Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants
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SUBMITTER: Mitra S
PROVIDER: S-EPMC6389336 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8812277 | biostudies-literature
Project description:Background: Currently, the first line treatment of persistent ductus arteriosus (PDA) is either indomethacin or ibuprofen. However, the potentially life-threatening side effects associated to their use have prompted physicians to look for alternative options. The incorporation of paracetamol as an alternative to ibuprofen in the management of PDA is still based on insufficient clinical evidence. Hence, more clinical trials are needed to establish a therapeutic role for paracetamol in the management of PDA that take into consideration short- and long-term safety and efficacy outcomes. Study Design: This is a non-inferiority, randomized, multicenter, double-blinded study to evaluate the efficacy, and safety of intravenous (IV) paracetamol vs. IV ibuprofen (standard treatment) for PDA in preterm patients with a gestational age ≤ 30 weeks. At baseline, patients will be randomized (1:1) to treatment with paracetamol or ibuprofen. The primary endpoint is closure of the ductus after the first treatment course. Secondary endpoints are related to effectiveness (need for a second treatment course, rescue treatment, reopening rate, time to definitive closure, need for surgical ligation), safety (early and long-term complications), pharmacokinetics, and pharmacodynamics, pharmacogenetics, pharmacoeconomics, and genotoxicity. Long-term follow-up to 24 months of corrected postnatal age will be performed using Bayley III neurodevelopmental scale. Trial Registration: ClinicalTrials.gov Identifier: NCT04037514. EudraCT: 2015-003177-14.
| S-EPMC7380081 | biostudies-literature
Project description:BackgroundSymptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored.ObjectivesTo determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA.Search methodsWe used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.Selection criteriaWe included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants.Data collection and analysisWe used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding.Main resultsWe included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision.Authors' conclusionsHigh-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.
| S-EPMC8095061 | biostudies-literature
Project description:BackgroundControversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/designThe BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial registrationClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.
| S-EPMC8444433 | biostudies-literature
Project description:ImportanceDespite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA.ObjectivesTo estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates.Data sources and study selectionThe databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA.Data extraction and synthesisData were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses.Main outcomes and measuresPrimary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.ResultsIn 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.Conclusions and relevanceA high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage.Trial registrationPROSPERO Identifier: CRD42015015797.
| S-EPMC5885871 | biostudies-literature
Project description:Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to approximately 70% in infants born at 25 weeks' gestation. Our major goal was to determine if genetic risk factors play a role in patent ductus arteriosus seen in preterm infants.We investigated whether single-nucleotide polymorphisms in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation, and other processes are markers for persistent patency of ductus arteriosus. Initially, 377 single-nucleotide polymorphisms from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of <32 weeks. A family-based association test was performed on genotyping data to evaluate overtransmission of alleles.P values of <.01 were detected for genetic variations found in 7 genes. This prompted additional analysis with an additional set of 162 infants, focusing on the 7 markers with initial P values of <.01, and 1 genetic variant in the angiotensin II type I receptor previously shown to be related to patent ductus arteriosus. Of the initial positive signals, single-nucleotide polymorphisms in the transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 genes remained significant. Additional haplotype analysis revealed genetic variations in prostacyclin synthase to be associated with patent ductus arteriosus. An angiotensin II type I receptor polymorphism previously reported to be associated with patent ductus arteriosus after prophylactic indomethacin administration was not associated with the presence of a patent ductus arteriosus in our population.Overall, our data support a role for genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.
| S-EPMC2734952 | biostudies-literature
Project description:ObjectivePatent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants.Study designPreterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables.ResultsSNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons.ConclusionWe identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.
| S-EPMC6391165 | biostudies-literature
Project description:ObjectivesTo standardize the diagnosis of patent ductus arteriosus (PDA) and report its association with adverse neonatal outcomes in very low birth weight infants (VLBW, birth weight < 1500 g).Study designA multicenter prospective observational study was conducted in Emilia Romagna from March 2018 to October 2019. The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age. A diagnosis of hemodynamically significant PDA (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow pattern, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present.Results218 VLBW infants were included. Among infants treated for PDA closure in the first postnatal week, up to 40% did not have hsPDA on ultrasound, but experienced clinical worsening. The risk of death was 15 times higher among neonates with non-hemodynamically significant PDA (non-hsPDA) compared to neonates with no PDA. In contrast, the risk of death was similar between neonates with hsPDA and neonates with no PDA. The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early treatment for PDA closure. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) increased by 8.7-fold and 18-fold, respectively, when both systemic hypoperfusion and pulmonary overcirculation were present in hsPDA.ConclusionsThe increased risk of mortality in neonates with non-hsPDA underscores the potential inadequacy of criteria for defining hsPDA within the first 3 postnatal days (as they may be adversely affected by other clinically severe factors, i.e. persistent pulmonary hypertension and mechanical ventilation). Parameters such as length, diameter, and morphology may serve as more suitable ultrasound indicators during this period, to be combined with clinical data for individualized management. Additionally, BPD, IVH (grade ≥ 3) and ROP (grade ≥ 3) are associated with hsPDA. The existence of an optimal timeframe for closing PDA to minimize these adverse neonatal outcomes remains uncertain.
| S-EPMC11233010 | biostudies-literature
Project description:The patent ductus arteriosus (PDA) is the most commonly found cardiac condition in neonates. While there have been several studies and thousands of publications on the topic, the decision to treat the PDA is still strongly debated among cardiologists, surgeons, and neonatologists. This is in part due to the shortage of long-term benefits with the interventions studied. Practice variations still exist within sub-specialties and centers. This article briefly summarizes the history, embryology and histology of the PDA. It also succinctly discusses the hemodynamic significance of a PDA which builds the framework to review all the available literature on PDA closure in premature infants, though not a paradigm shift just yet; it introduces transcatheter PDA closure (TCPC) as a possible armament to the clinician for this age-old problem.
| S-EPMC7904697 | biostudies-literature
Project description:Changes in kidney function in extremely preterm infants (EPT) with conservatively managed hemodynamically significant (HS) patent ductus arteriosus (PDA) are not known well. We aimed to present the postnatal course in serum creatinine levels (sCr), prevalence of acute kidney injury (AKI), then relevance between AKI and adverse outcomes in EPT with conservatively managed HS PDA. By review of medical records, we analyzed the postnatal course of sCr and prevalence of stage 3 AKI defined by the modified Kidney Disease Improving Global Outcome (KDIGO) in EPT at gestational age of 23 to 26 weeks with conservatively treated HS PDA. We investigated if the presence and/or prolonged duration of stage 3 AKI elevated the risk of adverse outcomes. The results showed that, neither factor was associated with adverse outcomes. While the average PDA closure date was at postnatal day (P) 41 and 53, sCr peaked at P 10 and 14 and the cumulative prevalence of stage 3 AKI was 57% and 72% in the EPT of 25-26 and 23-24 weeks' gestation, respectively. The high prevalence of stage 3 AKI without adverse outcomes in EPT with conservatively managed HS PDA suggests that it might reflect renal immaturity rather than pathologic conditions.
| S-EPMC7141372 | biostudies-literature