Ricki F. Goldstein

Childhood outcomes after hypothermia for neonatal encephalopathy

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.).

Nursery neurobiologic risk score : important factors in predicting outcome in very low birth weight infants

We developed a nursery Neurobiologic Risk Score (NBRS) based on potential mechanisms of brain cell injury in preterm infants and correlated it with developmental outcome at the corrected ages of 6, 15, and 24 months. The NBRS was determined at 2 weeks of age and at the time of discharge from intensive care in 58 preterm infants with birth weights less than or equal to 1500 gm. The NBRS correlated significantly with the Bayley Scales of Infant Development, Mental Development Index (MDI) (r = -0.61 to -0.40) and Psychomotor Development Index (PDI) (r = -0.59 to -0.46), and with abnormal neurologic examination findings (r = 0.59 to 0.73) at the three testing periods. Although 12 of the 13 items composing the NBRS individually correlated with one or more outcome variables, seven items (infection, blood pH, seizures, intraventricular hemorrhage, assisted ventilation, periventricular leukomalacia, and hypoglycemia) accounted for almost all of the explained variance. Logistic regression of individual items demonstrated intraventricular hemorrhage to be the most important item for predicting the MDI at 24 months; pH was the most influential item for predicting the PDI at every testing period. A shorter, revised NBRS that included only the seven significant items demonstrated as strong a correlation with developmental outcome as the original NBRS. A revised 2-week score of greater than or equal to 5 or a discharge score of greater than or equal to 6 demonstrated 100% specificity and had a 100% positive predictive value for an abnormal outcome at 24 months of age in this group of infants. We conclude that the NBRS identifies during the intensive care nursery stay those infants at highest risk for an abnormal outcome related to nursery events. In addition, analysis of NBRS items provides insight into the relative importance of individual factors for influencing mental, motor, and neurologic outcome.

Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes

OBJECTIVES To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Developments Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2). STUDY DESIGN Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates. RESULTS Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001). CONCLUSION Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial

BACKGROUND Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046). CONCLUSIONS We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Nursery neurobiologic risk score: levels of risk and relationships with nonmedical factors.

ABSTRACT. This study compares the Neurobiologic Risk Score (NBRS) with developmental outcome in 199 infants ≤1500 g birth weight to determine levels of risk and to investigate the relative contributions of the NBRS and nonmedical factors to developmental outcome. The NBRS correlated significantly (p < .0001) with the Bayley Mental (MDI) and Psychomotor (PDI) Indexes, and neurologic examination score (NS) at 6, 15, and 24 months. Three risk groups were identified: low, NBRS ≤4; intermediate, NBRS 5 to 7; and high, NBRS ≥8 with an incidence of major handicaps at 24 months of 7%, 32%, and 50%, respectively. Of eight factors considered, the NBRS accounted for the greatest variance: MDI, 14 to 27%; PDI, 25 to 29%; NS, 34 to 42%. Additional increments of variance were contributed by gender (MDI, PDI, NS), maternal intelligence and race (MDI), and maternal education (PDI). The NBRS is a useful tool for identifying risk for developmental abnormalities due to neonatal medical events. J Dev Behav Pediatr 14:375–380, 1993. Index terms: very low birth weight infants, developmental outcome, developmental follow-up, biologic risk, prematurity.

Use of Medications for Gastroesophageal Reflux at Discharge Among Extremely Low Birth Weight Infants

OBJECTIVES. Our goals were (1) to determine the use of medications to treat gastroesophageal reflux in extremely low birth weight infants (birth weight of <1000 g) at discharge; (2) to identify risk factors associated with the use of medications to treat gastroesophageal reflux at discharge; and (3) to assess the contribution of gastroesophageal reflux medication use at discharge to growth and development at corrected ages of 18 to 22 months. METHODS. This retrospective cohort analysis included extremely low birth weight infants enrolled at National Institute of Child Health and Human Development Neonatal Research Network Centers between 2002 and 2003 who survived to follow-up evaluations at corrected ages of 18 to 22 months. Analyses were used to identify factors associated with discharge with antireflux medications and poor growth or neurodevelopmental impairment after discharge. RESULTS. A total of 1598 infants were included in the analyses; 24.8% were discharged from the hospital with medications to treat gastroesophageal reflux. A total of 19.3% of the 1287 infants discharged at postmenstrual age of ≤42 weeks were discharged with antireflux medications. For those infants, center, lower gestational age, and race had significant effects on the use of antireflux medications at discharge. A total of 47.6% of the 311 infants discharged at postmenstrual age of >42 weeks were discharged with antireflux medications. For those infants, no tested variables were associated with treatment with antireflux medications at discharge. Use of antireflux medications at discharge was not associated with either poor growth or neurodevelopmental impairment at corrected ages of 18 to 22 months. CONCLUSIONS. Use of antireflux medications at the time of discharge seems to be common for extremely low birth weight infants, especially those discharged at postmenstrual age of >42 weeks, but does not seem to have effects on growth or development at the time of follow-up evaluations.

Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks’ gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Infant Arousal in an En-Face Exchange with a New Partner: Effects of Prematurity and Perinatal Biological Risk.

Very low birth weight (VLBW) infants of higher (n = 18) and lower (n = 29) perinatal biological risk were contrasted at 4 months adjusted age with healthy full-term infants (n = 32) in their arousal during a standardized peekaboo game with an examiner. VLBW infants showed less positive arousal, more negative arousal, and 3 mixtures of behavioral cues across the peekaboo game seldom seen for full-term infants-strong cues of both positive and negative arousal, strong cues of negative arousal alone, and no strong cues of either positive or negative arousal. Contrary to expectations, perinatal biological risk did not strongly predict variations in arousal within the VLBW group. Possible changes in how internal and external sources of arousal are integrated provide one explanation for the presence of strong relationships between perinatal biological risk and social responsiveness near term age and their disappearance by 4 months of age.

Long-term morbidities associated with vocal cord paralysis after surgical closure of a patent ductus arteriosus in extremely low birth weight infants

Objective:Determine associations between left vocal cord paralysis (LVCP) and poor respiratory, feeding and/or developmental outcomes in extremely low birth weight (ELBW) infants following surgical closure of a patent ductus arteriosus (PDA).Study Design:ELBW infants who underwent PDA ligation between January 2004 and December 2006 were identified. We compared infants with and without LVCP following ligation to determine relationships between LVCP and respiratory morbidities, feeding and growth difficulties and neurodevelopmental impairment at 18 to 22-month follow-up. Students t-test, Fishers exact test and multivariable regression analyses were used to determine associations.Result:In all, 60 ELBW infants with a mean gestational age of 25 weeks and mean birth weight of 725 g had a PDA surgically closed. Twenty-two of 55 survivors (40%) were diagnosed with LVCP post-operatively. Infants with LVCP were significantly more likely to develop bronchopulmonary dysplasia (82 vs 39%, P=0.002), reactive airway disease (86 vs 33%, P<0.0001), or need for gastrostomy tube (63 vs 6%, P<0.0001).Conclusion:LVCP as a complication of surgical ductal ligation in ELBW infants is associated with persistent respiratory and feeding problems. Direct laryngoscopy should be considered for all infants who experience persistent respiratory and/or feeding difficulties following PDA ligation.

Survival and neurodevelopmental outcomes among periviable infants

BACKGROUND Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth‐year epochs (2000–2003 [epoch 1], 2004–2007 [epoch 2], and 2008–2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three‐level outcome — survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively). CONCLUSIONS The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633.)