Abstract
RATIONALE: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclo-oxygenase (COX) inhibitor drugs are used to prevent or treat a PDA. There are concerns regarding adverse effects of COX inhibitors in preterm infants. Controversy exists about whether early targeted treatment of a hemodynamically significant (hs)-PDA improves clinical outcomes. This review updates our previous Cochrane review (2020). OBJECTIVES: To assess the effectiveness and safety of early treatment strategies versus expectant management for hemodynamically significant patent ductus arteriosus (hs-PDA) in preterm infants. SEARCH METHODS: We searched the following sources on 18 October 2024: CENTRAL, MEDLINE, Embase, trial registries, and conference abstracts. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) in which early pharmacological treatment, defined as treatment initiated within the first seven days after birth, was compared to no intervention, placebo, or other non-pharmacological expectant management strategies for treatment of an hs-PDA in preterm (< 37 weeks' postmenstrual age) or low birthweight infants (< 2500 g). OUTCOMES: The critical outcome was all-cause mortality during hospital stay. Important outcomes included the need for interventional PDA closure, receipt of any PDA pharmacotherapy, chronic lung disease (CLD), severe intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and moderate/severe neurodevelopmental impairment. RISK OF BIAS: We assessed risk of bias in the included studies using Cochrane's RoB 1 tool. SYNTHESIS METHODS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal (fixed-effect meta-analysis using the inverse-variance method). We used the GRADE approach to assess the certainty of evidence for selected clinical outcomes. INCLUDED STUDIES: We included 19 RCTs (2323 participants) and specified two comparisons: seven RCTs (526 participants) compared early treatment (treatment initiated by seven days) and 12 RCTs (1797 participants) compared very early treatment (treatment initiated by 72 hours) versus expectant management. The latter comparison included five new RCTs (1413 participants) published since the 2020 version of this review. We identified one trial awaiting classification and five ongoing trials. SYNTHESIS OF RESULTS: Early treatment compared to expectant management for preterm infants Early treatment versus expectant management (no treatment initiated within the first seven days after birth) for an hs-PDA probably results in little to no difference for all-cause mortality (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.46 to 1.39; risk difference (RD) -0.00, 95% CI -0.03 to 0.02; 6 studies, 500 infants; moderate-certainty evidence), or other important outcomes such as CLD (RR 0.90, 95% CI 0.62 to 1.29; RD -0.03, 95% CI -0.10 to 0.03; 4 studies, 339 infants; moderate-certainty evidence); may result in little to no difference in severe IVH (RR 0.83, 95% CI 0.32 to 2.16; RD -0.01, 95% CI -0.08 to 0.06; 2 studies, 171 infants; low-certainty evidence), and NEC (RR 2.34, 95% CI 0.86 to 6.41; RD 0.04, 95% CI 0.01 to 0.08; 5 studies, 473 infants; low-certainty evidence). Early treatment in the first seven days after birth may result in a large increase in any PDA pharmacotherapy compared to expectant management (RR 2.30, 95% CI 1.86 to 2.83; RD 0.57, 95% CI 0.48 to 0.66; 2 studies, 232 infants; low-certainty evidence). The evidence is very uncertain on the need for surgical PDA ligation or transcatheter occlusion (RR 1.08, 95% CI 0.65 to 1.80; RD -0.03, 95% CI -0.09 to 0.03; 4 studies, 432 infants; very low-certainty evidence). Neurodevelopmental outcomes were not reported. Very early treatment compared to expectant management for preterm infants Very early treatment versus expectant management (no treatment initiated within the first 72 hours after birth) for an hs-PDA probably results in little to no difference for all-cause mortality (RR 1.20, 95% CI 0.96 to 1.51; RD 0.02, 95% CI -0.01 to 0.05; 12 studies, 1797 infants; moderate-certainty evidence) or other important outcomes such as CLD (RR 1.03, 95% CI 0.92 to 1.14; RD 0.01, 95% CI -0.03 to 0.06; 12 studies, 1797 infants; moderate-certainty evidence), severe IVH (RR 1.24, 95% CI 0.93 to 1.65; RD 0.01, 95% CI -0.01 to 0.04; 9 studies, 1653 infants; moderate-certainty evidence), NEC (RR 1.00, 95% CI 0.76 to 1.31; RD 0.00, 95% CI -0.02 to 0.03; 10 studies, 1745 infants; high-certainty evidence), and moderate/severe neurodevelopmental impairment (RR 0.95, 95% CI 0.75 to 1.21; RD -0.02, 95% CI -0.09 to 0.06; 2 studies, 635 infants; moderate-certainty evidence). Very early treatment in the first 72 hours after birth may result in a large increase in any PDA pharmacotherapy (RR 2.02, 95% CI 1.84 to 2.22; RD 0.88, 95% CI 0.86 to 0.90; 8 studies, 1361 infants; low-certainty evidence), but results in a trivial reduction in invasive PDA closure (RR 0.50, 95% CI 0.32 to 0.79; RD -0.01, 95% CI -0.02 to 0.01; 10 studies, 1706 infants; high-certainty evidence) compared to expectant management. For outcomes with moderate to very-low certainty, we downgraded the certainty of the evidence due to risk of bias, inconsistency, and imprecision, or a combination thereof. Sensitivity analysis showed that very early use of ibuprofen may lead to a moderate increase in mortality in extremely preterm infants (RR 1.35, 95% CI 1.01 to 1.80; RD 0.04, 95% CI 0.00 to 0.08). AUTHORS' CONCLUSIONS: Early or very early pharmacotherapeutic treatment of an hs-PDA probably results in little to no difference in mortality in preterm infants (moderate-certainty evidence). However, very early use of ibuprofen may lead to a moderate increase in mortality in extremely preterm infants. Conversely, very early treatment of an hs-PDA leads to a trivial reduction in the need for invasive PDA closure (high-certainty evidence). Early or very early hs-PDA treatment may result in little to no difference in CLD, severe IVH, or NEC (low- to moderate-certainty evidence). Very early treatment of an hs-PDA also probably results in little to no difference in moderate to severe neurodevelopmental impairment (moderate-certainty evidence). Given the potential adverse effects of medical therapy, future research should focus on identifying the appropriate patient population for clinical trials to maximize the chances of detecting a clinically meaningful effect while avoiding potential harm. FUNDING: No funding was received for this review. REGISTRATION: The protocol was published in 2019 (https://10.1002/14651858.CD013278).