| Efficacy and safety (patent ductus arteriosus)
A systematic review of eight studies reported comparisons in 916 infants of paracetamol versus placebo, ibuprofen and indomethacin.4 Two studies (80 infants) showed a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention (typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); 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). A third randomised controlled trial [in press] comparing paracetamol to placebo showed less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs 17 [59%] infants [p=0.003]; relative risk reduction 0.35 [95%CI 0.16-0.77; NNT 2.6]).5 Five studies (559 infants) showed no significant difference between paracetamol and ibuprofen for failure of ductal closure (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). Gastrointestinal bleeding 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). There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence). Two studies (277 infants) showed no significant difference between paracetamol and indomethacin for failure of ductal closure (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. A second systematic review of studies involving the use of paracetamol in preterm infants reported on sixteen studies: Two randomised controlled trials and 14 uncontrolled studies. The quality of selected studies was rated as poor. Proportion meta-analysis of uncontrolled studies demonstrated a pooled ductal closure rate of 49% (95% CI 29% to 69%) and 76% (95% CI 61% to 88%) after 3 and 6 days of treatment with paracetamol, respectively.7 The majority of studies used 15 mg/kg every 6 hours for 3–7 days.
Recommendation: Low-moderate quality evidence suggests that paracetamol is more effective than placebo and as effective as ibuprofen and indomethacin for ductal closure. 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. Further research is required before recommendations for the routine use of paracetamol in the newborn population can be made.4 (LOE I GOR B)
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