Souvik Mitra1, Alexandra Scrivens2, Adelaide M von Kursell3, Tim Disher4. 1. Departments of Pediatrics, Community Health & Epidemiology, Dalhousie University & IWK Health Centre, Halifax, Canada. 2. Neonatal Care Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 3. Community Health and Epidemiology, Dalhousie University, Halifax, Canada. 4. Evidence Synthesis and Data Analytics, EVERSANA Inc, Sydney, Canada.
Abstract
BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to prevent or treat a PDA. There are concerns regarding adverse effects of NSAIDs in preterm infants. Controversy exists on whether early targeted treatment of a hemodynamically significant (hs) PDA improves clinical outcomes. OBJECTIVES: To assess the effectiveness and safety of early treatment strategies versus expectant management for an hs-PDA in reducing mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 6) in the Cochrane Library; MEDLINE via PubMed (1966 to 31 May 2019), Embase (1980 to 31 May 2019), and CINAHL (1982 to 31 May 2019). An updated search was run on 2 October 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCT) and quasi-randomized trials. SELECTION CRITERIA: We included 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 birth weight (< 2500 grams) infants. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. Our primary outcome was all-cause mortality during hospital stay. We used the GRADE approach to assess the certainty of evidence for selected clinical outcomes. MAIN RESULTS: We included 14 RCTs that enrolled 910 infants. Seven RCTs compared early treatment (defined as treatment initiated by seven days of age) versus expectant management and seven RCTs compared very early treatment (defined as treatment initiated by 72 hours of age) versus expectant management. No difference was demonstrated between early treatment versus expectant management (no treatment initiated within the first seven days after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (6 studies; 500 infants; typical RR 0.80, 95% CI 0.46 to 1.39; typical RD -0.02; 95% CI -0.07 to 0.03; moderate-certainty evidence), or other important outcomes such as surgical PDA ligation (4 studies; 432 infants; typical RR 1.08, 95% CI 0.65 to 1.80; typical RD -0.03; 95% CI -0.09 to 0.03; very low-certainty evidence), chronic lung disease (CLD) (4 studies; 339 infants; typical RR 0.90, 95% CI 0.62 to 1.29; typical RD -0.03; 95% CI -0.10 to 0.03; moderate-certainty evidence), severe intraventricular hemorrhage (IVH) (2 studies; 171 infants; typical RR 0.83,95% CI 0.32 to 2.16; typical RD -0.01; 95% CI -0.08 to 0.06; low-certainty evidence), and necrotizing enterocolitis (NEC) (5 studies; 473 infants; typical RR 2.34,95% CI 0.86 to 6.41; typical RD 0.04; 95% CI 0.01 to 0.08; low-certainty evidence). Infants receiving early treatment in the first seven days after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (2 studies; 232 infants; typical RR 2.30, 95% CI 1.86 to 2.83; typical RD 0.57; 95% CI 0.48 to 0.66; low-certainty evidence). No difference was demonstrated between very early treatment versus expectant management (no treatment initiated within the first 72 hours after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (7 studies; 384 infants; typical RR 0.94, 95% CI 0.58 to 1.53; typical RD -0.03; 95% CI -0.09 to 0.04; moderate-certainty evidence) or other important outcomes such as surgical PDA ligation (5 studies; 293 infants; typical RR 0.88, 95% CI 0.36 to 2.17; typical RD -0.01; 95% CI -0.05 to 0.02; moderate-certainty evidence), CLD (7 studies; 384 infants; typical RR 0.83, 95% CI 0.63 to 1.08; typical RD -0.05; 95% CI -0.13 to 0.04; low-certainty evidence), severe IVH (4 studies, 240 infants; typical RR 0.64, 95% CI 0.21 to 1.93; typical RD -0.02; 95% CI -0.07 to 0.04; moderate-certainty evidence), NEC (5 studies; 332 infants; typical RR 1.08, 95% CI 0.53 to 2.21; typical RD 0.01; 95% CI -0.04 to 0.06; moderate-certainty evidence) and neurodevelopmental impairment (1 study; 79 infants; RR 0.27, 95% CI 0.03 to 2.31 for moderate/severe cognitive delay at 18 to 24 months; RR 0.54, 95% CI 0.05 to 5.71 for moderate/severe motor delay at 18 to 24 months; RR 0.54, 95% CI 0.10 to 2.78 for moderate/severe language delay at 18 to 24 months; low-certainty evidence). Infants receiving very early treatment in the first 72 hours after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (4 studies; 156 infants; typical RR 1.64, 95% CI 1.31 to 2.05; typical RD 0.69; 95% CI 0.60 to 0.79; very low-certainty evidence). Very early treatment, however, shortened the duration of hospitalization compared to expectant management (4 studies; 260 infants; MD -5.35 days; 95% CI -9.23 to -1.47; low-certainty evidence). AUTHORS' CONCLUSIONS: Early or very early pharmacotherapeutic treatment of an hs-PDA probably does not reduce mortality in preterm infants (moderate-certainty evidence). Early pharmacotherapeutic treatment of hs-PDA may increase NSAID exposure (low-certainty evidence) without likely reducing CLD (moderate-certainty evidence), severe IVH or NEC (low-certainty evidence). We are uncertain whether very early pharmacotherapeutic treatment of hs-PDA also increases NSAID exposure (very low-certainty evidence). Very early treatment probably does not reduce surgical PDA ligation, severe IVH or NEC (moderate-certainty evidence), and may not reduce CLD or neurodevelopmental impairment (low-certainty evidence). Additional large trials that specifically include preterm infants at the highest risk of PDA-attributable morbidity, are adequately powered for patient-important outcomes and are minimally contaminated by open-label treatment are required to explore if early targeted treatment of hs-PDA improves clinical outcomes. There are currently two trials awaiting classification and two ongoing trials exploring this question.
BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to prevent or treat a PDA. There are concerns regarding adverse effects of NSAIDs in preterm infants. Controversy exists on whether early targeted treatment of a hemodynamically significant (hs) PDA improves clinical outcomes. OBJECTIVES: To assess the effectiveness and safety of early treatment strategies versus expectant management for an hs-PDA in reducing mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 6) in the Cochrane Library; MEDLINE via PubMed (1966 to 31 May 2019), Embase (1980 to 31 May 2019), and CINAHL (1982 to 31 May 2019). An updated search was run on 2 October 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCT) and quasi-randomized trials. SELECTION CRITERIA: We included 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 birth weight (< 2500 grams) infants. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. Our primary outcome was all-cause mortality during hospital stay. We used the GRADE approach to assess the certainty of evidence for selected clinical outcomes. MAIN RESULTS: We included 14 RCTs that enrolled 910 infants. Seven RCTs compared early treatment (defined as treatment initiated by seven days of age) versus expectant management and seven RCTs compared very early treatment (defined as treatment initiated by 72 hours of age) versus expectant management. No difference was demonstrated between early treatment versus expectant management (no treatment initiated within the first seven days after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (6 studies; 500 infants; typical RR 0.80, 95% CI 0.46 to 1.39; typical RD -0.02; 95% CI -0.07 to 0.03; moderate-certainty evidence), or other important outcomes such as surgical PDA ligation (4 studies; 432 infants; typical RR 1.08, 95% CI 0.65 to 1.80; typical RD -0.03; 95% CI -0.09 to 0.03; very low-certainty evidence), chronic lung disease (CLD) (4 studies; 339 infants; typical RR 0.90, 95% CI 0.62 to 1.29; typical RD -0.03; 95% CI -0.10 to 0.03; moderate-certainty evidence), severe intraventricular hemorrhage (IVH) (2 studies; 171 infants; typical RR 0.83,95% CI 0.32 to 2.16; typical RD -0.01; 95% CI -0.08 to 0.06; low-certainty evidence), and necrotizing enterocolitis (NEC) (5 studies; 473 infants; typical RR 2.34,95% CI 0.86 to 6.41; typical RD 0.04; 95% CI 0.01 to 0.08; low-certainty evidence). Infants receiving early treatment in the first seven days after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (2 studies; 232 infants; typical RR 2.30, 95% CI 1.86 to 2.83; typical RD 0.57; 95% CI 0.48 to 0.66; low-certainty evidence). No difference was demonstrated between very early treatment versus expectant management (no treatment initiated within the first 72 hours after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (7 studies; 384 infants; typical RR 0.94, 95% CI 0.58 to 1.53; typical RD -0.03; 95% CI -0.09 to 0.04; moderate-certainty evidence) or other important outcomes such as surgical PDA ligation (5 studies; 293 infants; typical RR 0.88, 95% CI 0.36 to 2.17; typical RD -0.01; 95% CI -0.05 to 0.02; moderate-certainty evidence), CLD (7 studies; 384 infants; typical RR 0.83, 95% CI 0.63 to 1.08; typical RD -0.05; 95% CI -0.13 to 0.04; low-certainty evidence), severe IVH (4 studies, 240 infants; typical RR 0.64, 95% CI 0.21 to 1.93; typical RD -0.02; 95% CI -0.07 to 0.04; moderate-certainty evidence), NEC (5 studies; 332 infants; typical RR 1.08, 95% CI 0.53 to 2.21; typical RD 0.01; 95% CI -0.04 to 0.06; moderate-certainty evidence) and neurodevelopmental impairment (1 study; 79 infants; RR 0.27, 95% CI 0.03 to 2.31 for moderate/severe cognitive delay at 18 to 24 months; RR 0.54, 95% CI 0.05 to 5.71 for moderate/severe motor delay at 18 to 24 months; RR 0.54, 95% CI 0.10 to 2.78 for moderate/severe language delay at 18 to 24 months; low-certainty evidence). Infants receiving very early treatment in the first 72 hours after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (4 studies; 156 infants; typical RR 1.64, 95% CI 1.31 to 2.05; typical RD 0.69; 95% CI 0.60 to 0.79; very low-certainty evidence). Very early treatment, however, shortened the duration of hospitalization compared to expectant management (4 studies; 260 infants; MD -5.35 days; 95% CI -9.23 to -1.47; low-certainty evidence). AUTHORS' CONCLUSIONS: Early or very early pharmacotherapeutic treatment of an hs-PDA probably does not reduce mortality in preterm infants (moderate-certainty evidence). Early pharmacotherapeutic treatment of hs-PDA may increase NSAID exposure (low-certainty evidence) without likely reducing CLD (moderate-certainty evidence), severe IVH or NEC (low-certainty evidence). We are uncertain whether very early pharmacotherapeutic treatment of hs-PDA also increases NSAID exposure (very low-certainty evidence). Very early treatment probably does not reduce surgical PDA ligation, severe IVH or NEC (moderate-certainty evidence), and may not reduce CLD or neurodevelopmental impairment (low-certainty evidence). Additional large trials that specifically include preterm infants at the highest risk of PDA-attributable morbidity, are adequately powered for patient-important outcomes and are minimally contaminated by open-label treatment are required to explore if early targeted treatment of hs-PDA improves clinical outcomes. There are currently two trials awaiting classification and two ongoing trials exploring this question.
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