Understanding the patent ductus arteriosus (PDA) in preterm infants
The patent ductus arteriosus (PDA) is a common cardiovascular condition affecting preterm infants. In healthy term infants, the ductus arteriosus, a fetal blood vessel that connects the aorta and pulmonary artery, typically closes within the first few days after birth. However, in preterm infants, particularly those born before 30 weeks’ gestation, the PDA may fail to close spontaneously, leading to a persistent shunt of blood from the aorta to the pulmonary arteries.
A persistent PDA can have significant clinical implications for preterm infants. The shunting of blood from the aorta to the lungs, known as a “ductal steal,” can result in pulmonary overcirculation, pulmonary edema, and worsening respiratory distress. Conversely, the diversion of blood away from the systemic circulation can lead to systemic hypoperfusion, compromising the perfusion of vital organs such as the kidneys, gut, and brain.
The association between a persistent PDA and adverse neonatal outcomes, including higher rates of mortality, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and cerebral palsy, has been well-documented. However, the causal relationship between these associations has not been definitively established, as preterm infants with a PDA often have other comorbidities that may contribute to these adverse outcomes.
Strategies for managing the PDA in preterm infants
The management of the PDA in preterm infants is a complex and controversial topic in neonatal care. Several approaches, including pharmacological, surgical, and conservative strategies, have been explored to prevent or treat a PDA.
Pharmacological interventions
Non-steroidal anti-inflammatory drugs (NSAIDs):
NSAIDs, such as indomethacin and ibuprofen, act by inhibiting the cyclooxygenase (COX) enzyme, thereby reducing the production of prostaglandin E2, a potent vasodilator that helps maintain the patency of the ductus arteriosus. While NSAIDs have been shown to be effective in closing a PDA, their use has been associated with adverse effects, including transient or permanent renal dysfunction, necrotizing enterocolitis, gastrointestinal bleeding or perforation, and impairment of cerebral blood flow.
Acetaminophen:
Acetaminophen, a derivative of acetanilide with anti-inflammatory properties, is thought to exert its action by inhibiting the peroxidase enzyme, leading to a reduction in prostaglandin E2 production. Acetaminophen has been explored as an alternative to NSAIDs for the management of PDAs, with the potential for a more favorable safety profile. However, the long-term neurodevelopmental effects of acetaminophen in preterm infants are not yet fully understood.
Surgical interventions
Surgical ligation:
Surgical ligation of the PDA has been a traditional approach, primarily reserved for infants with a persistent symptomatic PDA following the failure of medical management. While surgical ligation has been associated with a reduced mortality rate, it has also been linked to an increased risk of neurodevelopmental impairment, potentially due to the lack of studies addressing survival bias and confounding by indication.
Transcatheter occlusion:
Transcatheter occlusion of the PDA, a less invasive alternative to surgical ligation, is an emerging approach in the management of preterm infants with a PDA. This procedure involves the placement of a small device or coil to occlude the PDA through a catheter inserted into a blood vessel, typically the femoral artery.
Conservative management
In recent years, there has been growing interest in a more conservative approach to the management of the PDA in preterm infants, particularly for asymptomatic or clinically stable infants. This approach involves closely monitoring the PDA and refraining from immediate pharmacological or surgical intervention, with the goal of avoiding the potential adverse effects associated with early treatment.
Cochrane Neonatal evidence on PDA management
To summarize the current evidence on the management of the PDA in preterm infants, the Cochrane Neonatal group has published several systematic reviews examining various interventions, including both pharmacological and surgical approaches.
Prophylactic interventions for PDA prevention
Indomethacin:
Cochrane reviews have found that prophylactic indomethacin, administered within the first 24 hours of life, can reduce the incidence of symptomatic PDA and the need for surgical PDA ligation. However, it does not appear to improve mortality or the rate of survival without neurosensory impairment at 18 months. Concerns have also been raised about the increased incidence of spontaneous gastrointestinal perforation with prophylactic indomethacin.
Ibuprofen:
Similar to indomethacin, prophylactic ibuprofen has been shown to reduce the need for rescue treatment with COX inhibitors and the need for surgical PDA closure. However, it has also been associated with an increased risk of oliguria (reduced urine output) and gastrointestinal hemorrhage.
Acetaminophen:
The evidence on the use of prophylactic acetaminophen for PDA prevention is limited, with Cochrane reviews unable to draw firm conclusions due to the paucity of available data.
Interventions for the management of asymptomatic PDA
The Cochrane Neonatal group has examined the use of indomethacin for the treatment of asymptomatic PDA. The available evidence suggests that indomethacin can reduce the development of a symptomatic PDA, but it does not appear to improve clinical outcomes, such as the need for invasive PDA closure, chronic lung disease, or mortality.
Interventions for the management of symptomatic PDA
NSAIDs and acetaminophen:
Cochrane reviews have found that NSAIDs, including indomethacin and ibuprofen, as well as acetaminophen, are more effective than placebo in closing a symptomatic PDA. Ibuprofen appears to be as effective as indomethacin in closing a symptomatic PDA, while reducing the risk of necrotizing enterocolitis and transient renal insufficiency.
Surgical interventions:
The evidence on the efficacy and safety of surgery as the initial treatment for a symptomatic PDA, compared to pharmacological management, is inconclusive, according to Cochrane reviews.
Challenges and limitations in the existing evidence
The management of the PDA in preterm infants is a complex and controversial topic, with several challenges and limitations in the existing evidence:
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Heterogeneity in PDA definitions and diagnostic criteria: There is a lack of consensus on the precise definition and diagnostic criteria for a symptomatic PDA, with variations in the use of clinical signs and echocardiographic parameters across studies.
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Uncertainty about the clinical significance of PDA: The causal relationship between a persistent PDA and adverse neonatal outcomes, such as mortality, BPD, NEC, and IVH, has not been definitively established. It remains unclear which PDA shunts, if any, are associated with clinically significant morbidities.
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High rates of open-label treatment: Many of the randomized controlled trials examining PDA interventions have experienced high rates of open-label or rescue treatment, where infants in the control groups received the study intervention, potentially diluting the observed treatment effects.
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Lack of long-term follow-up data: The available evidence primarily focuses on short-term outcomes, with limited data on the long-term neurodevelopmental and other important clinical outcomes associated with PDA management strategies.
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Variation in practice patterns: There is significant variation in the management of the PDA across neonatal intensive care units, reflecting the uncertainty and lack of consensus in the field.
Implications for clinical practice and future research
The management of the PDA in preterm infants remains a challenging and complex topic, with ongoing debates and uncertainty regarding the most appropriate approach. The Cochrane Neonatal reviews have provided valuable insights, but the quality of the available evidence varies, and important gaps remain.
Implications for clinical practice:
– Prophylactic indomethacin may be considered in extremely preterm infants at high risk of severe intraventricular hemorrhage, but the overall benefits and harms need to be carefully weighed.
– For the management of a symptomatic PDA, ibuprofen or acetaminophen can be considered as effective pharmacological options, with ibuprofen potentially having a more favorable safety profile.
– Surgical or transcatheter PDA closure may be considered for infants with a persistent symptomatic PDA and signs of pulmonary overcirculation, after failed medical management.
– A conservative, expectant approach to the management of asymptomatic or clinically stable PDAs may be appropriate in many cases, given the uncertainty about the clinical significance of these shunts.
Implications for future research:
– Future clinical trials should focus on defining the specific patient population and PDA characteristics that are most likely to benefit from PDA closure, rather than enrolling a heterogeneous group of preterm infants.
– Researchers should explore highly effective and safe strategies for PDA shunt elimination, including innovative pharmacological approaches and advancements in minimally invasive procedural techniques.
– Long-term follow-up studies are needed to better understand the impact of PDA management strategies on important clinical outcomes, such as neurodevelopmental and respiratory outcomes.
– Collaborative efforts to establish consensus on PDA definitions, diagnostic criteria, and clinically meaningful endpoints would help to improve the quality and comparability of future research in this field.
By addressing these challenges and limitations, future research can help to guide clinicians in the optimal management of the PDA in preterm infants, ultimately improving the care and outcomes for this vulnerable population.
Conclusion
The management of the patent ductus arteriosus in preterm infants is a complex and contentious topic, with ongoing debates and uncertainties. The Cochrane Neonatal reviews have provided valuable insights, but the quality of the available evidence varies, and important gaps remain. Clinicians must carefully weigh the potential benefits and harms of different management strategies, considering the specific clinical context and characteristics of the individual patient. Future research should focus on defining the patient population most likely to benefit from PDA closure, exploring innovative and effective shunt elimination strategies, and evaluating long-term clinical outcomes. By addressing the challenges and limitations in the existing evidence, researchers and clinicians can work together to optimize the care and outcomes for preterm infants with a patent ductus arteriosus.
References
https://pmc.ncbi.nlm.nih.gov/articles/PMC10091483/
https://cps.ca/documents/position/patent-ductus-arteriosus
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00533-3/fulltext
