Does Early Neonatal Thrombocytopenia Affect Ductal Therapeutic Respose to Acetaminophen in Preterm Neonates?

Perinatal thrombocytopenia has been shown to affect responsiveness to therapeutic ductal closure with cyclo-oxygenase inhibitors. This has not been studied in responsiveness to acetaminophen, which has less effect on platelet function. Objective: To evaluate whether thrombocytopenia affects ductal responsiveness to acetaminophen. Study Design: Retrospective review of preterm neonates <1500 gm. Echocardiograms were performed within the first week of life; if ductal status was found to be hemodynamically significant, infants were treated with acetaminophen. Results: We studied 254 infants. Fifty seven of these (22%) had a hemodynamically significant PDA (hsPDA) and were treated with acetaminophen. Forty (70%) of those treated responded with ductal closure after 1-2 courses of acetaminophen. Seventeen infants were considered non-responsive, requiring the addition of ibuprofen and/or surgical ligation. Sixty-seven of the 254 infants (26%) developed moderate thrombocytopenia [platelets <100,000] within the first ten days of life, more within the hsPDA group (54% vs. 18% p<0.001); however, no differences in platelet related parameters were observed when comparing infants with hsPDA who did or did not respond to acetaminophen treatment. Twenty-six of the 67 thrombocytopenic were already thrombocytopenic prior to acetaminophen treatment; and 19 of these 26 (73%) with pre-treatment thrombocytopenia responded to acetaminophen treatment – similar to the overall response rate of 70% . Conclusions: This study is the first to document that, in contrast to the cyclo-oxygenase inhibitors, there is no association between early neonatal thrombocytopenia and ductal therapeutic responsiveness to acetaminophen.

10 High spontaneous ductal closure even at the extreme of prematurity

Primary Subject area Neonatal-Perinatal Medicine Background Extremely preterm newborns are at risk of prolonged patency of the ductus arteriosus (PDA). Current literature has failed to indicate improvement in outcomes after exposure to strategies promoting ductal closure. As such, our center abandoned these practices in 2013. Objectives Describe the spontaneous PDA closure in premature infants, including those infants born at the extreme of gestational age (&lt; 26 weeks). Design/Methods Retrospective study of newborns &lt; 29 weeks, admitted within 24 hours after birth between 2015 and 2019 and without genetic or congenital anomalies. Newborns who were last known to be alive, with an available echocardiography, and who were not exposed to any intervention to accelerate PDA closure were included. Images were reviewed by experts blinded to the outcomes. Results 296 infants were analyzed. 37 (12%) did not survive their hospitalization, and 16 were exposed to interventions to accelerate ductal closure at some point during their lifetime (4 ligations, 4 catheter-closure, 5 ibuprofen and 3 acetaminophen). Out of the 243 remaining newborns, 214 had at least one echocardiography to ascertain ductal patency or closure (100% of those &lt;26 weeks). The average gestational age was 26.3±1.5 weeks, with 84 (39%) being &lt;26 weeks. PDA closed spontaneously in 194 (91%), with 60 having closure ascertainment after discharge (average age at closure ascertainment of 36.4 [IQR: 34.4 – 40.1] weeks). Of the 84 &lt;26 weeks, 76 (90%) had confirmation of ductal closure. The 20 infants with an open PDA at the last evaluation were followed in an outpatient setting and considered small/restrictive. In our cohort, 92/243 (38%) were exposed to post-natal steroids. In the &lt;26 weeks group, 74% were exposed to steroids, at a cumulative dose of 1.64 [0.89 – 2.44] mg/kg. BPD was found in 57% of the overall cohort and in 79% of &lt;26 weeks. Conclusion The majority of newborns &lt; 29 weeks, and even those at the extreme of gestational age (&lt; 26 weeks) spontaneously closed their PDA before term-corrected age. While BPD rate was similar to previous cohorts, post-natal steroids use was high.

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants

<b><i>Introduction:</i></b> This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. <b><i>Methods:</i></b> This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at &#x3c;29-week gestation with a ductus arteriosus &#x3e;0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. <b><i>Results:</i></b> Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [<i>p</i> = 0.003]; relative risk reduction 0.35 [95% CI 0.16–0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [<i>p</i> = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; <i>p</i> = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. <b><i>Discussion/Conclusion:</i></b> Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.

The Comparison Between Intravenous Acetaminophen Versus Oral Ibuprofen in Preterm Newborns With Patent Ductus Arteriosus: A Clinical Trial

Oral ibuprofen has been known as a conventional treatment for closing patent ductus arteriosus (PDA) in preterm newborns. Since the use of it might lead to various side effects, other treatments needed to be evaluated. Therefore in a prospective study, we compared the efficacy and safety of intravenous acetaminophen versus oral ibuprofen for the closure of PDA. In this study which was done prospectively and under control, 50 preterm neonates with gestational ages and weights less than 37 weeks old and 2500 grams, respectively, who had PDA, large enough hemodynamically, were included in the study. The patients were divided into two groups: A (intravenous acetaminophen) & B (oral ibuprofen). The two groups were given at most two 3-day courses of the medication (the second course if necessary) and evaluated at the end of each course by echocardiography so as to determine the response to the treatment at each step. The rate of ductal closure, the need for additional treatment, side effects, complications and the newborn’s clinical status were recorded. The rate of ductal closure in the both groups after one course of treatment was similar and showed no meaningful significance statistically (P=0.306). But that of the side effects was much higher in group B with a P=0.021. Intravenous Acetaminophen is not only as efficacious as oral Ibuprofen for the treatment of PDA in preterm infants, but also is less likely to lead to side effects and complications.

Early Urinary Metabolomics in Patent Ductus Arteriosus Anticipates the Fate: Preliminary Data

Introduction: In premature neonates, the persistence of hemodynamically significant ductus arteriosus (hsPDA) can be associated with short- and long-term consequences, impairing their outcome. The correct strategy of management for such condition is under debate, especially regarding contraindications and/or side effects. In recent years, metabolomics was applied to several perinatal, pediatric, and adult conditions to investigate potential biomarkers of disease, which have become useful for early diagnosis and/or therapeutic management.Aim of the Study: The main purpose of our exploratory study was to asses, through 1H-NMR metabolomics analysis of urinary samples at birth, possible metabolic pathways differentiating, with a significant predictive power, those preterm neonates who will subsequently develop hsPDA and neonates of comparable gestational age (GA) who will undergo spontaneous ductal closure or the persistence of an irrelevant PDA (no-hsPDA). Moreover, we investigated potential prenatal or perinatal clinical factors potentially influencing the development of hsPDA.Materials and Methods: We enrolled n = 35 preterm neonates with GA between 24 and 32 weeks; urinary samples were collected within the first 12 h of life. Patients were closely monitored regarding intensive care, respiratory support, fluid balance and administered drugs; an echocardiogram was performed at 48–72 h.Results: Our results reported a significant correlation between lower GA at birth and the development of hsPDA. Moreover, neonates with GA ≤ 30w developing hsPDA were characterized by lower Apgar scores at 1′ and 5′, higher rates of perinatal asphyxia, higher need of delivery room resuscitation and subsequent surfactant administration. Interestingly, metabolomics analysis at birth detected a clear separation between the 1H-NMR urinary spectra of subjects GA ≤ 30w not developing hsPDA (n = 19) and those of subjects born at GA ≤ 30w in which hsPDA was confirmed at 48–72 h of life (n = 5).Conclusions: This is the first study applying metabolomics to investigate the PDA condition. Although preliminary and conducted on a limited sample, our results reveal that metabolomics could be a promising tool in the early identification of hsPDA, potentially superior to the clinical or laboratory predictive tools explored to date and even to the clinical observations and correlations in our sample, through the detection of specific urinary metabolites.

Use of Prophylactic Indomethacin in Preterm Infants: A Systematic Review and Meta-analysis

BackgroundProphylactic indomethacin has been widely used as an effective intervention for reducing mortalities and morbidities in preterm infants including the cardiopulmonary and neurodevelopmental morbidities as intraventricular hemorrhage (IVH), but many studies have reported contraindicated outcomes of its significance. Therefore, we aim to systematically review and meta-analyze the data of prophylactic indomethacin on preterm infants. MethodsOur systematic search included the following databases: Pubmed, Google Scholar, Scopus, Web of Science, The New York Academy of Medicine (NYAM), Virtual health library (VHL), and the System for Information on Grey Literature in Europe (SIGLE) to include studies that assessed the use of prophylactic indomethacin in preterm infants until August 12, 2020. ResultsThe final list of our included studies is comprised of 22 randomized trials and cohort studies. Our analysis of observational data showed that intubation in the delivery room/first day (74%), bronchopulmonary dysplasia (BPD) (33.2%), and patent ductus arteriosus (PDA) (32.2%) were the most prevalent outcomes in infants that received prophylactic indomethacin. Among all the studies outcomes, the only significant favorable outcome was lowering the rate of PDA (P< 0.001) while no significance was recorded with BPD, pulmonary hemorrhage, neurodevelopmental delays (IVH), mortality, length of hospital stays, and time spent on ventilators outcomes (P = 0.106, 0.123, 0.460, 0.340, 0.625, and 0.732, respectively). Moreover, necrotizing enterocolitis was significantly increased when applying prophylactic indomethacin in these infants (P< 0.001). ConclusionThe use of prophylactic indomethacin in preterm infants should be generally discouraged due to its neutral effect on most of the mortality and morbidity outcomes and the significant occurrence of its adverse events despite the positive effect on ductal closure.

A case series of three patients with unilateral disconnected pulmonary artery supplied by an ipsilateral patent ductus arteriosus: neonatal ductal stenting as palliation to preserve pulmonary arterial patency

Background Disconnected branch pulmonary arteries with a systemic arterial origin of the disconnected vessel is a rare, but well-described entity. Most will have ductal tissue connecting the pulmonary artery to the aorta. Case summary We describe in this paper the haemodynamic result in three neonates presenting with ductal origin of a single branch pulmonary artery in the context of trans-catheter stenting procedures to maintain or re-recruit vessel patency. All were faced with potential or actual ductal closure and proceeded to trans-catheter stenting to re-cannalate the duct-dependent pulmonary artery. Two patients with otherwise normal anatomy struggled post-procedure with pulmonary hypertension and right ventricular dilatation. Both required surgical re-anastomosis of the disconnected pulmonary artery during the same admission—one 26 days post-stenting following failure to wean from high-flow respiratory support and the second 8 days post-stenting following failed extubation. In contrast, a patient with tetralogy of Fallot born at 2.5 kg underwent sequential stenting of the right ventricular outflow tract and then the left-sided ductus. He had a good post-procedural course and thrived for several months before complete repair. Discussion We describe the clinical courses and discuss the resultant haemodynamics, highlighting the importance of flow to each lung, the resulting haemodynamic implications and the compounding effects of additional lesions.

Surgical ligation of patent ductus arteriosus in preterm neonates weighing less than 1,500 g: A 9-year single center experience

Background: The aim of this study was to determine the feasibility and outcomes of early surgical ligation in preterm neonates with hemodynamically significant patent ductus arteriosus (HSPDA) and to investigate predictors for surgical treatment after unsuccessful medical management.Methods: Medical records from the neonatal intensive care unit of Hanyang University Seoul Hospital from January 2010 to December 2018 were retrospectively reviewed. 233 preterm neonates weighing less than 1,500 g with HSPDA were enrolled in our study. Of these preterm neonates, 134 underwent surgical ligation and were subdivided into the early ligation group (n = 49; within 10 days of age) and the late ligation group (n = 85; after 10 days of age).Results: The mean gestational age and birth weight were significantly lower in the patent ductus arteriosus (PDA) ligation group than in the Non-ligation group (p < 0.001). PDA ductal diameter > 2.0 mm (p < 0.001), low Apgar score at 5 minutes (p = 0.033), and chorioamnionitis (p = 0.037) were the predictors for receiving surgical treatment for PDA. Early ligation was significantly associated with a low incidence of culture-proven sepsis (p = 0.004), mechanical ventilator time > 4 weeks (p = 0.007), necrotizing enterocolitis stage (NEC) ≥ III (p = 0.022), and intraventricular hemorrhage (IVH) grade ≥ III (p = 0.035).Conclusions: Early surgical ligation minimizes the adverse effects of HSPDA in predicted preterm neonates who subsequently require surgical treatment for PDA. This result suggests that in preterm neonates weighing less than 1,500 g with HSPDA that is unresponsive to medical treatment, delayed ductal closure should be avoided to reduce severe NEC, severe IVH, culture-proven sepsis, and facilitate earlier endotracheal extubation.