Deanne Wilson-Costello

Improved Survival Rates With Increased Neurodevelopmental Disability for Extremely Low Birth Weight Infants in the 1990s

Background. Advances in perinatal care have resulted in increased survival rates for extremely low birth weight children. We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods, before and after the introduction of surfactant therapy in 1990. Methods. Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I (1982–1989) (mean body weight: 762 g; mean gestational age: 25.8 weeks) and 682 during period II (1990–1998) (mean body weight: 756 g; mean gestational age: 25.5 weeks). Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses, with adjustment for gestational age. Results. Survival rates increased from 49% during period I to 67% during period II. Neonatal morbidity rates also increased during period II, including rates of sepsis (from 37% to 51%), periventricular leukomalacia (from 2% to 7%), and chronic lung disease, defined as oxygen dependence at 36 weeks of corrected age (from 32% to 43%). Rates of severe cranial ultrasound abnormalities were similar (22% vs 22%). Among children monitored, the rate of neurologic abnormalities, including cerebral palsy, increased from 16% during period I to 25% during period II and the rate of deafness increased from 3% to 7%. The overall rate of neurodevelopmental impairment (major neurosensory abnormality and/or Bayley Mental Developmental Index score of <70) increased from 26% to 36%. Compared with period I, in period II there were decreased rates of death (odds ratio [OR]: 0.3; 95% confidence interval [CI]: 0.2–0.4) and increased rates of survival with impairment (OR: 2.3; 95% CI: 1.7–3.3) but also increased rates of survival without impairment (OR: 1.7; 95% CI: 1.3–2.2). Compared with period I, for every 100 infants with birth weights of 500 to 999 g born in period II, 18 additional infants survived, of whom 7 were unimpaired and 11 were impaired. Conclusions. The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment. Prospective parents of extremely low birth weight infants should be advised of this substantial risk, to facilitate decision-making in the delivery room.

Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age.

Objective. The Bayley Scales of Infant Development, Second Edition (BSID II) are commonly used to assess outcomes of extremely low birth weight (ELBW) infants. We sought to assess the predictive validity of the BSID II Mental Developmental Index (MDI) for cognitive function at school age. Design/Methods. Of 330 ELBW infants admitted in 1992–1995, 238 (72%) survived to the age of 8 years, of whom 200 (84%) were tested at both 20 months’ corrected age (CA) and 8 years. Mean birth weight was 811 g, mean gestational age was 26.4 weeks, 41% were boys, and 60% were black. Measures included the BSID II at 20 months’ CA and the Kaufman Assessment Battery for Children (KABC) Mental Processing Composite (MPC) at 8 years’ postnatal age. BSID II MDI and MPC scores were compared and the predictive validity calculated for all 200 ELBW children and for the 154 ELBW neurosensory-intact subgroup. Predictors of stability or change in cognitive scores were examined via logistic regression adjusting for gender and sociodemographic status. Results. For all ELBW children, the mean MDI was 75.6 ± 16 versus a mean KABC of 87.8 ± 19. For the neurosensory-intact subgroup, the mean MDI was 79.3 ± 16 and the mean KABC was 92.3 ± 15. Rates of cognitive impairment, defined as an MDI or KABC of <70, dropped from 39% at 20 months’ CA to 16% at 8 years for the total ELBW population and from 29% to 7% for the neurosensory-intact subgroup. The positive predictive value of having an MPC of <70 given an MDI of <70 was 0.37 (95% confidence interval [CI]: 0.27, 0.49) for all ELBW infants, 0.20 (95% CI: 0.10, 0.35) for the neurosensory-intact subgroup, and 0.61 (95% CI: 0.42, 0.77) for the neurosensory-impaired subgroup. The negative predictive values were 0.98, 0.99, and 0.85 for the 3 groups, respectively. Neurosensory impairment at 20 months’ CA predicted lack of improvement of cognitive function (odds ratio: 6.9; 95% CI: 2.4, 20.2). Children whose cognitive scores improved between 20 months and 8 years had significantly better school performance than those whose scores stayed at <70, but they did less well than those whose scores were persistently >70. Conclusions. The predictive validity of a subnormal MDI for cognitive function at school age is poor but better for ELBW children who have neurosensory impairments. We are concerned that decisions to provide intensive care for ELBW infants in the delivery room might be biased by reported high rates of cognitive impairments based on the use and presumptive validity of the BSID II MDI.

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.).

Perinatal Correlates of Cerebral Palsy and Other Neurologic Impairment Among Very Low Birth Weight Children

Background and Objective. The etiology of neurologic impairments among very low birth weight (VLBW, <1.5 kg) children is poorly understood. We sought to investigate the perinatal predictors of major neurologic impairment, including cerebral palsy, among VLBW children. Methods. Antenatal, intrapartum, and neonatal events and therapies were compared between 72 singleton inborn VLBW children born between 1983 to 1991 who had neurologic impairment at 20 months corrected age (including 50 with cerebral palsy and 22 with other neurologic impairments) and 72 neurologically normal VLBW children matched by birth weight, gestational age, race, and sex via a retrospective case-control method. Multiple logistic regression was conducted, entering only those variables found to be significant at the bivariate level. Results. There were no significant differences in the rates of pregnancy-induced hypertension, maternal tocolytic use including magnesium, or antenatal steroid therapy. Higher rates of clinical chorioamnionitis were found among the mothers of the neurologically impaired children as compared with controls (31% vs 11%), but not among the subgroup of mothers of children with cerebral palsy (22% vs 12%). Significant differences in neonatal factors among the total neurologically-impaired group (n = 72) versus controls included oxygen dependence at 36 weeks (31% vs 15%), septicemia (53% vs 31%), severe cranial ultrasound abnormality (50% vs 17%), and hypothyroxinemia (43% vs 25%). In the subgroup with cerebral palsy (n = 50), significant differences included days on the ventilator (23 vs 14 days), septicemia (54% vs 33%), and severe cranial ultrasound abnormality (52% vs 12%). Multivariate analysis controlling for birth weight, gestational age, race, sex, and the birth period (before 1990 versus 1990 and after) revealed direct and independent effects of clinical chorioamnionitis [odds ratio (OR), 3.79; confidence interval (CI), 1.34–10.78], severe cranial ultrasound abnormality (OR, 9.97; CI, 3.84–25.87), and septicemia (OR, 2.46; CI, 1.10–5.52) on total neurologic impairment. Consideration of the 50 cases with cerebral palsy revealed direct and independent effects of severe cranial ultrasound abnormality only (OR, 15.01; CI, 4.34–51.93). Conclusions. Both antenatal and neonatal risk factors contribute to the development of severe neurologic impairment, including cerebral palsy among VLBW children. Because prevention of chorioamnionitis may not be feasible in the near future, attempts to decrease neonatal risk factors such as severe cranial ultrasound abnormalities and sepsis may be most feasible at this time.

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.).

Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants

BACKGROUND. Neonatal hypotension may be a risk factor for neurologic impairment. Few studies have examined the impact of low blood pressure in extremely low birth weight (ELBW) infants weighing 400 to 999 g on neurodevelopmental outcome. OBJECTIVES. We set out to explore the relationship between treated hypotension in the first 72 hours of life and perinatal factors, morbidity, and mortality in ELBW infants and then to compare neurosensory outcome in ELBW infants with treated hypotension and those who never received treatment for hypotension. DESIGN/METHODS. We performed chart review of all 156 ELBW infants admitted to our level III NICU in 1998–1999. Infants had “treated hypotension” if they received fluid pushes, corticosteroids, and/or vasopressors during the first 72 hours of life in an attempt to increase blood pressure. Follow-up included neurologic examination, Bayley Scales of Infant Development, vision and hearing evaluation. Statistical analysis was performed by using SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with treated hypotension. RESULTS. Fifty-nine infants received treatment for hypotension. Ninety-seven infants did not. The groups had similar race, gender, delivery mode, chorioamnionitis, and maternal socioeconomic status. Thirty-eight (24%) infants expired, including 20 who received treatment for hypotension. Of the 156 infants in the study group, 110 underwent neurodevelopment testing, and 103 were able to undergo complete neurodevelopment testing and Bayley examination. Multivariate analysis controlling for socioeconomic status and neonatal morbidity revealed that treated hypotension is associated with delayed motor development and hearing loss. CONCLUSIONS. Treated hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with treated hypotension are more likely to have delayed motor development, hearing loss, and death.

Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants

To clarify the relationship between chorioamnionitis and chronic lung disease (CLD) in very low birth weight (VLBW) infants, we performed a retrospective cohort study of all inborn patients between 1995–1997 with gestational age (GA) less than 32 wk, birth weight less than 1.5 kg, survival to 36 wk adjusted GA, and placentas submitted to pathology (n = 371). Racial distribution as defined by the mother was 40% white/60% nonwhite. Prevalence of CLD, defined as O2 dependence at 36 wk adjusted GA, was 30%. In a preliminary analysis GA and birth weight for GA (standard deviations from the mean, Z-score), considered together, were inversely related to CLD. After adjustment for GA and Z-score, other risk factors for CLD were white race, acute respiratory distress, pulmonary air leak, patent ductus arteriosus, and septicemia. Two placental lesions were inversely related to CLD: histologic chorioamnionitis and acute atherosis (a placental indicator of preeclampsia). Following multivariate analysis, independent risk factors for CLD were GA (OR, 0.6; 95% CI = 0.5, 0.7), birthweight for GA (OR, 0.4; 95% CI = 0.3, 0.6), white race (OR, 1.9; 95% CI = 1.0, 3.3), patent ductus arteriosus (OR, 2.0; 95% CI = 1.0, 3.5), and pulmonary air leak (OR, 3.0; 95% CI = 1.3, 7.1). Acute atherosis was inversely related to CLD (OR, 0.2; 95% CI = 0.1, 0.8). Chorioamnionitis was stratified by subtype and again no association with CLD was seen in the population as a whole. Finally, chorioamnionitis of all subtypes tended to be increased in white infants and decreased in black infants with CLD. This dichotomy was not explained by differences in death rates, acute respiratory distress, intubation on d 2 of life, or total duration of assisted ventilation. We conclude that while chorioamnionitis was not a risk factor for CLD in our total population, racial differences in its relationship to CLD are worthy of further study.

Outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia: effects of practice changes in 2000 to 2003.

OBJECTIVE. The goal was to evaluate whether changes in neonatal intensive care have improved outcomes for children with bronchopulmonary dysplasia (oxygen dependence at corrected age of 36 weeks). METHODS. We compared outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia between 2 periods (period I, 1996–1999: extremely low birth weight, n = 122; extremely low gestational age, n = 118; period II, 2000–2003: extremely low birth weight, n = 109; extremely low gestational age, n = 107). RESULTS. For both groups, significant practice changes between period I and period II included increased prenatal and decreased postnatal steroid therapy and increased surfactant therapy, indomethacin therapy, and patent ductus arteriosus ligation. Significant morbidity changes included decreased rates of severe cranial ultrasound abnormalities and increased rates of ventilator dependence. Rates of bronchopulmonary dysplasia did not change (52% vs 53%). Follow-up evaluation revealed significantly lower rates of neurosensory abnormalities during period II (extremely low birth weight: 29% vs 16%; extremely low gestational age: 31% vs 16%). There were no changes in rates of Mental Developmental Index scores of <70 (extremely low birth weight: 42% vs 42%; extremely low gestational age: 37% vs 45%) or overall developmental impairment (extremely low birth weight: 51% vs 49%; extremely low gestational age: 50% vs 51%). For the extremely low gestational age group, predictors of neurosensory abnormalities were severe cranial ultrasound abnormality and postnatal steroid therapy. Predictors of overall impairment included severe cranial ultrasound abnormalities, ventilator dependence, postnatal steroid therapy, and patent ductus arteriosus ligation. For the extremely low birth weight group, the only predictor of neurosensory abnormalities was severe cranial ultrasound abnormality. Predictors of overall impairment included multiple birth, ventilator dependence, and severe cranial ultrasound abnormalities. CONCLUSIONS. Neurosensory outcomes of infants with bronchopulmonary dysplasia improved during 2000 to 2003 but overall neurodevelopmental outcomes did not change.

The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weight children.

Placental abnormalities reflect antenatal disease processes that may interact with other perinatal risk factors to affect long-term outcome. We performed a nested case control analysis of placental and clinical risk factors associated with neurologic impairment (NI) at 20-mo corrected age (60 cases and 59 controls) using data collected in a prospective study of very low birth weight (less than 1500 g) infants born between 1983 and 1991. In a preliminary analysis we explored the relationship between clinical infection and histologic chorioamnionitis (CA). Only histologic CA with a fetal vascular response correlated with either clinical CA or early onset neonatal sepsis. We then assessed the relative contribution of the nine risk factors (four placental and five clinical) associated with NI at the univariate level by multiple logistic regression. Three risk factors were independent predictors of NI: severe cranial ultrasound abnormalities (odds ratio 13.6, 95% confidence intervals 4.5–66.7), multiple placental lesions (odds ratio 13.2, 95% confidence intervals 1.3–137.0), and oxygen dependence at 36 wk (odds ratio 4.2, 95% confidence intervals 1.2–14.6). Finally, a series of logistic regressions was conducted with the dependent variable changing as we-moved back along the causal chain to explore the relationships between risk factors operating at different stages. This analysis suggested that antenatal variables that were not independent predictors of NI by multiple logistic regression exerted their effects through the following intermediate pathways: fetal grade 3 histologic CA via chorionic vessel thrombi, clinical CA via grade 3 villous edema, and grade 3 villous edema via severe cranial ultrasound abnormalities.