Abstract: Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)]. Implications for practice  Prolonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. Implications for research  There is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.

Plain-language summary: Five randomized trials are included in this review. These studies were published between 1988 and 2000 and included a total of 431 preterm and low birth weight infants. Indomethacin was given intravenously in four trials and orally in one, in total amounts of 0.6 to 1.6 mg/kg for the prolonged course (six to eight doses) and 0.3 to 0.6 mg/kg for the short course (two to three doses). There was no significant benefit of prolonged indomethacin administration on failure of the PDA to close after completion of allocated treatment (four studies, 361 infants). Prolonged course of indomethacin compared to the short course did not reduce the rate of PDA re-opening after initial closure (three studies, 322 infants), rate of PDA re-treatment (five studies, 431 infants), or ligation rate (four studies, 310 infants). The prolonged course was associated with decreased incidence of renal function impairment (three studies, 318 infants). However, a prolonged indomethacin course increased the risk of NEC (four studies, 310 infants). The number of deaths was no different.