Double Jeopardy: A Distinct Mortality Pattern Among Preterm Infants with Congenital Heart Disease.

Contemporary United States (US) data on the survival of preterm infants with congenital heart disease (CHD) are unavailable despite the over-representation of CHD and improving surgical outcomes in the preterm population. The aim of this study is to use population-based data to compare 1-year survival and early mortality (< 3 days) by gestational age (GA) between preterm infants with and without cyanotic CHD (CCHD) in the US. This national retrospective cohort included all liveborn, preterm infants between 21 and 36 weeks GA with a birth certificate indicating the presence or absence of CCHD (n = 2,654,253) born between 2014 and 2019 in the US. Data were provided by the US Center for Disease Control database linking birth and death certificates. Of liveborn preterm infants, 0.13% (n = 3619) had CCHD. 1-year survival was significantly lower in infants 23-36 weeks with CCHD compared to those without. The greatest survival gap occurred between 28 and 31 weeks (28 weeks adjusted risk difference 37.5%; 95% CI 28.4, 46.5; 31 weeks 37.9%; 30.5, 45.3). Early mortality accounted for more than half of deaths among infants 23-31 weeks with CCHD (23 weeks-68%, CI 46.7, 83.7; 31 weeks-63.9%, 52.9, 73.6). Survival trends demonstrated worsened 1-year survival in infants 35-36 weeks with CCHD over the study period. The pattern of mortality for preterm infants with CCHD is distinct from those without. The significant survival gap in the very preterm population and notably high rate of early death in the infants with CCHD calls for renewed attention to early neonatal intensive care for this dually affected population.

Practice variations for fetal and neonatal congenital heart disease within the Children's Hospitals Neonatal Consortium.

BACKGROUND: Many aspects of care for fetuses and neonates with congenital heart disease (CHD) fall outside standard practice guidelines, leading to the potential for significant variation in clinical care for this vulnerable population. METHODS: We conducted a cross-sectional survey of site sponsors of the Children's Hospitals Neonatal Consortium, a multicenter collaborative of 41 Level IV neonatal intensive care units to assess key areas of clinical practice variability for patients with fetal and neonatal CHD. RESULTS: We received responses from 31 centers. Fetal consult services are shared by neonatology and pediatric cardiology at 70% of centers. Three centers (10%) routinely perform fetal magnetic resonance imaging (MRI) for women with pregnancies complicated by fetal CHD. Genetic testing for CHD patients is routine at 76% of centers. Preoperative brain MRI is standard practice at 5 centers (17%), while cerebral NIRS monitoring is regularly used at 14 centers (48%). Use of electroencephalogram (EEG) after major cardiac surgery is routine in 5 centers (17%). Neurodevelopmental follow-up programs are offered at 30 centers (97%). CONCLUSIONS: Many aspects of fetal and neonatal CHD care are highly variable with evolving shared multidisciplinary models. IMPACT: Many aspects of fetal and neonatal CHD care are highly variable. Genetic testing, placental examination, preoperative neuroimaging, and postoperative EEG monitoring carry a high yield of finding abnormalities in patients with CHD and these tests may contribute to more precise prognostication and improve care. Evidence-based standards for prenatal and postnatal CHD care may decrease inter-center variability.

Safety and Feasibility of Skin-to-Skin Contact in the Delivery Room for High-Risk Cardiac Neonates.

Early skin-to-skin contact (SSC), beginning in the delivery room, provides myriad health benefits for mother and baby. Early SSC in the delivery room is the standard of care for healthy neonates following both vaginal and cesarean delivery. However, there is little published evidence on the safety of this practice in infants with congenital anomalies requiring immediate postnatal evaluation, including critical congenital heart disease (CCHD). Currently, the standard practice following delivery of infants with CCHD in many delivery centers has been immediate separation of mother and baby for neonatal stabilization and transfer to a different hospital unit or a different hospital altogether. However, most neonates with prenatally diagnosed congenital heart disease, even those with ductal-dependent lesions, are clinically stable in the immediate newborn period. Therefore, we sought to increase the percentage of newborns with prenatally diagnosed CCHD who are born in our regional level II-III delivery hospitals who receive mother-baby SSC in the delivery room. Using quality improvement methodology, through a series of Plan-Do-Study-Act cycles we successfully increased mother-baby skin-to-skin contact in the delivery room for eligible cardiac patients born across our city-wide delivery hospitals from a baseline 15% to greater than 50%.

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..

Management of Hypertrophic Cardiomyopathy in a Newborn with Dextro-Transposition of the Great Arteries.

Impaired maternal glucose metabolism during pregnancy can have significant effects on the cardiovascular system of the developing fetus. Early in pregnancy the teratogenic effects may lead to structural heart defects, while later in gestation a form of hypertrophic cardiomyopathy can develop due to overgrowth driven by fetal hyperinsulinism. We describe an infant with the uncommon combination of both dextro-transposition of the great arteries and hypertrophic cardiomyopathy. We emphasize the importance of a longitudinal multi-disciplinary approach, from fetal diagnosis to post-operative management, that allowed for an excellent outcome in this rare combination of severe cardiac malformations.

Impact of Maternal-Fetal Environment on Outcomes Following the Hybrid Procedure in the Single Ventricle Population.

Treatment of infants with hypoplastic left heart syndrome (HLHS) remains challenging, and those affected remain with significant risks for mortality and morbidity throughout their lifetimes. The maternal-fetal environment (MFE) has been shown to affect outcomes for infants with HLHS after the Norwood procedure. The hybrid procedure, comprised of both catheterization and surgical components, is a less invasive option for initial intervention compared to the Norwood procedure. It is unknown how the MFE impacts outcomes following the hybrid procedure. This is a single-center, retrospective study of infants born with HLHS who underwent hybrid palliation from January 2009 to August 2021. Predictor variables analyzed included fetal, maternal, and postnatal factors. The primary outcome was mortality prior to Stage II palliation. We studied a 144-subject cohort. There was a statistically significant difference in mortality prior to stage II palliation in infants with prematurity, small for gestational age, and aortic atresia subtype (p < 0.001, p = 0.009, and p = 0.008, respectively). There was no difference in mortality associated with maternal diabetes, hypertension, obesity, smoking or illicit drug use, or advanced maternal age. State and national area deprivation index scores were associated with increased risk of mortality in the entire cohort, such that infants born in areas with higher deprivation had a higher incidence of mortality. Several markers of an impaired MFE, including prematurity, small for gestational age, and higher deprivation index scores, are associated with mortality following hybrid palliation. Individual maternal comorbidities were not associated with higher mortality. The MFE may be a target for prenatal counseling and future interventions to improve pregnancy and neonatal outcomes in this population.

Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care). DATA SOURCES: PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020. STUDY ELIGIBILITY CRITERIA: Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I2 statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model. RESULTS: Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2-41.6; 31 studies, 2226 infants; I2=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0-14.3; 10 studies, 374 infants; I2=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6-61.5; 5 studies, 39 infants; I2=45%; Luis Furuya-Kanamori index=-0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported. CONCLUSION: The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient-level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.

Follow-up after Percutaneous Patent Ductus Arteriosus Occlusion in Lower Weight Infants.

OBJECTIVES: To describe longer term outcomes for infants <6 kg undergoing percutaneous occlusion of the patent ductus arteriosus (PDA). STUDY DESIGN: This was a retrospective cohort study of infants <6 kg who underwent isolated percutaneous closure of the PDA at a single, tertiary center (2003-2017). Cardiopulmonary outcomes and device-related complications (eg, left pulmonary artery obstruction) were examined for differences across weight thresholds (very low weight, <3 kg; low weight, 3-<6 kg). We assessed composite measures of respiratory status during and beyond the initial hospitalization using linear mixed effects models. RESULTS: In this cohort of lower weight infants, 92 of 106 percutaneous occlusion procedures were successful. Median age and weight at procedure were 3.0 months (range, 0.5-11.1 months) and 3.7 kg (range, 1.4-5.9 kg), respectively. Among infants with pulmonary artery obstruction on initial postprocedural echocardiograms (n = 20 [22%]), obstruction persisted through hospital discharge in 3 infants. No measured variables were associated with device-related complications. Rates of oxygenation failure (28% vs 8%; P < .01) and decreased left ventricular systolic function (29% vs 5%; P < .01) were higher among very low weight than low weight infants. Pulmonary scores decreased (indicating improved respiratory status) following percutaneous PDA closure. CONCLUSIONS: Percutaneous PDA occlusion among lower weight infants is associated with potential longer term improvements in respiratory health. Risks of device-related complications and adverse cardiopulmonary outcomes, particularly among very low weight infants, underscore the need for continued device modification. Before widespread use, clinical trials comparing percutaneous occlusion vs alternative treatments are needed.

Neonatal Compartment Syndrome Associated With Disseminated Intravascular Coagulation.

Neonatal compartment syndrome is a rare, but devastating limb-threatening condition that requires early recognition and timely surgical intervention. We discuss the clinical presentation and management challenges of a neonate with forearm compartment syndrome and disseminated intravascular coagulation.

Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α.

RATIONALE: Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. OBJECTIVES: We sought to determine the contribution of HIF-1α in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. METHODS: We used mice with homozygous conditional deletion of HIF-1α combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses. MEASUREMENTS AND MAIN RESULTS: Tamoxifen-induced smooth muscle-specific deletion of HIF-1α attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures. CONCLUSIONS: These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.

Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation.

RATIONALE: The role of reactive oxygen species (ROS) signaling in the O(2) sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses. OBJECTIVES: We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). METHODS: A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC). MEASUREMENTS AND MAIN RESULTS: In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca(2+)](i). In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca(2+)](i) of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice. CONCLUSIONS: Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca(2+)](i) that cause acute hypoxic pulmonary vasoconstriction.

Hemodynamic instability in the transitional period after birth.

It is not uncommon for a patient to experience hemodynamic instability following birth. This is due to the fact that the transitional period requires dramatic cardiorespiratory changes. When it goes well, improved lung compliance and successful transition to the postnatal circulation is seen. However, it is highly beneficial that clinicians have a solid understanding of all of the required changes, the unique aspects of the neonatal myocardium, and the influence of cardiovascular disease on normal adaptive mechanisms. In this manuscript, we will review the physiology of the normal postnatal circulatory adaptation, the unique characteristics of the neonatal myocardium and how it behaves in states of altered loading conditions, and the impact of hemodynamic disease states on health and wellbeing during the immediate postnatal time-period.

Meconium aspiration syndrome: a comprehensive review.

Meconium aspiration syndrome (MAS) is a complex respiratory disease that continues to be associated with significant morbidities and mortality. The pathophysiological mechanisms of MAS include airway obstruction, local and systemic inflammation, surfactant inactivation and persistent pulmonary hypertension of the newborn (PPHN). Supplemental oxygen and non-invasive respiratory support are the main therapies for many patients. The management of the patients requiring invasive mechanical ventilation could be challenging because of the combination of atelectasis and air trapping. While studies have explored various ventilatory modalities, evidence to date does not clearly support any singular modality as superior. Patient's pathophysiology, symptom severity, and clinician/unit expertise should guide the respiratory management. Early identification and concomitant management of PPHN is critically important as it contributes significantly to mortality and morbidities.

Structural Racism, Social Determinants of Health, and Provider Bias: Impact on Brain Development in Critical Congenital Heart Disease.

Critical congenital heart disease (cCHD) has neurodevelopmental sequelae that can carry into adulthood, which may be due to aberrant brain development or brain injury in the prenatal and perinatal/neonatal periods and beyond. Health disparities based on the intersection of sex, geography, race, and ethnicity have been identified for poorer pre- and postnatal outcomes in the general population, as well as those with cCHD. These disparities are likely driven by structural racism, disparities in social determinants of health, and provider bias, which further compound negative brain development outcomes. This review discusses how aberrant brain development in cCHD early in life is affected by reduced access to quality care (ie, prenatal care and testing, postnatal care) due to divestment in non-White neighbourhoods (eg, redlining) and food insecurity, differences in insurance status, location of residence, and perceived interpersonal racism and bias that disproportionately affects pregnant people of colour who have fewer economic resources. Suggestions are discussed for moving forward with implementing strategies in medical education, clinical care, research, and gaining insight into the communities served to combat disparities and bias while promoting cultural humility.

Perioperative Care Models for Neonates With Congenital Heart Disease: Evolving Role of Neonatology Within the Cardiac Intensive Care Unit.

A multidisciplinary team is needed to optimally care for infants with congenital heart disease (CHD). Different compositions of teams trained in cardiology, critical care, cardiothoracic surgery, anesthesia, and neonatology have been identified as being primarily responsible for perioperative care of this high-risk population in dedicated cardiac intensive care units (CICUs). Although the specific role of cardiac intensivists has become more well defined over the past two decades, the responsibilities of neonatologists remain highly variable in the CICU with neonatologists providing care along with a unique spectrum of primary, shared, or consultative care. The neonatologist can function as the primary physician and assume all or share responsibility with the cardiac intensivists for the management of infants with CHD. A neonatologist can provide care as a secondary consultant physician in a supportive role for the primary CICU team. Additionally, neonates with CHD can be mixed with older children in a CICU, cohorted in a dedicated space within the CICU or placed in a stand-alone infant CICU without older children. Although variations exist between centers on which model of care is deployed and the location within a CICU, characterization of current practice patterns represents the initial step required to determine optimal best practices to improve the quality of care for neonates with cardiac disease. In this manuscript, we present four models utilized in the United States in which the neonatologist provides neonatal-cardiac-focused care in a dedicated CICU. We also outline the different permutations of location where neonates can be cared for in dedicated pediatric/infant CICUs.

Rethinking Congenital Heart Disease in Preterm Neonates.

Congenital heart disease (CHD) and prematurity are the leading causes of infant mortality in the United States. Importantly, the combination of prematurity and CHD results in a further increased risk of mortality and significant morbidity. The key factors in these adverse outcomes are not well understood, but likely include maternal-fetal environment, perinatal and neonatal elements, and challenging postnatal care. Preterm neonates with CHD are born with "double jeopardy": not only do they experience challenges related to immaturity of the lungs, brain, and other organs, but they also must undergo treatment for cardiac disease. The role of the neonatologist caring for preterm infants with CHD has changed with the evolution of the field of pediatric cardiac critical care. Increasingly, neonatologists invested in the cardiovascular care of the newborn with CHD engage at multiple stages in their course, including fetal consultation, delivery room management, preoperative care, and postoperative treatment. A more comprehensive understanding of prematurity and CHD may inform clinical practice and ultimately improve outcomes in preterm infants with CHD. In this review, we discuss the current evidence surrounding neonatal and cardiac outcomes in preterm infants with CHD; examine the prenatal, perinatal, and postnatal factors recognized to influence these outcomes; identify knowledge gaps; consider research and clinical opportunities; and highlight the ways in which a neonatologist can contribute to the care of preterm infants with CHD.

Training pathways and careers for neonatologists interested in cardiovascular care.

Neonatologists and neonatal-perinatal trainees continue to be invested in the cardiovascular care of the newborn, many focusing their careers in this area of expertise. Multiple formalized structured and non-structured training pathways have evolved for neonatologists caring for infants with congenital heart disease and other cardiovascular pathologies. Furthermore, the evolution of neonatal hemodynamic science over the past decade has also spawned a formal training pathway in hemodynamics consultation to enhance standard of care and guide the management of infants at risk for cardiovascular compromise. Neonatologists have also chosen to expand upon on their neonatology training with clinical and research exposure to enhance their roles in neonatal cardiovascular care, including fetal care consultation, delivery room management, and perioperative cardiac intensive care consultation. To provide insight and career guidance to interested neonatal trainees and early career physicians, this perspective article highlights several different pathways in the care of neonates with cardiovascular disease.

Primary Pulmonary Vein Stenosis: A New Look at a Rare but Challenging Disease.

Primary pulmonary vein stenosis (PPVS) represents a rare but emerging, often progressive heterogeneous disease with high morbidity and mortality in the pediatric population. Although our understanding of PPVS disease has improved markedly in recent years, much remains unknown regarding disease pathogenesis, distinct disease phenotypes, and patient- and disease-related risk factors driving the unrelenting disease progression characteristic of PPVS. In the pediatric population, risk factors identified in the development of PPVS include an underlying congenital heart disease, prematurity and associated conditions, and an underlying genetic or congenital syndrome. Continued improvement in the survival of high-risk populations, coupled with ongoing advances in general PPVS awareness and diagnostic imaging technologies suggest that PPVS will be an increasingly prevalent disease affecting pediatric populations in the years to come. However, significant challenges persist in both the diagnosis and management of PPVS. Standardized definitions and risk stratification for PPVS are lacking. Furthermore, evidence-based guidelines for screening, monitoring, and treatment remain to be established. Given these limitations, significant practice variation in management approaches has emerged across centers, and contemporary outcomes for patients affected by PPVS remain guarded. To improve care and outcomes for PPVS patients, the development and implementation of universal definitions for disease and severity, as well as evidence-based guidelines for screening, monitoring, cardiorespiratory care, and indications for surgical intervention will be critical. In addition, collaboration across institutions will be paramount in the creation of regionalized referral centers as well as a comprehensive patient registry for those requiring pulmonary vein stenosis.