Efficacy of Paracetamol in The Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants : A Single-Center Study from A Moroccan Neonatal Intensive Care Unit

Abstract

Background : Hemodynamically Significant Patent Ductus Arteriosus (hsPDA) remains a frequent morbidity in preterm infants. While non-steroidal anti-inflammatory drugs are traditionally used for pharmacologic closure, paracetamol has emerged as a potential alternative with a favorable safety profile.

Objective : To evaluate the efficacy of paracetamol in achieving ductal closure in preterm infants diagnosed with hsPDA in a tertiary neonatal intensive care unit.

Methods : This prospective observational study was conducted in the neonatal intensive care unit of the Military Hospital of Rabat between January 2023 and December 2025. A total of 40 preterm infants diagnosed with hsPDA based on clinical and echocardiographic criteria between days 3^rd and 14^th day of life were included. Gestational age ranged from 28 weeks to 35 weeks, and birth weight from 1000 g to 2500 g. All neonates received paracetamol at a dose of 15 mg/kg every 6 hours for 3 days. Echocardiographic reassessment was performed after completion of therapy to evaluate ductal closure.

Results : Effective ductal closure was achieved in 32 patients (80%) after a single treatment cycle. Five infants (12.5%) required a seconde course of paracetamol to obtain closure. Two patients (5%) had a residual ductus without hemodynamic significance and did not require further intervention. Surgical ligation was necessary in one case (2.5%) due to persistent hemodynamically significant PDA despite medical therapy.

Conclusion : Paracetamol appears to be an effective and well-tolerated therapeutic option for the closure of hsPDA in preterm infants. Larger randomized studies are warranted to confirm its efficacy and safety in comparison with conventional therapies.

Keywords: Patent ductus arteriosus, Preterm infants, Paracetamol, Neonatal intensive care, Pharmacologic closure

1. Introduction

Patent Ductus Arteriosus (PDA) is one of the most common cardiovascular complications in preterm infants, with incidence inversely proportional to gestational age and birth weight. When the ductus becomes hemodynamically significant (hsPDA), it may lead to pulmonary overcirculation and systemic hypoperfusion, contributing to morbidities such as bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and prolonged mechanical ventilation¹.

Pharmacologic closure using cyclooxygenase inhibitors, including indomethacin and ibuprofen, has long been considered first-line therapy. However, these agents are associated with potential adverse effects such as renal impairment, gastrointestinal bleeding, and platelet dysfunction, limiting their use in fragile preterm populations.

Paracetamol has emerged as an alternative therapeutic option for PDA closure. Its mechanism involves inhibition of prostaglandin synthesis at the peroxidase segment of the prostaglandin H₂ synthase enzyme, differing from traditional NSAIDs. Increasing evidence suggests comparable efficacy with a more favorable safety profile².

This study aims to evaluate the efficacy of paracetamol in achieving closure of hsPDA in preterm infants admitted to the neonatal intensive care unit of the Military Hospital of Rabat.

2. Methods

All preterm neonates born at <35 weeks of gestation and diagnosed with Hemodynamically Significant Patent Ductus Arteriosus (hsPDA) were prospectively enrolled in this study after obtaining informed parental consent. The study was conducted in the neonatal intensive care unit of the Military Hospital of Rabat, Morocco, between January 2023 and December 2025. A total of 40 preterm infants meeting inclusion criteria were included.

Neonates with major congenital heart disease, significant structural congenital malformations, life-threatening sepsis with multiorgan failure, intraventricular hemorrhage, renal impairment defined as serum creatinine >1.5 mg/dL, thrombocytopenia <60,000/mm³, or severe hyperbilirubinemia requiring exchange transfusion were excluded.

For all enrolled neonates, detailed antenatal and perinatal history was obtained, followed by comprehensive general and systemic clinical examination. The diagnosis of hsPDA was established based on combined clinical and echocardiographic criteria (Table 1).

Table 1: Demographic and clinical characteristics of the study population.

Clinical suspicion of hemodynamically significant ductus arteriosus was based on features suggestive of cardiac failure and pulmonary overcirculation, including tachypnea, tachycardia, hyperdynamic precordium, bounding peripheral pulses, widened pulse pressure, and persistent or increasing requirement for respiratory support such as Continuous Positive Airway Pressure (CPAP) or mechanical ventilation.

Echocardiographic evaluation was performed in all cases by an experienced neonatologist or pediatric cardiologist. hsPDA was defined by the presence of one or more of the following parameters: internal ductal diameter ≥1.5 mm, left atrium-to-aortic root (LA/Ao) ratio >1.6, pulsatile unrestrictive left-to-right ductal shunting, and absent or reversed end-diastolic flow in the descending aorta.

Baseline laboratory investigations, including serum creatinine, total bilirubin, liver function tests, prothrombin time, activated partial thromboplastin time, and stool examination for occult blood, were obtained prior to initiation of therapy and repeated after 72 hours of treatment to monitor drug safety.

All included neonates received paracetamol either orally or intravenously at a total daily dose of 60 mg/kg/day administered in four divided doses (15 mg/kg every 6 hours) for three consecutive days. Oral paracetamol suspension was administered via orogastric tube in enterally fed neonates, while intravenous paracetamol was used in cases of feeding intolerance or contraindication to enteral administration. Supportive neonatal intensive care management was continued as clinically indicated.

Table 2: Echocardiographic findings of Hemodynamically Significant PDA.

3. Results

A total of 40 preterm neonates diagnosed with Hemodynamically Significant Patent Ductus Arteriosus (hsPDA) were included in the study. Baseline demographic, clinical, and echocardiographic characteristics are summarized in (Tables 1 and 2).

Post-intervention echocardiographic evaluation performed after completion of paracetamol therapy (Table 3) demonstrated complete ductal closure in 37 neonates. Two additional babies showed persistence of a residual ductal shunt without hemodynamic significance, which did not require further medical or surgical intervention. Only one neonate had persistent hemodynamically significant PDA requiring surgical ligation after failure of medical management.

Clinically, significant improvement was observed following treatment. Oxygen requirement decreased progressively, and signs of congestive cardiac failure resolved within 3 to 4 days after initiation of therapy. Among neonates who required invasive mechanical ventilation, successful extubation was achieved within 3 to 5 days following treatment.

No significant adverse events were observed during the course of paracetamol therapy. Specifically, there were no cases of gastrointestinal bleeding, renal impairment, hepatic dysfunction, or thrombocytopenia attributable to the intervention.

Laboratory parameters assessed before and after treatment, including renal function tests, liver enzymes, coagulation profile, and bilirubin levels, remained comparable. The differences observed between pre- and post-treatment values were not statistically significant, confirming the favorable safety profile of paracetamol in this cohort.

Table 3: Post-intervention Echocardiographic findings.

4. Discussion

In the present study, we evaluated the efficacy and safety of paracetamol for the pharmacological closure of Hemodynamically Significant Patent Ductus Arteriosus (hsPDA) in preterm infants born at <35 weeks of gestation. Our findings demonstrate a high rate of ductal closure, with complete echocardiographic closure achieved in 92.5% of neonates and only one patient requiring surgical ligation. In addition, clinical improvement was rapid, with resolution of congestive cardiac failure and reduction in respiratory support requirements within a few days of therapy initiation. No significant adverse events were observed, and laboratory safety parameters remained stable³.

These results are consistent with growing evidence supporting paracetamol as an effective alternative to cyclooxygenase inhibitors for PDA closure. Since the first report by Hammerman et al.¹ describing successful ductal closure using paracetamol, multiple observational studies and randomized trials have confirmed its efficacy. Reported closure rates in the literature range between 70% and 90%, depending on gestational age, ductal size, and timing of therapy initiation.

El-Mashad et al.² conducted a randomized controlled trial comparing paracetamol and ibuprofen and demonstrated comparable closure rates between the two drugs, with fewer renal and gastrointestinal side effects in the paracetamol group. Similarly, Dang et al.³ reported non-inferiority of paracetamol versus ibuprofen in preterm neonates, reinforcing its therapeutic potential.

A recent meta-analysis by Ohlsson et al.⁴ including randomized and quasi-randomized trials concluded that paracetamol is as effective as ibuprofen for ductal closure, particularly when administered enterally. Moreover, paracetamol showed a more favorable safety profile, especially regarding renal perfusion, platelet function, and risk of necrotizing enterocolitis.

The mechanism by which paracetamol induces ductal constriction differs from that of non-steroidal anti-inflammatory drugs. Rather than inhibiting cyclooxygenase directly, paracetamol acts at the peroxidase segment of prostaglandin H₂ synthase, reducing prostaglandin production under low peroxide conditions such as those present in the ductus arteriosus^5-7. This distinct pathway may explain its efficacy even in cases where ibuprofen fails.

In our cohort, clinical improvement paralleled echocardiographic closure. Oxygen requirements decreased rapidly, and ventilated neonates were extubated within 3 to 5 days, suggesting meaningful hemodynamic benefit beyond anatomical closure. Similar respiratory outcomes have been described in prior neonatal studies, where successful PDA closure translated into shorter ventilation duration and improved pulmonary mechanics⁸.

Importantly, no significant hepatic, renal, hematologic, or gastrointestinal adverse effects were observed in our study. This finding aligns with safety data from Terrin, et al.⁵ and Roofthooft, et al.⁶, who reported minimal toxicity even with repeated courses. The absence of significant laboratory derangement in our cohort further supports the short-term safety of paracetamol in fragile preterm populations⁹.

From a practical standpoint, paracetamol offers several advantages, particularly in resource-limited settings. It is widely available, inexpensive, and easier to administer than indomethacin, which requires strict renal and platelet monitoring. In centers where access to ibuprofen or surgical ligation is limited, paracetamol represents a valuable therapeutic option.

Nevertheless, some considerations remain. Closure rates may be lower in extremely low birth weight infants or when treatment is initiated late. Furthermore, long-term neurodevelopmental and pulmonary outcomes following paracetamol exposure require further investigation, as current data remain limited¹⁰.

Our study has certaine limitation. It is a single-center study with a relatively modest sample size and lacks a comparative control group receiving ibuprofen or indomethacin. However, it reflects real-world clinical practice and provides valuable data from a North African tertiary neonatal unit, a region underrepresented in PDA pharmacotherapy literature.

5. Conclusion

6. References

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