Comparison between the Efficacy of Oral Acetaminophen and Ibuprofen in the Treatment of Preterm Infants with PDA (A Clinical Trial)

Patent ductus arteriosus (PDA) is one of the most common congenital heart defects in premature infants. Despite the relatively high prevalence of PDA in preterm infants, there is still no clear treatment pattern for these patients. The main treatment options for PDA include surgical obstruction of the duct or the use of medications such as prostaglandin synthetase inhibitors. Previous studies have reported that surgery leads to complications, the most important of which include pneumothorax, chylothorax, infections, and ultimately increased mortality. Therefore, the option of surgical treatment for PDA is largely limited. Finding a suitable treatment option for uncomplicated recovery of PDA in premature infants is very valuable to increase the life of premature infants. Indomethacin was the first prostaglandin synthetase inhibitor to be used to treat PDA. However, due to its relatively common side effects, attempts were made to replace the drug, and the US Food and Drug Administration eventually authorized the intravenous administration of ibuprofen lysine (neoprofen) to premature infants with PDA. At present, according to the results of previous studies, ibuprofen is mainly used to close PDAs. Ibuprofen is as effective as indomethacin and has fewer renal side effects. Recent studies have shown that acetaminophen can also be used effectively to treat PDA in premature infants. However, the use of this drug (orally and parenteral) has not been widely studied in clinical trials. On the other hand, recent studies have examined the positive and uncomplicated effect of intravenous acetaminophen as well as ibuprofen on treat PDA. Therefore, conducting a study comparing the oral use of acetaminophen and ibuprofen in PDA closure in preterm infants is valuable and will greatly help in choosing the best treatment option in them. Therefore, in this study, the effect of oral acetaminophen and ibuprofen on premature infants with PDA was investigated.

This interventional study was conducted from April to Nov 2020. A total of 60 preterm neonates with diagnosis of PDA admitted in NICU of Akbar Abadi Hospital Tehran were selected. Neonates were randomly assigned to two groups. In the first intervention group, oral Acetaminophen was prescribed every 6 hours at a dose of 15 mg/kg for 3 days. In the second intervention group, oral Ibuprofen was prescribed at a dose of 10 mg/kg for day one and 5 mg/kg for the next two consecutive days. Inclusion criteria included Parent's consent to participate in the study, Gestational age between 26 to 37 weeks, and Diagnosis of ductus arteriosus based on echocardiographic evidence at 24 to 72 hours after birth. Exclusion criteria included premature newborn with fever and seizure, life-threatening infections, clinical or radiographic evidence of necrotizing enterocolitis, evidence of bleeding, platelets less than 50,000 per ml, Liver failure, congenital brain-neurological disorders, metabolic and genetic syndromes, pulmonary hypoplasia syndrome, congenital heart anomalies or other fatal abnormalities. Finally, the extent and duration of PDA closure, and echocardiographic findings before and after the intervention and side effects in infants of both groups were evaluated. Data were entered in SPSS and analyzed.

The demographic characteristics in neonates showed that in terms of gender variability, the frequency  of boys and girls in the group of oral acetaminophen and ibuprofen were 16 (53.3%), 14 (46.7%) and 17 (56.7%) and 13(43.3%), respectively. The mean of gestational age was 33.15± 6 weeks. Total of 78.33% of patients underwent cesarean section. The mean birth weight of neonates at the time of diagnosis in the acetaminophen and ibuprofen groups was 2231.41± 690.25 and 1854± 453.47 gr, respectively. About 26.66% of patients had Large PDA. The results of statistical analysis showed that the mean gestational age and weight in the two groups receiving Acetaminophen and Ibuprofen were not significantly different (P = 0.14), (P = 0.746). The LA / AO ratio in the acetaminophen and ibuprofen groups at the beginning of treatment was 0.42 ± 1.57 and 0.56 ± 1.74, respectively, which were not significantly different from each other. At the end of the treatment period, patients in both groups had a significant decrease in LA / AO ratio. After the intervention in the acetaminophen group was 0.36 ± 1.20 and compared to before the intervention was statistically significant (P = 0.013) and in the Ibuprofen group was 0.40 ± 1.38 .There was a statistically significant decrease compared to the results before the intervention (P = 0.017). However, the LA / AO ratio at the end of the treatment period did not differ significantly between the Acetaminophen and Ibuprofen groups (P = 0.412). PDA size in acetaminophen and ibuprofen groups at the beginning of treatment was 2.85(0.48) and 2.81(0.75), respectively, which was not significantly different from each other, but at the end of treatment patients in both groups was significantly reduced. There was a significant decrease in PDA size, this ratio was 1.72(0.92) in the acetaminophen group after the intervention and had a statistically significant decrease compared to the results before the intervention. (P = 0.001) In the ibuprofen group, it was equal to 1.74(1.02) which was significantly lower than before the intervention (P = 0.024). But PDA size at the end of treatment was not significantly different between acetaminophen and ibuprofen groups.After the first course of treatment in the ibuprofen and acetaminophen groups, 43.33% and 46.66% of PDA s were closed, respectively, which was not significantly different between the two groups (P = 09.79). After the second course of treatment, PDA closure was observed in 33.3% and 26.66% of ibuprofen and acetaminophen groups respectively, and there was no statistically significant difference between the two groups (P = 0.653). The most common clinical complications in patients receiving acetaminophen and ibuprofen were short-term hyperbilirubinemia (26.66% and 43.33%, respectively), which was significantly higher in the ibuprofen group (p = 0.03).

Although the rate of PDA closure with oral acetaminophen compared to oral ibuprofen was not different, the incidence of side effects in acetaminophen group was lower than ibuprofen and this drug can be a suitable alternative for use in the treatment of preterm infants with PDA.