Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials

Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials Rajanikant Kumar, Efeoghene Praise Epia, Mark W Abdelnour, Joo Young Belen Kim Kim, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4810365/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: In recent years, there has been a rise in the adoption of conservative approaches to managing patent ductus arteriosus (PDA) in preterm infants. Systematic appraisal of the clinical evidence supporting this approach is essential for guiding recommendations in clinical guidelines. Methods: A comprehensive search of MEDLINE (PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov, spanning from inception to April 2024, was conducted to identify all relevant randomized controlled trials (RCTs) that evaluated conservative management versus active treatment of PDA in preterm infants. We used RevMan 5.4 to pool risk ratios (RRs) under a random-effects model. Results: Our review included 6 RCTs. There was no difference in the risk of mortality (RR 0.83; 95% CI: 0.64-1.08, I 2 = 0%) and BPD (RR 0.89; 95% CI: 0.76-1.03, I 2 = 22%) between the conservative management and active treatment groups. The rates of necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, sepsis, pulmonary hemorrhage, and the need for surgical ligation or transcatheter occlusion were similar between the two groups. Conclusions: The meta-analysis showed no difference in the risk of all-cause mortality, BPD, or other clinical outcomes between a strategy of conservative management compared to active treatment. Future large-scale RCTs focusing on targeted therapy for infants at the highest risk of complications from PDA are required to improve the management of preterm infants further. patent ductus arteriosus PDA conservative management expectant management Figures Figure 1 Figure 2 Figure 3 Introduction Ductus arteriosus is a vascular shunt that connects the pulmonary artery and aorta during fetal life. This connection allows blood flowing from the right ventricle to divert from the high-pressure pulmonary circulation and enter the aorta, thus supporting systemic oxygenation.[ 1 ] At birth, increased oxygen tension and depleting levels of prostaglandin cause the ductus arteriosus to close.[ 1 ] In the majority of healthy newborns, the ductus arteriosus closes within 12–24 hours of birth.[ 1 ] Failure of the ductus arteriosus to close is known as a patent ductus arteriosus (PDA). A PDA is rarely seen in healthy infants born at term. However, in preterm infants, closure of the ductus arteriosus occurs later due to the immaturity of structure and physiology, which increases the likelihood of the ductus remaining patent by the time preterm babies attain term gestation.[ 2 , 3 ] The incidence of PDA on the third day of life of a preterm depends on the gestational age and varies from 40–60%.[ 4 – 6 ] There is a higher incidence of PDA in preterm infants that have very low birth weight (< 1500g).[ 1 , 7 ] The continuous left-to-right shunt in PDA is associated with mortality and morbidities like chronic lung disease, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH) in the preterm newborn.[ 7 ] PDA can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen, and acetaminophen; surgical ligation is used when pharmacological methods fail or are contraindicated.[ 8 ] The use of conservative management for the management of PDA has been on the rise within the last decade.[ 9 ] However, the evidence supporting this strategy is limited. Prior meta-analyses on this topic have been limited by the small number of available randomized control trials (RCTs).[ 7 , 10 ] In addition, the previous reviews have been restricted in their ability to draw sound conclusions due to the inclusion of observational studies or trials with a high rate of open-label treatment in the conservative management group.[ 7 ] Recently, the largest RCT on this topic to date has been published, thus necessitating an updated appraisal of the available evidence.[ 11 ] Therefore, we aimed to conduct this systematic review and meta-analysis to investigate a strategy of conservative management in comparison to active treatment in preterm infants with PDA. Methods This systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.[ 12 , 13 ] This review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under identifier (CRD42024533420). Our study did not require ethical approval. Data sources and searches We searched MEDLINE (via PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov from inception to April 2024 using terms related to “patent ductus arteriosus,” “expectant management,” and “preterm infants.” We also cross-checked the reference lists of the relevant records. Eligibility criteria The inclusion criteria were as follows: (1) study design: RCTs; (2) population: preterm infants with a PDA (regardless of the diagnostic criteria); (3) intervention: conservative management with approximately ≤ 25% incidence of post-randomization open-label PDA-closure treatment; (4) comparator: active treatment for PDA closure; and (5) outcome: reporting at least one outcome of interest. We excluded studies that evaluated prophylactic treatment. Study selection and data extraction We imported all the literature retrieved from our searches into Mendeley Desktop 1.19.8, where duplicate articles were searched and removed. After deduplication, two reviewers independently screened the titles and abstracts followed by full-length screening. Any disagreement was settled through discussion and by consulting a third reviewer. Data regarding study characteristics (including authors, study design, study location, sample size, and diagnostic criteria), patient characteristics (gestational age, birth weight, and gender), intervention and comparator details, and outcomes were extracted into a pre-piloted Excel sheet. Outcomes Our primary outcomes were the risk of all-cause mortality and BPD (any definition). Our secondary outcomes included the incidence of NEC (any stage), IVH (any grade), retinopathy of prematurity (ROP) (any stage), sepsis, pulmonary hemorrhage, and infants requiring surgical PDA ligation or transcatheter occlusion. Risk of bias assessment To evaluate the risk of bias in the included studies, we used the revised Cochrane Risk of Bias Tool for randomized trials (RoB 2.0).[ 14 ] RoB 2.0 assesses bias in 5 domains: (1) bias arising from the randomization process; (2) bias due to deviations from protocol; (3) bias because of missing outcome data; (4) bias in the measurement of outcome; and (5) bias in the selection of the reported result. The risk of bias in each included study was rated as low, high, or some concerns. Data synthesis The meta-analysis was conducted using Review Manager (RevMan, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) under a random-effects model utilizing risk ratio (RR) and mean difference (MD) with corresponding 95% confidence intervals (CIs) as the effect measures. The I 2 statistic was used to evaluate the statistical heterogeneity. Results Study selection and characteristics of included studies After screening, we included 6 RCTs in our meta-analysis.[ 11 , 15 – 19 ] A detailed illustration of the study selection process is reported in the PRISMA Flowchart (Fig. 1 ). The studies were published between 2020 and 2024 with a total sample size of 1401 participants (699 in the conservative management arm and 702 in the active treatment arm). One study was multinational, while the rest were conducted in a single country. All studies included patients with patent PDA detected on echocardiography using color Doppler at less than 72 hours of chronological age except one study, which included participants that underwent echocardiography for PDA detection at 6 and 14 postnatal days. Table 1 contains details of the characteristics of the included studies. Table 1 Characteristics of included studies. Study ID Location Sample size Gestational age (weeks) Birth weight Males, n (%) Expectant management Active treatment received Open-label/rescue therapy hs(PDA) diagnosis hs(PDA) definition de Waal 2021 Australia 72 (37 vs. 35) 26.4 (1.3) vs. 26.3 (1.3) 914 g (219) vs. 883 g (214) 18 (49%) vs. 17 (49%) Placebo (Normal saline) Site A (IV ibuprofen-lysine), Site B (IV indomethacin) 1/37 (2.7%) Echocardiography Not defined EL-Khuffash 2021 Ireland 60 (30 vs 30) 26.3 (1.3) vs 26.1 (1.4) 970 g (217) vs 830 g (235) 20 (67%) vs 16 (53%) Placebo (Normal saline) IV Ibuprofen (5mg/1ml) at an initial dose of 10mg/kg (2ml/kg), followed by 2 doses of 5mg/kg (1ml/kg) administered 24 hours apart 6/30 (20%) Echocardiography Not defined Gupta 2024 United Kingdom 646 (322 vs 324) 26.1 (1.6) vs 26.1 (1.5) 852.9 g (211.3) vs 839.9 g (204.8) 175 (54.3%) vs 180 (55.6%) Placebo (0.9% Sodium chloride) Ibuprofen sodium 82/322 (25.5%) Echocardiography Infants born between 23 weeks 0 days’ and 28 weeks 6 days’ gestation who were less than 72 hours old, who had confirmed by echocardiography to have a large PDA, and for whom there were no associated clinical concerns for acute pulmonary hypertension. Hundscheid 2022 Netherlands 273 (136 vs. 137) 26.1 (25.4–27.0) vs. 26.0 (25.1–27.0) 863 g (748–984) vs. 825 g (715–970) 70/136 (51.5%) vs. 70/137 (51.1%) Placebo Ibuprofen 1/136 (0.7%) Echocardiography Infants with extremely premature birth (gestational age, < 28 weeks) who had echocardiographically confirmed PDA with a diameter of more than 1.5 mm at the smallest point and who had a transductal left-to-right shunt between 24- and 72 hours postnatal age. Potsiurko 2022 Ukraine 208(104 vs. 104) 28 (26.5–30) vs. 28 (27–30) 1079.5 g (850–1300) vs. 1097.5 g (830–1345) 65 (62.5) vs. 52(50) Standard care Ibuprofen rectally, Acetaminophen IV 8 (8%) Echocardiography Infants with gestational age < 32 weeks, birth weight < 1,500 g, were 1.5 mm on echocardiography were included in the trial. Sung 2020 Korea 146 (42 vs. 41, 30 vs. 31) 26.7 (2.0) vs. 26.8 (2.1) 915 g (243) vs. 893 g (256) 41 (57%) vs. 28 (40%) Placebo (Normal saline) Oral ibuprofen 4/72 (6%) Echocardiography Hemodynamically significant PDA was defined as ductal size greater than 1.5 mm by an initial 2-dimensional echocardiogram with predominant left to right shunt flow, using gain-optimized color Doppler, through PDA performed during postnatal days 6 and 14. The hs(PDA), hemodynamically significant patent ductus arteriosus; NR, not reported. Risk of bias of included studies All six included studies had a low risk of bias. The risk of bias assessment is summarized in Supplementary Fig. 1. Primary outcomes All-Cause Mortality The analysis included 1399 participants. The pooled analysis showed no significant difference in the risk of all-cause mortality between the conservative management and active treatment groups (RR 0.83; 95% CI: 0.64–1.08, I 2 = 0%; Fig. 2 ). Bronchopulmonary dysplasia All six studies assessed the development of BPD. A total of 1303 participants were included in the analysis. There was no significant difference in the incidence of BPD between the two groups (RR 0.89; 95% CI: 0.76–1.03, I 2 = 22%; Fig. 3 ). Secondary outcomes There was no significant difference in the incidence of NEC (RR 0.94; 95% CI: 0.70–1.25, I 2 = 0%; Supplementary Fig. 2), IVH (RR 0.95; 95% CI: 0.82–1.09, I 2 = 0%; Supplementary Fig. 3), ROP (RR 0.97; 95% CI: 0.79–1.19, I 2 = 0%; Supplementary Fig. 4), sepsis (RR 0.93; 95% CI: 0.76–1.14, I 2 = 11%; Supplementary Fig. 5), and pulmonary hemorrhage (RR 0.8; 95% CI: 0.52–1.24, I 2 = 0%; Supplementary Fig. 6) between the conservative management and active treatment groups. The rates of surgical ligation or transcatheter occlusion of PDA were similar across the two groups (RR 1.41; 95% CI: 0.53–3.79, I 2 = 59%; Supplementary Fig. 7). Discussion In this meta-analysis, we included six high-quality RCTs that met the eligibility criteria of post-randomization open-label PDA-closure treatment. There was no statistically significant difference between the conservative management and active treatment arms in terms of all-cause mortality, BPD, NEC, IVH, ROP, sepsis, pulmonary hemorrhage, and surgical ligation or transcatheter occlusion. Our findings disagree with a prior review, which observed a higher mortality risk with the conservative management arm, but the findings are confounded due to the inclusion of data from observational studies.[ 7 ] However, the findings were nonsignificant when only data from RCTs were pooled; nevertheless, since the RCT-only cohort was small, their results may have been underpowered.[ 7 ] A previous Cochrane review echoed similar results regarding the primary outcome of all-cause mortality or other clinically relevant outcomes.[ 20 ] A recent meta-analysis observed findings consistent with ours; however, including studies that administered prophylactic treatment for PDA might have distorted its results.[ 10 ] These points highlight the complexity of PDA management and the potential influence of the study design on treatment outcomes. While active interventions have been the standard of care, recent literature questions the rationale for aggressive closure of PDA, given the lack of improvement in long-term outcomes and the potential for adverse effects.[ 21 , 22 ] Our systematic appraisal of the currently available evidence provides valuable results favoring conservative management. We included the latest large-scale RCTs, thus significantly increasing the statistical power of our analyses compared to prior reviews [ 20 , 23 ] and allowing us to draw more reliable and definitive conclusions. In addition, we set a strict criterion for using open-label treatment in the conservative management arm in contrast to many prior reviews that may have confounded their results. Our findings of no increase in mortality or morbidity with a strategy of conservative management support the current trend toward it. Active intervention of PDA exposes preterm infants to potentially harmful adverse effects of pharmacological treatments, in addition to the increased financial burden. Therefore, in light of current findings, conservative management is an attractive option in this population. Further studies are needed to explore precisely targeted treatment in the highest-risk subpopulations to improve the management of PDA. Acknowledging the limitations of the studies included in this review is essential. These include the unblinded nature of some trials and the lack of a universal scoring system for PDA severity. Since we did not have access to individual patient data and had to rely on aggregate data, we are unable to explore potential effect modifiers that may affect treatment results. Our stringent criteria for inclusion led to the exclusion of several RCTs with a significant prevalence of open-label PDA-closure treatment in the expectant management arm. As a result, we were able to generate unbiased estimates, which sets our meta-analysis apart from many previous ones and can be considered a strength. In conclusion, the current evidence from RCTs shows that conservative management does not increase the risk of all-cause mortality, BPD, NEC, IVH, ROP, sepsis, pulmonary hemorrhage, and surgical ligation or transcatheter occlusion as compared to active early treatment of PDA. Future large-scale RCTs focusing on targeted therapy for infants at the highest risk of complications from PDA are required to improve the management of preterm infants further. Statements and Declarations Financial support No financial support was received for this study. Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments Not applicable. Availability of data The data supporting this study's findings are available from the corresponding author upon reasonable request. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4810365","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":332869007,"identity":"a1f197c9-8cf1-49de-82ba-d90304a7bea9","order_by":0,"name":"Rajanikant Kumar","email":"","orcid":"","institution":"Jay Prabha Medanta Super Specialty Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rajanikant","middleName":"","lastName":"Kumar","suffix":""},{"id":332869008,"identity":"25726c5c-eda5-48ca-9d1e-15bb6535faa0","order_by":1,"name":"Efeoghene Praise Epia","email":"","orcid":"","institution":"Tbilisi State Medical University","correspondingAuthor":false,"prefix":"","firstName":"Efeoghene","middleName":"Praise","lastName":"Epia","suffix":""},{"id":332869009,"identity":"64c47247-f29a-4ca0-9923-ee382c1436a3","order_by":2,"name":"Mark W Abdelnour","email":"","orcid":"","institution":"University of California Irvine Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"W","lastName":"Abdelnour","suffix":""},{"id":332869010,"identity":"11844c6a-ef88-48e6-a5c7-da7aac23e05c","order_by":3,"name":"Joo Young Belen Kim Kim","email":"","orcid":"","institution":"National University of Asunción","correspondingAuthor":false,"prefix":"","firstName":"Joo","middleName":"Young Belen Kim","lastName":"Kim","suffix":""},{"id":332869011,"identity":"f190d6b2-d8b5-4837-93cf-4dc41718c6c4","order_by":4,"name":"Anne Boakyewaa Anokye-Kumatia","email":"","orcid":"","institution":"Komfo Anokye Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"Boakyewaa","lastName":"Anokye-Kumatia","suffix":""},{"id":332869012,"identity":"47ad6041-9999-42a0-86db-5de0177eb982","order_by":5,"name":"Rimmo Loyi Lego","email":"","orcid":"","institution":"Stevens Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Rimmo","middleName":"Loyi","lastName":"Lego","suffix":""},{"id":332869013,"identity":"45cb3b24-e099-4b79-8781-ba19a87ffd8c","order_by":6,"name":"Vrunda Kulkarni","email":"","orcid":"","institution":"Smt. 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Dani","email":"","orcid":"","institution":"Beth Israel Lahey Health, Lahey Hospital and Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sourbha","middleName":"S.","lastName":"Dani","suffix":""}],"badges":[],"createdAt":"2024-07-26 22:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4810365/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4810365/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62627637,"identity":"489b58ba-6ba6-475d-9242-0a1b88c4cd82","added_by":"auto","created_at":"2024-08-16 15:35:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":778070,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA 2020 flowchart of included studies\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4810365/v1/dc66be0ae0f7059be40b1cfb.jpg"},{"id":62627639,"identity":"13219a3f-1485-47b5-bc4d-72d1dfe347e7","added_by":"auto","created_at":"2024-08-16 15:35:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":203597,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of conservative management versus active treatment on the risk of all-cause mortality in preterm infants with a PDA.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4810365/v1/1563362df73932830765dcad.jpg"},{"id":62627638,"identity":"8789bc13-c8c8-4d73-a849-2043b3369084","added_by":"auto","created_at":"2024-08-16 15:35:25","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":205164,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of conservative management versus active treatment on the risk of bronchopulmonary dysplasia in preterm infants with a PDA.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4810365/v1/174da30420ffda3bab29a8e0.jpg"},{"id":62629522,"identity":"309853f8-49c8-485b-aa7f-efbc2b55656f","added_by":"auto","created_at":"2024-08-16 15:51:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1695214,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4810365/v1/836c671d-b42c-409d-89a3-1c132491d6d6.pdf"},{"id":62627636,"identity":"3ae56f8c-50cb-48ef-af89-6441bac2de30","added_by":"auto","created_at":"2024-08-16 15:35:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":107016,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4810365/v1/87b7e5cc44e7090d6567ddaf.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDuctus arteriosus is a vascular shunt that connects the pulmonary artery and aorta during fetal life. This connection allows blood flowing from the right ventricle to divert from the high-pressure pulmonary circulation and enter the aorta, thus supporting systemic oxygenation.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] At birth, increased oxygen tension and depleting levels of prostaglandin cause the ductus arteriosus to close.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] In the majority of healthy newborns, the ductus arteriosus closes within 12\u0026ndash;24 hours of birth.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Failure of the ductus arteriosus to close is known as a patent ductus arteriosus (PDA).\u003c/p\u003e \u003cp\u003eA PDA is rarely seen in healthy infants born at term. However, in preterm infants, closure of the ductus arteriosus occurs later due to the immaturity of structure and physiology, which increases the likelihood of the ductus remaining patent by the time preterm babies attain term gestation.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] The incidence of PDA on the third day of life of a preterm depends on the gestational age and varies from 40\u0026ndash;60%.[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] There is a higher incidence of PDA in preterm infants that have very low birth weight (\u0026lt;\u0026thinsp;1500g).[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The continuous left-to-right shunt in PDA is associated with mortality and morbidities like chronic lung disease, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH) in the preterm newborn.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePDA can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen, and acetaminophen; surgical ligation is used when pharmacological methods fail or are contraindicated.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] The use of conservative management for the management of PDA has been on the rise within the last decade.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] However, the evidence supporting this strategy is limited. Prior meta-analyses on this topic have been limited by the small number of available randomized control trials (RCTs).[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] In addition, the previous reviews have been restricted in their ability to draw sound conclusions due to the inclusion of observational studies or trials with a high rate of open-label treatment in the conservative management group.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Recently, the largest RCT on this topic to date has been published, thus necessitating an updated appraisal of the available evidence.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Therefore, we aimed to conduct this systematic review and meta-analysis to investigate a strategy of conservative management in comparison to active treatment in preterm infants with PDA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] This review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under identifier (CRD42024533420). Our study did not require ethical approval.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData sources and searches\u003c/h2\u003e \u003cp\u003eWe searched MEDLINE (via PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov from inception to April 2024 using terms related to \u0026ldquo;patent ductus arteriosus,\u0026rdquo; \u0026ldquo;expectant management,\u0026rdquo; and \u0026ldquo;preterm infants.\u0026rdquo; We also cross-checked the reference lists of the relevant records.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria were as follows: (1) study design: RCTs; (2) population: preterm infants with a PDA (regardless of the diagnostic criteria); (3) intervention: conservative management with approximately\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;25% incidence of post-randomization open-label PDA-closure treatment; (4) comparator: active treatment for PDA closure; and (5) outcome: reporting at least one outcome of interest. We excluded studies that evaluated prophylactic treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and data extraction\u003c/h2\u003e \u003cp\u003eWe imported all the literature retrieved from our searches into Mendeley Desktop 1.19.8, where duplicate articles were searched and removed. After deduplication, two reviewers independently screened the titles and abstracts followed by full-length screening. Any disagreement was settled through discussion and by consulting a third reviewer.\u003c/p\u003e \u003cp\u003eData regarding study characteristics (including authors, study design, study location, sample size, and diagnostic criteria), patient characteristics (gestational age, birth weight, and gender), intervention and comparator details, and outcomes were extracted into a pre-piloted Excel sheet.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eOur primary outcomes were the risk of all-cause mortality and BPD (any definition). Our secondary outcomes included the incidence of NEC (any stage), IVH (any grade), retinopathy of prematurity (ROP) (any stage), sepsis, pulmonary hemorrhage, and infants requiring surgical PDA ligation or transcatheter occlusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eTo evaluate the risk of bias in the included studies, we used the revised Cochrane Risk of Bias Tool for randomized trials (RoB 2.0).[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] RoB 2.0 assesses bias in 5 domains: (1) bias arising from the randomization process; (2) bias due to deviations from protocol; (3) bias because of missing outcome data; (4) bias in the measurement of outcome; and (5) bias in the selection of the reported result. The risk of bias in each included study was rated as low, high, or some concerns.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData synthesis\u003c/h2\u003e \u003cp\u003eThe meta-analysis was conducted using Review Manager (RevMan, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) under a random-effects model utilizing risk ratio (RR) and mean difference (MD) with corresponding 95% confidence intervals (CIs) as the effect measures. The I\u003csup\u003e2\u003c/sup\u003e statistic was used to evaluate the statistical heterogeneity.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy selection and characteristics of included studies\u003c/h2\u003e\n \u003cp\u003eAfter screening, we included 6 RCTs in our meta-analysis.[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] A detailed illustration of the study selection process is reported in the PRISMA Flowchart (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The studies were published between 2020 and 2024 with a total sample size of 1401 participants (699 in the conservative management arm and 702 in the active treatment arm). One study was multinational, while the rest were conducted in a single country. All studies included patients with patent PDA detected on echocardiography using color Doppler at less than 72 hours of chronological age except one study, which included participants that underwent echocardiography for PDA detection at 6 and 14 postnatal days. Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e contains details of the characteristics of the included studies.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of included studies.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy ID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLocation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGestational age (weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBirth weight\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMales, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExpectant management\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eActive treatment received\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOpen-label/rescue therapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ehs(PDA) diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ehs(PDA) definition\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ede Waal 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (37 vs. 35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.4 (1.3) vs. 26.3 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e914 g (219) vs. 883 g (214)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (49%) vs. 17 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo (Normal saline)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSite A (IV ibuprofen-lysine), Site B (IV indomethacin)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1/37 (2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot defined\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEL-Khuffash 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIreland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (30 vs 30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.3 (1.3) vs 26.1 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e970 g (217) vs 830 g (235)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (67%) vs 16 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo (Normal saline)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIV Ibuprofen (5mg/1ml) at an initial dose of 10mg/kg (2ml/kg), followed by 2 doses of 5mg/kg (1ml/kg) administered 24 hours apart\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/30 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot defined\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGupta 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e646 (322 vs 324)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.1 (1.6) vs 26.1 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e852.9 g (211.3) vs 839.9 g (204.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e175 (54.3%) vs 180 (55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo (0.9% Sodium chloride)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIbuprofen sodium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82/322 (25.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfants born between 23 weeks 0 days\u0026rsquo; and 28 weeks 6 days\u0026rsquo; gestation who were less than 72 hours old, who had confirmed by echocardiography to have a large PDA, and for whom there were no associated clinical concerns for acute pulmonary hypertension.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHundscheid 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNetherlands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e273 (136 vs. 137)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.1 (25.4\u0026ndash;27.0) vs. 26.0 (25.1\u0026ndash;27.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e863 g (748\u0026ndash;984) vs. 825 g (715\u0026ndash;970)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70/136 (51.5%) vs. 70/137 (51.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIbuprofen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1/136 (0.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfants with extremely premature birth (gestational age, \u0026lt;\u0026thinsp;28 weeks) who had echocardiographically confirmed PDA with a diameter of more than 1.5 mm at the smallest point and who had a transductal left-to-right shunt between 24- and 72 hours postnatal age.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePotsiurko 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUkraine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e208(104 vs. 104)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (26.5\u0026ndash;30) vs. 28 (27\u0026ndash;30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1079.5 g (850\u0026ndash;1300) vs. 1097.5 g (830\u0026ndash;1345)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (62.5) vs. 52(50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIbuprofen rectally, Acetaminophen IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfants with gestational age\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks, birth weight\u0026thinsp;\u0026lt;\u0026thinsp;1,500 g, were \u0026lt;\u0026thinsp;72 hours of chronological age, and had PDA diameter\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mm on echocardiography were included in the trial.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSung 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKorea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146 (42 vs. 41, 30 vs. 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.7 (2.0) vs. 26.8 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e915 g (243) vs. 893 g (256)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (57%) vs. 28 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo (Normal saline)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOral ibuprofen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4/72 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemodynamically significant PDA was defined as ductal size greater than 1.5 mm by an initial 2-dimensional echocardiogram with predominant left to right shunt flow, using gain-optimized color Doppler, through PDA performed during postnatal days 6 and 14. The\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003ehs(PDA), hemodynamically significant patent ductus arteriosus; NR, not reported.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eRisk of bias of included studies\u003c/h2\u003e\n \u003cp\u003eAll six included studies had a low risk of bias. The risk of bias assessment is summarized in Supplementary Fig.\u0026nbsp;1.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary outcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\n \u003ch2\u003eAll-Cause Mortality\u003c/h2\u003e\n \u003cp\u003eThe analysis included 1399 participants. The pooled analysis showed no significant difference in the risk of all-cause mortality between the conservative management and active treatment groups (RR 0.83; 95% CI: 0.64\u0026ndash;1.08, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eBronchopulmonary dysplasia\u003c/h2\u003e\n \u003cp\u003eAll six studies assessed the development of BPD. A total of 1303 participants were included in the analysis. There was no significant difference in the incidence of BPD between the two groups (RR 0.89; 95% CI: 0.76\u0026ndash;1.03, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;22%; Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eThere was no significant difference in the incidence of NEC (RR 0.94; 95% CI: 0.70\u0026ndash;1.25, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Supplementary Fig.\u0026nbsp;2), IVH (RR 0.95; 95% CI: 0.82\u0026ndash;1.09, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Supplementary Fig.\u0026nbsp;3), ROP (RR 0.97; 95% CI: 0.79\u0026ndash;1.19, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Supplementary Fig.\u0026nbsp;4), sepsis (RR 0.93; 95% CI: 0.76\u0026ndash;1.14, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;11%; Supplementary Fig.\u0026nbsp;5), and pulmonary hemorrhage (RR 0.8; 95% CI: 0.52\u0026ndash;1.24, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Supplementary Fig.\u0026nbsp;6) between the conservative management and active treatment groups. The rates of surgical ligation or transcatheter occlusion of PDA were similar across the two groups (RR 1.41; 95% CI: 0.53\u0026ndash;3.79, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;59%; Supplementary Fig.\u0026nbsp;7).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this meta-analysis, we included six high-quality RCTs that met the eligibility criteria of post-randomization open-label PDA-closure treatment. There was no statistically significant difference between the conservative management and active treatment arms in terms of all-cause mortality, BPD, NEC, IVH, ROP, sepsis, pulmonary hemorrhage, and surgical ligation or transcatheter occlusion.\u003c/p\u003e \u003cp\u003eOur findings disagree with a prior review, which observed a higher mortality risk with the conservative management arm, but the findings are confounded due to the inclusion of data from observational studies.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] However, the findings were nonsignificant when only data from RCTs were pooled; nevertheless, since the RCT-only cohort was small, their results may have been underpowered.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] A previous Cochrane review echoed similar results regarding the primary outcome of all-cause mortality or other clinically relevant outcomes.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] A recent meta-analysis observed findings consistent with ours; however, including studies that administered prophylactic treatment for PDA might have distorted its results.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] These points highlight the complexity of PDA management and the potential influence of the study design on treatment outcomes. While active interventions have been the standard of care, recent literature questions the rationale for aggressive closure of PDA, given the lack of improvement in long-term outcomes and the potential for adverse effects.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Our systematic appraisal of the currently available evidence provides valuable results favoring conservative management. We included the latest large-scale RCTs, thus significantly increasing the statistical power of our analyses compared to prior reviews [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and allowing us to draw more reliable and definitive conclusions. In addition, we set a strict criterion for using open-label treatment in the conservative management arm in contrast to many prior reviews that may have confounded their results.\u003c/p\u003e \u003cp\u003eOur findings of no increase in mortality or morbidity with a strategy of conservative management support the current trend toward it. Active intervention of PDA exposes preterm infants to potentially harmful adverse effects of pharmacological treatments, in addition to the increased financial burden. Therefore, in light of current findings, conservative management is an attractive option in this population. Further studies are needed to explore precisely targeted treatment in the highest-risk subpopulations to improve the management of PDA.\u003c/p\u003e \u003cp\u003eAcknowledging the limitations of the studies included in this review is essential. These include the unblinded nature of some trials and the lack of a universal scoring system for PDA severity. Since we did not have access to individual patient data and had to rely on aggregate data, we are unable to explore potential effect modifiers that may affect treatment results. Our stringent criteria for inclusion led to the exclusion of several RCTs with a significant prevalence of open-label PDA-closure treatment in the expectant management arm. As a result, we were able to generate unbiased estimates, which sets our meta-analysis apart from many previous ones and can be considered a strength.\u003c/p\u003e \u003cp\u003eIn conclusion, the current evidence from RCTs shows that conservative management does not increase the risk of all-cause mortality, BPD, NEC, IVH, ROP, sepsis, pulmonary hemorrhage, and surgical ligation or transcatheter occlusion as compared to active early treatment of PDA. Future large-scale RCTs focusing on targeted therapy for infants at the highest risk of complications from PDA are required to improve the management of preterm infants further.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no relationships that could be construed as a conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting this study's findings are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGillam-Krakauer M, Mahajan K (2024) Patent Ductus Arteriosus. In: StatPearls. StatPearls Publishing, Treasure Island (FL)\u003c/li\u003e\n \u003cli\u003eKoch J, Hensley G, Roy L, et al (2006) Prevalence of Spontaneous Closure of the Ductus Arteriosus in Neonates at a Birth Weight of 1000 Grams or Less. Pediatrics 117:1113\u0026ndash;1121. https://doi.org/10.1542/peds.2005-1528\u003c/li\u003e\n \u003cli\u003eSemberova J, Sirc J, Miletin J, et al (2017) Spontaneous Closure of Patent Ductus Arteriosus in Infants \u0026le;1500 g. Pediatrics 140:e20164258. https://doi.org/10.1542/peds.2016-4258\u003c/li\u003e\n \u003cli\u003eClyman RI, Couto J, Murphy GM (2012) Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 36:123\u0026ndash;129. https://doi.org/10.1053/j.semperi.2011.09.022\u003c/li\u003e\n \u003cli\u003eAbdel-Hady H, Nasef N, Shabaan AE, Nour I (2013) Patent Ductus Arteriosus in Preterm Infants: Do We Have the Right Answers? BioMed Res Int 2013:e676192. https://doi.org/10.1155/2013/676192\u003c/li\u003e\n \u003cli\u003eKhasawneh W, Hakim F, Abu Ras O, et al (2020) Incidence and Patterns of Congenital Heart Disease Among Jordanian Infants, a Cohort Study From a University Tertiary Center. Front Pediatr 8:219. https://doi.org/10.3389/fped.2020.00219\u003c/li\u003e\n \u003cli\u003eHundscheid T, Jansen EJS, Onland W, et al (2021) Conservative Management of Patent Ductus Arteriosus in Preterm Infants\u0026mdash;A Systematic Review and Meta-Analyses Assessing Differences in Outcome Measures Between Randomized Controlled Trials and Cohort Studies. Front Pediatr 9:\u003c/li\u003e\n \u003cli\u003eHamrick SEG, Sallmon H, Rose AT, et al (2020) Patent Ductus Arteriosus of the Preterm Infant. Pediatrics 146:e20201209. https://doi.org/10.1542/peds.2020-1209\u003c/li\u003e\n \u003cli\u003eSankar MN, Bhombal S, Benitz WE (2019) PDA: To treat or not to treat. Congenit Heart Dis 14:46\u0026ndash;51. https://doi.org/10.1111/chd.12708\u003c/li\u003e\n \u003cli\u003eCheema HA, Majeed Z, Hayat T, et al (2023) Expectant management of patent ductus arteriosus for preterm infants: A meta-analysis of randomized controlled trials. Am Heart J 266:179\u0026ndash;183. https://doi.org/10.1016/j.ahj.2023.07.007\u003c/li\u003e\n \u003cli\u003eGupta S, Subhedar NV, Bell JL, et al (2024) Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. N Engl J Med 390:314\u0026ndash;325. https://doi.org/10.1056/NEJMoa2305582\u003c/li\u003e\n \u003cli\u003eChandler J, Cumpston M, Li T Cochrane Handbook for Systematic Reviews of Interventions\u003c/li\u003e\n \u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj 372:\u003c/li\u003e\n \u003cli\u003eSterne JA, Savović J, Page MJ, et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj 366:\u003c/li\u003e\n \u003cli\u003eEL-Khuffash A, Bussmann N, Breatnach CR, et al (2021) A Pilot Randomized Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score (The PDA RCT). J Pediatr 229:127\u0026ndash;133. https://doi.org/10.1016/j.jpeds.2020.10.024\u003c/li\u003e\n \u003cli\u003ede Waal K, Phad N, Stubbs M, et al (2021) A Randomized Placebo-Controlled Pilot Trial of Early Targeted Nonsteroidal Anti-Inflammatory Drugs in Preterm Infants with a Patent Ductus Arteriosus. J Pediatr 228:82-86.e2. https://doi.org/10.1016/j.jpeds.2020.08.062\u003c/li\u003e\n \u003cli\u003eSung SI, Lee MH, Ahn SY, et al (2020) Effect of Nonintervention vs Oral Ibuprofen in Patent Ductus Arteriosus in Preterm Infants. JAMA Pediatr 174:755\u0026ndash;755. https://doi.org/10.1001/jamapediatrics.2020.1447\u003c/li\u003e\n \u003cli\u003eHundscheid T, Onland W, Kooi EMW, et al (2022) Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. https://doi.org/10.1056/NEJMoa2207418\u003c/li\u003e\n \u003cli\u003ePotsiurko S, Dobryanskyy D, Sekretar L, Salabay Z (2022) Randomized Noninferiority Trial of Expectant Management versus Early Treatment of Patent Ductus Arteriosus in Preterm Infants. Am J Perinatol. https://doi.org/10.1055/a-1782-5860\u003c/li\u003e\n \u003cli\u003eMitra S, Scrivens A, Kursell AM, Disher T (2020) Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev 2020:CD013278. https://doi.org/10.1002/14651858.CD013278.pub2\u003c/li\u003e\n \u003cli\u003ePrescott S, Keim-Malpass J (2017) Patent Ductus Arteriosus in the Preterm Infant: Diagnostic and Treatment Options. Adv Neonatal Care 17:10. https://doi.org/10.1097/ANC.0000000000000340\u003c/li\u003e\n \u003cli\u003eTakeuchi K, Hirota A, Minegishi S, et al (2013) Current treatment options for the management of patent ductus arteriosus. Pediatr Health Med Ther 4:23\u0026ndash;27. https://doi.org/10.2147/PHMT.S31661\u003c/li\u003e\n \u003cli\u003eMitra S, Florez ID, Tamayo ME, et al (2018) Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA 319:1221\u0026ndash;1238. https://doi.org/10.1001/jama.2018.1896\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"patent ductus arteriosus, PDA, conservative management, expectant management","lastPublishedDoi":"10.21203/rs.3.rs-4810365/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4810365/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eIn recent years, there has been a rise in the adoption of conservative approaches to managing patent ductus arteriosus (PDA) in preterm infants. Systematic appraisal of the clinical evidence supporting this approach is essential for guiding recommendations in clinical guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA comprehensive search of MEDLINE (PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov, spanning from inception to April 2024, was conducted to identify all relevant randomized controlled trials (RCTs) that evaluated conservative management versus active treatment of PDA in preterm infants. We used RevMan 5.4 to pool risk ratios (RRs) under a random-effects model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOur review included 6 RCTs. There was no difference in the risk of mortality (RR 0.83; 95% CI: 0.64-1.08, I\u003csup\u003e2\u003c/sup\u003e = 0%) and BPD (RR 0.89; 95% CI: 0.76-1.03, I\u003csup\u003e2\u003c/sup\u003e = 22%) between the conservative management and active treatment groups. The rates of necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, sepsis, pulmonary hemorrhage, and the need for surgical ligation or transcatheter occlusion were similar between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe meta-analysis showed no difference in the risk of all-cause mortality, BPD, or other clinical outcomes between a strategy of conservative management compared to active treatment. Future large-scale RCTs focusing on targeted therapy for infants at the highest risk of complications from PDA are required to improve the management of preterm infants further.\u003c/p\u003e","manuscriptTitle":"Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-16 15:35:20","doi":"10.21203/rs.3.rs-4810365/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"81124723-d3e9-4502-8a5a-c74c3275da79","owner":[],"postedDate":"August 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-16T15:35:22+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-16 15:35:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4810365","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4810365","identity":"rs-4810365","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}