Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.
ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.
Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.
Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.
Phototherapy; bilirubin; severity of illness; ELBW infant; impairment; randomized clinical trial; statistical interaction; Bayesian analysis
Decreases below target temperature were noted among neonates undergoing cooling in the NICHD Neonatal Research Network Trial of whole body hypothermia for neonatal hypoxic-ischemic encephalopathy.
To examine the temperature profile and impact on outcome among ≥ 36 week gestation neonates randomized at ≤ 6 hours of age targeting esophageal temperature of 33.5°C for 72 hours.
Infants with intermittent temperatures recorded < 32.0°C during induction and maintenance of cooling were compared to all other cooled infants and relationship with outcome at 18 months was evaluated.
There were no differences in stage of encephalopathy, acidosis, or 10 minute Apgar scores between infants with temperatures < 32.0°C during induction (n=33) or maintenance (n=10) and all other infants who were cooled (n=58); however birth weight was lower and need for blood pressure support higher among infants with temperatures < 32.0 °C compared to all other cooled infants. No increase in acute adverse events were noted among infants with temperatures < 32.0 °C and hours spent < 32°C were not associated with the primary outcome of death or moderate/severe disability or the Bayley II Mental Developmental Index at 18 months.
Term infants with a lower birth weight are at risk for decreasing temperatures < 32.0°C while undergoing body cooling using a servo controlled system. This information suggests extra caution during the application of hypothermia as these lower birth weight infants are at risk for overcooling. Our findings may assist in planning additional trials of lower target temperature for neonatal hypoxic-ischemic encephalopathy.
temperature; hypothermia; newborn; hypoxia-ischemia; encephalopathy; whole-body cooling
Data from the whole body hypothermia trial was analyzed to examine the effects of phenobarbital administration prior to cooling (+PB) on the esophageal temperature (Te) profile, during the induction phase of hypothermia. A total of 98 infants were analyzed. At enrollment, +PB infants had a higher rate of severe HIE and clinical seizures and lower Te and cord pH than infants that have not received PB (−PB). There was a significant effect of PB itself and an interaction between PB and time in the Te profile. Mean Te in the +PB group was lower than in the −PB group and the differences decreased over time. In +PB infants the time to surpass target Te of 33.5°C and to reach the minimum Te during overshoot were shorter. In conclusion, the administration of PB prior to cooling was associated with changes that may reflect a reduced thermogenic response associated with barbiturates.
phenobarbital; hypoxic-ischemic encephalopathy; hypothermia; temperature control
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
Secondhand smoke exposure (SHSe) threatens fragile infants discharged from a neonatal intensive care unit (NICU). Smoking practices were examined in families with a high respiratory risk infant (born at very low birth weight; ventilated > 12 hr) in a Houston, Texas, NICU. Socioeconomic status, race, and mental health status were hypothesized to be related to SHSe and household smoking bans.
Data were collected as part of The Baby's Breath Project, a hospital-based SHSe intervention trial targeting parents with a high-risk infant in the NICU who reported a smoker in the household (N = 99). Measures of sociodemographics, smoking, home and car smoking bans, and depression were collected.
Overall, 26% of all families with a high-risk infant in the NICU reported a household smoker. Almost half of the families with a smoker reported an annual income of less than $25,000. 46.2% of families reported having a total smoking ban in place in both their homes and cars. Only 27.8% families earning less than $25,000 reported having a total smoking ban in place relative to almost 60% of families earning more (p < .01). African American and Caucasian families were less likely to have a smoking ban compared with Hispanics (p < .05). Mothers who reported no smoking ban were more depressed than those who had a household smoking ban (p < .02).
The most disadvantaged families were least likely to have protective health behaviors in place to reduce SHSe and, consequently, are most at-risk for tobacco exposure and subsequent tobacco-related health disparities. Innovative SHSe interventions for this vulnerable population are sorely needed.
To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.
Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n = 12) or discontinuous normal voltage (n = 12), or abnormal, with burst suppression (n = 22), continuous low voltage (n = 26), or flat tracing (n = 36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P = .19).
The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
To evaluate the association between early hypocarbia and 18-22 month outcome among neonates with hypoxic-ischemic encephalopathy (HIE).
Data from the NICHD NRN randomized controlled trial of whole body hypothermia for neonatal HIE were used for this secondary observational study. Infants (n=204) had multiple blood gases recorded from birth-12h of study intervention (hypothermia vs. intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18-22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO2 and cumulative exposure to PCO2 <35 mmHg. The relationship between cumulative PCO2 <35 mmHg (calculated as the difference between 35mmHg and the sampled PCO2 multiplied by the duration of time spent <35 mmHg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), time to spontaneous respiration and ventilator days; results were expressed as OR and 95% confidence intervals. Alternative models of CO2 concentration were explored to account for fluctuations in CO2.
Both minimum PCO2 and cumulative PCO2 <35mmHg were associated with poor outcome (P<0.05). Moreover, death/disability increased with greater cumulative exposure to PCO2 <35mmHg.
Hypocarbia is associated with poor outcome following HIE.
hypocarbia; hypoxic ischemic encephalopathy; whole body hypothermia; outcome; neurodevelopmental impairment
This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).
BAER latencies of 751–1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501–750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.
The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.
Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.
It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy
To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
To assess the association between urinary lactate to creatinine ratio (ULCR) and neurodevelopmental outcome in term infants with hypoxic ischemic encephalopathy and examine the effect of hypothermia on the change in ULCR.
Spot urine samples were collected in 58 term infants (28 hypothermia, 30 control subjects) with hypoxic ischemic encephalopathy. Urinary lactate and creatinine were measured by using 1H nuclear magnetic resonance spectroscopy and expressed as ULCR. Survivors were examined at 18 months of age.
The ULCR was significantly higher in infants who died or had moderate/severe neurodevelopmental disability. Logistic regression analysis controlling for hypothermia and severity of encephalopathy confirmed the association (adjusted odds ratio, 5.52; 95% CI, 1.36, 22.42; P < .02). Considerable overlap in ULCR was observed between infants with normal/mild disability and those who died or survived with moderate/severe disability. ULCR fell significantly between 6 and 24 hours and 48 and 72 hours of age for all infants. The magnitude of decline did not differ between hypothermia and control groups.
High ULCR is associated with death or moderate/severe neurodevelopmental disability. Significant overlap in values between the normal/mild and moderate/severe disability groups limits predictive value of this measure. Whole-body hypothermia did not affect the decline in ULCR.
To identify among extremely low birth weight (≤ 1000 grams) live births, the percent of infants who are unimpaired at 18–22 months corrected age.
Unimpaired outcome was defined as both Bayley-II MDI and PDI Scores ≥ 85, a normal neurological exam, normal vision, normal hearing and normal swallowing and ambulating. Outcomes at 18–22 months were determined for 5250 (86%) of 6090 ELBW inborn infants. Group comparisons were made and regression models were developed to identify factors associated with unimpaired outcome.
Of the 5250 infants whose outcome was known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 (22%) had moderate to severe neurodevelopmental impairments and 2100 (40%) had died. Unimpaired survival rates varied by birth weight from <1% for infants ≤ 500 grams to 24% for infants 901–1000 grams for all live births. The regression model to predict unimpaired survival versus death or impairment for live births ( n=5250) identified that 25.3% of the variance was derived from infant factors present at birth including female gender, higher birth weight, singleton, and small for gestation, and less than 2% was explained either by maternal demographic factors or selected obstetric interventions. For the 3232 infants discharged from the NICU, the unimpaired survival rate was 26%. The regression model to predict unimpaired survival for discharged infants identified that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographics (15.7%) and only 8.5% was derived from infant factors present at birth.
Although <1% of ELBW live births ≤ 500 grams survive free of impairment at 18 months this increases to almost 24% for infants 901–1000 grams. Female gender, singleton, higher birth weight, absence of neonatal morbidities, private health insurance and White race increase the likelihood of unimpaired status.
Extremely low birth weight; outcomes; neurodevelopmental impairment
To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers ≥ 40 years to the corresponding rates among infants of younger mothers.
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
The sample consisted of 14,671 live ELBW births divided into maternal age groups: <20; 20–29; 30–39; and ≥ 40 years. Of infants born to mothers ≥ 40 years, 20% were multiples. Mothers ≥ 40 years had high rates of obstetrical interventions and medical morbidities compared to mothers < 40 years. ELBW live births of mothers ≥ 40 years were 22 % more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared to mothers< 20. Multiple birth, however, was associated with a 10 % greater risk or neurodevelopmental impairment or death.
Although mothers ≥ 40 years had high pregnancy related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.
outcomes; neurodevelopmental impairment; death
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial.
Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age.
A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups.
Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non–central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5°C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories.
Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.
hypoxic-ischemic encephalopathy; whole-body hypothermia; safety; effectiveness
To relate volumetric MRI findings to hypothermia therapy and neurosensory impairments.
Newborns ≥ 36 weeks’ gestation with hypoxic-ischemic encephalopathy who participated in the NICHD hypothermia randomized trial at our center were eligible. We determined the relationship between hypothermia treatment and usual care (control) to absolute and relative cerebral tissue volumes. Further, we correlated brain volumes with death or neurosensory impairments at 18 to 22 months.
Both treatment groups were comparable before randomization. Total brain tissue volumes did not differ in relation to treatment assignment. However, relative volumes of subcortical white matter were significantly larger in hypothermia-treated than control infants. Furthermore, relative total brain volumes correlated significantly with death or neurosensory impairments. Relative volumes of the cortical gray and subcortical white matter also correlated significantly with Bayley Scales psychomotor development index.
Selected volumetric MRI findings correlated with hypothermia therapy and neurosensory impairments. Larger studies utilizing MRI brain volumes as a secondary outcome measure are needed.
hypoxia-ischemia, brain; hypothermia, induced; magnetic resonance imaging; cerebral palsy; outcome assessment
Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients.
We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.
Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.
The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 and NCT00009633.)
We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.
In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.
Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80).
The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.)