaglandin synthesis and promote ductal constriction [12]. Ibuprofen has become widely used due to its comparable efficacy and lower risk of adverse renal and gastrointestinal effects compared with indomethacin [13]. Recently, acetaminophen [paracetamol] has emerged as a potential alternative treatment for PDA closure. Unlike cyclooxygenase inhibitors, acetaminophen inhibits the peroxidase component of the prostaglandin H₂ synthetase enzyme, thereby reducing prostaglandin production through a different pathway [14]. Several studies have reported comparable efficacy between acetaminophen and ibuprofen with potentially fewer renal side effects [15–17]. However, the comparative effectiveness and safety of these medications remain under investigation, particularly in premature infants with varying gestational ages. Therefore, this study aimed to evaluate the efficacy of oral ibuprofen and oral acetaminophen for the medical closure of PDA in premature infants and to assess associated clinical outcomes and adverse effects.

Patients and Methods

This prospective comparative study was conducted in the Neonatal Intensive Care Units (NICUs) of Dr. Jamal Ahmed Rashid Pediatric Teaching Hospital and the Maternity Hospital in Sulaymaniyah City, Kurdistan Region, Iraq. The study was carried out over an eight-month period from July 2023 to February 2024.

Study Population

A total of 75 preterm neonates admitted to the NICUs during the study period with echocardiographically confirmed patent ductus arteriosus were included in the study.

Inclusion Criteria

Neonates were eligible for inclusion if they met the following criteria:

• Gestational age less than 36 weeks

• Postnatal age less than 1 month

• Echocardiographically confirmed PDA

Exclusion Criteria

Neonates were excluded if they had:

• Major congenital heart disease

• Intraventricular hemorrhage

• Necrotizing enterocolitis

• Sepsis

• Platelet count <50,000/µL

• Renal insufficiency (serum creatinine >1.6 mg/dL)

Clinical Evaluation

All neonates underwent full clinical examination and laboratory investigations including:

• Complete blood count

• Renal function tests

• Liver function tests

• Cranial and abdominal ultrasonography

Echocardiographic Assessment

Echocardiography was performed using the Acuson P300 machine by the same operator to ensure consistency. PDA size was classified as:

• Small (<0.5 mm)

• Medium (0.5–1 mm)

• Large (1–1.5 mm)

• Huge (>1.5 mm)

Treatment Groups

Neonates were divided into three groups:

Ibuprofen Group (n=25)

Oral ibuprofen was administered as:

• 10 mg/kg initial dose

• 5 mg/kg at 24 hours

• 5 mg/kg at 48 hours

Acetaminophen Group (n=25)

Oral acetaminophen was administered as:

• 20 mg/kg loading dose

• 15 mg/kg every 8 hours for three doses

Conservative Group (n=25)

These infants did not receive treatment due to parental refusal and were monitored with echocardiography at 1 week and 3 months.

Outcome Measures

Primary Outcome

• PDA closure confirmed by echocardiography

Secondary Outcomes

• Drug safety

• Adverse effects (renal impairment, thrombocytopenia, NEC, liver dysfunction)

Ethical Approval

The study protocol was approved by the Scientific Research Ethics Committee, and informed consent was obtained from parents.

Statistical Analysis

Data were analyzed using SPSS version 26. Continuous variables were expressed as mean±standard deviation, while categorical variables were presented as frequencies and percentages. The Chi-square test was used to compare categorical variables, and Student’s t-test was used for continuous variables. A p-value <0.05 was considered statistically significant.

The study encompassed 75 cases of Patent Ductus Arteriosus (PDA), with 43 cases (57.3%) being male and 32 cases (42.7%) being female. Gestational age among the cases ranged from 25 to 37 weeks, with a majority (64%) exceeding 27 weeks. Postnatal age varied from less than 1 week to 2 weeks, with 82% of cases being less than 1 week old.

As shown in this Table 1 geographic distribution, 56% of cases originated from rural areas, while the remaining 44% were from Sulaimani city, classified as an urban area as is. Clinical presentations predominantly included respiratory distress (86.6%), with rare occurrences of meconium aspiration syndrome (1.3%), hypoglycemia (5.33%), and incidental diagnosis due to murmur on auscultation (6.66%). In terms of required airway support, 29.3% of cases required none, 53.33% needed oxygen, 16% were on CPAP, and 1.3% necessitated a ventilator.

Table 1: Demographic Characteristics

As shown in Table 2 Among the 25 cases administered with ibuprofen, 7 of them (28%) had a gestational age (GA) less than 27 weeks. Among these, 3 (12%) experienced closure of their Patent Ductus Arteriosus (PDA), while 4 (16%) did not. Conversely, among the 18 cases (72%) with a GA exceeding 27 weeks, 16 (64%) responded positively to ibuprofen, with only 2 (8%) showing no response.In contrast, among the 25 cases treated with acetaminophen, 11 (44%) had a GA less than 27 weeks. Within this group, 6 (24%) responded to the treatment, while 5 (20%) did not. Among the 14 cases (56%) with a GA greater than 27 weeks, 9 (36%) responded to the treatment, while 5 (20%) did not respond. This suggests a higher likelihood of PDA closure among cases with a GA exceeding 27 weeks.there is a significant association between the treatment administered (ibuprofen or acetaminophen) and the closure of Patent Ductus Arteriosus (PDA) among preterm neonates. Among the 25 patients who received ibuprofen, 19 (76%) experienced closure of PDA, while 6 (24%) did not. In contrast, among the 25 patients treated with acetaminophen, 15 (60%) experienced PDA closure, and 10 (40%) did not. The total closure rate was 68%, with 34 out of 50 patients achieving closure of PDA as as is shown in Table 2.

Table 2: The association between Treatments (ibuprofen and acetaminophen) and PDA Closure based on Gestational Age

Furthermore, 25 patients did not receive any treatment. Among them, 9 (36%) had a GA less than 27 weeks, and only 3 (12%) experienced PDA closure. Among the 16 cases (64%) with a GA exceeding 27 weeks, 7 (28%) experienced PDA closure. This indicates a closure rate of 40% among untreated cases, significantly lower than the 68% closure rate observed in cases receiving treatment as is shown in Table 3.

Table 3: Closure of the PDA in those Patients not Received Treatment according to G.A

Among the 25 patients administered ibuprofen, 19 (76%) remained free from side effects. In 2 instances (8%), a reduction in platelet count was observed, while in 3 cases (12%), there was an elevation in renal function test results. Notably, necrotizing enterocolitis (NEC) occurred in 1 case (4%). Conversely, among the 25 patients who received acetaminophen, 21 (84%) experienced no adverse reactions. A decrease in platelet count was noted in just 2 cases (8%), and elevated liver function test (LFT) levels were observed in 2 cases (8%) (Table 4).

Table 4: Association between treatment and side effects:

As shown in Table 5, among the 75 cases, 7 children (9.3%) died prior to discharge. Among these, 6 (8%) had a GA less than 27 weeks, with 5 (6.6%) having received ibuprofen and 1 (1.3%) having received acetaminophen. Among the 3 cases (4%) with a GA greater than 27 weeks, all received ibuprofen.

Table 5: Mortality Rate in Association with Treatment and G.A

In our study, the mean age of newborns at birth was 31±6 weeks, which is comparable to the findings of a study conducted by Habibi et al. [25]. Their study included a total of 77 preterm infants with PDA, with 51.9% (40 patients) receiving acetaminophen treatment and 48.1% (37 patients) receiving ibuprofen. The mean age of newborns at birth in their study was 31.8±4 weeks. Additionally, another study by Dang et al. (26) involved one hundred and sixty infants with echocardiographically confirmed PDA, with a gestational age of approximately 34 weeks. These infants were randomly assigned to receive either oral paracetamol (n = 80) or ibuprofen (n = 80). The study found that the ductus was closed in 65 (81.2%) infants in the paracetamol group compared to 63 (78.8%) in the ibuprofen group, demonstrating that the effectiveness of paracetamol treatment was not inferior to that of ibuprofen. In our study, among the 25 cases that received paracetamol, PDA closure was observed in 60% (15 cases), while among the 25 cases that received ibuprofen, PDA closure was observed in 76% (19 cases). Our research indicates that ibuprofen has a positive effect on closing the ductus arteriosus. These results are consistent with a study by Ghanem [27], which investigated the efficacy of orally administered ibuprofen in closing PDA in premature infants with respiratory distress syndrome (RDS). The study found that oral ibuprofen was effective and safe, with a success rate of 93.9% (31 out of 33 infants) [27]. Furthermore, in our study, there was no significant difference between the two groups of infants treated with paracetamol and ibuprofen in terms of PDA closure, which is consistent with findings from study done by Habibi [25]. In the two groups of infants, it was observed that 75.7 percent (n = 28) of infants treated with ibuprofen and 87.5 percent (35) of infants treated with acetaminophen had recovered by the end of the first period, while the remaining infants required further treatment. However, statistically, the difference between the two groups was not significant. Regarding side effects, in our study, among the 25 patients who received ibuprofen, 76% [19] experienced no side effects, while 24% [6] developed side effects. Among those who received acetaminophen, 84% [21] experienced no side effects, with only a small percentage experiencing decreased platelet count or increased liver function tests (LFT). However, other studies have reported different side effects, such as impaired renal function and necrotizing enterocolitis (NEC), associated with both ibuprofen and acetaminophen treatments. For instance, a study by Yang [28] showed that oral ibuprofen was associated with impaired renal function in 14% of cases and NEC in 11.6% of cases, while paracetamol was associated with impaired renal function in 2.3% of cases and NEC in 4% of cases, with no decrease in platelet count observed in either group.

Oral ibuprofen demonstrated a higher PDA closure rate compared with oral acetaminophen in premature infants. However, acetaminophen showed a comparable safety profile and may represent a reasonable alternative treatment option when ibuprofen is contraindicated or not tolerated. Further studies with larger sample sizes and longer follow-up periods are recommended to determine the optimal pharmacological approach for PDA closure in preterm infants.

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