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

Bonny Jasani; Souvik Mitra; Prakeshkumar S Shah

doi:10.1002/14651858.CD010061.pub5

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Figure 1

Study flow diagram for 2022 review update

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 4

Funnel plot: failure of PDA closure after first course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'

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Figure 5

Funnel plot: failure of PDA closure after second course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'

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Analysis 1.1

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment

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Analysis 1.2

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2: Neurodevelopmental impairment

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Analysis 1.3

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3: All‐cause mortality during initial hospital stay

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Analysis 1.4

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Neonatal mortality (deaths during the first 28 days of life)

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Analysis 1.5

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Re‐opening of the ductus arteriosus

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Analysis 1.6

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Failure of PDA closure after second course of treatment

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Analysis 1.7

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Surgical closure of the PDA

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Analysis 1.8

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Duration of ventilator support (days)

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Analysis 1.9

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 9: Duration of need for supplementary oxygen (days)

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Analysis 1.10

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 10: Pulmonary hemorrhage

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Analysis 1.11

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 11: Pulmonary hypertension

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Analysis 1.12

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 12: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA

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Analysis 1.13

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 13: Moderate to severe BPD (according to the new criteria)

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Analysis 1.14

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 14: Severe BPD (according to the new criteria)

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Analysis 1.15

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 15: Intraventricular hemorrhage (IVH, Grade I‐IV)

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Analysis 1.16

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 16: Severe IVH (Grade III‐IV)

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Analysis 1.17

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 17: Periventricular leukomalacia

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Analysis 1.18

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 18: Necrotizing enterocolitis (NEC)

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Analysis 1.19

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 19: Intestinal perforation

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Analysis 1.20

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 20: Gastrointestinal bleed

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Analysis 1.21

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 21: Retinopathy of prematurity stage ≥ 3

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Analysis 1.22

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 22: Retinopathy of prematurity requiring treatment

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Analysis 1.23

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 23: Oliguria (< 1 mL/kg/h)

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Analysis 1.24

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 24: Sepsis

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Analysis 1.25

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)

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Analysis 1.26

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 26: Serum levels of aspartate transaminase (AST) IU/L

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Analysis 1.27

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)

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Analysis 1.28

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 28: Serum bilirubin following treatment (µmol/L)

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Analysis 1.29

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)

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Analysis 1.30

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 30: Duration of hospitalization (days)

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Analysis 1.31

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 31: Mental developmental index (MDI) < 70

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Analysis 1.32

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 32: Psychomotor developmental index (PDI) < 70

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Analysis 1.33

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 33: Moderate to severe cerebral palsy

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Analysis 1.34

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 34: Deafness

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Analysis 1.35

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 35: Blindness

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Analysis 1.36

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 36: Mental developmental index

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Analysis 1.37

Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 37: Psychomotor developmental index

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Analysis 2.1

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment

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Analysis 2.2

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay

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Analysis 2.3

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 3: Failure of PDA closure after second course of treatment

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Analysis 2.4

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of the PDA

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Analysis 2.5

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Pulmonary hemorrhage

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Analysis 2.6

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA

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Analysis 2.7

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Intraventricular hemorrhage (IVH, Grade I‐IV)

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Analysis 2.8

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: IVH (Grade III‐IV)

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Analysis 2.9

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 9: Periventricular leukomalacia

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Analysis 2.10

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 10: Necrotizing enterocolitis (NEC)

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Analysis 2.11

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 11: Gastrointestinal bleed

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Analysis 2.12

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 12: Retinopathy of prematurity requiring treatment

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Analysis 2.13

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 13: Acute kidney injury

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Analysis 2.14

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 14: Sepsis

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Analysis 2.15

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 15: Post‐pre difference in serum creatinine (mg/dL)

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Analysis 2.16

Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 16: Serum bilirubin following treatment (µmol/L)

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Analysis 3.1

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 1: Failure of PDA closure after first course of prophylaxis

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Analysis 3.2

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 2: All‐cause mortality during initial hospital stay

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Analysis 3.3

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 3: Duration of need for supplementary oxygen (days)

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Analysis 3.4

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA

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Analysis 3.5

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)

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Analysis 3.6

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 6: Severe IVH (Grade III‐IV)

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Analysis 3.7

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 7: Intestinal perforation

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Analysis 3.8

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 8: Retinopathy of prematurity requiring treatment

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Analysis 3.9

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 9: Oliguria (< 1 mL/kg/h)

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Analysis 3.10

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 10: Sepsis

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Analysis 3.11

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 11: Cerebral palsy (5 years' follow‐up)

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Analysis 3.12

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 12: Autism spectrum disorder (5 years' follow‐up)

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Analysis 3.13

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 13: Attention deficit hyperactivity disorder (5 years' follow‐up)

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Analysis 3.14

Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 14: Pervasive developmental disorder (5 years' follow‐up)

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Analysis 4.1

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

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Analysis 4.2

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

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Analysis 5.1

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

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Analysis 5.2

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 2: Surgical closure of PDA

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Analysis 5.3

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 3: Pulmonary hemorrhage

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Analysis 5.4

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA

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Analysis 5.5

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 5: Necrotizing enterocolitis (NEC)

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Analysis 5.6

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 6: Retinopathy of prematurity requiring treatment

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Analysis 5.7

Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 7: Acute kidney injury

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Analysis 5.8

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

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Analysis 6.1

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

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Analysis 6.2

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

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Analysis 6.3

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

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Analysis 6.4

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)

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Analysis 6.5

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)

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Analysis 6.6

Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 6: Periventricular leukomalacia

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Analysis 6.7

Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 7: Necrotizing enterocolitis (NEC)

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Analysis 6.8

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)

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Analysis 7.1

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

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Analysis 7.2

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

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Analysis 7.3

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

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Analysis 7.4

Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Surgical closure of PDA

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Analysis 7.5

Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)

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Analysis 7.6

Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)

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Analysis 7.7

Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)

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Analysis 7.8

Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Gastrointestinal bleed

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Analysis 8.1

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

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Analysis 8.2

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

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Analysis 8.3

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

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Analysis 8.4

Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of PDA

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Analysis 8.5

Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)

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Analysis 8.6

Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)

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Analysis 8.7

Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)

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Analysis 8.8

Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: Gastrointestinal bleed

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Summary of findings 1. Paracetamol versus ibuprofen for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)
Paracetamol (oral or IV) versus ibuprofen (oral or IV) for PDA in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants with PDA Settings: hospitals in China, Egypt, Jordan, Iran, India, Italy, and Turkey Intervention: paracetamol Comparison: ibuprofen
	Assumed risk	Corresponding risk
	Oral/IV ibuprofen	Oral/IV paracetamol
Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO)	High‐risk study population		RR 1.02 (0.88 to 1.18)	1535 (18 studies)	⊕⊕⊕⊝ Moderate^a
	299 per 1000	308 per 1000 (266 to 355)	RR 1.02 (0.88 to 1.18)	1535 (18 studies)	⊕⊕⊕⊝ Moderate^a
All‐cause mortality during initial hospital stay (by clinical assessment)	High‐risk study population		RR 1.09 (0.80 to 1.48)	734 (8 studies)	⊕⊕⊕⊝ Moderate^a
	166 per 1000	181 per 1000 (133 to 245)	RR 1.09 (0.80 to 1.48)	734 (8 studies)	⊕⊕⊕⊝ Moderate^a
Necrotizing enterocolitisduring initial hospital stay (by radiological diagnosis)	70 per 1000	91 per 1000 (61 to 136)	RR 1.30 (0.87 to 1.94)	1015 (10 studies)	⊕⊕⊕⊝ Moderate^a
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aFor all three key critical outcomes, we downgraded the evidence by one level to moderate certainty, due to concerns regarding blinding of personnel and outcome assessment.

Summary of findings 1. Paracetamol versus ibuprofen for PDA in preterm or low birth weight infants

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Summary of findings 2. Paracetamol versus indomethacin for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)
Paracetamol (oral or IV) versus indomethacin (IV) for PDA in preterm or low birth weight infants
Patient or population: preterm infants with PDA Settings: neonatal intensive care unit in India, Egypt, and the USA Intervention: paracetamol Comparison: indomethacin
	Assumed risk	Corresponding risk
	Indomethacin	Paracetamol
Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO)	High‐risk study population		RR 1.02 (0.78 to 1.33)	380 (4 studies)	⊕⊕⊝⊝ Low^a
	297 per 1000	303 per 1000 (232 to 395)	RR 1.02 (0.78 to 1.33)	380 (4 studies)	⊕⊕⊝⊝ Low^a
All‐cause mortality during initial hospital stay (by clinical assessment)	186 per 1000	160 per 1000 (73 to 358)	RR 0.86 (0.39 to 1.92)	114 (2 studies)	⊕⊕⊝⊝ Low^b
Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis)	93 per 1000	39 per 1000 (18 to 89)	RR 0.42 (0.19 to 0.96)	384 (4 studies)	⊕⊕⊝⊝ Low^b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe downgraded evidence by two levels to low certainty due to concerns regarding blinding of personnel and outcome assessment, and high heterogeneity. ^bWe downgraded evidence by two levels to low certainty due to concerns regarding blinding of personnel and outcome assessment, and imprecision.

Summary of findings 2. Paracetamol versus indomethacin for PDA in preterm or low birth weight infants

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Summary of findings 3. Prophylactic administration of paracetamol versus placebo or no intervention for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention for PDA in preterm or low birth weight infants
Patient or population: preterm infants with PDA Settings: neonatal intensive care units in Finland and Iran Intervention: paracetamol Comparison: placebo or no intervention
	Assumed risk	Corresponding risk
	Placebo or no intervention	Paracetamol
Failure of PDA closure after first course (assessed by post‐treatment ECHO)	High‐risk study population		RR 0.27 (0.18 to 0.42)	240 (3 studies)	⊕⊕⊝⊝ Low^a
	612 per 1000	165 per 1000 (110 to 257)	RR 0.27 (0.18 to 0.42)	240 (3 studies)	⊕⊕⊝⊝ Low^a
All‐cause mortality during initial hospital stay (by clinical assessment)	High‐risk study population		RR 0.59 (0.24 to 1.44)	240 (3 studies)	⊕⊕⊝⊝ Low^b
	91 per 1000	54 per 1000 (22 to 131)	RR 0.59 (0.24 to 1.44)	240 (3 studies)	⊕⊕⊝⊝ Low^b
Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis)	High‐risk study population		Not reported	Not reported	Not reported	Not reported
	Data not available	Data not available	Not reported	Not reported	Not reported	Not reported
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe downgraded the evidence by two levels to low certainty due to concerns regarding selection bias, blinding of personnel, and high heterogeneity. ^bWe downgraded the evidence by two levels to low certainty due to concerns regarding selection bias, blinding of personnel, and imprecision.

Summary of findings 3. Prophylactic administration of paracetamol versus placebo or no intervention for PDA in preterm or low birth weight infants

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Summary of findings 4. Early paracetamol versus placebo/no intervention for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Early paracetamol (oral or IV, < 14 days postnatal age) versus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants with PDA Settings: hospitals in Iran and Australia Intervention: paracetamol Comparison: placebo/no intervention
	Assumed risk	Corresponding risk
	Placebo/no intervention	Oral/IV paracetamol
Failure of PDA closure after first course of treatment (by post‐treatment ECHO)	High‐risk study population		RR 0.35 (0.23 TO 0.53)	127 (2 studies)	⊕⊕⊝⊝ Low^a
	790 per 1000	277 per 1000 (182 to 419)	RR 0.35 (0.23 TO 0.53)	127 (2 studies)	⊕⊕⊝⊝ Low^a
All‐cause mortality during initial hospital stay (by clinical assessment)	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis)	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe downgraded the evidence by two levels to low certainty due to concerns regarding selection bias, blinding of personnel and outcome assessors, and high heterogeneity.

Summary of findings 4. Early paracetamol versus placebo/no intervention for PDA in preterm or low birth weight infants

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Summary of findings 5. Late paracetamol versus placebo/no intervention for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Late paracetamol (oral or IV, ≥ 14 days postnatal age) versus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants with PDA Settings: hospital in Australia Intervention: paracetamol Comparison: placebo/no intervention
	Assumed risk	Corresponding risk
	Placebo/no intervention	Oral/IV paracetamol
Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO)	High‐risk study population		RR 0.85 (0.72 to 1.01)	55 (1 study)	⊕⊕⊝⊝ Low^a
	1000 per 1000	850 per 1000 (720 to 1000)	RR 0.85 (0.72 to 1.01)	55 (1 study)	⊕⊕⊝⊝ Low^a
All‐cause mortality during initial hospital stay (by clinical assessment)	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis)	36 per 1000	37 per 1000 (3 to 563)	RR 1.04 (0.07 to 15.76)	55 (1 study)	⊕⊕⊝⊝ Low^a
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe downgraded the evidence for both failure of PDA closure after first course of treatment and NEC by two levels to low certainty due to concerns regarding indirectness and imprecision.

Summary of findings 5. Late paracetamol versus placebo/no intervention for PDA in preterm or low birth weight infants

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Summary of findings 6. Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants with PDA Settings: hospitals in Israel and Iran Intervention: paracetamol plus ibuprofen Comparison: ibuprofen plus placebo or no intervention
	Assumed risk	Corresponding risk
	Ibuprofen plus placebo	Paracetamol plus ibuprofen
Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO)	313 per 1000	241 per 1000 (134 to 425)	RR 0.77 (0.43 to 1.36)	111 (2 studies)	⊕⊕⊝⊝ Low^a
All‐cause mortality during initial hospital stay (by clinical assessment)	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Necrotizing enterocolitis during initial hospital stay (radiological diagnosis)	83 per 1000	28 per 1000 (1 to 621)	RR 0.33 (0.01 to 7.45)	24 (1 study)	⊕⊕⊝⊝ Low^a
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ECHO: echocardiography; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aWe downgraded the evidence for both failure of PDA closure after first course of treatment and NEC by two levels to low certainty due to concerns regarding selection bias, blinding of personnel, outcome assessment, and imprecision.

Summary of findings 6. Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants

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Comparison 1. Paracetamol (oral or IV) versus ibuprofen (oral or IV)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Failure of PDA closure after first course of treatment Show forest plot	18	1535	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.88, 1.18]

1.2 Neurodevelopmental impairment Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.44, 1.96]

1.3 All‐cause mortality during initial hospital stay Show forest plot	8	734	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.80, 1.48]

1.4 Neonatal mortality (deaths during the first 28 days of life) Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.43, 3.20]

1.5 Re‐opening of the ductus arteriosus Show forest plot	5	458	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.85, 2.12]

1.6 Failure of PDA closure after second course of treatment Show forest plot	13	393	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.78, 1.21]

1.7 Surgical closure of the PDA Show forest plot	6	603	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.34, 1.08]

1.8 Duration of ventilator support (days) Show forest plot	3	260	Mean Difference (IV, Fixed, 95% CI)	‐0.56 [‐1.19, 0.08]

1.9 Duration of need for supplementary oxygen (days) Show forest plot	1	90	Mean Difference (IV, Fixed, 95% CI)	‐12.40 [‐22.97, ‐1.83]

1.10 Pulmonary hemorrhage Show forest plot	5	442	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.36, 2.09]

1.11 Pulmonary hypertension Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.97]

1.12 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot	2	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.45, 1.38]

1.13 Moderate to severe BPD (according to the new criteria) Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.22, 2.87]

1.14 Severe BPD (according to the new criteria) Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.32, 1.23]

1.15 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	8	800	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.77, 1.22]

1.16 Severe IVH (Grade III‐IV) Show forest plot	6	544	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.28, 1.43]

1.17 Periventricular leukomalacia Show forest plot	4	421	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.56, 3.50]

1.18 Necrotizing enterocolitis (NEC) Show forest plot	10	1015	Risk Difference (M‐H, Fixed, 95% CI)	0.02 [‐0.01, 0.05]

1.19 Intestinal perforation Show forest plot	2	191	Risk Ratio (M‐H, Fixed, 95% CI)	2.83 [0.12, 67.87]

1.20 Gastrointestinal bleed Show forest plot	7	693	Risk Difference (M‐H, Fixed, 95% CI)	‐0.05 [‐0.09, ‐0.02]

1.21 Retinopathy of prematurity stage ≥ 3 Show forest plot	2	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.12, 1.55]

1.22 Retinopathy of prematurity requiring treatment Show forest plot	3	353	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.48, 1.85]

1.23 Oliguria (< 1 mL/kg/h) Show forest plot	5	608	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.30, 0.76]

1.24 Sepsis Show forest plot	7	844	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.72, 1.22]

1.25 Post‐pre difference in serum or plasma levels of creatinine (mg/dL) Show forest plot	6	557	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.13, ‐0.10]

1.26 Serum levels of aspartate transaminase (AST) IU/L Show forest plot	4	270	Mean Difference (IV, Fixed, 95% CI)	1.08 [‐0.16, 2.32]

1.27 Post‐pre difference in serum levels of alanine aminotransferase (ALT) (IU/L) Show forest plot	6	557	Mean Difference (IV, Fixed, 95% CI)	0.52 [0.00, 1.05]

1.28 Serum bilirubin following treatment (µmol/L) Show forest plot	4	400	Mean Difference (IV, Fixed, 95% CI)	‐10.56 [‐13.16, ‐7.96]

1.29 Hyperbilirubinemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW) Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.34, 0.97]

1.30 Duration of hospitalization (days) Show forest plot	4	361	Mean Difference (IV, Fixed, 95% CI)	2.79 [0.34, 5.24]

1.31 Mental developmental index (MDI) < 70 Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.41, 2.59]

1.32 Psychomotor developmental index (PDI) < 70 Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.33, 3.21]

1.33 Moderate to severe cerebral palsy Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	2.07 [0.41, 10.46]

1.34 Deafness Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.13]

1.35 Blindness Show forest plot	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.13]

1.36 Mental developmental index Show forest plot	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐8.19, 7.39]

1.37 Psychomotor developmental index Show forest plot	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐7.44, 7.04]

Comparison 1. Paracetamol (oral or IV) versus ibuprofen (oral or IV)

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Comparison 2. Paracetamol (oral or IV) versus indomethacin (oral or IV)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Failure of PDA closure after first course of treatment Show forest plot	4	380	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.78, 1.33]

2.2 All‐cause mortality during initial hospital stay Show forest plot	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.39, 1.92]

2.3 Failure of PDA closure after second course of treatment Show forest plot	2	86	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.70, 1.50]

2.4 Surgical closure of the PDA Show forest plot	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.72, 2.38]

2.5 Pulmonary hemorrhage Show forest plot	3	347	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.28, 2.10]

2.6 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot	2	94	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.77, 1.75]

2.7 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	2	275	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.42, 1.63]

2.8 IVH (Grade III‐IV) Show forest plot	2	112	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.28, 4.31]

2.9 Periventricular leukomalacia Show forest plot	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.14]

2.10 Necrotizing enterocolitis (NEC) Show forest plot	4	384	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.19, 0.96]

2.11 Gastrointestinal bleed Show forest plot	3	347	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.32, 1.25]

2.12 Retinopathy of prematurity requiring treatment Show forest plot	2	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.58, 2.99]

2.13 Acute kidney injury Show forest plot	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	3.08 [0.13, 73.26]

2.14 Sepsis Show forest plot	3	314	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.59, 1.82]

2.15 Post‐pre difference in serum creatinine (mg/dL) Show forest plot	2	270	Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐0.40, ‐0.34]

2.16 Serum bilirubin following treatment (µmol/L) Show forest plot	1	200	Mean Difference (IV, Fixed, 95% CI)	1.03 [0.13, 1.93]

Comparison 2. Paracetamol (oral or IV) versus indomethacin (oral or IV)

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Comparison 3. Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Failure of PDA closure after first course of prophylaxis Show forest plot	3	240	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.18, 0.42]

3.2 All‐cause mortality during initial hospital stay Show forest plot	3	240	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.24, 1.44]

3.3 Duration of need for supplementary oxygen (days) Show forest plot	1	48	Mean Difference (IV, Fixed, 95% CI)	‐2.40 [‐16.41, 11.61]

3.4 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.45]

3.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.28, 1.51]

3.6 Severe IVH (Grade III‐IV) Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.07, 16.39]

3.7 Intestinal perforation Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.45]

3.8 Retinopathy of prematurity requiring treatment Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.14, 76.01]

3.9 Oliguria (< 1 mL/kg/h) Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.29, 2.11]

3.10 Sepsis Show forest plot	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.36, 5.79]

3.11 Cerebral palsy (5 years' follow‐up) Show forest plot	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.07, 15.66]

3.12 Autism spectrum disorder (5 years' follow‐up) Show forest plot	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

3.13 Attention deficit hyperactivity disorder (5 years' follow‐up) Show forest plot	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.02, 8.10]

3.14 Pervasive developmental disorder (5 years' follow‐up) Show forest plot	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.02, 8.10]

Comparison 3. Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention

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Comparison 4. Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Failure of PDA closure after first course of treatment Show forest plot	2	127	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.23, 0.53]

4.2 Failure of PDA closure after two courses of treatment Show forest plot	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.25]

Comparison 4. Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention

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Comparison 5. Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Failure of PDA closure after one course of treatment Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.72, 1.01]

5.2 Surgical closure of PDA Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	3.11 [0.13, 73.11]

5.3 Pulmonary hemorrhage Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	2.07 [0.20, 21.56]

5.4 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.61, 1.40]

5.5 Necrotizing enterocolitis (NEC) Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.07, 15.76]

5.6 Retinopathy of prematurity requiring treatment Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	3.11 [0.34, 28.09]

5.7 Acute kidney injury Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

5.8 Failure of PDA closure/non‐significant PDA after treatment Show forest plot	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.29, 0.84]

Comparison 5. Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention

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Comparison 6. Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Failure of PDA closure after first course of treatment Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.43, 1.36]

6.2 Failure of PDA closure after two courses of treatment Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.08, 0.99]

6.3 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.28, 2.27]

6.4 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.38, 4.72]

6.5 Severe IVH (Grade III‐IV) Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.30, 7.43]

6.6 Periventricular leukomalacia Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.45]

6.7 Necrotizing enterocolitis (NEC) Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.45]

6.8 Oliguria (< 1 mL/kg/h) Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.05, 4.81]

Comparison 6. Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention

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Comparison 7. Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Failure of PDA closure after first course of treatment Show forest plot	6	584	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [1.00, 1.66]

7.2 All‐cause mortality during initial hospital stay Show forest plot	4	374	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.85, 1.91]

7.3 Failure of PDA closure after two courses of treatment Show forest plot	4	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.48, 1.01]

7.4 Surgical closure of PDA Show forest plot	5	543	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.36, 1.16]

7.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	4	413	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.75, 1.19]

7.6 Severe IVH (Grade III‐IV) Show forest plot	4	354	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.14, 1.24]

7.7 Necrotizing enterocolitis (NEC) Show forest plot	5	552	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.71, 2.51]

7.8 Gastrointestinal bleed Show forest plot	2	290	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.05, 1.01]

Comparison 7. Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV)

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Comparison 8. Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Failure of PDA closure after first course of treatment Show forest plot	3	310	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.86, 1.87]

8.2 All‐cause mortality during initial hospital stay Show forest plot	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.39, 1.92]

8.3 Failure of PDA closure after two courses of treatment Show forest plot	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.55, 1.40]

8.4 Surgical closure of PDA Show forest plot	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.72, 2.38]

8.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot	2	275	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.42, 1.63]

8.6 Severe IVH (Grade III‐IV) Show forest plot	2	112	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.28, 4.31]

8.7 Necrotizing enterocolitis (NEC) Show forest plot	3	314	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.20, 1.07]

8.8 Gastrointestinal bleed Show forest plot	2	277	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.33]

Comparison 8. Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV)

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