Magnesium sulfate and risk of hypoxic ischemic encephalopathy in a high-risk cohort.

BACKGROUND: Hypoxic ischemic encephalopathy contributes to morbidity and mortality among neonates ≥ 360 weeks' gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic ischemic encephalopathy and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with pre-eclampsia with severe features. OBJECTIVES: 1) Determine trends in incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate and hypoxic ischemic encephalopathy, 2) evaluate the association between hypertensive disorders of pregnancy and hypoxic ischemic encephalopathy and 3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate. STUDY DESIGN: We conducted an analysis of a prospective cohort of live births ≥360 weeks' gestation between 2012-2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization, and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic ischemic encephalopathy. RESULTS: Among 44,314 unique infants, the diagnosis of hypoxic ischemic encephalopathy, maternal hypertensive disorders of pregnancy and the use of magnesium sulfate increased over time. Compared to patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a higher risk population. They were more likely to be publicly insured, born 36-38 weeks' gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, preterm labor, fetal distress, and undergo operative delivery (all p-values <0.002). Hypertensive disorders of pregnancy were associated with hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.13-1.40, p-value <.001) and specifically moderate/severe hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.11-1.42, p-value <.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic ischemic encephalopathy (aOR 0.71, 95% CI 0.52-0.97, p-value= 0.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic ischemic encephalopathy (aOR 0.63, 95% CI 0.42-0.94, p-value=0.03). CONCLUSION: Hypertensive disorders of pregnancy are associated with hypoxic ischemic encephalopathy and specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with significant reduction in the odds of hypoxic ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to the NICU ≥360 weeks' gestation. The findings of this observational study cannot prove causality and are intended to be hypothesis generating for future clinical trials on MgSO4 in term infants.

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial.

OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Association of Primary Language with Very Low Birth Weight Outcomes in Hispanic Infants in California.

OBJECTIVE: To determine the association of Spanish as a primary language for a family with the health outcomes of Hispanic infants with very low birth weight (VLBW, <1500g). STUDY DESIGN: Data from the California Perinatal Quality Care Collaborative (CPQCC) linked to hospital discharge records were analyzed. Hispanic infants with VLBW born between 2009 and 2018 with a primary language of English or Spanish were included. Outcomes selected were hypothesized to be sensitive to language barriers. Multivariable logistic regression models and mixed models estimated associations between language and outcomes. RESULTS: Of 18 364 infants meeting inclusion criteria, 27% (n = 4976) were born to families with Spanish as a primary language. In unadjusted analyses, compared with infants of primarily English-speaking families, these infants had higher odds of hospital readmission within 1 year (OR 1.11 [95% CI 1.02-1.21]), higher odds to receive human milk at discharge (OR 1.32 [95% CI 1.23-1.42]), and lower odds of discharge home with oxygen (OR 0.83 [95% CI 0.73-0.94]). In multivariable analyses, odds of readmission and home oxygen remained significant when adjusting for infant but not maternal and hospital characteristics. Higher odds for receipt of any human milk at discharge were significant in all models. Remaining outcomes did not differ between groups. CONCLUSIONS: Significant differences exist between Hispanic infants with VLBW of primarily Spanish-vs English-speaking families. Exploration of strategies to prevent readmissions of infants of families with Spanish as a primary language is warranted.

Cardiac Dysfunction in Neonatal HIE Is Associated with Increased Mortality and Brain Injury by MRI.

OBJECTIVE: Describe the association between cardiac dysfunction and death or moderate-to-severe abnormalities on brain magnetic resonance imaging (MRI) in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Retrospective study in neonates with moderate or severe HIE undergoing therapeutic hypothermia between 2008 and 2017. Primary outcome was death or moderate-to-severe brain injury using the Barkovich score. Conventional and speckle-tracking echocardiography measures were extracted from available echocardiograms to quantify right (RV) and left (LV) ventricular functions. RESULTS: A total of 166 newborns underwent therapeutic hypothermia of which 53 (36.5%) had echocardiography performed. Ten (19%) died prior to hospital discharge, and 11 (26%) had moderate-to-severe brain injury. There was no difference in chronologic age at echocardiography between the normal and adverse outcome groups (22 [±19] vs. 28 [±21] hours, p = 0.35). Cardiac findings in newborns with abnormal outcome included lower systolic and diastolic blood pressure (BP) at echocardiography (p = 0.004) and decreased tricuspid annular plane systolic excursion (a marker of RV systolic function; p = 0.01), while the ratio of systolic pulmonary artery (PA) pressure to systolic BP indicated isosystemic pressures (>2/3 systemic) in both groups. A multilogistic regression analysis, adjusting for weight and seizure status, indicated an association between abnormal outcome and LV function by longitudinal strain, as well as by ejection fraction. CONCLUSION: Newborns who died or had moderate-to-severe brain injury had a higher incidence of cardiac dysfunction but similar PA pressures when compared with those who survived with mild or no MRI abnormalities. KEY POINTS: · Newborns with HIE with functional LV/RV dysfunction are at risk for death or brain injury.. · All neonates with HIE had elevated pulmonary pressure, but neonates with poor outcome had RV dysfunction.. · When evaluating newborns with HIE by echocardiography, beyond estimation of pulmonary pressure, it is important to assess biventricular function..

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations.

Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

Seizure Severity and Treatment Response in Newborn Infants with Seizures Attributed to Intracranial Hemorrhage.

OBJECTIVE: We sought to characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born term and preterm. For infants born term, we sought to compare seizure severity and treatment response for multisite vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs without ICH. STUDY DESIGN: We studied 112 newborn infants with seizures attributed to ICH and 201 infants born at term with seizures attributed to HIE, using a cohort of consecutive infants with clinically diagnosed and/or electrographic seizures prospectively enrolled in the multicenter Neonatal Seizure Registry. We compared seizure severity and treatment response among infants with complicated ICH, defined as multisite vs single-site ICH and HIE with vs without ICH. RESULTS: ICH was a more common seizure etiology in infants born preterm vs term (27% vs 10%, P < .001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multisite ICH was associated with more subclinical seizures than single-site ICH (93% vs 66%, P = .05) and an incomplete response to the initial ASM (100% vs 66%, P = .02). Status epilepticus was more common in HIE with ICH vs HIE alone (38% vs 17%, P = .05). CONCLUSIONS: Seizure severity was greater and treatment response was lower among infants born term with complicated ICH. These data support the use of continuous video electroencephalogram monitoring to accurately detect seizures and a multistep treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH.

Neuroimaging in the term newborn with neonatal encephalopathy.

Neuroimaging is widely used to aid in the diagnosis and clinical management of neonates with neonatal encephalopathy (NE). Yet, despite widespread use clinically, there are few published guidelines on neuroimaging for neonates with NE. This review outlines the primary patterns of brain injury associated with hypoxic-ischemic injury in neonates with NE and their frequency, associated neuropathological features, and risk factors. In addition, it provides an overview of neuroimaging methods, including the most widely used scoring systems used to characterize brain injury in these neonates and their utility as predictive biomarkers. Last, recommendations for neuroimaging in neonates with NE are presented.

Proposing a care practice bundle for neonatal encephalopathy during therapeutic hypothermia.

Neonates with neonatal encephalopathy (NE) often present with multi-organ dysfunction that requires multidisciplinary specialized management. Care of the neonate with NE is thus complex with interaction between the brain and various organ systems. Illness severity during the first days of birth, and not only during the initial hypoxia-ischemia event, is a significant predictor of adverse outcomes in neonates with NE treated with therapeutic hypothermia (TH). We thus propose a care practice bundle dedicated to support the injured neonatal brain that is based on the current best evidence for each organ system. The impact of using such bundle on outcomes in NE remains to be demonstrated.

Unanswered questions regarding therapeutic hypothermia for neonates with neonatal encephalopathy.

Therapeutic hypothermia (TH) is now well established to improve intact survival after neonatal encephalopathy (NE). However, many questions could not be addressed by the randomized controlled trials. Should late preterm newborns with NE be cooled? Is cooling beneficial for mild NE? Is the current therapeutic time window optimal, or could it be shortened or prolonged? Will either milder or deeper hypothermia be effective? Does infection/inflammation exposure in the perinatal period in combination with NE offer potentially beneficial preconditioning or might it obviate hypothermic neuroprotection? In the present review, we dissect the evidence, for whom, when and how can TH best be delivered, and highlight areas that need further research.

Characterization of Death in Infants With Neonatal Seizures.

BACKGROUND: Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die. METHODS: This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice. RESULTS: We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice. CONCLUSION: In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures.

Neonatal Neurocritical Care: Providing Brain-Focused Care for All at Risk Neonates.

Neonatal neurocritical care is an evolving subsubspecialty whose goal is to implement neuroprotective care strategies, continuous bedside monitoring of neurologic function, and therapies in order to reduce the risk of neurologic injury and improve long-term neurodevelopmental outcomes in neonates who require intensive care. The provision of neonatal neurocritical care requires a culture change across a Neonatal Intensive Care Unit (NICU) in which equal importance is placed on the neurologic care and the cardiorespiratory care of a given patient. It is a multidisciplinary framework of care in which neonatologist and pediatric neurologist come together to address the unique needs of NICU patients whose brains are still developing and are vulnerable to injury. Advances in bedside brain monitoring techniques and the use of therapeutic hypothermia for Hupoxic-Ischemic Encephalopathy have accelerated the development of NeuroNICUs across the United States and abroad. Neonatologists, neurologists, neurophysiologists, nurses, and other ancillary members of the team work together to develop guidelines for commonly encountered neurological conditions in the NICU. The use of these guidelines helps provide standardized care across a unit and can reduce morbidity and length of hospital stay.

Differences in patient characteristics and care practices between two trials of therapeutic hypothermia.

BACKGROUND: The Induced Hypothermia (IH) and Optimizing Cooling (OC) trials for hypoxic-ischemic encephalopathy (HIE) had similar inclusion criteria. The rate of death/moderate-severe disability differed for the subgroups treated with therapeutic hypothermia (TH) at 33.5 °C for 72 h (44% vs. 29%, unadjusted p = 0.03). We aimed to evaluate differences in patient characteristics and care practices between the trials. METHODS: We compared pre/post-randomization characteristics and care practices between IH and OC. RESULTS: There were 208 patients in the IH trial, 102 cooled, and 364 in the OC trial, 95 cooled to 33.5 °C for 72 h. In OC, neonates were less ill, fewer had severe HIE, and the majority were cooled prior to randomization. Differences between IH and OC were observed in the adjusted difference in the lowest PCO2 (+3.08 mmHg, p = 0.005) and highest PO2 (-82.7 mmHg, p < 0.001). In OC, compared to IH, the adjusted relative risk (RR) of exposure to anticonvulsant prior to randomization was decreased (RR 0.58, (0.40-0.85), p = 0.005) and there was increased risk of exposure during cooling to sedatives/analgesia (RR 1.86 (1.21-2.86), p = 0.005). CONCLUSION: Despite similar inclusion criteria, there were differences in patient characteristics and care practices between trials. Change in care practices over time should be considered when planning future neuroprotective trials.

Response to antiseizure medications in neonates with acute symptomatic seizures.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.