3. Paracetamol.

RCT ID	Population	Intervention	Comparison	Outcomes	Notes
Jafari 2019	30 preterm infants, postnatal age 48 to 72 hours with moderate to large hsPDA. Mean GA ± SD: not reported. Mean BW (g) ± SD: not reported.	Paracetamol iv 15 mg/kg BW every 6 hours for 3 days. N = 16	Ibuprofen iv 10 mg/kg of BW on the first day and 5 mg/kg on the second and third day. N = 14	Primary outcomes: postintervention PDA grades, length of stay, duration of MV, patient outcomes (i.e. death, discharge). Other outcomes: germinal matrix hemorrhage‐intraventricular hemorrhage (GMH‐IVH) (grade 1 to 4 or no GMH‐IVH); retinopathy of prematurity, pneumothorax, bronchopulmonary dysplasia.
Hochwald 2018	24 preterm infants, 24 to 31 weeks GA, with diagnosis of hsPDA. Mean GA ± SD: 27.7 ± 1.3 in ibuprofen + paracetamol group; 27.2 ± 1.4 in ibuprofen + placebo group. Mean BW (g) ± SD: 1120 ± 171 in IBU + PAR group; and 951 ± 157 in IBU + PLA group. NIPPV, n (%): 2(17) in IBU + PAR group; and 3 (25) in IBU + PLA group. SIMV, n (%): 6 (50) in IBU + PAR group; and 5 (42) in IBU + PLA group. HFOV, n (%): 2 (17) in IBU + PAR group; and 4 (33) in IBU + PLA group.	Ibuprofen (initial dose: 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours) and paracetamol (Perfalgan, Bristol‐Meyer Squibb; a loading dose of 20 mg/kg (2 ml/kg) followed by 10 mg/kg (1 ml/kg) given every 6 hours for 3 days (a total of 12 doses). N = 12	Ibuprofen (identical to intervention group) and placebo (similar volume of saline 0.9% was given at the same time intervals). N = 12	Primary outcome: closed duct on echocardiography after the completion of the pharmacologic treatment (1 or 2 courses) or a trivial and constrictive PDA after treatment without the need for treatment until discharge. Secondary outcomes: need for a second course, need for surgical ligation, rates of ductal reopening, clinical parameters including mode and duration of ventilation, pneumothorax, pulmonary hemorrhage, bronchopulmonary dysplasia, GMH‐IVH, NEC, gastrointestinal bleeding, retinopathy of prematurity, definite sepsis, death. Safety parameters also included increase in serum creatinine, decrease in urine output to < 1 ml/kg/h, AST/ALT levels and paracetamol level	First dose of study drug (paracetamol) or placebo was given within 1 hour of starting the first ibuprofen dose. If hsPDA persisted after the first course, a second course of the same treatment was given. If hsPDA persisted after the second course, a surgical PDA ligation was considered.
Schindler 2021	58 infants born at < 29 weeks GA, < 6 hours old and with PDA ≥ 1.0 mm with < 30% right to left shunt. Mean GA (wks)(SD): 26.6 (1.6) in PAR group, 26.5 (1.6) in PLA group. Mean BW (g) ± SD: 924.1 ± 240.7 in PAR group, 951.6 ± 266.9 in PLA group.	Paracetamol iv at a dose of 15 mg/kg (1.5 mL/kg) initially, followed by every 6 hours at a dose of 7.5 mg/kg (0.75 mL/kg) for 5 days. N = 29	5% dextrose (placebo) iv 1.5 mL/kg initially, followed by 0.75 mL every 6 hours for 5 days. N = 29	Primary outcome: any intervention for management of PDA up to 5‐day postnatal age. Secondary outcomes: closure of ductus arteriosus at 5‐day postnatal age; size of the ductus arteriosus at 48‐hours and 5‐day postnatal age; ductal reopening during admission; ductus arteriosus parameters; systemic blood flow measurements; adverse events during the treatment period; clinical outcomes including mortality and significant morbidities (pulmonary hemorrhage, necrotizing enterocolitis, early‐onset sepsis, late‐onset sepsis, GMH‐IVH, periventricular leukomalacia, chronic lung disease, or retinopathy of prematurity). Safety measures were also reported.

ALT = alanine transaminase; AST = aspartate transaminase; BW = body weight; d = days; GA = gestational age; GMH‐IVH = germinal matrix hemorrhage‐intraventricular hemorrhage; HFOV = high frequency oscillatory ventilation; hsPDA = hemodynamically significant patent ductus arteriosus; IBU = ibuprofen; iv = intravenous; MV = mechanical ventilation; NEC = necrotizing enterocolitis; NIPPV =; nasal intermittent positive pressure ventilation; PAR = paracetamol; PDA = patent ductus arteriosus; PLA = platelet; SD = standard deviation; SIMV = synchronized intermittent mandatory ventilation.