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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.

Background While intercenter variation (ICV) in anti-epileptic drug (AED) use in neonates with seizures has been previously reported, variation in AED practices across regional NICUs has not been specifically and systematically evaluated. This is important as these centers typically have multidisciplinary neonatal neurocritical care teams and protocolized approaches to treating conditions such as hypoxic ischemic encephalopathy (HIE), a population at high risk for neonatal seizures. To identify opportunities for quality improvement (QI), we evaluated ICV in AED utilization for neonates with HIE treated with therapeutic hypothermia (TH) across regional NICUs in the US. Methods Children’s Hospital Neonatal Database and Pediatric Health Information Systems data were linked for 1658 neonates ≥36 weeks’ gestation, > 1800 g birthweight, with HIE treated with TH, from 20 NICUs, between 2010 and 2016. ICV in AED use was evaluated using a mixed-effect regression model. Rates of AED exposure, duration, prescription at discharge and standardized AED costs per patient were calculated as different measures of utilization. Results Ninety-five percent (range: 83–100%) of patients with electrographic seizures, and 26% (0–81%) without electrographic seizures, received AEDs. Phenobarbital was most frequently used (97.6%), followed by levetiracetam (16.9%), phenytoin/fosphenytoin (15.6%) and others (2.4%; oxcarbazepine, topiramate and valproate). There was significant ICV in all measures of AED utilization. Median cost of AEDs per patient was $89.90 (IQR $24.52,$258.58). Conclusions Amongst Children’s Hospitals, there is marked ICV in AED utilization for neonatal HIE. Variation was particularly notable for HIE patients without electrographic seizures, indicating that this population may be an appropriate target for QI processes to harmonize neuromonitoring and AED practices across centers.

To compare treatment failure between: (1) infants treated with phenobarbital versus levetiracetam for first-line treatment and (2) infants treated with phenytoin versus levetiracetam for second-line treatment following phenobarbital.This retrospective cohort study included infants with seizures receiving phenobarbital or levetiracetam as the initial anti-seizure medication. Treatment failure was defined as the need for additional anti-seizure medication within 24-72 h and compared using mixed-effect logistic regression after adjustment for confounding factors, including center.In this cohort of 6842 infants, the incidence of treatment failure was 31% vs. 38% in infants receiving first-line phenobarbital versus levetiracetam (adjusted OR: 0.70; 95% CI 0.58-0.84). There was no significant difference in second-line treatment failure (adjusted OR: 1.31; 95% CI 0.92-1.86).First-line treatment of neonatal seizures with phenobarbital is associated with a lower rate of treatment failure than levetiracetam. There was no significant difference in second-line treatment failure.

OBJECTIVES: To develop predictive models for death or neurodevelopmental impairment (NDI) after neonatal hypoxic-ischemic encephalopathy (HIE) from data readily available at the time of NICU admission (“early”) or discharge (“cumulative”). METHODS: In this retrospective cohort analysis, we used data from the Children’s Hospitals Neonatal Consortium Database (2010–2016). Infants born at ≥35 weeks’ gestation and treated with therapeutic hypothermia for HIE at 11 participating sites were included; infants without Bayley Scales of Infant Development scores documented after 11 months of age were excluded. The primary outcome was death or NDI. Multivariable models were generated with 80% of the cohort; validation was performed in the remaining 20%. RESULTS: The primary outcome occurred in 242 of 486 infants; 180 died and 62 infants surviving to follow-up had NDI. HIE severity, epinephrine administration in the delivery room, and respiratory support and fraction of inspired oxygen of 0.21 at admission were significant in the early model. Severity of EEG findings was combined with HIE severity for the cumulative model, and additional significant variables included the use of steroids for blood pressure management and significant brain injury on MRI. Discovery models revealed areas under the curve of 0.852 for the early model and of 0.861 for the cumulative model, and both models performed well in the validation cohort (goodness-of-fit χ2: P = .24 and .06, respectively). CONCLUSIONS: Establishing reliable predictive models will enable clinicians to more accurately evaluate HIE severity and may allow for more targeted early therapies for those at highest risk of death or NDI.

Objective This study was aimed to describe utilization of therapeutic hypothermia (TH) in neonates presenting with mild hypoxic-ischemic encephalopathy (HIE) and associated neurological injury on magnetic resonance imaging (MRI) scans in these infants. Study Design Neonates ≥ 36 weeks' gestation with mild HIE and available MRI scans were identified. Mild HIE status was assigned to hyper alert infants with an exaggerated response to arousal and mild HIE as the highest grade of encephalopathy recorded. MRI scans were dichotomized as “injury” versus “no injury.” Results A total of 94.5% (257/272) neonates with mild HIE, referred for evaluation, received TH. MRI injury occurred in 38.2% (104/272) neonates and affected predominantly the white matter (49.0%, n = 51). Injury to the deep nuclear gray matter was identified in (10.1%) 20 infants, and to the cortex in 13.4% (n = 14 infants). In regression analyses (odds ratio [OR]; 95% confidence interval [CI]), history of fetal distress (OR = 0.52; 95% CI: 0.28–0.99) and delivery by caesarian section (OR = 0.54; 95% CI: 0.31–0.92) were associated with lower odds, whereas medical comorbidities during and after cooling were associated with higher odds of brain injury (OR = 2.31; 95% CI: 1.37–3.89). Conclusion Majority of neonates with mild HIE referred for evaluation are being treated with TH. Odds of neurological injury are over two-fold higher in those with comorbidities during and after cooling. Brain injury predominantly involved the white matter. Key Points

Importance Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, setting, and participants This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main outcomes and measures The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and relevance Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial registration ClinicalTrials.gov Identifier: NCT01192776.

Quantify antimicrobial therapy (AMT) use in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia (HIE/TH). Newborns with HIE/TH were identified from the Children’s Hospital Neonatal Database (CHND). Early infection (onset ≤7 days of life) was defined as “confirmed” (culture proven) or “suspected infection” (culture negative but treated) and compared with a “no infection” group. 1501/1534 (97.8%) neonates received AMT. 36 (2.3%) had confirmed, 255 (16.6%) suspected, and 1243 (81.0%) had no infection. The median (IQR) AMT duration was 13 (8–21), 8 (7–10), and 3 (3–7) days for the three groups, respectively (p

Purpose We describe the frequency and timing of withdrawal of life-support (WLS) in moderate or severe hypoxic-ischemic encephalopathy (HIE) and examine its associations with medical and sociodemographic factors. Procedures We undertook a secondary data analysis of a prospective multicenter data registry of regional level IV Neonatal Intensive Care Units participating in the Children's Hospitals Neonatal Database. Infants ≥36 weeks gestational age with HIE admitted to a Children's Hospitals Neonatal Database Neonatal Intensive Care Unit between 2010 and 2016, who underwent therapeutic hypothermia were categorized as (1) infants who died following WLST and (2) survivors with severe HIE (requiring tube feedings at discharge). Results Death occurred in 267/1,925 (14%) infants with HIE, 87.6% following WLS. Compared to infants with WLS (n = 234), the survived severe group (n = 74) had more public insurance (73% vs 39.3%, P = 0.00001), lower household income ($37,020 vs $41,733, P = 0.006) and fewer [20.3% vs 35.0%, P = 0.0212] were from the South. Among infants with WLS, electroencephalogram was performed within 24 hours in 75% and was severely abnormal in 64% cases; corresponding rates for MRI were 43% and 17%, respectively. Private insurance was independently associated with WLS, after adjustment for HIE severity and center. Conclusions In a multicenter cohort of infants with HIE, WLS occurred frequently and was associated with sociodemographic factors. The rationale for decision-making for WLS in HIE require further exploration.

Introduction Amplitude-integrated EEG (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated. Methods Inborn infants 230/7 – 286/7 weeks gestation or birth weight 401–1000 grams were eligible. Serial, six-hour aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed. Results 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality. Conclusions Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier:NCT00614744

Importance Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). Main Outcomes and Measures The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed ( P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Conclusions and Relevance Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. Trial Registration clinicaltrials.gov Identifier:NCT01192776

Cardiac surgery in infants results in a profound inflammatory response secondary to cardiopulmonary bypass (CPB) and the need for blood products. It is not clear how this inflammatory response modulates postoperative course or whether quantification of proinflammatory cytokines can aid with risk stratification. In this study, we prospectively assessed a panel of candidate markers to determine the time course for inflammation and the association of specific markers with clinical outcomes defined as intensive care unit length of stay (LOS).We obtained preoperative blood samples from 92 neonates undergoing surgery with CPB and then serially for 5 days after surgery. Numerous interleukins were assayed along with tumor necrosis factor (TNF)-alpha and interferon (INF)-gamma. The most common surgical procedures were arterial switch procedure (n = 35) and Norwood operation (n = 34). Multivariate analysis was performed to determine if inflammatory mediators could independently predict prolonged intensive care unit LOS.Compared with the presurgery level, there were statistically significant increases (p0.005) for 8 out of 11 inflammatory markers: INF-gamma, interleukin (IL)-10, IL-13, IL-2, IL-5, IL-8, TNF-alpha, and IL-6 after surgery. The only cytokine on the first postoperative day that was independently associated with prolonged length of stay was IL-8 (p = 0.002). Cytokine values measured on postoperative day 3 were most valuable in predicting prolonged LOS. A model that included use of circulatory arrest, and day 3 measures of IL-6 and IL-8 yielded an area under of the curve of 0.88 (95% confidence interval 0.79 to 0.96) for predicting a prolonged LOS.In summary, neonatal heart surgery for complex lesions elicits a broad inflammatory response. This early inflammatory response appears nonspecific and did not predict clinical course. Persistence of specific inflammatory mediators on the third day after surgery, however, provided important prognostic information. As such, select cytokines may serve as valuable biomarkers in this population. Whether strategies targeting specific cytokines can alter clinical course is not known.

The purpose of this study is to characterize the cytokine response of preterm newborns with surgical necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) before surgical treatment and to relate these finding to intestinal disease (NEC vs. SIP).The study was a 14-month prospective, cohort study of neonates undergoing surgery or drainage for NEC or SIP or surgical ligation of patent ductus arteriosus (PDA). Multiplex cytokine detection technology was used to analyze six inflammatory markers: interleukin-2, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 β (IL-1β), interferon-gamma, and tumor necrosis factor-α (TNF-α).Patients with NEC had much higher median preoperative levels of IL-6 (NEC: 8,381 pg/mL; SIP: 36 pg/mL; PDA: 25 pg/mL, p 0.001), IL-8 (NEC: 18,438 pg/mL; SIP: 2,473 pg/mL; PDA: 1,110 pg/mL, p = 0.001), TNF-α (NEC: 161 pg/mL; SIP: 77 pg/mL; PDA: 71 pg/mL, p 0.001), and IL-1β (NEC: 85 pg/mL; SIP: 31 pg/mL; PDA: 24 pg/mL, p = 0.001). Patients with NEC totalis (NEC-totalis had the highest levels of IL-8 and were significantly different from infants with limited NEC (28,141 vs. 11,429 pg/mL, p = 0.03).Surgical NEC is a profoundly more proinflammatory disease than SIP. The cytokine profiles of patients with SIP are closer to those of a nonseptic surgical neonate.

Our objective was to evaluate the relationship between congenital gastrointestinal anomalies requiring neonatal surgery and neurodevelopmental outcome. Among the children born in metropolitan Atlanta during 1982–2001 who survived to age 1 year (N = 762,824), we identified children with congenital gastrointestinal anomalies via linkage with the Metropolitan Atlanta Congenital Defects Program and children who received special education services via linkage with the Special Education Database of Metropolitan Atlanta. Several modest increases in special education service use were observed among children with isolated congenital gastrointestinal anomalies; no association was statistically significant. Among children with Hirschsprung disease, gastroschisis, esophageal atresia, intestinal malrotation, bowel atresia, or imperforate anus who had multiple anomalies, we observed statistically significant increases in special education service use.

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 (

Importance Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models. Objective To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy. Design, Setting, and Participants A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013. Interventions Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours. Main Outcomes and Measures The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes). Results The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%. Conclusions and Relevance Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials. Trial Registration clinicaltrials.gov Identifier:NCT01192776

The objective was to determine whether an elevated nucleated red blood cell count at birth after perinatal depression is associated with brain injury as measured by (1) proton magnetic resonance spectroscopy and (2) abnormal neurodevelopmental outcome at 30 months of age. The nucleated red blood cell counts from the first 24 hours of life were statistically analyzed in 33 term infants enrolled in a prospective study of the value of magnetic resonance imaging for the determination of neurodevelopmental outcome after perinatal depression. Nucleated red blood cell counts were elevated in 13/33 (39%). Abnormal outcome (19/33, 54%) was associated with Score for Neonatal Acute Physiology-Perinatal Extension (P = 0.04), decreased N-acetylaspartate to choline ratio in the basal ganglia (P = 0.009), and increased lactate to choline ratio in the basal ganglia (P = 0.02), but not with cord pH, Apgar score, or nucleated red blood cell value. In a logistic regression model, increasing nucleated red blood cell counts did not increase the odds of an abnormal outcome at 30 months of age (OR 1.02, P = 0.17). In a population of neonates with perinatal depression, the nucleated red blood cell count at birth does not correlate with magnetic resonance spectroscopy or 30-month neurodevelopmental outcome. The nucleated red blood cell count should not be used as a surrogate marker for subsequent brain injury.

The cause of intraventricular hemorrhage in term neonates is poorly understood. Among 29 neonates of at least 36 weeks' gestation with intraventricular hemorrhage, 9 (31%) had cerebral sinovenous thrombosis. Of the 26 neonates who underwent computed tomography or magnetic resonance studies, those with thalamic hemorrhage were more likely to have sinovenous thrombosis than those without thalamic involvement (4/5 vs 5/21, p = 0.03). Term neonates with intraventricular hemorrhage should undergo neuroimaging to evaluate the presence of sinovenous thrombosis. Ann Neurol 2003

Objective Evaluate the relationship between initial haemostatic parameters and the frequency and severity of bleeding in neonates with hypoxic–ischaemic encephalopathy (HIE). Design Retrospective observational cohort study. Setting 2 academically affiliated level III neonatal intensive care units in Atlanta, Georgia. Participants 98 neonates with moderate-to-severe HIE who underwent haemostatic testing within 12 hours of birth and were born from 1 January 2008 to 31 December 2013. Primary and secondary outcome measures Initial haemostatic dysfunction was defined as one or more of the following: prothrombin time (PT) ≥18 s, platelet count

Importance Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine. Objective To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants. Design, Setting, and Participants A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months’ corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses. Exposures Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia). Main Outcomes and Measures Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006. Results A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower. Conclusions and Relevance Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.

White matter injury (WMI) is a known complication following neonatal heart surgery in term infants. In preterm infants, WMI has been associated with the degree of systemic inflammation. It is not known whether inflammation is an important mechanism of WMI as documented by magnetic resonance imaging (MRI) following neonatal heart surgery with cardiopulmonary bypass. Term neonates with congenital heart disease were enrolled in a prospective study with postoperative MRI. White matter injury was recorded by the number of T1 hyperintense foci with >5 foci consistent with significant WMI. Eleven candidate cytokine markers (INF-gamma, TNF-alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-13) were assayed preoperatively and daily for 5 days following surgery. Multiple clinical factors were recorded and correlated with WMI. Ninety-two subjects were enrolled in the study. The median age at surgery was 5 days (interquartile range 4-7 days). Compared with the presurgery level, there were statistically significant increases (p < 0.005) for 8 out of 11 inflammatory markers. In all, 64 postoperative MRIs were performed. No significant correlation was detected between WMI and clinical variables or inflammatory markers assessed immediately postoperative and on postoperative days 1 and 3, with exception of IL-1 beta on postoperative day 1. WMI correlates poorly with the systemic inflammatory response after congenital heart surgery and a number of herein measured clinical factors. WMI following neonatal heart surgery is a complex, still incompletely understood phenomenon that warrants continued investigation.

Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998, and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index

Recent evidence suggests that the current ILCOR guidelines regarding hypothermia for the treatment of neonatal encephalopathy need urgent revision. In 2005 when the current ILCOR guidelines were finalised one large (CoolCap trial, n = 235) and one small RCT (n = 67), in addition to pilot trials, had been published, and demonstrated that therapeutic hypothermia after perinatal asphyxia was safe. The CoolCap trial showed a borderline overall effect on death and disability at 18 months of age, but significant improvement in a large subset of infants with less severe electroencephalographic changes. Based on this and other available evidence, the 2005 ILCOR guidelines supported post resuscitation hypothermia in paediatric patients after cardiac arrest, but not after neonatal resuscitation. Subsequently, a whole body cooling trial supported by the NICHD reported a significant overall improvement in death or disability. Further large neonatal trials of hypothermia have stopped recruitment and their final results are likely to be published 2009–2011. Many important questions around the optimal therapeutic use of hypothermia remain to be answered. Nevertheless, independent meta-analyses of the published trials now indicate a consistent, robust beneficial effect of therapeutic hypothermia for moderate to severe neonatal encephalopathy, with a mean NNT between 6 and 8. Given that there is currently no other clinically proven treatment for infants with neonatal encephalopathy we propose that an interim advisory statement should be issued to support and guide the introduction of therapeutic hypothermia into routine clinical practice.

Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery.We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age.As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P0.001), and a decrease of 12% in white-matter fractional anisotropy (P0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns.Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero.

To compare changes in regional cerebral or flank oxygen saturation measured by near-infrared spectroscopy with changes in central venous oxygen saturation (ScvO2) and to determine clinical variables associated with these changes.Prospective observational cohort study.University tertiary care center, pediatric cardiac intensive care unit.Seventy postoperative congenital cardiac surgical patients (median age 0.3 yrs; interquartile range 0.02-0.46 yrs).None.We measured temporally correlated regional oxygen saturation (rSO2) with hematologic (hematocrit), biochemical (arterial blood gas, ScvO2, and lactate) and physiologic (temperature, heart rate, mean blood pressure, and pulse oximetry) variables in the first postoperative day. Cerebral and flank rSO2 were strongly correlated with ScvO2, in both cyanotic or acyanotic patients and single- or two-ventricle physiology with and without aortic arch obstruction (all p.001). However, individual values had wide limits of agreement on Bland-Altman analysis. The correlations of change in these measurements were weaker but still significant (all p.0001), again with wide limits of agreement. Similar direction of change in cerebral rSO2 and ScvO2 was present 64% (95% confidence interval, 55-73%) of the time. Change in arterial pressure of carbon dioxide (delta PaCO2) was associated with cerebral delta rSO2 (delta PaCO2 beta = 0.35, p.0001) but not flank delta rSO2 or delta ScvO2. A pattern of relative cerebral desaturation (flank rSO2cerebral rSO2) was noted in a majority of patients (81%) with two-site monitoring regardless of bypass method or age.Neither individual values nor changes in rSO2 are interchangeable measures of ScvO2 in postoperative pediatric cardiac patients. The unique relationship between changes in PaCO2 and cerebral rSO2 supports the hypothesis that cerebral near-infrared spectroscopy monitors regional cerebral oxygenation. Clinical application of this monitor must include recognition of the clinical variables that affect regional brain oxygenation.

Background and Purpose— Brain injury is common in newborns with congenital heart disease (CHD) requiring neonatal surgery. The purpose of this study is to define the risk factors for preoperative and postoperative brain injuries and their association with functional cardiac anatomic groups. Methods— Sixty-two neonates with CHD were studied with preoperative MRI, and 53 received postoperative scans. Clinical and therapeutic characteristics were compared in newborns with and without newly acquired brain injuries. A subset of 16 consecutive patients was monitored with intraoperative cerebral near-infrared spectroscopy. Results— Brain injury was observed in 56% of patients. Preoperative brain injury, seen in 39%, was most commonly stroke and was associated with balloon atrial septostomy ( P =0.002). Postoperative brain injury, seen in 35%, was most commonly white matter injury and was particularly common in neonates with single-ventricle physiology and aortic arch obstruction ( P =0.001). Risk factors associated with acquired postoperative brain injury included cardiopulmonary bypass (CPB) with regional cerebral perfusion ( P =0.01) and lower intraoperative cerebral hemoglobin oxygen saturation during the myocardial ischemic period of CPB ( P =0.008). In a multivariable model, new postoperative white matter injury was specifically associated with low mean blood pressure during the first postoperative day ( P =0.04). Conclusions— Specific modifiable risk factors can be identified for preoperative and postoperative white matter injury and stroke associated with neonatal surgery for CHD. The high incidence of postoperative injury observed despite new methodologies of CPB indicates the need for ongoing evaluation to optimize neurological outcome.

OBJECTIVES. Newborns delivered before 28 weeks' gestation commonly have white matter lesions on MRI that are associated with adverse neurodevelopmental outcomes. Our objective was to determine the risk factors for MRI-detectable white matter injury in infants delivered before 28 weeks' gestation who were treated with prophylactic indomethacin.METHODS. This was a prospective cohort study conducted at the intensive care nursery at University of California San Francisco Children's Hospital. Patients included 57 premature newborns between 24 and 27 (+6 days) weeks' gestation at birth (October 1998 to October 2004). We identified perinatal and neonatal risk factors associated with moderate-severe “white matter injuries” (T1 signal abnormalities >2 mm or >3 areas of T1 abnormality) and moderate-severe “brain abnormality” (moderate-severe white matter injuries, any degree of ventriculomegaly, or severe intraventricular hemorrhage) on MRI. Infants were studied with MRI at 31.1 weeks’ postmenstrual age (median).RESULTS. Moderate-severe white matter injuries were detected in 12 (21%) of 53 preterm newborns, and 20 (35%) of 57 had moderate-severe brain abnormality. Prolonged indomethacin exposure was the only risk factor independently associated with a lower risk of white matter injury or brain abnormality, even when adjusting for the presence of a hemodynamically significant PDA, gestational age at birth, prenatal betamethasone, systemic infection, and days of mechanical ventilation.CONCLUSIONS. In this observational study, a longer duration of indomethacin exposure was associated with less white matter injury in infants delivered before 28 weeks' gestation. A randomized trial of prolonged indomethacin treatment is needed to determine whether indomethacin can decrease white matter injury and neurodevelopmental abnormalities.

Objectives To determine if the incidence of sonographically detected cystic periventricular leukomalacia (PVL) and periventricular hemorrhagic infarction (PVHI) have changed over the past decade and to determine if a decline in cystic PVL was associated with a change in neurodevelopmental outcome. Study design Premature newborn infants admitted to our intensive care nursery from 1992 to 2002 were identified in a comprehensive nursery database. Premature newborn infants had routine neurosonography by means of a standardized protocol. Infants weighing ≤1500 g at birth surviving to nursery discharge were enrolled in a nursery follow-up clinic. Results Adjusting for gestational age, there was a significant decrease in cystic PVL from 1992 to 2002 (P = .003) without a concurrent decrease in PVHI (P = 0.5). Cystic PVL and PVHI accounted for only 9 of the 28 cases of cerebral palsy and 12 of 90 cases of abnormal Developmental Scores in infants weighing

The objective was to determine the timing and mechanism of brain injury using preoperative and postoperative magnetic resonance imaging (MRI) and three-dimensional MR spectroscopic imaging (MRSI) in newborns with transposition of the great arteries (TGA) repaired with full-flow cardiopulmonary bypass.Ten term newborns with TGA undergoing an arterial switch operation were studied with MRI, MRSI, and neurologic examination preoperatively and postoperatively at a median of 5 days (2 to 9 days) and 19 days (14 to 26 days) of age, respectively. Five term historical controls were studied at a median of 4 days (3 to 9 days). Lactate/choline (marker of cerebral oxidative metabolism) and N-acetylaspartate (NAA)/choline (marker of cerebral metabolism and density) were measured bilaterally from the basal ganglia, thalamus, and corticospinal tracts.Four TGA newborns had brain injury on the preoperative MRI. The only new lesion detected on the postoperative study was a focal white matter lesion in one newborn with a normal preoperative MRI. The MRSI of age-adjusted lactate/choline was quantitatively higher in newborns with TGA compared with those without heart disease (p0.0001), even in newborns without MRI evidence of preoperative brain injury. Lactate/choline decreased after surgery but remained elevated compared with controls. In newborns with TGA, those with preoperative brain injury on MRI had lower NAA/choline globally (p = 0.04) than those with normal preoperative MRI. Five newborns had a decline in NAA/choline from the preoperative to postoperative studies.Abnormal brain metabolism and injury was observed preoperatively in newborns with TGA. Brain injury is not solely related to the operative course.

Objectives. To evaluate the long-term neurodevelopmental outcome of infants who underwent cardiac surgery and required extracorporeal membrane oxygenation (ECMO) support, and to examine variables that predict death or disability in these patients.Methods. We studied all infants who had congenital heart disease and were supported postoperatively with ECMO from 1990 to 2001 at our institution (n = 53). Medical records were reviewed retrospectively to obtain clinical variables. Neurologic and age-appropriate developmental examinations occurred at ages 1, 1.5, 2.5, and 4.5 years. Median age at follow-up was 55 months (9–101). Cognitive outcome was defined as suspect when scores were between 1 and 2 SD below the mean for age and abnormal when scores were >2 SD below mean for age. Neuromotor outcome was defined as suspect when the patient manifested clumsiness, tremor, or mild tone and reflex changes without functional limitations, and abnormal when there were functional limitations.Results. In-hospital survival was 17 (32%) of 53. Of survivors, 14 (88%) of 16 are living and 1 patient was lost to follow-up. Of the 53 patients, 7 survived completely intact (13%). Seven (50%) of 14 patients had a normal cognitive outcome, 3 (21%) had a suspect cognitive outcome, and 4 (29%) were abnormal. Ten (72%) of 14 patients had a normal neuromotor outcome, 1 (7%) patient had a suspect neuromotor outcome, and 3 (21%) were abnormal. No survivor with an aortic cross-clamp time >40 minutes had a normal cognitive outcome. Nonsurvivors were more likely than survivors to have had cardiac arrest as an indication for ECMO (31% vs 6%), to have had a longer aortic cross-clamp time (mean 73 minutes vs 32 minutes), and to have required continuous arteriovenous hemofiltration (78% vs 35%). The age and weight at cannulation, gender, cardiac diagnosis, interval from surgery to ECMO, cardiopulmonary bypass time, diagnosis of sepsis or mediastinitis, and duration of ECMO were not significantly associated with survival.Conclusions. Although mortality was 68% in infants who had congenital heart disease and were treated with ECMO postoperatively, of those who survive to hospital discharge, 75% have a normal neuromotor outcome and 50% have a normal cognitive outcome. These high rates of mortality and disability suggest that increased attention be paid to neuroprotection in these complex disorders.

Perinatal hypoxia-ischemia is responsible for significant morbidity and mortality in term infants. The developing brain is uniquely vulnerable to hypoxic-ischemic injury, with a complex evolution of injury that affords opportunities for intervention, yet potentially jeopardizes normal maturational processes.Data published over the past year have provided insights into the evolution of injury, and have suggested a greater role for oxidants and inflammatory mediators.The search for ideal neuroprotective agents and techniques for timely injury detection is actively progressing and has led to advances in our understanding of pathogenesis.

Previous studies have suggested a relationship between reproductive history, pregnancy and birth factors, and the risk of neuroblastoma. We conducted a case-control telephone interview study that included a total of 504 children under the age of 19 years with newly diagnosed neuroblastoma identified by two national collaborative clinical trials groups, the Children's Cancer Group and the Pediatric Oncology Group. A total of 504 controls, matched to cases on age, were identified by random digit dialing. Conditional logistic regression was used to estimate the matched odds ratio (OR) and 95% confidence interval (CI) with adjustment for household income, and maternal race and education. In addition, case subgroups defined by age at diagnosis, tumour MYCN oncogene amplification status, and stage were evaluated. A suggestive pattern of increased risk was seen for a greater number of prior pregnancies, history of previous miscarriages and induced abortions, with nearly a twofold increase in risk for two or more prior induced abortions (OR = 1.9, 95% CI [1.0,3.7]). No association was found for the following diseases or conditions during pregnancy: hepatitis, rubella, measles, mumps, chickenpox, mononucleosis, vaccinations, morning sickness, pre-eclampsia, bleeding, proteinuria, anaemia, urinary tract infections, heart disease, kidney disease, liver disease and diabetes. A weak association was found for hypertension during pregnancy. Several labour and delivery factors were related to an increased risk, including threatened miscarriage, anaesthetic during labour (specifically epidural) and caesarean delivery. We found associations between premature delivery (