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Patent Ductus Arteriosus of the Preterm Infant.
Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, Hansmann G
(2020) Pediatrics 146:
MeSH Terms: Algorithms, Ductus Arteriosus, Patent, Humans, Infant, Newborn, Infant, Premature
Show Abstract · Added January 7, 2021
Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.
Copyright © 2020 by the American Academy of Pediatrics.
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MeSH Terms
Pharmacological closure of the patent ductus arteriosus: when treatment still makes sense.
Gillam-Krakauer M, Hagadorn JI, Reese J
(2019) J Perinatol 39: 1439-1441
MeSH Terms: Acetaminophen, Cyclooxygenase Inhibitors, Decision Making, Ductus Arteriosus, Patent, Humans, Indomethacin, Infant, Infant, Low Birth Weight, Infant, Newborn, Infant, Premature
Added July 28, 2020
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is associated with indomethacin treatment failure for patent ductus arteriosus.
Rooney SR, Shelton EL, Aka I, Shaffer CM, Clyman RI, Dagle JM, Ryckman K, Lewis TR, Reese J, Van Driest SL, Kannankeril PJ
(2019) Pharmacogenomics 20: 939-946
MeSH Terms: Cohort Studies, Cyclooxygenase Inhibitors, Cytochrome P-450 CYP2C9, Ductus Arteriosus, Patent, Female, Gestational Age, Humans, Indomethacin, Infant, Infant, Newborn, Infant, Premature, Male, Treatment Failure, Treatment Outcome
Show Abstract · Added July 28, 2020
To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). This is a multicenter cohort study of 144 preterm infants (22-32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60-0.96), surfactant use (AOR 9.77, 95% CI 1.15-83.26), and (AOR 3.74; 95% CI 1.34-10.44) were each associated with indomethacin failure. Age, surfactant use, and influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.
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Molecular and mechanical factors contributing to ductus arteriosus patency and closure.
Crockett SL, Berger CD, Shelton EL, Reese J
(2019) Congenit Heart Dis 14: 15-20
MeSH Terms: Cardiac Surgical Procedures, Ductus Arteriosus, Ductus Arteriosus, Patent, Hemodynamics, Humans, Infant, Newborn, Oxidative Stress
Show Abstract · Added November 26, 2018
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.
© 2019 Wiley Periodicals, Inc.
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7 MeSH Terms
PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.
Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A, PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators
(2019) J Pediatr 205: 41-48.e6
MeSH Terms: Acetaminophen, Conservative Treatment, Continuous Positive Airway Pressure, Cyclooxygenase Inhibitors, Ductus Arteriosus, Patent, Female, Gestational Age, Humans, Ibuprofen, Indomethacin, Infant, Extremely Premature, Infant, Newborn, Male, Prospective Studies, Single-Blind Method, Treatment Outcome
Show Abstract · Added March 23, 2019
OBJECTIVE - To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.
STUDY DESIGN - A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.
RESULTS - At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).
CONCLUSIONS - In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.
TRIAL REGISTRATION - ClinicalTrials.gov: NCT01958320.
Copyright © 2018 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.
Shelton EL, Waleh N, Plosa EJ, Benjamin JT, Milne GL, Hooper CW, Ehinger NJ, Poole S, Brown N, Seidner S, McCurnin D, Reese J, Clyman RI
(2018) Pediatr Res 84: 458-465
MeSH Terms: Animals, Betamethasone, Ductus Arteriosus, Ductus Arteriosus, Patent, Echocardiography, Female, Gene Expression Profiling, Gene Expression Regulation, Humans, Infant, Premature, Maternal Exposure, Mice, Oxygen, Papio, Polymerase Chain Reaction, Prostaglandins
Show Abstract · Added November 26, 2018
BACKGROUND - Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.
METHODS - We used preterm baboons, mice, and humans (≤27 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.
RESULTS - In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤25 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.
CONCLUSIONS - We speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth.
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16 MeSH Terms
Changing patterns of patent ductus arteriosus surgical ligation in the United States.
Reese J, Scott TA, Patrick SW
(2018) Semin Perinatol 42: 253-261
MeSH Terms: Cerebral Intraventricular Hemorrhage, Cross-Sectional Studies, Ductus Arteriosus, Patent, Enterocolitis, Necrotizing, Female, Humans, Infant, Extremely Low Birth Weight, Infant, Newborn, Infant, Very Low Birth Weight, Ligation, Male, Practice Patterns, Physicians', Retrospective Studies, Treatment Outcome, United States, Vocal Cord Paralysis
Show Abstract · Added November 26, 2018
Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids' Inpatient Database (2000-2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2-3.9%); however, mortality decreased (12.4-6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Copyright © 2018 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing.
Yarboro MT, Durbin MD, Herington JL, Shelton EL, Zhang T, Ebby CG, Stoller JZ, Clyman RI, Reese J
(2018) Semin Perinatol 42: 212-220
MeSH Terms: Animals, Animals, Newborn, Ductus Arteriosus, Embryo, Mammalian, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genetic Association Studies, Humans, Microarray Analysis, Models, Animal, Rodentia, Sequence Analysis, RNA, Species Specificity, Vascular Patency
Show Abstract · Added November 26, 2018
DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Towards a greater understanding of the ductus arteriosus.
Reese J
(2018) Semin Perinatol 42: 199-202
MeSH Terms: Cardiovascular Surgical Procedures, Ductus Arteriosus, Ductus Arteriosus, Patent, History, 15th Century, History, 20th Century, History, Ancient, Humans, Infant, Newborn, Infant, Premature, Perinatology
Added November 26, 2018
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10 MeSH Terms
Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment.
Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J
(2018) Semin Fetal Neonatal Med 23: 232-238
MeSH Terms: Acetaminophen, Animals, Disease Models, Animal, Ductus Arteriosus, Patent, Genetic Predisposition to Disease, Humans, Ibuprofen, Indomethacin, Infant, Newborn, Infant, Premature, Pharmacogenetics
Show Abstract · Added March 31, 2018
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.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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11 MeSH Terms