Key messages
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Early or very early treatment of a patent ductus arteriosus (PDA) that is symptomatic (causing ongoing medical problems) may make little to no difference to death or other poor clinical outcomes in preterm infants (those who are born prematurely) when compared to expectant management (waiting and watching without providing any treatment to close the PDA).
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Very early use of the drug ibuprofen may increase death in extremely preterm infants born at less than 28 weeks of gestation.
What is patent ductus arteriosus (PDA)?
Patent ductus arteriosus is a common complication in preterm (born before nine months of pregnancy) or low birthweight infants. Patent ductus arteriosus is an open blood vessel between the lungs and the heart, which usually closes shortly after birth.
How is the condition treated?
The condition is treated using a class of drugs called cyclo-oxygenase inhibitors (which include indomethacin, ibuprofen, and acetaminophen). If the drugs do not work, then the PDA is closed by surgery or by a special procedure using a tiny tube called a catheter that is inserted through a small cut in the skin that allows doctors to reach the heart without making a large incision (catheter-based closure). Due to the side effects related to the drugs, some doctors may choose to wait and watch to see if the PDA closes off on its own (expectant management).
What did we want to find out?
We wanted to find out if early (drug treatment started within seven days of birth) or very early treatment (drug treatment started within 72 hours of birth) was better at reducing death or other poor clinical outcomes in preterm infants, such as chronic lung disease or a serious bowel condition where part of the bowel dies (known as necrotizing entercolitis).
What did we do?
We searched for randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) in preterm (born at less than 37 weeks into pregnancy) or low birthweight infants (weighing less than 2500 g) with PDA diagnosed using a combination of specific clinical features and ultrasound of the heart. The included studies compared early treatment or very early treatment of symptomatic PDA with cyclo-oxygenase inhibitors compared to expectant management (without the use of cyclo-oxygenase inhibitors). We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 19 studies that involved 2323 infants. We are moderately certain that early or very early treatment of symptomatic PDA does not reduce death or other poor clinical outcomes in preterm infants. We noted that in the most prematurely born babies (born less than 28 weeks of gestation) very early use of the drug ibuprofen may increase the risk of death. There is currently one trial awaiting classification and five ongoing trials exploring this question.
What are the limitations of the evidence?
Our confidence in the evidence is very low to high, and the results of further research could differ from the results of this review. Three main factors reduced our confidence in the evidence. First, the results of some studies may have been affected by the study researchers’ own biases. Second, the results from different studies varied widely for some outcomes. Finally, many studies involved only small numbers of infants.
How up to date is this evidence?
This review updates our previous review (2020). The evidence is up to date to 18 October 2024.
閱讀完整摘要
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.
目的
To assess the effectiveness and safety of early treatment strategies versus expectant management for hemodynamically significant patent ductus arteriosus (hs-PDA) in preterm infants.
搜尋策略
We searched the following sources on 18 October 2024: CENTRAL, MEDLINE, Embase, trial registries, and conference abstracts.
選擇標準
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.
資料收集與分析
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.
主要結果
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).
作者結論
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).
