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 guideline recommendations.
Aim of review
This systematic review and meta-analysis aims to investigate a strategy of conservative management in comparison to active treatment in preterm infants with PDA.
Key scientific concepts of review
From inception to April 2024, we conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov to identify 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).
Our review included 6 RCTs. There was no difference in the risk of mortality (RR 0.83; 95 % CI: 0.64–1.08) and BPD (RR 0.89; 95 % CI: 0.76–1.03) 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. In conclusion, our 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. Further, large-scale RCTs focusing on targeted therapy for infants at the highest risk of complications from PDA are required.
Highlights
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We evaluated conservative management versus active treatment of PDA in preterm infants.
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Our review included 6 RCTs.
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Our meta-analysis showed no difference in the risk of all-cause mortality or BPD between the two groups.
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Further large-scale RCTs focusing on infants at the highest risk of complications from PDA are required.
1
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 [ ]. At birth, increased oxygen tension and depleting levels of prostaglandin cause the ductus arteriosus to close [ ]. In the majority of healthy newborns, the ductus arteriosus closes within 12–24 h of birth [ ]. 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 [ , ]. The incidence of PDA on the third day of life of a preterm depends on the gestational age and varies from 40 % to 60 % [ ]. There is a higher incidence of PDA in preterm infants that have very low birth weight (<1500 g) [ , ]. 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 [ ].
The approach to managing PDA is not standardized and is based on multiple clinical indicators, including the hemodynamic significance of the PDA, ventilator support settings, feeding intolerance, and growth of the infants when deciding between conservative and active management [ ]. 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 [ ]. The use of conservative management for the management of PDA has been on the rise within the last decade [ ]. 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) [ , ]. 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 [ ]. Recently, the largest RCT on this topic to date has been published, thus necessitating an updated appraisal of the available evidence [ ]. 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.
2
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 [ , ]. This review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under identifier (CRD42024533420). Our study did not require ethical approval.
2.1
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.
2.2
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 pharmacological treatment; (4) comparator: active pharmacological treatment for PDA closure; and (5) outcome: reporting at least one outcome of interest. We excluded studies that evaluated prophylactic treatment.
2.3
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.
2.4
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.
2.5
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) [ ]. 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.
2.6
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.
3
Results
3.1
Study selection and characteristics of included studies
After screening, we included 6 RCTs in our meta-analysis [ , ]. 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 <72 h 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.
| Study ID | Location | Sample size | Gestational age (weeks) | Birth weight | Males, n (%) | Expectant management | Active treatment received | Open-label/rescue pharmacological 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 (5 mg/1 ml) at an initial dose of 10 mg/kg (2 ml/kg), followed by 2 doses of 5 mg/kg (1 ml/kg) administered 24 h 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) | Parenteral ibuprofen at a loading dose of 10 mg/kg followed by two doses of 5 mg/kg | 82/322 (25.5 %) | Echocardiography | Infants born between 23 weeks 0 days’ and 28 weeks 6 days’ gestation who were <72 h 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 at a loading dose of 10 mg/kg followed by two doses of 5 mg/kg | 1/136 (0.7 %) | Echocardiography | Infants with extremely premature birth (gestational age, <28 weeks) who had echocardiographically confirmed PDA with a diameter of >1.5 mm at the smallest point and who had a transductal left-to-right shunt between 24- and 72 h 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 at 20 mg/kg followed by two 10 mg/kg doses after 24 and 48 h, IV acetaminophen 15 mg/kg every 6 h for 3 days | 8 (8 %) | Echocardiography | Infants with gestational age <32 weeks, birth weight <1500 g, were <72 h of chronological age, and had PDA diameter >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 at an initial dose of 10 mg/kg followed by two doses of 5 mg/kg at 24 and 48 h, respectively | 4/72 (6 %) | Echocardiography | Hemodynamically significant PDA was defined as ductal size >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. |
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