Charlene M.T. Robertson

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term

School performance testing was completed at 8 years of age on 145 children who had had neonatal encephalopathy associated with birth asphyxia as term infants and on a comparison peer group of 155 children. The prospectively identified clinical categories of encephalopathy for the neonates were 56 mild (hyperalertness, hyperexcitability), 84 moderate (lethargy, hypotonia, suppressed primitive reflexes), and 5 severe (stupor, flaccidity, absent primitive reflexes). The mortality rate to 8 years of age was 13%. The incidence of impairment, which included cerebral palsy, blindness, cognitive delay, convulsive disorder, and severe hearing loss, was 16% among those assessed at 8 years (75% of survivors). Intellectual, visual-motor integration, and receptive vocabulary scores, as well as reading, spelling, and arithmetic grade levels for those with moderate or severe encephalopathy, were significantly below (p less than 0.01) those in the mild encephalopathy or peer comparison groups. Predictors of reading performance for the study group included category of encephalopathy, birth weight for gestational age, native language, and mothers educational level (multiple R = 0.58). Nonimpaired survivors of moderate encephalopathy were more likely to be more than one grade level delayed than were children from the peer group (reading 35% vs 15%, spelling 18% vs 8%, arithmetic 20% vs 12%, p less than 0.01). Thus children who had moderate and severe neonatal encephalopathy are at risk for physical and mental impairment and reduced school performance. Children with mild encephalopathy had school performance scores similar to those of their peers.

TERM INFANTS WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY: OUTCOME AT 3.5 YEARS

A total of 167 term neonates with a diagnosis of hypoxic‐ischemic encephalopathy (HIE) had detailed neurodevelopmental follow‐up at 3–5 years of age. All 66 children with mild HIE were free from handicap; all seven with severe HIE were severely handicapped; and of the 94 with moderate HIE at birth, 21‐3 per cent were handicapped. Mean IQ was significantly related to the category of HIE. Within the moderate HIE category, the neurological examination at discharge from the Neonatal Intensive Care Unit was more useful than the presence of neonatal convulsions in identifying children with subsequent developmental delay. Abnormalities on this examination related significantly to an increased number of handicapped children, decreased motor and language skills, and lower IQs. Although neonatal convulsions were associated with an increased number of handicapped children, they did not significantly affect most other developmental outcome measures. In term infants with documented HIE at birth, major neurodevelopmental dysfunction at 3–5 years depended more on prospectively established category of HIE than on other perinatal or social factors.

Determinants of outcomes after head cooling for neonatal encephalopathy

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion

BACKGROUND AND OBJECTIVE. Extremely low birth weight infants frequently receive red cell transfusions. We sought to determine whether a restrictive versus liberal hemoglobin transfusion threshold results in differences in death or adverse neurodevelopmental outcomes of extremely low birth weight infants. PATIENTS AND METHODS. Extremely low birth weight infants previously enrolled in the Preterm Infants in Need of Transfusion Trial, a randomized, controlled trial of low versus high hemoglobin transfusion thresholds, were followed up at 18 to 21 months’ corrected age. Erythrocyte transfusion was determined by an algorithm of low (restrictive) or high (liberal) hemoglobin transfusion thresholds, differing by 10 to 20 g/L and maintained until first hospital discharge. The primary composite outcome was death or the presence of cerebral palsy, cognitive delay, or severe visual or hearing impairment. RESULTS. Of 451 enrolled infants, the primary outcome was available in 430. There was no statistically significant difference in the primary outcome, found in 94 (45%) of 208 in the restrictive group and 82 (38%) of 213 in the liberal group. There were no statistically significant differences in preplanned secondary outcomes. However, the difference in cognitive delay (Mental Development Index score < 70) approached statistical significance. A posthoc analysis with cognitive delay redefined (Mental Development Index score < 85) showed a significant difference favoring the liberal threshold group. CONCLUSIONS. Maintaining the hemoglobin of extremely low birth weight infants at these restrictive rather than liberal transfusion thresholds did not result in a statistically significant difference in combined death or severe adverse neurodevelopmental outcome.

Eight-year school performance and growth of preterm, small for gestational age infants: a comparative study with subjects matched for birth weight or for gestational age.

Eight-year school performance and growth outcome are reported for three groups of preterm infants: one group that was small for gestational age (SGA; 36 infants) and two comparison groups that were appropriate in size for gestational age, one matched for birth weight and the other for gestational age. The subjects all had white parents whose mother tongue was English and were matched for gender, mothers height, mothers education, and fathers socioeconomic status (Blishen Scale). A comparison peer group of term infants was also studied. The three preterm groups did not differ in school performance or physical growth, with the exception of head circumference, which was smaller in the SGA children. All preterm groups had growth measures, intellectual and visual-motor integration scores, reading and arithmetic grade levels, and behavior rating levels significantly inferior to those of the peer group. Receptive vocabulary scores and spelling grade levels did not differ between the preterm groups and the peer group. On multivariate analyses, mothers education was the primary predictor of academic grade levels for the preterm SGA group, and the only predictor when the disabled children were excluded from analyses. Preterm SGA children without disabilities had academic scores similar to those of their term peers, but their scores indicated more hyperactivity. Intrauterine growth retardation did not appear to impose a disadvantage on the preterm children in this study.

Permanent Bilateral Sensory and Neural Hearing Loss of Children After Neonatal Intensive Care Because of Extreme Prematurity: A Thirty-Year Study

OBJECTIVE. We present population-based, childhood prevalence rates of and neonatal risk factors for permanent hearing loss among extremely premature infants. METHODS. By using an inception-cohort, longitudinal study design for 1974–2003, we studied permanent hearing loss among 1279 survivors with gestational age of ≤28 weeks and birth weight of <1250 g (mortality rate: 42.7%; lost to follow-up monitoring: 4.7%) Newborn hearing screening, performed by experienced pediatric audiologists, used click-evoked auditory brainstem response testing after 1975. Survivors underwent repeated behavioral audiologic testing and multidisciplinary follow-up monitoring. Permanent hearing loss was defined as mild/moderate (26–70 dB hearing level), severe/profound (71 to >90 dB hearing level), delayed-onset (diagnosed after previously normal hearing), or progressive (increase in loss of ≥15 dB hearing level). Permanent hearing loss rates were established at 3 years of age, with newborn, infant, and >5-year final hearing outcomes being recorded. Risk factors were compared for children with and without hearing loss, odds ratios were calculated, and prediction performance was determined through area under the curve analysis. RESULTS. Forty (3.1%) of 1279 survivors 3 years of age had permanent hearing loss and 24 (1.9%) had severe/profound loss, with no changes over time. Bilateral delayed-onset loss occurred for 4 children (10%) and progressive loss for 11 children (28%). One child had auditory neuropathy, and 29 (73%) had multiple disabilities. Prolonged oxygen use, gastrointestinal surgery, patent ductus arteriosus ligation, and low socioeconomic index yielded good prediction of permanent hearing loss; oxygen use was the most significant predictor of severe/profound loss. CONCLUSIONS. Permanent hearing loss remains an adverse outcome of extreme prematurity, complicated by significant delayed-onset and progressive loss. Prolonged supplemental oxygen use is a marker for predicting permanent hearing loss; this requires detailed analysis of the pathophysiologic features, to reduce the prevalence of permanent hearing loss.

Comparative Study of Mortality and Morbidity in Premature Infants (Birth Weight, <1,250 g) with Candidemia or Candidal Meningitis

Little information is available on long-term neurodevelopment of premature neonates with invasive candidal infections. We retrospectively studied the outcomes for 25 premature neonates (birth weight, < 1,250 g) with candidemia or candidal meningitis (cases) and compared them with 25 neonates matched for birth weight (+/- 100 g) and gestational age (+/- 1 week) (controls). Durations of antibiotic therapy, artificial ventilation, invasive catheterizations, and hyperalimentation were longer for cases than for controls. Cases had a higher final grade of intraventricular hemorrhage than did controls (median: 3.0 vs. 2.5, respectively; P < .05). Forty-four percent (11 of 25) of cases and 16% (4 of 25) of controls died (P > .05), and 29% (4 of 14) of surviving cases and 14% (3 of 21) of controls were disabled (P > .05). More cases had combined mortality and neurodevelopmental disabilities than did controls (60% vs. 28%, respectively; P < .05). Use of invasive therapies should be minimized for premature neonates at risk for invasive candidal infection that is associated with adverse outcomes.

Neurocognitive, Functional, and Health Outcomes at 5 Years of Age for Children After Complex Cardiac Surgery at 6 Weeks of Age or Younger

OBJECTIVE. This work provides neurocognitive, functional, and health outcomes for 5-year survivors of early infant complex cardiac surgery, including those with chromosomal abnormalities. PATIENTS AND METHODS. Of 85 children (22.4% mortality), 61 received multidisciplinary, individual evaluation and parental questionnaires at 5 years. Full-scale, verbal, and performance IQ scores were compared by using analysis of variance among children who received different surgeries (arterial switch, 20; Norwood for hypoplastic left heart syndrome, 14; simple total anomalous pulmonary venous connection, 6; miscellaneous, 21; and chromosomal abnormalities, 8). Predictions from mental scores at 2 years for IQ scores at 5 years were determined. RESULTS. Children with chromosomal abnormalities had lower full-scale and verbal IQs at 5 years than other survivors, with no differences found among the remaining groups. For children post-Norwood, performance IQ scores remained lower than for children after the arterial-switch operation. Prediction of full-scale IQ (<70) from 2-year mental scores for all 61 children were as follows: sensitivity, 87.5%; specificity, 88.1%; positive predictive value, 53.8%; and negative predictive value, 97.9%. For full-scale IQ of <85, predictions were 90.0%, 87.8%, 78.3%, and 94.7%, respectively. For those 53 without chromosomal abnormalities, full-scale IQ <70, respective predictions were 86.7%, 90.0%, 28.6%, and 97.8%, and for full-scale IQ <85, respective predictions were 85.7%, 89.7%, 75.0%, and 94.6%. Parental report indicated good health in 80% and adequate function in 67% to 88% of the children, although health-utilization numbers suggest that these reports are optimistic. CONCLUSIONS. Five-year full-scale and verbal IQs were similar among groups, excluding those with chromosomal abnormalities. Children with chromosomal abnormalities had the lowest scores. Excluding those with chromosomal abnormalities, the mean mental scores for the children as a group tended to increase from 2 to 5 years of age, with an overall high percentage of correct classifications at 2 years.

Two-Year Survival and Mental and Psychomotor Outcomes After the Norwood Procedure An Analysis of the Modified Blalock-Taussig Shunt and Right Ventricle–to–Pulmonary Artery Shunt Surgical Eras

Background— The Norwood procedure for stage 1 palliation of hypoplastic left heart syndrome is performed with either the modified Blalock-Taussig (MBTS) or the right ventricle–to–pulmonary artery (RVPA) shunt. In our institution, surgical practice changed from use of the MBTS to use of the RVPA shunt in 2002. We analyzed survival and mental and psychomotor outcomes of the 2 consecutive surgical eras. Methods and Results— Between September 1996 and July 2005, 94 neonates with hypoplastic left heart syndrome underwent the Norwood procedure. Patients were recruited as neonates and followed up prospectively. Health, mental, and psychomotor outcomes (Bayley Scales of Infant Development-II) were assessed at 2 years. The study subjects were from the Norwood-MBTS era (n=62; 1996 to 2002) or the Norwood-RVPA era (n=32; 2002 to 2005). In the MBTS era, early and 2-year mortality rates were 23% (14/62) and 52% (32/62); the mean (SD) mental and psychomotor developmental indices were 79 (18) and 67 (19). In the RVPA era, early and 2-year mortality rates were 6% (2/32) and 19% (6/32); the mean (SD) mental and psychomotor developmental indices were 85 (18) and 78 (18). The 2-year mortality rate (P=0.002) and the psychomotor developmental index (P=0.029) were improved in the more recent surgical era. On multivariable Cox regression analysis, postoperative highest serum lactate independently predicted 2-year mortality in the MBTS and RVPA eras. Conclusions— Analysis of 2 consecutive surgical eras of hypoplastic left heart syndrome patients undergoing the Norwood procedure showed a significant improvement in 2-year survival and psychomotor development in the more recent era. Adverse neurodevelopmental outcome in this patient population remains a concern.