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Meta-Analysis
. 2018 Apr 6;4(4):CD010061.
doi: 10.1002/14651858.CD010061.pub3.

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

Arne Ohlsson  1 , Prakeshkumar S Shah
Affiliations
Meta-Analysis

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

Arne Ohlsson et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported.

Objectives: To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or low birth weight infants.

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials.

Selection criteria: We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol.

Data collection and analysis: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L).

Main results: We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence).Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence).Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group.

Authors' conclusions: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.

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Conflict of interest statement

Arne Ohlsson ‒ no conflict of interest to declare.

Prakeshkumar Shah ‒ no conflict of interest to declare.

Figures

Figure 1
Figure 1
Study flow diagram: review update
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Forest plot of comparison: 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), outcome: 1.1 Failure of ductal closure after the first course of treatment.
Analysis 1.1
Analysis 1.1
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1 Failure of ductal closure after the first course of treatment.
Analysis 1.2
Analysis 1.2
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2 Neurodevelopmental impairment.
Analysis 1.3
Analysis 1.3
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3 All‐cause mortality during initial hospital stay.
Analysis 1.4
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).
Analysis 1.5
Analysis 1.5
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5 Infant mortality (death during the first year of life).
Analysis 1.6
Analysis 1.6
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6 Re‐opening of the ductus arteriosus.
Analysis 1.7
Analysis 1.7
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7 Surgical closure of the PDA following treatment failure with paracetamol or ibuprofen.
Analysis 1.8
Analysis 1.8
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8 Duration of ventilator support (days).
Analysis 1.9
Analysis 1.9
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 9 Pulmonary haemorrhage.
Analysis 1.10
Analysis 1.10
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 10 Pulmonary hypertension.
Analysis 1.11
Analysis 1.11
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 11 Duration for need of supplementary oxygen (days).
Analysis 1.12
Analysis 1.12
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 12 BPD at 28 days.
Analysis 1.13
Analysis 1.13
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 13 BPD at 36 weeks' PMA.
Analysis 1.14
Analysis 1.14
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 14 Moderate to severe BPD (according to the new criteria).
Analysis 1.15
Analysis 1.15
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 15 Severe BPD (according to the new criteria).
Analysis 1.16
Analysis 1.16
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 16 Intraventricular haemorrhage (grade I‐IV).
Analysis 1.17
Analysis 1.17
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 17 Severe IVH (Grade III‐IV).
Analysis 1.18
Analysis 1.18
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 18 Periventricular leukomalacia.
Analysis 1.19
Analysis 1.19
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 19 Necrotizing enterocolitis.
Analysis 1.20
Analysis 1.20
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 20 Intestinal perforation.
Analysis 1.21
Analysis 1.21
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 21 Gastrointestinal bleed or stools positive for occult blood.
Analysis 1.22
Analysis 1.22
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 22 Retinopathy of prematurity ‐ any stage.
Analysis 1.23
Analysis 1.23
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 23 Retinopathy of prematurity stage ≥ 3.
Analysis 1.24
Analysis 1.24
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 24 Retinopathy of prematurity requiring laser therapy.
Analysis 1.25
Analysis 1.25
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 25 Sepsis.
Analysis 1.26
Analysis 1.26
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 26 Oliguria (< 1 mL/kg/h).
Analysis 1.27
Analysis 1.27
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 27 Serum levels of creatinine after treatment µmol/L.
Analysis 1.28
Analysis 1.28
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 28 Serum levels of aspartate transaminase (AST) IU/L.
Analysis 1.29
Analysis 1.29
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 29 Serum levels of alanine aminotransferase (ALT) (IU/L).
Analysis 1.30
Analysis 1.30
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 30 Serum bilirubin following treatment (µmol/L).
Analysis 1.31
Analysis 1.31
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 31 Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW).
Analysis 1.32
Analysis 1.32
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 32 Duration of hospitalisation (days).
Analysis 1.33
Analysis 1.33
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 33 MDI < 70.
Analysis 1.34
Analysis 1.34
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 34 PDI < 70.
Analysis 1.35
Analysis 1.35
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 35 Moderate to severe cerebral palsy.
Analysis 1.36
Analysis 1.36
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 36 Deafness.
Analysis 1.37
Analysis 1.37
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 37 Blindness.
Analysis 1.38
Analysis 1.38
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 38 MDI.
Analysis 1.39
Analysis 1.39
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 39 PDI.
Analysis 1.40
Analysis 1.40
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 40 BPD (age not stated).
Analysis 1.41
Analysis 1.41
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 41 Plasma PGE2 (ng/L).
Analysis 1.42
Analysis 1.42
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 42 Urine PGE2 (ng/L).
Analysis 1.43
Analysis 1.43
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 43 Platelet count (x109/L).
Analysis 1.44
Analysis 1.44
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 44 Glutamic‐pyruvic transaminase (U/L).
Analysis 1.45
Analysis 1.45
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 45 Failure of PDA closure after the 2nd course of IV paracetamol versus IV ibuprofen.
Analysis 1.46
Analysis 1.46
Comparison 1 Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 46 Daily urine output (mL/kg/hour).
Analysis 2.1
Analysis 2.1
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 1 Failure of ductal closure after 4 to 5 days of treatment.
Analysis 2.2
Analysis 2.2
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 2 Death.
Analysis 2.3
Analysis 2.3
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 3 Oliguria (< 1 mL/kg/h).
Analysis 2.4
Analysis 2.4
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 4 Polyuria (> 5 mL/kg/h).
Analysis 2.5
Analysis 2.5
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 5 Hypernatraemia (> 150 µmol/L).
Analysis 2.6
Analysis 2.6
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 6 Sepsis.
Analysis 2.7
Analysis 2.7
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 7 Supplemental oxygen at 28 days.
Analysis 2.8
Analysis 2.8
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 8 Supplemental oxygen at 36 weeks' PMA.
Analysis 2.9
Analysis 2.9
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 9 ROP (treated).
Analysis 2.10
Analysis 2.10
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 10 IVH grades 1 to 2.
Analysis 2.11
Analysis 2.11
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 11 IVH grades 3 to 4.
Analysis 2.12
Analysis 2.12
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 12 NEC stage 3.
Analysis 2.13
Analysis 2.13
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 13 Days of supplemental oxygen.
Analysis 2.14
Analysis 2.14
Comparison 2 Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 14 Highest serum bilirubin µmol/L.
Analysis 3.1
Analysis 3.1
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 1 Failure to close a PDA.
Analysis 3.2
Analysis 3.2
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 2 Renal impairment.
Analysis 3.3
Analysis 3.3
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 3 GI bleed.
Analysis 3.4
Analysis 3.4
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 4 NEC (all grades).
Analysis 3.5
Analysis 3.5
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 5 Sepsis.
Analysis 3.6
Analysis 3.6
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 6 Pulmonary haemorrhage.
Analysis 3.7
Analysis 3.7
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 7 ROP (all grades).
Analysis 3.8
Analysis 3.8
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 8 Severe ROP needing treatment.
Analysis 3.9
Analysis 3.9
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 9 IVH (all grades).
Analysis 3.10
Analysis 3.10
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 10 IVH (grades III to IV).
Analysis 3.11
Analysis 3.11
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 11 Periventricular leukomalacia.
Analysis 3.12
Analysis 3.12
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 12 Oxygen requirement at 28 days of age.
Analysis 3.13
Analysis 3.13
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 13 Oxygen requirement at ≥ 36 weeks' PMA.
Analysis 3.14
Analysis 3.14
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 14 Death.
Analysis 3.15
Analysis 3.15
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 15 Serum creatinine (µmol/L).
Analysis 3.16
Analysis 3.16
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 16 Failure to close a PDA after a 2nd course of IV paracetamol versus IV indomethacin.
Analysis 3.17
Analysis 3.17
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 17 Surgical ligation of PDA.
Analysis 3.18
Analysis 3.18
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 18 Serum bilirubin µmol/L.
Analysis 3.19
Analysis 3.19
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 19 Platelet count (x109/L).
Analysis 3.20
Analysis 3.20
Comparison 3 Paracetamol (oral or IV) versus indomethacin (IV), Outcome 20 Daily urine output (mL/kg/h).
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Update of

References

References to studies included in this review

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    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]
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References to studies awaiting assessment

    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.
    1. Bagheri MM, Niknafs P, Sabsevari F, Torabi MH, Bijari BB, 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; PUBMED: 27713809] - DOI - PMC - PubMed
    1. Kluckow MR, Carlisle H, Broom M, Woods P, Jeffery M, Desai D, et al. A randomised blinded placebo controlled trial of paracetamol to treat later PDA. Journal of Paediatrics and Child Health 2016;52(Suppl 2):100.

References to ongoing studies

    1. ACTRN12613000289718. Paracetamol for patent ductus arteriosus treatment: comparison between oral and intravenous administration. Australian New Zealand Clinical Trials Registry (first received 8 March 2013).
    1. ACTRN12616001517460. Early paracetamol (EPAR) to promote early closure of the ductus arteriosus in preterm infants. Australian New Zealand Clinical Trials Registry (first received 1 November 2016).
    1. ChiCTR‐TRC‐13003912. Comparison of oral paracetamol versus ibuprofen in premature infants<1500g with patent ductus arteriosus: A randomized controlled trial. Chinese Clinical Trial Register (ChiCTR) (first received 7 December 2013). - PMC - PubMed
    1. CTRI/2016/09/007261. Oral ibuprofen versus paracetamol on ductus arteriosus [Comparison of oral paracetamol versus ibuprofen for PDA closure in preterms ‐ a randomized controlled single blinded study ‐ IPOD]. apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2016/09/007261 (first received 8 September 2016).
    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).

Additional references

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    1. Avella‐Garcia CB, Julvez J, Fortuny J, Rebordosa C, García‐Esteban R, Galán IR, et al. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. International Journal of Epidemiology 2016;45(6):1987‐96. [DOI: 10.1093/ije/dyw115; PUBMED: 27353198] - DOI - PubMed
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References to other published versions of this review

    1. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low‐birth‐weight infants. Cochrane Database of Systematic Reviews 2015, Issue 3. [DOI: 10.1002/14651858.CD010061.pub2] - DOI - PubMed

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