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. 2022 Dec 15;12(12):CD010061.
doi: 10.1002/14651858.CD010061.pub5.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants

Bonny Jasani  1 , Souvik Mitra  2 , Prakeshkumar S Shah  3
Affiliations

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants

Bonny Jasani et al. Cochrane Database Syst Rev. .

Abstract

Background: The different management strategies for patent ductus arteriosus (PDA) in preterm infants are expectant management, surgery, or medical treatment with non-selective cyclo-oxygenase inhibitors. Randomized controlled trials (RCTs) have suggested that paracetamol may be an effective and safe agent for the closure of a PDA.

Objectives: To determine the efficacy and safety of paracetamol as monotherapy or as part of combination therapy via any route of administration, compared with placebo, no intervention, or another prostaglandin inhibitor, for prophylaxis or treatment of an echocardiographically-diagnosed PDA in preterm or low birth weight infants.

Search methods: We searched CENTRAL, MEDLINE, Embase, and three trials registers on 13 October 2021, and one other database on 1 March 2022. We also checked references and contacted study authors to identify additional studies.

Selection criteria: We included RCTs and quasi-RCTs in which paracetamol (single-agent or combination therapy) was compared to no intervention, placebo, or other agents used for closure of PDA, irrespective of dose, duration, and mode of administration in preterm infants. Two independent authors reviewed the search results and made a final selection of potentially eligible articles through discussion.

Data collection and analysis: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of ductal closure after the first course of treatment; all-cause mortality during initial hospital stay; and necrotizing enterocolitis (NEC).

Main results: For this update, we included 27 studies enrolling 2278 infants. We considered the overall risk of bias in the 27 studies to vary from low to unclear. We identified 24 ongoing studies. Paracetamol versus ibuprofen There was probably little to no difference between paracetamol and ibuprofen for failure of ductal closure after the first course (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.18; 18 studies, 1535 infants; moderate-certainty evidence). There was likely little to no difference between paracetamol and ibuprofen for all-cause mortality during hospital stay (RR 1.09, 95% CI 0.80 to 1.48; 8 studies, 734 infants; moderate-certainty evidence), and for NEC (RR 1.30, 95% CI 0.87 to 1.94; 10 studies, 1015 infants; moderate-certainty evidence). Paracetamol versus indomethacin There was little to no difference between paracetamol and indomethacin for failure of ductal closure after the first course (RR 1.02, 95% CI 0.78 to 1.33; 4 studies, 380 infants; low-certainty evidence). There was little to no difference between paracetamol and indomethacin for all-cause mortality during hospital stay (RR 0.86, 95% CI 0.39 to 1.92; 2 studies, 114 infants; low-certainty evidence). The rate of NEC may be lower in the paracetamol group (3.7%) versus the indomethacin group(9.2%) (RR 0.42, 95% CI 0.19 to 0.96; 4 studies, 384 infants; low-certainty evidence). Prophylactic paracetamol versus placebo/no intervention Prophylactic paracetamol (17%) compared to placebo/no intervention (61%) may reduce failure of ductal closure after one course (RR 0.27, 95% CI 0.18 to 0.42; 3 studies, 240 infants; low-certainty evidence). There was little to no difference between prophylactic paracetamol and placebo/no intervention for all-cause mortality during hospital stay (RR 0.59, 95% CI 0.24 to 1.44; 3 studies, 240 infants; low-certainty evidence). No studies reported on NEC. Early paracetamol treatment versus placebo/no intervention Early paracetamol treatment (28%) compared to placebo/no intervention (79%) may reduce failure of ductal closure after one course when used before 14 days' postnatal age (RR 0.35, 95% CI 0.23 to 0.53; 2 studies, 127 infants; low-certainty evidence). No studies reported on all-cause mortality during hospital stay or NEC. Late paracetamol treatment versus placebo/no intervention There was little to no difference between late paracetamol and placebo for failure of ductal closure after one course of treatment when used at or after 14 days' postnatal age (RR 0.85, 95% CI 0.72 to 1.01; 1 study, 55 infants; low-certainty evidence) or NEC (RR 1.04, 95% CI 0.07 to 15.76; 1 study, 55 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay. Paracetamol combined with ibuprofen versus ibuprofen combined with placebo or no intervention There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for failure of ductal closure after the first course (RR 0.77, 95% CI 0.43 to 1.36; 2 studies, 111 infants; low-certainty evidence). There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for NEC (RR 0.33, 95% CI 0.01 to 7.45; 1 study, 24 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and ibuprofen; low-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and indomethacin; low-certainty evidence suggests that prophylactic paracetamol may be more effective than placebo/no intervention; low-certainty evidence suggests that early paracetamol treatment may be more effective than placebo/no intervention; low-certainty evidence suggests that there is probably little or no difference between late paracetamol treatment and placebo, and probably little or no difference in effectiveness between the combination of paracetamol plus ibuprofen versus ibuprofen alone for the closure of PDA after the first course of treatment. The majority of neonates included in these studies were of moderate preterm gestation. Thus, establishing the efficacy and safety of paracetamol for PDA treatment in extremely low birth weight (ELBW: birth weight < 1000 grams) and extremely low gestational age neonates (ELGANs < 28 weeks' gestation) requires further studies.

Trial registration: ClinicalTrials.gov NCT02422966 NCT01938261 NCT01536158.

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Conflict of interest statement

BJ: no relevant interests; staff neonatologist, Hospital for Sick Children, Toronto.

SM: no relevant interests; works as a neonatologist at a tertiary care neonatal intensive care unit in IWK Health Center (Halifax, Nova Scotia, Canada) where they attend to preterm infants diagnosed with a PDA; Associate Editor, Cochrane Neonatal Group.

PS: no relevant interests; works as health professional at Mount Sinai Hospital, Toronto, Canada; Associate Editor, Cochrane Neonatal Group.

Figures

1
1
Study flow diagram for 2022 review update
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
4
4
Funnel plot: failure of PDA closure after first course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'
5
5
Funnel plot: failure of PDA closure after second course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'
1.1
1.1. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
1.2
1.2. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2: Neurodevelopmental impairment
1.3
1.3. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3: All‐cause mortality during initial hospital stay
1.4
1.4. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Neonatal mortality (deaths during the first 28 days of life)
1.5
1.5. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Re‐opening of the ductus arteriosus
1.6
1.6. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Failure of PDA closure after second course of treatment
1.7
1.7. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Surgical closure of the PDA
1.8
1.8. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Duration of ventilator support (days)
1.9
1.9. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 9: Duration of need for supplementary oxygen (days)
1.10
1.10. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 10: Pulmonary hemorrhage
1.11
1.11. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 11: Pulmonary hypertension
1.12
1.12. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 12: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
1.13
1.13. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 13: Moderate to severe BPD (according to the new criteria)
1.14
1.14. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 14: Severe BPD (according to the new criteria)
1.15
1.15. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 15: Intraventricular hemorrhage (IVH, Grade I‐IV)
1.16
1.16. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 16: Severe IVH (Grade III‐IV)
1.17
1.17. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 17: Periventricular leukomalacia
1.18
1.18. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 18: Necrotizing enterocolitis (NEC)
1.19
1.19. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 19: Intestinal perforation
1.20
1.20. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 20: Gastrointestinal bleed
1.21
1.21. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 21: Retinopathy of prematurity stage ≥ 3
1.22
1.22. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 22: Retinopathy of prematurity requiring treatment
1.23
1.23. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 23: Oliguria (< 1 mL/kg/h)
1.24
1.24. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 24: Sepsis
1.25
1.25. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 25: Post‐pre difference in serum or plasma levels of creatinine (mg/dL)
1.26
1.26. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 26: Serum levels of aspartate transaminase (AST) IU/L
1.27
1.27. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 27: Post‐pre difference in serum levels of alanine aminotransferase (ALT) (IU/L)
1.28
1.28. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 28: Serum bilirubin following treatment (µmol/L)
1.29
1.29. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 29: Hyperbilirubinemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW)
1.30
1.30. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 30: Duration of hospitalization (days)
1.31
1.31. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 31: Mental developmental index (MDI) < 70
1.32
1.32. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 32: Psychomotor developmental index (PDI) < 70
1.33
1.33. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 33: Moderate to severe cerebral palsy
1.34
1.34. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 34: Deafness
1.35
1.35. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 35: Blindness
1.36
1.36. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 36: Mental developmental index
1.37
1.37. Analysis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 37: Psychomotor developmental index
2.1
2.1. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
2.2
2.2. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
2.3
2.3. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 3: Failure of PDA closure after second course of treatment
2.4
2.4. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of the PDA
2.5
2.5. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Pulmonary hemorrhage
2.6
2.6. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
2.7
2.7. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Intraventricular hemorrhage (IVH, Grade I‐IV)
2.8
2.8. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: IVH (Grade III‐IV)
2.9
2.9. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 9: Periventricular leukomalacia
2.10
2.10. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 10: Necrotizing enterocolitis (NEC)
2.11
2.11. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 11: Gastrointestinal bleed
2.12
2.12. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 12: Retinopathy of prematurity requiring treatment
2.13
2.13. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 13: Acute kidney injury
2.14
2.14. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 14: Sepsis
2.15
2.15. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 15: Post‐pre difference in serum creatinine (mg/dL)
2.16
2.16. Analysis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 16: Serum bilirubin following treatment (µmol/L)
3.1
3.1. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 1: Failure of PDA closure after first course of prophylaxis
3.2
3.2. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 2: All‐cause mortality during initial hospital stay
3.3
3.3. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 3: Duration of need for supplementary oxygen (days)
3.4
3.4. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
3.5
3.5. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
3.6
3.6. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 6: Severe IVH (Grade III‐IV)
3.7
3.7. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 7: Intestinal perforation
3.8
3.8. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 8: Retinopathy of prematurity requiring treatment
3.9
3.9. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 9: Oliguria (< 1 mL/kg/h)
3.10
3.10. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 10: Sepsis
3.11
3.11. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 11: Cerebral palsy (5 years' follow‐up)
3.12
3.12. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 12: Autism spectrum disorder (5 years' follow‐up)
3.13
3.13. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 13: Attention deficit hyperactivity disorder (5 years' follow‐up)
3.14
3.14. Analysis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 14: Pervasive developmental disorder (5 years' follow‐up)
4.1
4.1. Analysis
Comparison 4: Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after first course of treatment
4.2
4.2. Analysis
Comparison 4: Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 2: Failure of PDA closure after two courses of treatment
5.1
5.1. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after one course of treatment
5.2
5.2. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 2: Surgical closure of PDA
5.3
5.3. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 3: Pulmonary hemorrhage
5.4
5.4. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
5.5
5.5. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 5: Necrotizing enterocolitis (NEC)
5.6
5.6. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 6: Retinopathy of prematurity requiring treatment
5.7
5.7. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 7: Acute kidney injury
5.8
5.8. Analysis
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 8: Failure of PDA closure/non‐significant PDA after treatment
6.1
6.1. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after first course of treatment
6.2
6.2. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 2: Failure of PDA closure after two courses of treatment
6.3
6.3. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 3: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
6.4
6.4. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 4: Intraventricular hemorrhage (IVH, Grade I‐IV)
6.5
6.5. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 5: Severe IVH (Grade III‐IV)
6.6
6.6. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 6: Periventricular leukomalacia
6.7
6.7. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 7: Necrotizing enterocolitis (NEC)
6.8
6.8. Analysis
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 8: Oliguria (< 1 mL/kg/h)
7.1
7.1. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
7.2
7.2. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
7.3
7.3. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3: Failure of PDA closure after two courses of treatment
7.4
7.4. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Surgical closure of PDA
7.5
7.5. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
7.6
7.6. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)
7.7
7.7. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)
7.8
7.8. Analysis
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Gastrointestinal bleed
8.1
8.1. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
8.2
8.2. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
8.3
8.3. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 3: Failure of PDA closure after two courses of treatment
8.4
8.4. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of PDA
8.5
8.5. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
8.6
8.6. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)
8.7
8.7. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)
8.8
8.8. Analysis
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: Gastrointestinal bleed
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Update of

References

References to studies included in this review

Al‐Lawama 2017 {published data only}
    1. Al-Lawama M, Alammori I, Abdelghani T, Badran E. Oral paracetamol versus oral ibuprofen for treatment of patent ductus arteriosus. Journal of International Medical Research 2017;46(2):811-8. [DOI: 10.1177/0300060517722698] [PMID: ] - DOI - PMC - PubMed
Asadpour 2018 {published data only}
    1. Asadpour N, Harandi PS, Hamidi M, Malek Ahmadi MR, Malekpour-Tehrani A. Comparison of the effect of oral acetaminophen and ibuprofen on patent ductus arteriosus closure in premature infants referred to Hajar hospital in Shahrekord in 2016-2017. Journal of Clinical Neonatology 2018;7(4):224-30. [DOI: 10.4103/jcn.JCN_47_18] - DOI
Asbagh 2015 {published data only}
    1. Asbagh PA, Zarkesh MR, Nili F, Sadat Nayeri FS, Naeem AT. Prophylactic treatment with oral paracetamol for patent ductus arteriosus in preterm infants: a randomized clinical trial. Tehran University Medical Journal 2015;73(2):86-92. [http://tumj.tums.ac.ir/article-1-6603-en.html]
Babaei 2018 {published data only}
    1. Babaei H, Nemati R, Daryoshi H. Closure of patent ductus arteriosus with oral acetaminophen in preterm neonates: a randomized trial. Biomedical Research and Therapy 2018;5(2):2034-44. [DOI: 10.15419/bmrat.v5i02.418] - DOI
Bagheri 2016 {published data only}
    1. Bagheri MM, Niknafs P, Sabsevari F, Torabi MH, Bahman Bijari B, Noroozi E, et al. Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus. Iranian Journal of Pediatrics 2016;26(4):e3975. [DOI: 10.5812/ijp.3975] [PMID: ] - DOI - PMC - PubMed
Bagheri 2018 {published data only}
    1. Bagheri M, Bahman-Bijari B, Torabi-Nejad M, Niknafs P, Mousavi H, Fatemeh S, et al. Is prophylactic parenteral paracetamol effective to diminish incidence of PDA in preterm neonates? A randomized trial. Iranian Journal of Pediatrics 2018;28(4):e11735. [DOI: 10.5812/ijp.11735] - DOI
Balachander 2020 {published data only}
    1. Balachander B, Mondal N, Bhat V, Adhisivam B, Kumar M, Satheesh S, et al. Comparison of efficacy of oral paracetamol versus ibuprofen for PDA closure in preterms - a prospective randomized clinical trial. Journal of Maternal-fetal & Neonatal Medicine 2020;33(9):1587-92. [DOI: 10.1080/14767058.2018.1525354] [PMID: ] - DOI - PubMed
Dang 2013 {published data only}
    1. Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PloS One 2013;8(11):e77888. [DOI: 10.1371/journal.pone.0077888] [PMID: ] - DOI - PMC - PubMed
Dani 2021 {published data only}
    1. Dani C, Lista G, Bianchi S, Mosca F, Schena F, Ramenghi L, et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. European Journal of Pediatrics 2021;180(3):807-16. [DOI: 10.1007/s00431-020-03780-8] [PMID: ] - DOI - PMC - PubMed
Dash 2015 {published data only}
    1. Dash SK, Kabra NS, Avasthi BS, Sharma SR, Padhi P, Ahmed J. Enteral paracetamol or intravenous indomethacin for closure of patent ductus arteriosus in preterm neonates: a randomized controlled trial. Indian Pediatrics 2015;52(7):573-8. [DOI: 10.1007/s13312-015-0677-z] [PMID: ] - DOI - PubMed
    1. Kabra NS, Dash SK. Comparison of enteral paracetamol and intravenous indomethacin in closure of patent ductus arteriosus (PDA) in preterm newborns: a randomized controlled trial. In: Pediatric Academic Societies Annual Meeting; 2014 July 17-18; Vienna, Austria. 2014.
Davidson 2021 {published data only}
    1. Davidson JM, Ferguson J, Ivey E, Philip R, Weems MF, Talati AJ. A randomized trial of intravenous acetaminophen versus indomethacin for treatment of hemodynamically significant PDAs in VLBW infants. Journal of Perinatology 2021;41(1):93-9. [DOI: 10.1038/s41372-020-0694-1] [PMID: ] - DOI - PubMed
El‐Farrash 2019 {published data only}
    1. El-Farrash RA, El Shimy MS, El-Sakka AS, Ahmed MG, Abdel-Moez DG. Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial. Journal of Maternal-fetal & Neonatal Medicine 2019;32(21):3647-54. [DOI: 10.1080/14767058.2018.1470235] [PMID: ] - DOI - PubMed
El Mashad 2017 {published data only}
    1. El-Mashad AE, El-Mahdy H, El Amrousy DE, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European Journal of Pediatrics 2017;176(2):233-40. [DOI: 10.1007/s00431-016-2830-7] [PMID: ] - DOI - PubMed
Ghaderian 2019a {published data only}
    1. Ghaderian M, Armanian AM, Sabri MR, Montaseri M. Low-dose intravenous acetaminophen versus oral ibuprofen for the closure of patent ductus arteriosus in premature neonates. Journal of Research in Medical Sciences 2019;24:13. [DOI: 10.4103/jrms.JRMS_631_17] [PMID: ] - DOI - PMC - PubMed
Ghaderian 2019b {published data only}
    1. Ghaderian M, Barekatain B, Dardashty AB. Comparison of oral acetaminophen with oral ibuprofen on closure of symptomatic patent ductus arteriosus in preterm neonates. Journal of Research in Medical Sciences 2019;24:96. [DOI: 10.4103/jrms.JRMS_197_19] [PMID: ] - DOI - PMC - PubMed
Härkin 2016 {published data only}
    1. Härkin P, Härmä A, Aikio O, Valkama M, Leskinen M, Saarela T, et al. Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. Journal of Pediatrics 2016;177:72-7. [DOI: 10.1016/j.jpeds.2016.04.066] [PMID: ] - DOI - PubMed
Hochwald 2018 {published data only}
    1. Hochwald O, Mainzer G, Borenstein-Levin L, Jubran H, Dinur G, Zucker M, et al. Adding paracetamol to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a double-blind, randomized, placebo-controlled pilot study. American Journal of Perinatology 2018;35(13):1319-25. [DOI: 10.1055/s-0038-1653946] [PMID: ] - DOI - PubMed
Jafari 2019 {published data only}
    1. Jafari N, Mahdian Jouibari R, Ebadi A, Kamali K, Abdolahzadeh S, Hosseini M. Comparison between the safety and efficacy of iv paracetamol (acetaminophen) and iv ibuprofen in treating premature neonates with patent ductus arteriosus (PDA). Journal of Iranian Medical Council 2019;2(4):66-73. [http://www.jimc.ir/article_96268_032a52ab47502ad6c9ff75d3c6e5b3eb.pdf]
Kluckow 2019 {published data only}
    1. Kluckow M, Carlisle H, Broom M, Woods P, Jeffery M, Desai D, et al. A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus. Journal of Perinatology 2019;39(1):102-7. [DOI: 10.1038/s41372-018-0265-x] [PMID: ] - DOI - PubMed
Kumar 2020 {published data only}
    1. Kumar A, Gosavi RS, Sundaram V, Oleti TP, Krishnan A, Kiran S, et al. Oral paracetamol vs oral ibuprofen in patent ductus arteriosus: a randomized, controlled, noninferiority trial. Journal of Pediatrics 2020;222:79-84.e2. [DOI: 10.1016/j.jpeds.2020.01.058] [PMID: ] - DOI - PubMed
Meena 2020 {published data only}
    1. Meena V, Meena DS, Rathore PS, Chaudhary S, Soni JP. Comparison of the efficacy and safety of indomethacin, ibuprofen, and paracetamol in the closure of patent ductus arteriosus in preterm neonates - a randomized controlled trial. Annals of Pediatric Cardiology 2020;13(2):130-5. [DOI: 10.4103/apc.APC_115_19] [PMID: ] - DOI - PMC - PubMed
Oboodi 2020 {published data only}
    1. Oboodi R, Najib KS, Amoozgar H, Pourarian S, Moghtaderi M, Mehdizadegan N, et al. Positive tendency toward synchronous use of acetaminophen and ibuprofen in treating patients with patent ductus arteriosus. Türk Kardiyoloji Derneği Arşivi 2020;48(6):605-12. [DOI: 10.5543/tkda.2020.03902] [PMID: ] - DOI - PubMed
Oncel 2014 {published data only}
    1. Oncel MY, Eras Z, Uras N, Canpolat FC, Erdeve O, Oguz SS. Neurodevelopmental outcomes of preterm infants treated with oral paracetamol versus ibuprofen for patent ductus arteriosus. American Journal of Perinatology 2017;34(12):1185–9. [DOI: 10.1055/s-0037-1601564] [PMID: ] - DOI - PubMed
    1. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. Journal of Pediatrics 2014;164(3):510-4.e1. [DOI: 10.1016/j.jpeds.2013.11.008] [PMID: ] - DOI - PubMed
Schindler 2021 {published data only}
    1. Schindler T, Smyth J, Bolisetty S, Michalowski J, Mallitt KA, Singla A, et al. Early PARacetamol (EPAR) trial: a randomized controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants. Neonatology 2021;118(3):274-82. [DOI: 10.1159/000515415] [PMID: ] - DOI - PubMed
Shahmirzadi 2021 {published data only}
    1. Shahmirzadi G, Nooripour S, Ziari A, Danaei N. Comparison of gastrointestinal complications of paracetamol and ibuprofen in the management of infants with patent ductus arteriosus: a randomized clinical trial study. International Journal of Preventive Medicine 2021;12:48. [PMID: ] - PMC - PubMed
Tauber 2020 {published data only}
    1. Tauber KA, King R, Colon M. Intravenous acetaminophen vs intravenous ibuprofen to close a patent ductus arteriosus closure: a pilot randomized controlled trial. Health Science Reports 2020;3(3):e183. [DOI: 10.1002/hsr2.183] [PMID: ] - DOI - PMC - PubMed
Yang 2016 {published data only}
    1. Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: a randomized controlled trial. Experimental and Therapeutic Medicine 2016;12(4):2531-6. [DOI: 10.3892/etm.2016.3676] [PMID: ] - DOI - PMC - PubMed

References to studies excluded from this review

Cakir 2021 {published data only}
    1. Cakir U, Tayman C, Karacaglar NB, Beser E, Ceran B, Unsal H. Comparison of the effect of continuous and standard intermittent bolus paracetamol infusion on patent ductus arteriosus. European Journal of Pediatrics 2021;180(2):433-40. [DOI: 10.1007/s00431-020-03822-1] [PMID: ] - DOI - PubMed
Höck 2020 {published data only}
    1. Höck M, Brunner B, Rier V, Thöni S, Trawöger R, Geiger R, et al. Prophylactic low-dose paracetamol administration associated with lowered rate of patent ductus arteriosus in preterm infants - impact on outcome and pain perception. Pediatrics and Neonatology 2020;61(1):84-91. [DOI: 10.1016/j.pedneo.2019.06.011] [PMID: ] - DOI - PubMed
King 2020 {published data only}
    1. King R, Colon M, Stanfel L, Tauber KA. Late acetaminophen therapy for patent ductus arteriosus in the preterm neonate. Journal of Pediatric Pharmacology and Therapeutics 2020;25(6):507-13. [DOI: 10.5863/1551-6776-25.6.507] [PMID: ] - DOI - PMC - PubMed
Shah 2021 {published data only}
    1. Shah SD, Makker K, Nandula P, Smotherman C, Kropf A, Hudak ML. Effectiveness of dual medication therapy (oral acetaminophen and oral ibuprofen) for the management of patent ductus arteriosus in extremely premature infants: a feasibility trial. American Journal of Perinatology 2021 Jan 17 [Epub ahead of print]. [DOI: 10.1055/s-0040-1722329] [PMID: ] - DOI - PubMed

References to ongoing studies

ACTRN12613000289718 {published data only}
    1. ACTRN12613000289718. Paracetamol for patent ductus arteriosus treatment: comparison between oral and intravenous administration. anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363736&isReview... (first received 8 March 2013).
ChiCTR‐TRC‐13003912 {published data only}
    1. ChiCTR-TRC-13003912. Comparison of oral paracetamol versus ibuprofen in premature infants < 1500g with patent ductus arteriosus: a randomized controlled trial. www.chictr.org.cn/hvshowproject.aspx?id=8209 (first received 7 December 2013).
CTRI/2017/10/009989 {published data only}
    1. CTRI/2017/10/009989. Paracetamol versus ibuprofen for closure of patent ductus arteriosus [Efficacy and safety of oral paracetamol versus oral ibuprofen in management of patent ductus arteriosus in preterm neonates less than or equal to 34 Weeks or less than or equal to 1800 gms: a randomized control trial - BAP trial]. apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2017/10/009989 (first received 10 October 2017).
CTRI/2017/10/010012 {published data only}
    1. CTRI/2017/10/010012. A clinical trial comparing low dose versus standard dose of intravenous paracetamol for PDA closure in very premature babies [Randomized controlled trial of two different doses of intravenous paracetamol for PDA closure in preterm infants less than 30 weeks]. www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=20401&EncHid... (first received 05 October 2017).
CTRI/2018/02/011942 {published data only}
    1. CTRI/2018/02/011942. To study the efficacy and safety of oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomised controlled trial [Paracetamol versus ibuprofen in the management of patent ductus arteriosus (congenital heart disease) in preterm infants]. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/02/011942 (first received 19 February 2018).
EUCTR2015‐003177‐14‐ES {published data only}
    1. EUCTR2015-003177-14-ES. Paracetamol versus ibuprofen in preterm infants with a hemodynamically significant patent ductus arteriosus: a randomized clinical trial. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2015-003177-14-ES (first received 20 April 2016).
EUCTR2019‐004297‐26‐FR {published data only}
    1. EUCTR2019-004297-26-FR. Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen - TREOCAPA. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 28 February 2020).
EUCTR2020‐004245‐37‐IE {published data only}
    1. EUCTR2020-004245-37-IE. Randomised placebo-controlled trial of early targeted treatment of patent ductus arteriosus with paracetamol in extremely low birth weight infants (ETAPA). www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:202... (first received 30 October 2020).
IRCT20111011007763N2 {published data only}
    1. IRCT20111011007763N2. Clinical trial of the effect of intravenous acetaminophen in patent ductus arteriosus prophylaxis of preterm infants with gestational age less than 32 weeks. en.irct.ir/trial/8223 (first received 3 March 2018).
IRCT20120215009014N321 {published data only}
    1. IRCT20120215009014N321. Effect of intravenous ibuprofen versus intravenous paracetamol on the occlusion of patent ductus arteriosus in preterm infants: a single-blind randomized clinical trial. en.irct.ir/trial/43951 (first received 10 December 2019).
IRCT20130812014333N118 {published data only}
    1. IRCT20130812014333N118. Comparison of the therapeutic and safety effect of oral and rectal acetaminophen for treatment and safety on the closure of ductus arteriosus in preterm neonates under 35 weeks and 6 days gestational old. en.irct.ir/trial/38155 (first received 11 April 2019).
IRCT20171227038102N1 {published data only}
    1. IRCT20171227038102N1. Investigation effect of oral acetaminophen and ibuprofen on patent ductus arteriosus in preterm neonates. www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20171227038102N1 (first received 3 July 2018).
IRCT20190505043478N1 {published data only}
    1. IRCT20190505043478N1. Comparison of the efficacy of oral acetaminophen and intravenous acetaminophen for closure of patent ductus arteriosus in preterm neonates. www.irct.ir/trial/39364 (first received 10 May 2019).
IRCT20200218046538N1 {published data only}
    1. IRCT20200218046538N1. Effect of prophylactic oral administration of acetaminophen on patent ductus arteriosus (PDA) closure in preterm neonate admitted in NICU section of Ali ibn Abitaleb Hospital in Zahedan in 2019-2020. en.irct.ir/trial/45975 (first received 10 March 2020).
NCT01291654 {published data only}
    1. NCT01291654. Paracetamol and patent ductus arteriosus (PDA) [Paracetamol in the treatment of patent ductus arteriosus in the premature neonate]. Clinicaltrials.gov/show/NCT01291654 (first received 6 February 2011).
NCT02056223 {published data only}
    1. NCT02056223. Paracetamol vs ibuprofen for PDA closure in preterm infants (PARIDA) [Paracetamol versus ibuprofen for patent ductus arteriosus closure in preterm infants. A prospective, randomized, controlled, double blind, multicenter clinical trial]. clinicaltrials.gov/show/NCT02056223 (first received 10 August 2005).
NCT02819414 {published data only}
    1. NCT02819414. Paracetamol treatment of the borderline significant PDA [Time to re-evaluate the kinder gentler approach to patent ductus arteriosus (PDA) in the preterm neonate]. clinicaltrials.gov/show/NCT02819414 (first received 30 June 2016).
NCT03604796 {published data only}
    1. NCT03604796. Alternative acetaminophen treatment of the hemodynamically significant patent ductus arteriosus in preterm neonates who are not candidates for enteral administration: a pilot study. clinicaltrials.gov/show/NCT03604796 (first received 30 July 2018).
NCT03641209 {published data only}
    1. NCT03641209. Extremely low gestational age infants' paracetamol study: a randomized trial. clinicaltrials.gov/show/NCT03641209 (first received 21 August 2018).
NCT03648437 {published data only}
    1. NCT03648437. Paracetamol and ibuprofen/indomethacin in closing patent ductus arteriosus (PAI). clinicaltrials.gov/show/NCT03648437 (first received 27 August 2018).
NCT04037514 {published data only}
    1. García-Robles A, Gimeno Navarro A, Serrano Martín MD, Párraga Quiles MJ, Parra Llorca A, Poveda-Andrés JL, et al. Paracetamol vs. ibuprofen in preterm infants with hemodynamically significant patent ductus arteriosus: a non-inferiority randomized clinical trial protocol. Frontiers in Pediatrics 2020;8:372. [DOI: 10.3389/fped.2020.00372] [PMID: ] - DOI - PMC - PubMed
    1. NCT04037514. Paracetamol versus ibuprofen in premature infants with hemodynamically significant patent ductus arteriosus (IBUPAR). clinicaltrials.gov/ct2/show/NCT04037514 (first received 30 July 2019).
NCT04459117 {published data only}
    1. NCT04459117. Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen. clinicaltrials.gov/show/NCT04459117 (first received 7 July 2020).
NCT04986839 {published data only}
    1. NCT04986839. PAIR (Paracetamol and Ibuprofen Research) Study: a randomised controlled trial comparing IV paracetamol with IV ibuprofen in the management of haemodynamically significant patent ductus arteriosus. clinicaltrials.gov/show/NCT04986839 (first registered on 19 July 2021).
TCTR20201104001 {published data only}
    1. TCTR20201104001. Paracetamol administration within the first 72 hours of life in early preterm infants with hemodynamically significant patent ductus arteriosus for prevention of bronchopulmonary dysplasia. www.thaiclinicaltrials.org/show/TCTR20201104001 (first received 30 August 2021).

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References to other published versions of this review

Ohlsson 2012
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