At a crossroads for early medical treatment of persistent patent ductus arteriosus in preterm infants.

Administration of early medical therapy for the patent ductus arteriosus has ebbed and flowed through the years, with a multitude of studies failing to demonstrate a reduction in morbidity or mortality from ductal closure in the preterm population. Concerningly, an increasing number of studies have demonstrated an increase in morbidity, such as bronchopulmonary dysplasia and mortality with the use of early medical therapy to close the ductus. Considering information regarding potential risk without clear benefit in an overall cohort of preterm patients with a patent ductus, use of early medical therapy is increasingly challenging to justify and necessitates studies that will aid in identifying a patient population that would benefit from ductal closure and timing of therapy.

Cardiorespiratory Instability after Percutaneous Patent Ductus Arteriosus Closure: A Multicenter Cohort Study.

OBJECTIVE: To evaluate postprocedural clinical characteristics of preterm infants undergoing transcatheter patent ductus arteriosus (PDA) closure, including oxygenation/ventilation failure and cardiovascular compromise. STUDY DESIGN: Multicenter retrospective cohort study of preterm infants who were ≤2 kg at the time of percutaneous PDA closure between August 2018 and July 2021. Indices of cardiorespiratory stability were collected pre-closure, immediately post-closure, and subsequently averaged every 4 hours for the first 24 hours post-procedure. The primary outcome was incidence of post-transcatheter cardiorespiratory syndrome: composite of hemodynamic instability (defined by systemic hypotension, systemic hypertension, or use of new inotropes/vasopressors in the first 24 hours after catheterization) and at least one of the following: (i) ventilation failure or (ii) oxygenation failure. RESULTS: A total of 197 patients were included with a median [IQR] age and weight at catheterization of 34 [25, 43] days and 1090 [900, 1367] grams, respectively. The primary composite outcome of post-transcatheter cardiorespiratory syndrome was reported in 46 (23.3%). CONCLUSION: Post-transcatheter cardiorespiratory syndrome is characterized primarily by systemic hypertension and oxygenation failure, with a very low incidence of hypotension and need for inotropes.

Association of the respiratory severity score with bronchopulmonary dysplasia-associated pulmonary hypertension in infants born extremely preterm.

OBJECTIVE: To test the hypothesis that elevations in the respiratory severity score (RSS) are associated with increased probability of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). STUDY DESIGN: Retrospective cohort study of infants born extremely preterm admitted to a BPD center between 2010 and 2018. Echocardiograms obtained ≥ 36 weeks' post-menstrual age (PMA) were independently adjudicated by two blinded cardiologists to determine the presence/absence of BPD-PH. Multivariable logistic regression estimated the association between RSS and BPD-PH. RESULT: BPD-PH was observed in 68/223 (36%) of subjects. The median RSS at time of echocardiography was 3.04 (Range 0-18.3). A one-point increase in the RSS was associated with BPD-PH, aOR 1.3 (95% CI 1.2-1.4), after adjustment for gestational age and PMA at time of echocardiography. CONCLUSION: Elevations in the RSS were associated with a greater probability of BPD-PH. Prospective studies are needed to determine the validity and performance of RSS as a clinical susceptibility/risk biomarker for BPD-PH.

Secular Trends in Patent Ductus Arteriosus Management in Infants Born Preterm in the National Institute of Child Health and Human Development Neonatal Research Network.

We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of US academic hospitals. PDA treatment decreased among infants born at 26-28 weeks but not among infants born at 22-25 weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.

Trends in Procedural Closure of the Patent Ductus Arteriosus among Infants Born at 22 to 30 Weeks' Gestation.

OBJECTIVE: To describe recent trend in procedural closure of the patent ductus arteriosus (PDA) among premature infants and compare the clinical characteristics of infants receiving surgical vs transcatheter closure. STUDY DESIGN: We conducted a descriptive, retrospective cohort study of preterm infants born between 220/7 and 296/7 weeks' gestation from 2014 through 2021. Infants were identified from the Pediatrix Clinical Data Warehouse. We excluded infants with any major congenital anomaly. We identified all preterm infants with a PDA and all those who underwent procedural closure (surgical ligation or transcatheter occlusion) and compared changes over time using ANOVA for continuous variables and the Cochran-Armitage trend test to evaluate time-related changes in proportions. RESULTS: The study cohort included 64 580 infants, of whom 24 028 (37.2%) were diagnosed with a PDA. The number of infants receiving any procedural closure of the PDA decreased from 371 (4.4%) in 2014 to 144 (1.9%) in 2021. During the same period, number of surgical ligations decreased from 369 (4.36%) to 64 (0.84%), and the number of transcatheter occlusions increased from 2 (0.02%) to 80 (1.05% p for all < 0.001). The median age at time of surgical ligation increased from 25 days (10th and 90th percentile, 10, 61) to 31 days (10th and 90th percentile, 16, 66), and the median age of transcatheter occlusion decreased from 103 days (10th and 90th percentile, 32, 150) to 43 days (10th and 90th percentile, 22, 91). CONCLUSIONS: There was a decrease in surgical closure and an increase in transcatheter occlusion of the PDA in infants born at 22-30 weeks' gestation from 2014 to 2021. Despite the decline in overall procedural closure, the rate of transcatheter occlusion surpassed surgical ligation by 2021. Narrowing differences in the median age and weight at closure suggest increasing overlap in the types of infants who received each type of procedural closure.

Percutaneous Closure of the Patent Ductus Arteriosus in Infants ≤2 kg: IMPACT Registry Insights.

OBJECTIVES: Percutaneous patent ductus arteriosus (PDA) closure is becoming the standard of care for definitive closure in progressively smaller and younger neonates. The objective of this study was to assess safety and feasibility of percutaneous PDA closure in patients ≤2 kg. METHODS: This was a cohort study using the IMPACT Registry (Improving Pediatric and Adult Congenital Treatments) from the American College of Cardiology Foundation's National Cardiovascular Data Registry. Patients who were ≤2 kg at the time of percutaneous PDA closure were included. The primary outcome was the composite of technical failure and/or major adverse event. RESULTS: A total of 1587 attempted PDA closures were included, with a 3% incidence of technical failure and 5.5% incidence of the composite outcome. Major adverse events were observed in 3.8% of the patients; the most common events were device embolization requiring retrieval and unplanned cardiac or vascular surgery in 1.3% and 1.3% of cases, respectively. The incidence of the composite outcome was associated with the need for arterial access (P < .001) as well as annual hospital volume of percutaneous PDA closures in infants ≤2 kg (P = .001). The incidence of the composite outcome has decreased overtime, whereas median weight at the time of procedure has also diminished. CONCLUSIONS: Percutaneous PDA closure appears to be safe and feasible procedures in infants ≤2 kg. The incidence of major adverse events has continued to decline over the years and seems to have a strong correlation with individual center case volumes and expertise.

Evaluating the evidence behind umbilical cord clamping practices in at-risk neonatal populations.

Umbilical cord clamping practices impact nearly 140 million births each year. Current evidence has led professional organizations to recommend delayed cord clamping (DCC), as opposed to early cord clamping (ECC), as the standard of care in uncomplicated term and preterm deliveries. However, variability remains in cord management practices for maternal-infant dyads at higher risk of complications. This review examines the current state of evidence on the outcomes of at-risk infant populations receiving differing umbilical cord management strategies. Review of contemporary literature demonstrates members of high-risk neonatal groups, including those affected by small for gestational age (SGA) classification, intrauterine growth restriction (IUGR), maternal diabetes, and Rh-isoimmunization, are frequently excluded from participation in clinical trials of cord clamping strategies. Furthermore, when these populations are included, outcomes are often underreported. Consequently, evidence regarding optimal umbilical cord management in at-risk groups is limited, and further research is needed to guide best clinical practice.

The MPRINT Hub Data, Model, Knowledge and Research Coordination Center: Bridging the gap in maternal-pediatric therapeutics research through data integration and pharmacometrics.

Maternal and pediatric populations have historically been considered "therapeutic orphans" due to their limited inclusion in clinical trials. Physiologic changes during pregnancy and lactation and growth and maturation of children alter pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Precision therapy in these populations requires knowledge of these effects. Efforts to enhance maternal and pediatric participation in clinical studies have increased over the past few decades. However, studies supporting precision therapeutics in these populations are often small and, in isolation, may have limited impact. Integration of data from various studies, for example through physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling or bioinformatics approaches, can augment the value of data from these studies, and help identify gaps in understanding. To catalyze research in maternal and pediatric precision therapeutics, the Obstetric and Pediatric Pharmacology and Therapeutics Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub. Herein, we provide an overview of the status of maternal-pediatric therapeutics research and introduce the Indiana University-Ohio State University MPRINT Hub Data, Model, Knowledge and Research Coordination Center (DMKRCC), which aims to facilitate research in maternal and pediatric precision therapeutics through the integration and assessment of existing knowledge, supporting pharmacometrics and clinical trials design, development of new real-world evidence resources, educational initiatives, and building collaborations among public and private partners, including other NICHD-funded networks. By fostering use of existing data and resources, the DMKRCC will identify critical gaps in knowledge and support efforts to overcome these gaps to enhance maternal-pediatric precision therapeutics.

Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn, or PPHN, represents a challenging condition associated with high morbidity and mortality. Management is complicated by complex pathophysiology and limited neonatal specific evidence-based literature, leading to a lack of universal contemporary clinical guidelines for the care of these patients. To address this need and to provide consistent high-quality clinical care for this challenging population in our neonatal intensive care unit, we sought to develop a comprehensive clinical guideline for the acute stabilization and management of neonates with PPHN. Utilizing cross-disciplinary expertise and incorporating an extensive literature search to guide best practice, we present an approachable, pragmatic, and clinically relevant guide for the bedside management of acute PPHN. KEY POINTS: · PPHN is associated with several unique diagnoses; the associated pathophysiology is different for each unique diagnosis.. · PPHN is a challenging, dynamic, and labile process for which optimal care requires frequent reassessment.. · Key management goals are adequate tissue oxygen delivery, avoiding harm..

A review and guide to nutritional care of the infant with established bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) remains the most common long-term morbidity of premature birth, and the incidence of BPD is not declining despite medical advancements. Infants with BPD are at high risk for postnatal growth failure and are often treated with therapies that suppress growth. Additionally, these infants may display excess weight gain relative to linear growth. Optimal growth and nutrition are needed to promote lung growth and repair, improve long-term pulmonary function, and improve neurodevelopmental outcomes. Linear growth in particular has been associated with favorable outcomes yet can be difficult to achieve in these patients. While there has been a significant clinical and research focus regarding BPD prevention and early preterm nutrition, there is a lack of literature regarding nutritional care of the infant with established BPD. There is even less information regarding how nutritional needs change as BPD evolves from an acute to chronic disease. This article reviews the current literature regarding nutritional challenges, enteral nutrition management, and monitoring for patients with established BPD. Additionally, this article provides a practical framework for interdisciplinary nutritional care based on our clinical experience at the Comprehensive Center for Bronchopulmonary Dysplasia.

Morbidity and mortality in neonates with Down Syndrome based on gestational age.

BACKGROUND: Greater than 50% of neonates with Down Syndrome (DS) have perinatal complications that require admission to the neonatal intensive care unit (NICU) at birth. Previous studies have shown increased morbidity and mortality rates in neonates without DS delivered prior to 39 weeks of completed gestation. OBJECTIVE: To determine if an association exists between gestational age at delivery and adverse outcomes in neonates with DS. STUDY DESIGN: Neonates with DS admitted to a large, tertiary care center NICU from 2010 to 2020 were evaluated. Gestational age (GA) was stratified into 4 groups: <34 (preterm), 34-36 (late-preterm), 37-38 (early-term) and ≥39 (term + post-term) completed weeks. Fisher's exact tests were used to evaluate morbidity and mortality rates between groups. RESULT: Of the 314 neonates with DS, 10% (N = 31) were <34 weeks, 22% (N = 68) 34-36 weeks, 40% (N = 127) 37-38 weeks, and 28% (N = 88) ≥39 completed weeks at birth. Baseline characteristics were similar between groups. GA at birth <34 weeks was associated with a higher in-hospital mortality rate when compared to those born 37-38 (19% vs. 0%, P < 0.001) and ≥39 (19% vs. 3%, P = 0.01). Neonates with DS born <34 weeks had a higher likelihood of oxygen requirement at time of discharge compared to 34-36, 37-38, and ≥39 groups (P = 0.01; P < 0.001; P < 0.001 respectively). Neonates with DS < 34 weeks were more likely to develop necrotizing enterocolitis (P = 0.02) and require nitric oxide (P = 0.014) compared to neonates with DS ≥ 39. We observed no differences in the need for surgical interventions between groups aside from the rate of gastrostomy/jejunostomy tube placement between 34-36 weeks and 37-38 weeks GA. CONCLUSION: Neonates with DS born preterm (<34 weeks) represent a highly vulnerable subgroup. Multidisciplinary strategies are needed to address their higher rates of morbidity and mortality.

Patent Ductus Arteriosus: A Contemporary Perspective for the Pediatric and Adult Cardiac Care Provider.

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer-term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence-based medicine.

Prevalence of and Risk Factors for Iron Deficiency in Twin and Singleton Newborns.

Iron deficiency (ID) in utero and in infancy can cause irreversible neurocognitive damage. Iron status is not routinely tested at birth, so the burden of neonatal ID in the United States is unknown. Infants born from twin or higher-order pregnancies may be at elevated risk of inadequate nutrient endowment at birth. The present study sought to compare the burden of neonatal ID in cord blood serum samples from twin (n = 54) and singleton pregnancies (n = 24). Iron status (serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) biomarker concentrations were measured by immunoassay. The prevalence of ID (SF < 76 ng/mL) among twins was 21% (23/108) and among singletons 20% (5/24). Gestational age at birth, maternal race and infant sex predicted SF levels. Maternal anemia (hemoglobin < 11 g/dL) was observed in 40% of mothers but was not associated with neonatal iron biomarkers. More research is needed to identify risk factors and regulatory mechanisms for inadequate fetal iron accrual to identify higher risk pregnancies and neonates for screening and intervention.

Trends in Active Treatment of Live-born Neonates Between 22 Weeks 0 Days and 25 Weeks 6 Days by Gestational Age and Maternal Race and Ethnicity in the US, 2014 to 2020.

Importance: Birth in the periviable period between 22 weeks 0 days and 25 weeks 6 days' gestation is a major source of neonatal morbidity and mortality, and the decision to initiate active life-saving treatment is challenging. Objective: To assess whether the frequency of active treatment among live-born neonates in the periviable period has changed over time and whether active treatment differed by gestational age at birth and race and ethnicity. Design, Setting, and Participants: Serial cross-sectional descriptive study using National Center for Health Statistics natality data from 2014 to 2020 for 61 908 singleton live births without clinical anomalies between 22 weeks 0 days and 25 weeks 6 days in the US. Exposures: Year of delivery, gestational age at birth, and race and ethnicity of the pregnant individual, stratified as non-Hispanic Asian/Pacific Islander, non-Hispanic Black, Hispanic/Latina, and non-Hispanic White. Main Outcomes and Measures: Active treatment, determined by whether there was an attempt to treat the neonate and defined as a composite of surfactant therapy, immediate assisted ventilation at birth, assisted ventilation more than 6 hours in duration, and/or antibiotic therapy. Frequencies, mean annual percent change (APC), and adjusted risk ratios (aRRs) were estimated. Results: Of 26 986 716 live births, 61 908 (0.2%) were periviable live births included in this study: 5% were Asian/Pacific Islander, 37% Black, 24% Hispanic, and 34% White; and 14% were born at 22 weeks, 21% at 23 weeks, 30% at 24 weeks, and 34% at 25 weeks. Fifty-two percent of neonates received active treatment. From 2014 to 2020, the overall frequency (mean APC per year) of active treatment increased significantly (3.9% [95% CI, 3.0% to 4.9%]), as well as among all racial and ethnic subgroups (Asian/Pacific Islander: 3.4% [95% CI, 0.8% to 6.0%]); Black: 4.7% [95% CI, 3.4% to 5.9%]; Hispanic: 4.7% [95% CI, 3.4% to 5.9%]; and White: 3.1% [95% CI, 1.1% to 4.4%]) and among each gestational age range (22 weeks: 14.4% [95% CI, 11.1% to 17.7%] and 25 weeks: 2.9% [95% CI, 1.5% to 4.2%]). Compared with neonates born to White individuals (57.0%), neonates born to Asian/Pacific Islander (46.2%; risk difference [RD], -10.81 [95% CI, -12.75 to -8.88]; aRR, 0.82 [95% CI, [0.79-0.86]), Black (51.6%; RD, -5.42 [95% CI, -6.36 to -4.50]; aRR, 0.90 [95% CI, 0.89 to 0.92]), and Hispanic (48.0%; RD, -9.03 [95% CI, -10.07 to -7.99]; aRR, 0.83 [95% CI, 0.81 to 0.85]) individuals were significantly less likely to receive active treatment. Conclusions and Relevance: From 2014 to 2020 in the US, the frequency of active treatment among neonates born alive between 22 weeks 0 days and 25 weeks 6 days significantly increased, and there were differences in rates of active treatment by race and ethnicity.

Percutaneous Closure of Patent Ductus Arteriosus.

Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of adverse events obscures current safety profile assessments. Although data on the risks of postdevice closure syndrome remain promising, a lack of comparative trials of surgical ductal ligation and inconsistent surveillance across published studies obscure confidence in present estimates of safety and efficacy. To minimize risk and yield the greatest benefits, clinical studies of patent ductus arteriosus treatment should consider incorporating more robust assessments to ensure that infants at greatest risk for adverse ductal consequences are included.