Faculty Bibliography

Hypoxic-ischemic encephalopathy is a subtype of neonatal encephalopathy and a major contributor to global neonatal morbidity and mortality. Despite advances in obstetric and neonatal care there are still challenges in accurate determination of etiology of neonatal encephalopathy. Thus, identification of intrapartum risk factors and comprehensive evaluation of the neonate is important to determine the etiology and severity of neonatal encephalopathy. In developed countries, therapeutic hypothermia as a standard of care therapy for neonates with hypoxic-ischemic encephalopathy has proven to decrease incidence of death and neurodevelopmental disabilities, including cerebral palsy in surviving children. Advances in neuroimaging, brain monitoring modalities, and biomarkers of brain injury have improved the ability to diagnose, monitor, and treat newborns with encephalopathy. However, challenges remain in early identification of neonates at risk for hypoxic-ischemic brain injury, and determination of the timing and extent of brain injury. Using imaging studies such as Neonatal MRI and MR spectroscopy have proven to be most useful in predicting outcomes in infants with encephalopathy within the first week of life, although comprehensive neurodevelopmental assessments still remains the gold standard for determining long term outcomes. Future studies are needed to identify other newborns with encephalopathy that might benefit from therapeutic hypothermia and to determine the efficacy of other adjunctive neuroprotective strategies. This review focuses on newer evidence and advances in diagnoses and management of infants with neonatal encephalopathy, including novel therapies, as well as prognostication of outcomes to childhood.

Background Earlier initiation of therapeutic hypothermia in term infants with hypoxic-ischemic encephalopathy has been shown to improve neurological outcomes. The objective of the study was to compare safety and effectiveness of servo-controlled active vs. passive cooling used during neonatal transport in achieving target core temperature. Methods We undertook a prospective cohort quality improvement study with historic controls of therapeutic hypothermia during transport. Primary outcome measures were analyzed: time to cool after initiation of transport, time to achieve target temperature from birth and temperature on arrival to cooling centers. Safety was assessed by group comparison of vital signs, diagnosis of persistent pulmonary hypertension (PPHN) and coagulation profiles on arrival. Results A total of 65 infants were included in the study. Time to cool after initiation of transport and time to achieve target temperature from birth were statistically significantly shorter in the actively cooled group with time reduction of 24% with P<0.01 and 15.6% with P<0.01, respectively. On arrival to our cooling center, we noted a significance difference in the mean core temperature (active 33.8°C vs. passive 35.4°C, P<0.01). Seven percent (2/30) of infants in the passively cooled group were overcooled (temperature <33°C). Patients in the actively cooled group had significantly lower mean heart rate compared to the passively cooled group. There was no statistically significant difference in diagnosis of PPHN or coagulation profiles on admission. Conclusions Our study indicates that active cooling with a servo-controlled device on neonatal transport is safe and more effective in achieving target temperature compared to passive cooling.

BACKGROUND:Evaluation of newborns for hypoxic ischemic encephalopathy (HIE) includes laboratory and clinical parameters, as well as amplitude integrated electroencephalogram (aEEG). Based on qualifying criteria, selective head cooling (SHC) is initiated for infants with evidence of moderate to severe HIE. However, some newborns may not qualify for hypothermia therapy based on normal aEEG. OBJECTIVE:To compare levels of serum glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase-1 (UCHL-1) protein and phosphorylated axonal neurofilament heavy chain (pNF-H), in newborns who met initial screening criteria for HIE but did not qualify for head cooling, to the levels in healthy newborns. STUDY DESIGN/METHODS:Newborns ≥36 weeks of gestational age at risk for HIE, who were evaluated but did not qualify for SHC from July 2013 through June 2014 at NYU Langone Medical Center and Bellevue Hospital center were enrolled. A control group included healthy newborns from the newborn nursery (NBN). Serum samples were collected between 24 and 48 h of life from both groups. RESULTS:There was no significant difference in the serum levels of GFAP, UCHL-1 protein and pNF-H between the two groups of infants. CONCLUSION/CONCLUSIONS:Newborns at risk for HIE who met the initial criteria for head cooling but who were excluded based on normal aEEG did not show significant elevation of biomarkers of brain injury compared to healthy newborns. These findings may help to validate using aEEG as an additional evaluation criteria in cooling.

Therapeutic hypothermia (TH) is provided to newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE) to improve survival and long-term neurodevelopmental outcomes. Although the benefits certainly outweigh the risks associated with therapeutic hypothermia, it is important to be mindful of potential rare side effects in the background of asphyxia-related injury to various body organs. One of those side effects includes subcutaneous fat necrosis (SCFN) that can occur in term newborns after perinatal hypoxia-ischemia or other stressing factors such as systemic hypothermia. It is usually a self-limited condition, however, in some cases, it can lead to severe hypercalcemia. We report three such cases of SCFN in newborns with HIE treated with TH. Due to potential long-term complications, such as metastatic calcifications, caregivers should be informed about this potential complication prior to discharge from hospital so that they can help diagnose or continue to monitor cases of severe hypercalcemia.

OBJECTIVE:To assess whether neonatologists show implicit racial and/or socioeconomic biases and whether these are predictive of recommendations at extreme periviability. STUDY DESIGN/METHODS:weeks of gestation asked physicians how likely they were to recommend intensive vs comfort care. Participants were randomized to 1 of 4 versions of the vignette in which racial and socioeconomic stimuli were varied, followed by 2 implicit association tests (IATs). RESULTS:IATs revealed implicit preferences favoring white (mean IAT score = 0.48, P < .001) and greater socioeconomic status (mean IAT score = 0.73, P < .001). Multivariable linear regression analysis showed that physicians with implicit bias toward greater socioeconomic status were more likely than those without bias to recommend comfort care when presented with a patient of high socioeconomic status (P = .037). No significant effect was seen for implicit racial bias. CONCLUSIONS:Building on previous demonstrations of unconscious racial and socioeconomic biases among physicians and their predictive validity, our results suggest that unconscious socioeconomic bias influences recommendations when counseling at the limits of viability. Physicians who display a negative socioeconomic bias are less likely to recommend resuscitation when counseling women of high socioeconomic status. The influence of implicit socioeconomic bias on recommendations at periviability may influence neonatal healthcare disparities and should be explored in future studies.

BACKGROUND:Due to the extremely low incidence of TORCH (toxoplasmosis, rubella, CMV, herpes simplex virus) infections, diagnostic testing of all small for gestational age (SGA) infants aimed at TORCH etiologies may incur unnecessary tests and cost. OBJECTIVE:To determine the frequency of urine CMV PCR and total IgM testing among infants with birth weight <10% and the rate of test positivity. To evaluate the frequency of alternative etiologies of SGA in tested infants. METHODS:Retrospective chart review of SGA infants admitted to the neonatal intensive care unit (NICU) at NYU Langone Medical Center between 2007 and 2012. Subjects were classified as being SGA with or without intrauterine growth restriction (IUGR). The IUGR subjects were then further categorized as having either symmetric or asymmetric IUGR utilizing the Fenton growth chart at birth. Initial testing for TORCH infections, which included serum total IgM, CMV PCR and head ultrasound, were reviewed and analyzed. RESULTS:Three hundred and eighty-six (13%) infants from a total of 2953 NICU admissions had a birth weight ≤10th percentile. Of these, 44% were IUGR; 34% being symmetric IUGR and 10% asymmetric. A total of 32% of SGA infants had urine CMV PCR and total IgM tested with no positive results. As expected, significantly higher percentage of symmetric IUGR infants were tested compared to asymmetric IUGR and non-IUGR SGA infants, (64% vs. 47% vs. 19%) P≤0.01. However, 63% of infants with a known cause for IUGR had same testing done aimed at TORCH infections. We calculated additional charges of $64,065 that were incurred by such testing. CONCLUSIONS:The majority of infants in our study who received testing for urine CMV PCR and total IgM aimed at TORCH infections had one or more other known non-infectious etiologies for IUGR. Because the overall yield of such testing is extremely low, we suggest tests for possible TORCH infections may be limited to symmetric IUGR infants without other known etiologies. Improved guidelines testing for TORCH infections can result in reducing hospital charges and unnecessary studies.

OBJECTIVES: Antacid medications are frequently administered to preterm infants. These medications can change gastric pH levels and can affect regular gastrointestinal function and gut micro-bacterial flora. We hypothesized that preterm infants exposed to antacid medications are at a greater risk of necrotizing enterocolitis (NEC) and sepsis, and set out to determine any association, as well as to assess the clinical efficacy of these medications. MATERIALS AND METHODS: Retrospective chart review of preterm infants /=Bell stage 2) or culture proven sepsis. RESULTS: The study comprised 65 eligible neonates, 28 in antacid treatment group and 37 in control. The incidence of NEC (21.4% vs. 2.7%, P=0.04) was significantly higher in the antacid group, but these infants tended to be born more prematurely than control subjects. There was a trend toward more culture proven sepsis cases in the antacid group. We found no difference in signs generally associated with neonatal reflux (apnea, bradycardia, and desaturation events) in subjects treated with antacid medications after treatment began. CONCLUSIONS: Treatment of preterm infants with antacid medications is potentially associated with a higher risk of NEC, and possibly sepsis, while appearing to provide little benefit.

AIM: Inhaled nitric oxide (iNO) is used to treat neonates with hypoxic respiratory failure (HRF). The aim of this study was to determine clinical characteristics and factors associated with non-response to iNO therapy that may assist in clinical management and weaning strategies. METHODS: Retrospective chart review. The study cohort included gestational age >/=34 weeks' infants with acute HRF who received iNO within 7 days of birth. Subjects were stratified as responders or non-responders to iNO. Non-responders were defined as infants with failure to improve their PaO2 >20 mm Hg within 6 h of iNO initiation, need for extracorporeal membrane oxygenation (ECMO), or mortality. Clinical and laboratory characteristics were then compared between groups. RESULTS: Forty four subjects were included. There were 31 responders and 13 non-responders to iNO therapy. Regression analysis showed significant correlation between a non-response to iNO therapy and changes in PaO2 and pH levels. We found for every 10 mm Hg decrease in PaO2 immediate post-iNO therapy there is a 17.5% decrease in the likelihood of responding to iNO (odds ratio [OR] 0.98, P=0.012). Similarly, for every 0.15 point decrease in pH, there is a 16.3% increased chance of not responding to iNO therapy (OR 1.16, P=0.002). The need for pressor support prior to iNO initiation was also found to be associated with a non-response (OR 2. 94, P=0.034). CONCLUSIONS: Hypotension requiring treatment with pressors at the time of iNO therapy, as well as changes in pH and PaO2 after iNO initiation can be used as early clinical predictors to identify patients quickly who may be iNO non-responders.

Objective This study aims to evaluate impact of respiratory and other neonatal comorbidities on neurodevelopmental outcome in late preterm infants (LPT). Method Retrospective study of LPT infants (34 (0/7)-36 (6/7) weeks' gestation) discharged from the New York University Langone Medical Center neonatal intensive care unit, during January 2006 to December 2010 and received follow-up care up to 2 years of age. Neonatal morbidities were correlated with neurodevelopmental outcomes and assessed by performance on the Mullen Scales of Early Learning during three developmental follow-up visits. Results A total of 99 LPT completed neurodevelopmental assessment up to 2 years of age. Infants with diagnosis of moderate-to-severe respiratory distress syndrome showed a significantly lower performance in the visual reception on the second (p < 0.01) and third visit (p = 0.02), as well as lower performance in the receptive language (visit 2, p = 0.02; visit 3, p < 0.01). A diagnosis of persistent pulmonary hypertension was found to be associated with significantly lower performance in the visual reception at all visits (p < 0.01; p = 0.02; p = 0.02) and in the receptive language on the second and third visit (p = 0.03; p = 0.02). Combined respiratory morbidities were also associated with lower developmental scores in fine motor (visit 2, p < 0.01; visit 3, p = 0.04) as well as expressive language (visit 3, p = 0.02). Conclusion LPT with significant respiratory morbidities are at higher risk for long-term developmental delays, mainly affecting cognitive developmental domains.

Neonatal encephalopathy after perinatal hypoxic-ischemic insult is a major contributor to global child mortality and morbidity. Brain injury in term infants in response to hypoxic-ischemic insult is a complex process evolving over hours to days, which provides a unique window of opportunity for neuroprotective treatment interventions. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy as well as predict their outcome. However, challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. Therapeutic hypothermia is the most promising neuroprotective intervention to date for infants with moderate to severe neonatal encephalopathy after perinatal asphyxia and has currently been incorporated in many neonatal intensive care units in developed countries. However, only 1 in 6 babies with encephalopathy will benefit from hypothermia therapy; many infants still develop significant adverse outcomes. To enhance the outcome, specific diagnostic predictors are needed to identify patients likely to benefit from hypothermia treatment. Studies are needed to determine the efficacy of combined therapeutic strategies with hypothermia therapy to achieve maximal neuroprotective effect. This review focuses on important concepts in the pathophysiology, diagnosis, and management of infants with neonatal encephalopathy due to perinatal asphyxia, including an overview of recently introduced novel therapies