-
Seminars in Perinatology Mar 2023Platelet plug formation is critically involved in murine ductus arteriosus closure and thrombocytopenia in preterm infants seems to negatively affect spontaneous and... (Randomized Controlled Trial)
Randomized Controlled Trial
Platelet plug formation is critically involved in murine ductus arteriosus closure and thrombocytopenia in preterm infants seems to negatively affect spontaneous and pharmacologically induced ductal closure. Furthermore, platelet dysfunction may contribute to ductal patency, especially in extremely immature infants. Neonatal platelets likely have multifaceted roles during ductal closure, such as secretion of several signaling molecules and facilitation of specific cell-cell interactions. The only available randomized-controlled trial on platelet transfusions in preterm infants with patent ductus arteriosus demonstrated that a liberal transfusion regimen did not promote ductal closure, but was associated with an increased rate of intraventricular hemorrhage. Herein, we discuss the available mechanistic evidence on the role of platelets in ductus arteriosus closure and their potential clinical implications in preterm infants. We further briefly outline future research directions aimed at a better understanding of platelet-endothelial interactions in neonatal health and disease.
Topics: Infant; Infant, Newborn; Humans; Animals; Mice; Indomethacin; Cyclooxygenase Inhibitors; Ibuprofen; Ductus Arteriosus; Ductus Arteriosus, Patent; Infant, Extremely Premature
PubMed: 36925318
DOI: 10.1016/j.semperi.2023.151719 -
JAMA Network Open Nov 2023Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies.
OBJECTIVE
To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies.
DATA SOURCES
PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH.
STUDY SELECTION
Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH.
DATA EXTRACTION AND SYNTHESIS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA.
MAIN OUTCOMES AND MEASURES
The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0).
RESULTS
A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable.
CONCLUSIONS AND RELEVANCE
In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.
Topics: Infant, Newborn; Infant; Female; Pregnancy; Humans; Ductus Arteriosus, Patent; Bronchopulmonary Dysplasia; Bayes Theorem; Hypertension, Pulmonary; Vascular Diseases; Infant, Extremely Premature; Observational Studies as Topic
PubMed: 38015504
DOI: 10.1001/jamanetworkopen.2023.45299 -
Seminars in Perinatology Mar 2023While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects... (Review)
Review
While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects and low efficacy in extremely low gestational age neonates (ELGANs) have highlighted a need for alternative options. Combination therapy with acetaminophen and ibuprofen is a novel strategy for PDA treatment in ELGANs, as it may facilitate higher ductal closure rates via additive action on two separate pathways inhibiting prostaglandin production. Initial small observational studies and pilot randomized clinical trials indicate potentially higher efficacy of the combination regime to induce ductal closure in comparison to treatment with ibuprofen alone. In this review, we examine the potential clinical impact of treatment failure in ELGANs with significant PDA, highlight the biological rationale in support of studying combination therapy, and review the randomized and non-randomized studies to date. With the rising number of ELGANs receiving neonatal intensive care, who are vulnerable to PDA-related morbidities, there is an urgent need for adequately powered clinical trials to systematically investigate the efficacy and safety of combination therapy for PDA treatment.
Topics: Infant, Newborn; Humans; Ductus Arteriosus, Patent; Infant, Premature; Ibuprofen; Indomethacin; Infant, Low Birth Weight
PubMed: 36914507
DOI: 10.1016/j.semperi.2023.151720 -
Seminars in Perinatology Mar 2023During fetal life, the ductus arteriosus (DA) acquires the mechanisms for its postnatal closure following a thorough developmental program. This program can be... (Review)
Review
During fetal life, the ductus arteriosus (DA) acquires the mechanisms for its postnatal closure following a thorough developmental program. This program can be interrupted by preterm birth and is also susceptible to alteration during fetal life by numerous physiological and pathological stimuli. In this review, we aim to summarize the evidence on how physiological and pathological factors affect DA development, eventually leading to patent DA (PDA). Specifically, we reviewed the associations of sex, race, and pathophysiological pathways leading to very preterm birth (endotypes) with PDA incidence and pharmacological closure. Summary of evidence suggests that there are no male-female differences in the incidence of PDA among very preterm infants. In contrast, risk of developing PDA appears to be higher in infants exposed to chorioamnionitis or who are small for gestational age. Finally, hypertensive disorders of pregnancy may be associated with a better response to pharmacological treatment of PDA. All of this evidence comes from observational studies and therefore associations do not imply causation. The current trend for many neonatologists is to wait for the natural evolution of preterm PDA. Continued research is needed to identify which fetal and perinatal factors modulate the eventual late closure of PDA in very and extremely preterm infants.
Topics: Infant; Infant, Newborn; Female; Humans; Ductus Arteriosus, Patent; Indomethacin; Premature Birth; Ibuprofen; Infant, Extremely Premature; Fetal Growth Retardation
PubMed: 36914506
DOI: 10.1016/j.semperi.2023.151717 -
Journal of Perinatology : Official... May 2021
Topics: Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Persistent Fetal Circulation Syndrome
PubMed: 33859354
DOI: 10.1038/s41372-021-01059-w -
PloS One 2015Chorioamnionitis has recently been reported as a risk factor for various neonatal diseases, including cerebral palsy, bronchopulmonary dysplasia, and necrotizing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chorioamnionitis has recently been reported as a risk factor for various neonatal diseases, including cerebral palsy, bronchopulmonary dysplasia, and necrotizing enterocolitis, but its effect on patent ductus arteriosus (PDA) is unclear. We performed a systematic review and meta-analysis to evaluate the effect of chorioamnionitis on PDA.
METHODS
We searched PubMed, EMBASE, Cochrane Library, and KoreaMed databases using the terms: "intrauterine infection" or "maternal infection" or "antenatal infection" or "chorioamnionitis" or "placenta inflammation" or "placenta pathology" or "neonatal outcome" or "neonatal morbidity" or "PDA or patent ductus arteriosus" or "ductus arteriosus," and "prematurity" or "very low birth weight infant." Studies were included if they were randomized controlled trials, case-control studies, or cohort studies that included information relating to chorioamnionitis and PDA.
RESULTS
Among 1,571 studies, a total of 23 studies (17,708 cases) were included in the meta-analysis to analyze the relationship between chorioamnionitis and PDA, except one study that only included PDA requiring surgical ligation. The association between chorioamnionitis and PDA was statistically significant (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.19, 1.72; P < 0.0001). In subgroup analysis, clinical chorioamnionitis was not associated with PDA (OR 1.28; 95% CI 1.00, 1.64, 1.790; P = 0.05), whereas histologic chorioamnionitis (OR 1.54; 95% CI 1.10, 2.15; P = 0.01) and chorioamnionitis diagnosed from both clinical and histologic findings (OR 1.75; 95% CI 1.07, 2.86; P = 0.03) showed significant associations with PDA. Chorioamnionitis did not increase the risk of PDA requiring surgical ligation (OR 1.23; 95% CI 0.69, 2.17; P = 0.48), and antenatal steroid use reduced the risk of PDA (OR 0.62; 95% CI 0.42, 0.90; P = 0.01) after chorioamnionitis.
CONCLUSIONS
The results from this meta-analysis support an association between maternal chorioamnionitis and PDA in offspring.
Topics: Chorioamnionitis; Ductus Arteriosus, Patent; Female; Humans; Pregnancy; Prevalence; Prognosis
PubMed: 26375582
DOI: 10.1371/journal.pone.0138114 -
Congenital Heart Disease Jan 2019Regulation of the ductus arteriosus, an essential fetal vessel connecting the pulmonary artery and aorta, is complex. Failure of this vessel to close after birth may... (Review)
Review
Regulation of the ductus arteriosus, an essential fetal vessel connecting the pulmonary artery and aorta, is complex. Failure of this vessel to close after birth may result in a persistent left-to-right shunt through the patent ductus arteriosus, a condition associated with significant morbidities. Numerous factors contribute to the shift from fetal ductus patency to postnatal closure, requiring precise coordination of molecular cues with biomechanical forces and underlying genetic influences. Despite significant advances, questions remain regarding signaling dynamics and the natural time course of ductus closure, particularly in preterm neonates. This review highlights the contributions of early investigators and more recent clinician scientists to our understanding of the molecular and mechanical factors that mediate ductus patency and closure.
Topics: Cardiac Surgical Procedures; Ductus Arteriosus; Ductus Arteriosus, Patent; Hemodynamics; Humans; Infant, Newborn; Oxidative Stress
PubMed: 30468303
DOI: 10.1111/chd.12714 -
Journal of Perinatology : Official... Oct 2023Patent ductus arteriosus (PDA) is the most common cardiovascular condition diagnosed in premature infants. Acetaminophen was first proposed as a potential treatment for... (Review)
Review
Patent ductus arteriosus (PDA) is the most common cardiovascular condition diagnosed in premature infants. Acetaminophen was first proposed as a potential treatment for PDA in 2011. Since that time acetaminophen use among extremely preterm neonates has increased substantially. The limited available data demonstrate that acetaminophen reduces PDA without evident hepatotoxicity. These findings have led some to suggest that acetaminophen is a safe and effective therapy for PDA closure. However, the lack of apparent hepatoxicity is predictable. Acetaminophen induced cellular injury is due to CYP2E1 derived metabolites; and hepatocyte CYP2E1 expression is low in the fetal and neonatal period. Here, we review preclinical and clinical data that support the hypothesis that the lung, which expresses high levels of CYP2E1 during fetal and early postnatal development, may be particularly susceptible to acetaminophen induced toxicity. Despite these emerging data, the true potential pulmonary risks and benefits of acetaminophen for PDA closure are largely unknown. The available clinical studies in are marked by significant weakness including low sample sizes and minimal evaluation of extremely preterm infants who are typically at highest risk of pulmonary morbidity. We propose that studies interrogating mechanisms linking developmentally regulated, cell-specific CYP2E1 expression and acetaminophen-induced toxicity as well as robust assessment of pulmonary outcomes in large trials that evaluate the safety and efficacy of acetaminophen in extremely preterm infants are needed.
Topics: Infant, Newborn; Humans; Ductus Arteriosus, Patent; Acetaminophen; Indomethacin; Infant, Low Birth Weight; Ibuprofen; Cytochrome P-450 CYP2E1; Infant, Extremely Premature
PubMed: 37169914
DOI: 10.1038/s41372-023-01697-2 -
Seminars in Fetal & Neonatal Medicine Aug 2018Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to... (Review)
Review
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.
Topics: Acetaminophen; Animals; Disease Models, Animal; Ductus Arteriosus, Patent; Genetic Predisposition to Disease; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Pharmacogenetics
PubMed: 29510900
DOI: 10.1016/j.siny.2018.02.006 -
Annals of Cardiac Anaesthesia 2021
Topics: Cardiomyopathy, Hypertrophic; Ductus Arteriosus, Patent; Humans
PubMed: 34747769
DOI: 10.4103/aca.ACA_53_20