Outcomes of Hypoxic- IschemicEncephalopathy in NeonatesTreated with Hypothermia

Seetha Shankaran, MD

KEYWORDS

� Encephalopathy � Neonatal � Hypothermia � Outcome � Predictors

KEY POINTS

� Hypothermia for neonatal hypoxic-ischemic encephalopathy is safe and effective inreducing death and disability at 18 months of age.

� This neuroprotection continues into childhood, as demonstrated by a reduction in mortal-ity and major disability at 6 to 7 years of age.

� Outcome at 18 months of age is a good predictor of childhood outcome.

OUTCOMES OF CHILDREN WITH BIRTH DEPRESSION/ENCEPHALOPATHY BEFOREHYPOTHERMIA THERAPY

Before the advent of neuroprotective therapy with hypothermia, studies evaluatingoutcomes of children born at term with birth depression or encephalopathy weregenerally cohort studies, each having unique inclusion criteria, evaluation methods,and duration of follow-up. Among these studies, the outcome of children with acuteperinatal asphyxia and/or neonatal encephalopathy was a disability rate of 6% to21% in children with moderate encephalopathy and 42% to 100% in those with severeencephalopathy.1–5 Among nondisabled children who were able to undergo psycho-metric and behavioral testing, lower executive function and delays in school readiness(reading, spelling, and arithmetic) and lower scores in language, memory, and senso-rimotor perception have been noted.1,3,6 The possibility of an increase in the rate ofsymptoms associated with attention-deficit/hyperactivity disorder, including anxiety,depression, attention regulation, time perception, and thought problems, as well asan increased risk of autism has been noted in children with encephalopathy or depres-sion at birth.6–9 A recent systematic review of long-term neurodevelopmental out-comes after intrauterine and neonatal insults, especially in low- and middle-incomecountries (LMIC), noted that the 27 studies evaluating 2708 infants reported sequelae

The author has no financial disclosures.Division of Neonatal/Perinatal Medicine, Children’s Hospital of Michigan, 3901 Beaubien,Detroit, MI, USAE-mail address: sshankar@med.wayne.edu

Clin Perinatol 41 (2014) 149–159http://dx.doi.org/10.1016/j.clp.2013.10.008 perinatology.theclinics.com0095-5108/14/$ – see front matter � 2014 Elsevier Inc. All rights reserved.

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in 1002 (37%) children. Cognitive, general developmental delay or learning difficultieswere noted in 45%, cerebral palsy (CP) in 29%, deafness/hearing loss in 9%, impairedvision/blindness in 26%, gross motor coordination problems in 17%, epilepsy in 12%,and behavioral problems in 1% of children. Multiple impairments were reported in20.5% of children while at least 1 impairment was noted in 44%, and severe sequelaein at least 1 domain in 27%.10

OUTCOMES OF CHILDREN WITH MODERATE OR SEVERE ENCEPHALOPATHY AT18 MONTHS OF AGE FOLLOWING HYPOTHERMIA THERAPY

All of the randomized controlled trials (RCTs) of neuroprotection with hypothermia forneonatal hypoxic-ischemic encephalopathy (HIE) have had very similar inclusioncriteria (�36 weeks gestational age, severe acidosis or birth depression, moderateor severe encephalopathy with or without an abnormal amplitude-integrated electro-encephalogram [aEEG]) and cooling initiated within 6 hours of age. The exclusioncriteria were infants of age greater than 6 hours, those with major congenital or chro-mosomal abnormalities, or those with severe intrauterine growth restriction. The neu-rodevelopmental assessment tools evaluating 18-month outcome were similar andcomparable between trials. Details of the results of the primary outcomes, compo-nents of the primary outcome, and predefined secondary outcomes are summarizedherein. Predictors of 18-month outcomes are also presented, as this information maybe helpful in discussions with families of infants with HIE.

CoolCap Trial

The CoolCap Trial was the first large RCT of hypothermia to be published.11 Selectivehead cooling to a target temperature of 34� to 35� for 72 hours, or intensive care alonefollowing moderate or severe encephalopathy and an abnormal aEEG or seizures, wascompared among 234 neonates, 116 infants assigned to cooling and 118 to conven-tional care. Eight infants were lost to follow-up in each group. The primary outcomewas mortality or severe neurodevelopmental disability at 18 months. Severe disabilitywas defined as gross motor function level (GMF) of 3 to 5, Bayley Scales of InfantDevelopment (BSID II) with either Mental Development Index (MDI) or a PsychomotorDevelopment Index (PDI) less than 70 (2 standard deviations [SD] below normal), orbilateral cortical visual impairment. Nine survivors did not have MDI scores and 4 of9 were missing visual outcome data, but all had GMF scores of 3 or higher. Deathor severe disability was noted in 59 of 108 (55%) cooled infants versus 73 of 110(66%) control-group infants, odds ratio (OR) 0.61 (95% confidence interval [CI]0.34–1.09); with mortality rates of 33% versus 38%, OR 0.81 (0.47–1.41) and severedisability in 14 of 72 (19%) versus 21 of 68 (31%), OR 0.54 (0.25–1.17) in the cooledand control groups, respectively. A Bayley MDI score of lower than 70 occurred in21 of 70 (30%) versus 24 of 61 (39%), and visual impairment in 7 of 72 (10%) versus11 of 64 (17%) cooled and control infants (P not significant).Predictors of 18-month outcome in the CoolCap RCT12:

1. The primary outcome was lower among infants who received hypothermia.2. Primary outcome was also lower among infants with a less severe aEEG pattern at

study intervention.3. A worse outcome was noted among infants with severe HIE in comparison with in-

fants with moderate HIE.4. The absence of seizures by aEEG was associated with better outcome.5. Elevated temperature in control-group infants was associated with worse

outcomes.

Outcomes of Hypoxic-Ischemic Encephalopathy 151

6. Age at randomization of study infants within 6 hours did not influence the outcome.7. Hypothermia altered the accuracy of the neuroexamination after cooling.13

The National Institute of Child Health and Human Development (NICHD) RCT

Whole-body hypothermia to a target temperature of 33� to 34�C or usual care wasassigned randomly following moderate or severe HIE.14 There were 102 infants inthe hypothermia group and 106 in the control group. The primary outcome wasdeath or moderate or severe disability at 18 months. Severe disability was definedas Bayley II MDI less than 70, Gross Motor Function Classification System (GMFCS)level 3 to 5, or hearing impairment requiring aids or blindness. Moderate disabilitywas defined as MDI 70 to 84 and GMFCS level 2, hearing impairment without ampli-fication, or a persistent seizure disorder. Data were unavailable for 3 infants. The pri-mary outcome was seen in 45 of 102 (44%) hypothermia and 64 of 103 (62%) controlinfants. Risk ratio (RR) adjusted for center was 0.72 (95% CI 0.54–0.95). Deathoccurred in 24 of 102 (24%) and 38 of 106 (37%) infants, RR 0.68 (0.44–1.05), inthe hypothermia and control groups, respectively. Moderate/severe CP occurredin 15 of 78 (19%) and 19 of 68 (30%), blindness in 7% and 14%, and hearing impair-ment in 4% and 6% of infants in the hypothermia and control groups, respectively.Moderate disability occurred in 3 infants, 2 in the hypothermia group and 1 in thecontrol group.15 The treatment was reported to be safe, and was associated witha consistent trend for decreasing frequency in each of the components ofdisability.15

Predictors of 18-month outcome in the NICHD whole-body hypothermia trial withsecondary analyses of data from the NICHD trial data have found the following:

1. An elevated temperature (in the control group of infants) was associated with anincrease in the risk of death or disability at 18 months.16

2. An elevated urinary lactate to creatinine ratio was associated with pooroutcome.17

3. Classification and regression-tree analysis revealed that cord pH, spontaneousactivity of the infants, base deficit of the first postnatal blood gas, and the levelof partial pressure of carbon dioxide (PCO2) in the cord gas was useful in predictingoutcome.18

4. Death or moderate severe HIE was noted to be common among infants with apersistently low 10-minute Apgar score; however, not all infants with an Apgarscore lower than 3 at 10 minutes had a uniformly poor outcome.19

5. Persistence of severe encephalopathy at 72 hours increased the risk of death ordisability, as did the presence of an abnormal neurologic examination at neonatalhospital discharge.20

6. Clinical seizures were not associated with outcome when adjusted for confound-ing variables.21

7. Location of birth (inborn vs outborn) did not influence outcome.22

8. Smaller, sicker infants had more decreases in temperature, both during inductionand maintenance phase of cooling.23

9. Time to initiation of cooling did not influence outcome.15

10. In a subset of trial infants and prospectively cooled infants (after trial accrualclosed), the aEEG was noted to add minimally to predictive value of stage ofencephalopathy.24

11. The administration of phenobarbital for seizures before the onset of initiation ofcooling was associated with a lower temperature during the induction phase ofcooling.25

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12. Both minimum PCO2 and cumulative PCO2 lower than 35 mm Hg from birth to12 hours of age were associated with poor outcome.26

13. The 18- to 22-month outcome was not associated with the APOE genotypeamong survivors.27

TOBY Trial

The TOBY Trial inclusion criteria involved both the presence of moderate or severe HIEand an abnormal aEEG.28 Whole-body hypothermia to a target of 33.5�C for 72 hoursor intensive care alone was compared between the 2 study arms. Primary outcomewas death or severe disability, defined as BSID II MDI lower than 70, GMFCS level3 to 5, or bilateral cortical visual impairment. The study is the largest to date, with325 (163 hypothermia and 162 control) infants enrolled. In both groups, 1 infant waslost to follow-up. The primary outcome was noted in 74 of 163 (45%) cooled versus86 of 162 (53%) control, RR 0.86 (95% CI 0.68–1.07). Results were unchangedwhen adjusted for severity of aEEG background, sex, or age at randomization. Survi-vors with severe disability were 32 of 120 (27%) hypothermia and 42 of 117 (36%) con-trol, RR 0.74 (0.51–1.09). The predefined secondary outcome of survival free ofneurologic abnormalities was 71 of 163 (44%) hypothermia and 45 of 162 (28%) con-trol, RR 1.57 (1.16–2.12). Among hypothermia and control-group infants, higher ratesof BSID MDI of 85 or higher (70% vs 55%) and PDI of 85 or higher (68% vs 53%),normal neurologic examination (71% vs 54%), and lower rates of CP (28 vs 41%)and multiple disabilities (19% and 30%) were noted in the hypothermia group (allP<.05).Predictors of 18-month outcome in the TOBY trial:

1. More infants with a severe abnormal aEEG background died in comparison withthose with a moderate background.

2. The effect of cooling did not vary according to the severity of abnormality on theaEEG.

3. Time to randomization did not influence outcome.

nEURO.Network RCT

This trial used both aEEG and moderate or severe HIE criteria and whole-body coolingto 33� to 34�C with cotreatment of morphine.29 The primary outcome was death or se-vere disability at 15 months with severe disability defined as GMFCS 3 to 5, GriffithDevelopmental Quotient less than 2 SD below normal of 100, or severe cortical visualdeficit. The sample size was 150, but the trial was stopped early because of lack ofequipoise among investigators. There were 64 infants assigned to the hypothermiagroup and 65 to the control group; data at 18 months were available for 53 and 58 in-fants in the hypothermia and control groups, respectively. Death or severe disabilityoccurred in 27 of 53 (51%) in the hypothermia group versus 48 of 58 (83%) in the con-trol group; OR adjusted for severity of HIE was 0.21 (95% CI 0.09–0.54). CP occurredin 4 of 32 (12%) versus 10 of 21 (48%), OR 0.15 (0.04–0.60), in the hypothermia andcontrol groups, respectively.Predictors of Outcome of nEURO RCT: In this study, the severity of encephalopathy

significantly affected the outcome.

ICE Trial

The ICE Trial involved cooling initiated at the birth hospital for outborn infants bydedicated neonatal retrieval teams, using gel packs on the chest and shoulderand discontinuing the overhead warmer and temperature in the transport

Outcomes of Hypoxic-Ischemic Encephalopathy 153

incubator.30 Clinical eligibility criteria were moderate or severe HIE, and target tem-perature was 33� to 34�C. Infants who required more than 80% oxygen therapy werealso excluded. The primary outcome was death or sensorineural disability at24 months, defined as moderate or severe CP, GMFCS 2 to 5, BSID II MDI or PDIless than 2 SD below normal, or BSID III cognitive, language, or motor score lessthan 2 SD below normal, blindness, or deafness. The sample size was 150 pergroup, but recruitment stopped early because of publication of earlier RCTs andloss of equipoise by investigators. The hypothermia and control groups had 110and 111 infants assigned; data were available for the primary outcome for 107and 101 infants, respectively. Mild HIE was noted in 42 infants. Death or disabilityoccurred in 55 of 107 (51%) hypothermia infants versus 67 of 101 (66%) controlinfants, RR 0.77 (95% CI 0.62–0.98); the effect persisted after excluding the infantswith mild HIE. Severe disability was seen in 28 of 80 (35%) hypothermia versus 25 of59 (42%) control infants (P not significant). Survival free of disability was 40%hypothermia versus 23% control (P 5 .01).

Trials in Low-Income and Middle-Income Countries

Seven RCTs with a total of 567 infants are included in a recent meta-analysis of hypo-thermia for HIE in LMIC.31 The largest study from China enrolled 100 hypothermia and94 control-group infants while another from India enrolled 62 infants in each group.Three studies involved head cooling, 4 involved whole-body cooling using water bot-tles, 1 study each used phase-changing materials or gel packs, and 1 study did notspecify the method of cooling. Follow-up data are not available from all the studies,and the overall mortality was RR 0.74 (95% CI 0.44–1.25). The study by Zhou and col-leagues32 excluded infants with infection and anemia as eligibility criteria. In this study,head cooling to a target of 34� to 35�C was used. Primary outcome was death ordisability at 18 months. Of the 256 infants recruited there were 21 postrandomizationexclusions, and 41 infants did not have follow-up data. Death or severe disabilitydefined as GMFCS 3 to 5 or developmental quotient less than 70 on the Gesell ChildDevelopment Age Scale was noted in 31% and 49%, OR 0.47 (0.26–0.84), and severedisability in 11 of 80 (14%) versus 19 of 67 (28%) infants, OR 0.40 (0.17–0.92), amongthe hypothermia and control groups, respectively. The inadequate quality of the LMICtrials, including lack of comprehensive follow-up of trial subjects, currently providesneither evidence of safety nor efficacy of hypothermia as neuroprotection for neonatalHIE. Prospective, well-designed RCTs are needed in LMIC; one such trial is evaluatingfeasibility (Hypothermia for Encephalopathy in Low Income Countries, the HELIX trial;NCT01760629).

META-ANALYSIS OF TRIALS WITH 18 MONTHS’ OUTCOME

The analysis by Edwards and colleagues33 after evaluation of the CoolCap, NICHD,and TOBY trials (all in high-income countries) clearly demonstrated with a sampleof 767 trial participants that hypothermia was neuroprotective, with a reduction inmortality and disability and an increase in survival free of disability (Table 1); lackof benefit was noted in infants with severe HIE. The recent meta-analysis by Taginand colleagues34 of 7 studies, including the aforementioned trial by Zhou and col-leagues,32 notes that cooling is effective in reducing death and all components ofdisability among survivors, and increasing the rate of normal survivors. In addition,cooling is effective in infants with severe HIE in addition to those with moderateHIE. Both approaches to cooling, either head or whole-body hypothermia, are neuro-protective (Table 2).34

Table 1Meta-analysis of CoolCap, NICHD, and TOBY trials

767 Participants RR (95% CI)

Death and disability 0.81 (0.71–0.93)

Mortality 0.78 (0.66–0.93)

Severe disability 0.71 (0.56–0.91)

Cerebral palsy 0.69 (0.54–0.89)

PDI <70 0.73 (0.56–0.95)

MDI <70 0.71 (0.54–0.92)

Blindness 0.57 (0.33–0.96)

Deafness 0.76 (0.36–1.62)

Normal survivors 1.53 (1.22–1.93)

Moderate HIE 0.73 (0.58–0.92)

Severe HIE 0.87 (0.75–1.01)

Abbreviations: CI, confidence interval; HIE, hypoxic-ischemic encephalopathy; MDI, mental devel-opmental index; PDI, psychomotor developmental index; RR, risk ratio.

Data from Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months ofage after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis andmeta-analysis of trial data. BMJ 2010;340:c363.

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OUTCOMES IN CHILDHOOD OF NEONATES WITH HYPOTHERMIA FOR MODERATE ORSEVERE HIESeven- to 8-Year Follow-Up of the CoolCap Trial

The CoolCap trial evaluated whether 18- to 22-month outcome predicted functionaloutcomes at 7 to 8 years of age among survivors by evaluating WeeFIM ratingmeasuring self-care, mobility, and cognitive functions by telephone interviews.35

There was 1 parent refusal, 14 of the CoolCap centers did not participate, and 58 chil-dren were lost to follow-up among participating centers. The demographic data of

Table 2Meta-analysis of trials by Gunn, CoolCap, NICHD, TOBY, nEURO, China, and ICE

1214 Participants RR (95% CI)

Death and disability 0.76 (0.69–0.84)

Death 0.75 (0.63–0.88)

Major disability 0.68 (0.56–0.83)

Cerebral palsy 0.62 (0.49–0.78)

Developmental delay 0.66 (0.52–0.82)

Blindness 0.56 (0.33–0.94)

Deafness 0.64 (0.32–1.27)

Normal survivors 1.63 (1.36–1.95)

Moderate HIE 0.67 (0.56–0.81)

Severe HIE 0.83 (0.74–0.92)

Whole-body cooling 0.75 (0.66–0.85)

Head cooling 0.77 (0.65–0.93)

Data from Tagin MA, Woolcott CG, Vincer MJ, et al. Hypothermia for neonatal hypoxic ischemicencephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med2012;166(6):558–66.

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children assessed (62 children) were similar to those not evaluated (73 children), hencethe study cohort was considered to be representative of the trial. The characteristicsbetween cooled (n5 32) and control (n5 30) children were also comparable. Status at18 months was associated with status at 7 to 8 years (P<.001) with a rating of 115� 19(mean� SD) in those with a favorable 18-month outcome and 67� 42 in those with anadverse outcome. Adjustment for confounding variables and treatment did not affectthe association. CP diagnosed at 18 months was highly associated with WeeFIMmobility score at 7 to 8 years.

Childhood Outcomes at 6 to 7 Years in the NICHD Trial

The primary outcome at 6- to 7-year outcome in the NICHD Trial was death or IQ ofless than 70 while secondary outcomes included death, severe disability, componentsof disability, higher cognitive function, and psychosocial health.36 Assessment toolsincluded the evaluation of IQ with the Wechsler Preschool and Primary Scale of Intel-ligence III (WPPSI) (n 5 96) and the Wechsler Intelligence Scale for Children IV (WAIS)(n5 18). Verbal comprehension, perceptual organization, and processing speed wereassessed yielding a verbal IQ and performance IQ, which were combined to give a full-scale IQ (normal value 100 � 15). Higher cognitive function was assessed by subtestsof attention, executive function, and visuospatial reasoning using the DevelopmentalNeuropsychological Assessment (NEPSY) (mean 100 � 15). Lastly, the Child HealthQuestionnaire assessed physical, emotional, and social well-being of the child andthe effects of the child’s health on the parents. All testing was conducted by examinerstrained to reliability and unaware of the treatment assignment. The neurologic func-tional assessment was evaluated using the GMFCS for 6- to 7-year-old children:GMFCS level 1, walking without restriction; II, walking without assisted device; III,walking with an assistive device; IV, self-mobility with limitation; and V, severe limita-tion of mobility. Severe disability was defined as IQ less than 3 SD below the mean(<55), GMFCS level IV or V, or bilateral blindness. Moderate disability was IQ lessthan 2 to 3 SD below the mean (55–69), a GMFCS level of III, bilateral deafness, or re-fractory epilepsy. Mild disability was IQ 1 to 2 SD below the mean (70–84) and aGMFCS level I or II. No disability was IQ greater than 1 SD below the mean (>85)with no CP, hearing, or vision deficit, or epilepsy. Among nondisabled survivors,everyday motor function was tested by the heel-to-toe test, ability to hop, standingon one foot, or Romberg test, while fine motor function tests of coordination includedfinger-nose, rapid alteration of hands, thumb–index finger apposition, thumb–4-fingerapposition sequentially, heel-to-shin test, and foot tapping. The primary outcome wasadjusted for center and level of HIE.Primary outcome data were available for 190 of 208 (91% of participants): 97 of 100

(97%) in the hypothermia group and 93 of 106 (88%) in the control group; 5 hypother-mia and 3 control-group children were lost to follow-up. The primary outcome wasseen in 46 of 97 (47%) hypothermia and 58 of 93 (62%) control children; RR 0.78(95% CI 0.61–1.01) adjusted for center. The mortality rate was 27 of 97 (28%) hypo-thermia versus 41 of 93 (44%) control, RR 0.66 (0.45–0.97); 3 in each group died afterthe 18-month visit. Death or severe disability was 41% versus 60% (P 5 .03), deathor IQ less than 55 was 41% versus 60% (P 5 .03), and death or CP 41% versus60%, P 5 .02 in the hypothermia and control groups, respectively. Among survivors,IQ less than 70 occurred in 27% versus 33%, and CP in 17% versus 29% (both P notsignificant). Attention and executive function scores lower than 70 occurred in 2 of 48and 4 of 32 children, and visuospatial scores lower than 70 in 2 of 53 and 1 of 36children who could be tested in the hypothermia and control group (P not significant).There were no differences between groups when parental assessment of child’s

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esteem was evaluated; the emotional impact of the child’s well-being on parents wasalso similar between groups. There were no differences between groups in the assess-ment of the child’s physical health.

Predictors of Outcome at 6 to 7 Years in the NICHD Trial

Among children in the trial who had moderate or severe disability at 18 months, thecorresponding rates at 6 to 7 years was 15 of 17 (88%) in the hypothermia groupand 18 of 19 (95%) in the control group. All children with CP at 18 months had CPat 6 to 7 years; among those with seizures at 18 months, the corresponding rates at6 to 7 years were 4 of 10 (40%) in the hypothermia group and 5 of 10 (50%) in the con-trol group. The predictive value of moderate or severe disability at 6 to 7 years for chil-dren disabled at 18 months in the hypothermia group was sensitivity 63%, specificity96%, positive predictive value (PPV) 88%, and negative predictive value (NPV) 83%,whereas the corresponding rates in the control group were 95%, 97%, 95%, and97%, respectively. The predictive value of moderate or severe CP at 6 to 7 years forchildren with moderate or severe CP at 18 months had sensitivity of 100%, specificity100%, PPV 100%, and NPV 100% in the hypothermia group and 93%, 100%, 100%,and 97% in the control group, respectively. The odds of disability at 6 to 7 years for aninfant disabled at an earlier age, compared with one not disabled, was 37 times higher(95% CI 7–189) in the hypothermia group and 576 times higher in the control group(34–9774). Thus, a high concordance was noted between assessment of moderateor severe disability at 18 to 22 months and similar assessments at 6 to 7 years orage.36

Secondary analysis of the 6- to 7-year outcome following hypothermia for neonatalHIE has yielded useful information.

1. The growth of children with HIE treated with hypothermia is similar to that ofcontrol-group children; growth failure seen in children with CP, irrespective of inter-vention, presents to childhood.37

2. Control-group infants who had elevated temperatures during the study interventionin the neonatal course continued to have an increased risk of death or disability at 6to 7 years.38

3. Among trial participants, 10-minute Apgar scores were associated with school-ageoutcomes. However, one-fifth of the children with 10-minute Apgar scores of 0 sur-vived without disability to school age.39

THE FUTURE OF HYPOTHERMIA THERAPY

Hypothermia therapy for neonatal HIE has demonstrated neuroprotection; however,mortality rates and disability rates continue to be high. The future of hypothermiatherapy will include adjunctive therapy with hypothermia.40 The following adjunctivetherapies are being examined in trials: xenon (NCT01545271 and NCT00934700),erythropoietin (NCT00719407), darbepoetin (NCT0147105), and topiramate(NCT01241019). The use of human cord blood for the hypoxic-ischemic neonate isalso being investigated. It remains to be seen whether early accurate neonatal bio-markers of neurologic and developmental assessments at follow-up will become avail-able. The TOBY, NICHD, and ICE trials have noted that brain injury on neonatalmagnetic resonance imaging in subsets of trial subjects is associated with 18-monthoutcome.41–43 Two ongoing trials, one of the optimum depth of temperature and dura-tion of cooling (NCT01192776) in term infants and the other evaluating neuroprotectionwith cooling of infants of 34 to 35 weeks gestational age (NCT00620711), will also yielduseful information in this evolving and exciting field.

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SUMMARY

Hypothermia is a safe and effective treatment for neonatal HIE. The data from child-hood outcomes have shown that the benefits seen at 18 months continue to child-hood, without an increase in survivors with disabilities. Outcome at 18 monthscorrelates well with that at 6 to 7 years of age, hence new innovative trials of hypother-mia plus therapies can continue to follow infants to 18 months of age. The search foran early neonatal biomarker for 18-month outcome should continue.

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