To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes.
This is a descriptive study evaluating the data collected prospectively in the Children’s Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children’s hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks’ gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010–July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge.
High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%.
Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.
Neonatal encephalopathy is characterized by disturbed neurological function in the term or near-term newborn.1 Perinatal hypoxic ischemic encephalopathy (HIE) is an important cause of neonatal encephalopathy, and contributes to both infant mortality and long-term disability in children.2, 3, 4 Therapeutic hypothermia has transformed clinicians’ treatment approaches and improved clinical outcomes.5, 6, 7, 8 However, the actual delivery of care to affected infants and their subsequent outcomes, particularly in the current era of advanced neurocritical care, are largely unmeasured. Systematic investigation of changes in clinical care and associated outcomes is an important extension of evaluating new interventions, as drifts in practice may influence the impact of treatments in the clinical setting.
The Children’s Hospitals Neonatal Database (CHND) was established to assess the quality of delivered care and disease-specific outcomes across participating regional neonatal intensive care units (NICUs) within children’s hospitals.9, 10 Although other registry-based data analyses of HIE have been described,11, 12, 13, 14 prior reports have not focused on infants referred to regional NICUs for treatment. Describing outcomes for HIE infants in this unique setting, with ready access to advanced diagnostic modalities and specialty services, is important for providing benchmark data to assess both the efficiency and the effectiveness of care. In addition, these data can help identify areas for quality improvement and define gaps where future research is needed.
Correspondingly, this study aims to describe the perinatal characteristics, the applied diagnostic evaluations and treatments, as well as the related short-term outcomes in a large, contemporary, multi-center cohort with perinatal HIE.
Since its inception in 2010, the CHND captures clinical data on all infants referred to 27 participating regional NICUs. Eligibility for participation in the database is based on NICU size (>400 admissions per year or >25 beds), serving as a regional referral center (with >50% outborn population) and designation as Level 4 NICU per American Academy of Pediatrics criteria.9, 10, 15 Chart abstractors at each site completed prospective training including review of clinical definitions, participation in web-based seminar tutorials and case-based practice. Both initial and semi-annual measurements of inter-rater agreement scores were calculated at each site; over 90% intrasite concordance in abstraction is required for initial and continued participation in the CHND.
For the current study, the CHND was accessed on 15 July 2013 to identify infants born ⩾36 weeks’ gestation with HIE. Infants were included in the study if they were identified as having a diagnosis of HIE defined in accordance with one of two sets of established criteria6, 12 (Table 1). Infants were excluded if they had open database records, were referred after 4 days of age, had HIE that was coded to be a ‘non-perinatal’ event or whose gestational age at birth was <36 weeks’ gestation.
Eligible infants were described using maternal and infant characteristics and were stratified by the severity of HIE (based on VON12/NICHD6 criteria). Severity was determined by the highest level of documented clinical encephalopathy observed during the first 7 days of life. Mild HIE was assigned when the infant was hyperalert with exaggerated response to arousal. Moderate HIE was assigned when three of the following were present: lethargy, decreased activity, distal flexion±complete extension, hypotonia, weak suck/Moro reflexes and/or constricted pupils, bradycardia or periodic irregular breathing. Severe HIE was assigned when three or more of the following were present: stupor/coma, no activity, decerebrate posturing, flaccid tone, absent suck or moro reflex and/or deviated/dilated, non-reactive pupils, variable cardiac rhythm or apnea.
Because over 90% of infants were born outside the participating CHND hospitals, selected variables were summarized depicting the clinical course before referral. These included maternal conditions, obstetric factors, peripartum and delivery room interventions and perinatal sentinel events (defined as a placental abruption, uterine rupture, nuchal cord or cord prolapse). Diagnostic evaluations received, including electroencephalogram (EEG)/amplitude-integrated EEG (aEEG) and neuroimaging studies with magnetic resonance imaging (MRI) or computed tomography (CT), were evaluated. Also, the methods of therapeutic cooling (selective head versus whole body), the timing of initiation, duration, as well as the target, peak and minimum temperatures were described. The reported outcomes were those achieved before hospital discharge including mortality, neuroimaging results, length of stay, feeding at discharge and receipt of tracheostomy or gastrostomy. Although mortality was measured through CHND hospital discharge for all infants, the ultimate disposition was unknown (or not measured) for some infants who were transferred to another institution.
Data description and analyses were performed with SAS v9.3 (Cary, NC, USA). Analysis of variance and ?2-test were applied to calculate the significant differences between those with mild, moderate and severe HIE, as appropriate. Non-parametric testing was applied when the distributions of selected measures did not conform to a normal distribution. The institutional review board at each participating institution approved participation in CHND and associated research studies.
Of the 55 581 infants in the CHND, there were 1177 infants with HIE. After excluding infants with open database records (n=45), admitted >4 days of age (n=80), who had their sentinel event postnatally (n=51) and of gestational age <36 weeks (n=56), there were 945 eligible infants with perinatal HIE. Nearly all patients (>99%) were born outside the CHND center and received maternal and delivery room care at a referral institution.
Maternal antenatal conditions including hypertension (14.8%) and diabetes (11.5%) were more frequently observed compared with reported rates in population-based studies.16, 17 Maternal clinical chorioamnionitis (8.9%) was analogously prevalent,18 and its frequency varied by the severity of HIE (mild, 9.4%; moderate, 11.2%; severe, 4.8%; P=0.009). Although not related to HIE severity, rates of cesarean (65%), operative vaginal deliveries (11%) and home births (2.3%) were over-represented compared with the National Birth Cohort.17
The median gestational age at birth (39 weeks; interquartile range (IQR) 38, 40) and birth weight (3256 g; IQR 2890, 3635) were similar by the severity of HIE, as were the prevalence of multiple gestations (2.5%), female gender (44.3%), Hispanic ethnicity (12.4%) and congenital anomalies (cardiac (6.5%), genetic (1.7%) and central nervous system (0.5%)). However, large for gestational age status, white race, Apgar score <5 beyond 5 min and profound metabolic acidosis (pH<7 or base deficit >16) were associated with increasing HIE severity. Also, infants with severe HIE more frequently received cardiopulmonary resuscitation in the delivery room and vasoactive support through referral to the CHND NICU. Of the recorded perinatal sentinel events, nuchal cord was observed most often in babies with mild HIE; conversely, uterine rupture was related to moderate or severe HIE (Table 2).
Therapeutic hypothermia was provided to 805/945 (85%) of infants, of whom 122 (15%) were classified as having mild HIE. Most infants received cooling on transport (80%), with the majority (69%) of them cooled passively. At the CHND center, most infants received whole-body hypothermia (74%). Infants were initiated on active cooling in the regional NICU at a median age of 5 h (IQR 2, 8). Most infants were cooled to a target temperature of 33.5 °C (IQR 33.5 °C, 34 °C) achieved at a median age of 5 h (IQR 2, 10).
The ability to maintain target temperature was related to the degree of encephalopathy. Infants’ peak temperatures during therapeutic hypothermia were inversely related to degree of encephalopathy (mild, 34.5 °C (IQR 33.9 °C, 35.4 °C); moderate, 34.1 °C (IQR 33.8 °C, 35.1 °C); severe, 34 °C (IQR 33.7 °C, 35 °C); P<0.001). Minimum temperatures were lower in infants with more severe disease: (mild, 33 °C (IQR 32.5 °C, 33.3 °C); moderate, 33 °C (IQR 32.4 °C, 33.2 °C); severe, 32.6 °C (IQR 31.8 °C, 33.1 °C); P<0.0001). Extreme hypothermia below 33 °C (32%) was the most frequently observed medical complication; others included severe bradycardia (13%) and skin necrosis (1%). Although these complications did not significantly differ by the severity of HIE, hyperglycemia occurred most frequently in infants with severe disease (mild (11.5%); moderate (15.6%); severe (30%); P<0.0001).
The majority (78%) of patients underwent EEG (61%) and/or aEEG (31%) monitoring during the first 24 h of life. Brain MRI was performed in 80% of infants at a median age of 5 days (IQR 4, 8). Head CT was performed in 14% of cases overall, but most frequently in cases of severe disease (mild, 14%; moderate, 11%; severe, 19%; P=0.004). Conversely, 159 infants (17%) did not have MRI or CT performed before discharge. Although some infants died (n=79) or were transferred to another institution (n=24) before imaging was performed, 56 (7%) of the surviving infants (mild, n=23; moderate, n=24; severe, n=9) were discharged from the regional NICU without receiving neuroimaging studies during their hospitalization.
Results of neurodiagnostic evaluations received in the regional NICU are summarized in Table 3. In general, abnormal EEG and neuroimaging findings were most frequently observed in those with severe HIE. Clinical seizures during hypothermia were observed in 15% of the cases, whereas electrographic seizures were noted in 26% of the cases. Late seizures occurring during or after rewarming were observed less frequently (4.9%). Of note, normal MRIs were observed in 31% of cases. Although the majority of normal MRIs were observed in the mild and moderate HIE groups, 20 infants (7%) with severe HIE had no documented MRI abnormality.
Rates of comorbidities were similar to those reported in the clinical trials.5, 6, 7, 8, 19, 20 Median total days of mechanical ventilation were directly related to the severity of HIE (mild, 3 (IQR 1,6); moderate, 4 (IQR 2,7); severe 5 (IQR 3,9); P<0.0001). Few patients received extracorporeal membrane oxygenation support (4.5%) and frequencies of necrotizing enterocolitis and sepsis were low (<2%) and unrelated to HIE severity.
Short-term outcomes stratified by HIE severity are presented in Table 4. Overall hospital mortality was 15%, with 86% of deaths following withdrawal of life-sustaining support. The median length of stay for survivors was 14 days [IQR 10, 24]. Disposition status was known for 706/790 (89%) survivors; outcomes were unavailable for patients transferred to another institution and not discharged to home from the participating regional NICU. Although 85% of the cohort were discharged with complete oral feeding, 15% required either partial or full gavage feeds with 7.6% of infants receiving a gastrostomy tube. In addition, few infants required tracheostomy (n=5, <1%), home ventilation (n=2, <1%) or home oxygen (n=43, 6%), and these outcomes were not specifically related to HIE severity.
This study characterizes a large, multi-center contemporary cohort of HIE infants referred to participating regional NICUs in the United States. By describing antenatal/perinatal factors, resource utilization in the high-level care setting and short-term outcomes, this study assesses the burden of disease associated with HIE in the current era of care. Moreover, this study demonstrates the power of the CHND to evaluate uncommon conditions and diseases, as well as the actualities of delivered care.
Similar to previous reports, presenting characteristics including low Apgar score at 5 min and beyond, profound degree of presenting metabolic acidosis and the need for extensive resuscitation efforts in the delivery room were more frequently observed in patients with severe encephalopathy.21, 22, 23, 24 The association between white race and HIE severity is of interest and requires further investigation. Also consistent with prior studies, perinatal sentinel events were identified in a minority of cases while maternal conditions, including chorioamnionitis, were over-represented.1, 18 These findings support the notion that peripartum asphyxial events do not explain or contribute to all the cases presenting with encephalopathy in the newborn period. Further investigation into the causative antecedents of HIE are warranted.
Rates of cesarean and operative vaginal deliveries were higher compared with national standards.17 These data have important obstetric and perinatal implications, and support the common practice of having a skilled neonatal attendant in the delivery room when these routes of delivery are anticipated or applied. This is of particular importance as early assessment of HIE and prompt initiation of therapeutic hypothermia for eligible infants improves pediatric outcomes. Indeed, widespread adoption of this practice has been endorsed and incorporated into the International Liaison Committee on Resuscitation (ILCOR) and American Academy of Pediatrics (AAP) guidelines since 2010.25, 26
That 15% of patients presenting with HIE to these regional NICUs did not undergo treatment with hypothermia and, conversely, that 15% of cooled infants were classified as having mild HIE is of interest given the established inclusion and exclusion criteria for this therapy.6 Several explanations may be considered for the finding that non-treated infants were not confined to the mild group. It is presumed that some infants with severe encephalopathy were not offered cooling due to presenting in extremis. Also, some clinicians and centers report not providing therapeutic hypothermia to infants with initial moderate encephalopathy who quickly improve and are reassessed as having mild encephalopathy shortly after referral. Conversely, some clinicians or centers would provide hypothermia based on presenting history of seizure or qualifying exam at the delivery/referring hospital, despite being assessed as mild HIE after referral. This may explain some of the rationale for delivering hypothermia in mildly affected infants. Alternatively, hypothermia for mild HIE may represent therapeutic drift. None of the hypothermia trials were designed to address mild encephalopathy, although there is evidence that these patients may be at risk for adverse outcomes.27 The observation that only 41% of infants with mild HIE that were referred to regional NICUs had normal MRI scans supports the notion that these patients warrant further systematic investigation.
Cooling-associated complications were low and consistent with those reported in prior studies.19, 20 The relative safety of this therapy may also help explain why clinicians chose to provide hypothermia even in milder cases. The associations between HIE severity and peak and minimum core temperatures during therapeutic hypothermia were unexpected and surprising given the use of servo-controlled cooling devices at all participating centers. These findings may reflect the relationship between brain injury severity and the integrity of autonomic control, and suggest that cooling techniques could be further optimized and perhaps tailored to the severity of HIE.
Neuromonitoring and neuroimaging in this population were used frequently. The importance of neuromonitoring is highlighted by the higher rates of seizures observed by EEG/aEEG compared to those noted clinically. However, both clinical and EEG-confirmed seizures are lower in this cohort than those reported in the randomized trials. Although this may be related to the inclusion of infants with mild HIE, most previous trials only reported rates of clinical seizures, which has been reported to be unreliable in estimating the true incidence of ictal activity.28 Thus, this study provides a more reliable estimate of seizure frequency among a large cohort, most of whom received EEG/aEEG monitoring during hypothermia. That EEG background abnormality was associated with degree of encephalopathy also supports its utility as a diagnostic aid, and is consistent with other reports associating EEG/aEEG background with outcome in HIE.29, 30
Similarly, the majority of infants surviving hypothermia underwent imaging with MRI, acknowledging the evidence that MRI is a useful diagnostic and prognostic indicator in infants with perinatal HIE.31, 32, 33 Other groups reporting registry-based data have described lower rates of EEG monitoring and MRI, which may be explained by the inclusion of smaller referring NICUs in those registries.12, 13 The use of head CT in 14% of cases remains significant despite concerns with ionizing radiation exposure. That head CT was performed most frequently in cases of severe HIE suggests that CT may have been used to redirect the goals of medical care.
Mortality in this study (15%) is lower than rates reported in the randomized trials,5, 6, 7, 8 although it is acknowledged that only one major trial 5 included infants with mild HIE. Need for tracheostomy and gastrostomy were similar to low rates described previously,19 providing some suggestion that the lower mortality in this study was not related to an increase in disabled survivors. However, the various post-discharge referrals highlight that these infants continue to have ongoing medical care needs following discharge from the NICU.
As in any analysis of registry-based data, unknown/unmeasured factors and coding errors could have modified the observed associations. However, for the vast majority of variables assessed, unknown/missing data was present in <2% cases (unless otherwise noted). In addition, proactive steps were taken to reduce the chance of misclassifications through systematic education and assessment (via serial inter-rater agreement scores) of data abstractors at each participating site. Consequently, the risk of systematic measurement errors was unlikely to significantly alter the reported results. The importance of early childhood neurodevelopmental assessment in survivors with this disease is clearly recognized, and cannot be addressed by the CHND. However, this data source can identify opportunities for quality improvement and direct future research by relating clinical and process variables to surrogate short-term outcomes (for example, mortality, EEG and MRI abnormalities) that are captured systematically.
Other limitations surround the issue of referral bias. This cohort may not be representative of all infants with HIE. It is likely that infants with mild HIE are under-represented as more severely affected infants are often more readily identified and referred to regional centers for care. Nevertheless, given that infants with moderate and severe encephalopathy are at highest risk for adverse outcomes, these ‘real-world’ data remain vitally important to clinicians managing infants with HIE beyond the setting of a clinical trial.
In a large contemporary cohort of infants with HIE, reflective of current clinical care practices in regional children’s hospital NICUs, several maternal and infant characteristics and short-term outcomes were associated with severity of HIE. Hypothermia treatment was widely applied, including in babies with mild HIE. EEG-confirmed seizures were observed in 26%, overall mortality was 15% and rates of complications and morbidities were similar to those reported in randomized hypothermia trials. These data can aid clinicians responsible for therapeutic decision making and familial counseling in babies with HIE.
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JMA, DJD, FD, JRE (Chair), KMR, MAP, EKP, KMR and BLS are members of the Children’s Hospital Neonatal Consortium. The CHNC (http://www.thechnc.org) has partnered with the Children’s Hospital Association, Inc. (CHA; Overland Park, KS, USA) in order to design, launch and maintain the CHND. We are indebted to the following institutions that serve infants and their families, and these institutions also have invested in and continue to participate in the CHND. For more information about CHND, please contact Kate Conrad, Vice President (firstname.lastname@example.org). We also thank the site sponsors for the CHND for their investments in this program. The site sponsors are Children's Healthcare of Atlanta, Atlanta, GA, USA (Francine Dykes, Anthony Piazza); Children’s Healthcare of Atlanta at Scottish Rite (Gregory Sysyn); Children's Hospital of Alabama, Birmingham, AL, USA (Carl Coghill); Le Bonheur Children's Hospital, Memphis, TN, USA (Ramasubbareddy Dhanireddy); Children's Hospital Boston, Boston, MA, USA (Anne Hansen); Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA (Karna Murthy); Nationwide Children's Hospital, Columbus, OH, USA (Kristina Reber); Children's Medical Center Dallas, Dallas, TX, USA (Rashmin Savani); Children's Hospital Colorado, Aurora, CO, USA (Theresa Grover); Children’s Hospital of Michigan, Detroit, MI, USA (Girija Natarajan); Cook Children's Health Care System, Fort Worth, TX, USA (Jonathan Nedrelow, Annie Chi); Texas Children's Hospital, Houston, TX, USA (Stephen Welty); Children's Mercy Hospitals & Clinics, Kansas City, MO, USA (Eugenia Pallotto); Arkansas Children's Hospital, Little Rock, AR, USA (Becky Rodgers, Robert Lyle); Children’s Hospital Los Angeles, Los Angeles, CA, USA (Lisa Kelly (deceased), Steven Chin); UCSF Benioff Children's Hospital, Oakland, CA, USA (David Durand, Jeanette Asselin, Priscilla Joe); The Children's Hospital of Philadelphia, Philadelphia, PA, USA (Jacquelyn Evans, Michael Padula); Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA (Beverly Brozanski); St Louis Children's Hospital, St Louis, MO, USA (Joan Rosenbaum, Tasmin Najaf, Amit Mathur, Rakesh Rao); All Children's Hospital, St Petersburg, FL, USA (Victor McKay); Rady Children's Hospital, San Diego, CA, USA (Mark Speziale); Children's National Medical Center, Washington, DC, USA (Billie Short); A.I. duPont Hospital for Children, Wilmington, DE, USA (Kevin Sullivan); Primary Children’s Medical Center, Salt Lake City, UT, USA (Donald Null, Robert Di Geronimo); Children’s Hospital of Wisconsin, Milwaukee, WI, USA (Michael Uhing); Children’s Hospital of Omaha, Omaha, NE (Lynne Willett, John Grebe); Florida Hospital for Children, Orlando, FL (Rajan Wadhawan), Seattle Children’s, Seattle, WA (Elizabeth Jacobson Misbe).
KM received a portion of salary support from the Children’s Hospital Association (CHA) in 2012. IZ is an employee of CHA. JMA received a portion of salary support from CHA in 2011–2013 for the development and maintenance of the database that was analyzed for this study. JRE received a stipend from CHA in 2012. The remanining authors declare no conflict of interest.
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Massaro, A., Murthy, K., Zaniletti, I. et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group. J Perinatol 35, 290–296 (2015). https://doi.org/10.1038/jp.2014.190
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