Donald J. Goldstein

Randomized Placebo-controlled Trial of a 42-Day Tapering Course of Dexamethasone to Reduce the Duration of Ventilator Dependency in Very Low Birth Weight Infants: Outcome of Study Participants at 1-Year Adjusted Age

Objective. Ventilator-dependent preterm infants are often treated with a prolonged tapering course of dexamethasone to decrease the risk and severity of chronic lung disease. The objective of this study was to assess the effect of this therapy on developmental outcome at 1 year of age. Methods. Study participants were 118 very low birth weight infants who, at 15 to 25 days of life, were not weaning from assisted ventilation and were then enrolled in a randomized, placebo-controlled, double-blind trial of a 42-day tapering course of dexamethasone. Infants were examined at 1 year of age, adjusted for prematurity, by a pediatrician and a child psychologist. A physical and neurologic examination was performed, and the Bayley Scales of Infant Development were administered. All examiners were blind to treatment group. Results. Groups were similar in terms of birth weight, gestational age, gender, and race. A higher percentage of dexamethasone recipients had major intracranial abnormalities diagnosed by ultrasonography (21% vs 11%). Group differences were not found for Bayley Mental Development Index (median [range] for dexamethasone-treated group, 94 [50–123]; for placebo group, 90 [28–117]) or Psychomotor Development Index Index (median [range]) for dexamethasone-treated group, 78 (50–109); for placebo-treated group, 81 [28–117]). More dexamethasone-treated infants had cerebral palsy (25% vs 7%) and abnormal neurologic examination findings (45% vs 16%). In stratified analyses, adjusted for major cranial ultrasound abnormalities, these associations persisted (OR values for cerebral palsy, 5.3; 95% CI: 1.3–21.4; OR values for neurologic abnormality 3.6; 95% CI: 1.2–11.0). Conclusions. A 42-day tapering course of dexamethasone was associated with an increased risk of cerebral palsy. Possible explanations include an adverse effect of this therapy on brain development and/or improved survival of infants who either already have neurologic injury or who are at increased risk for such injury.

Positive Screening on the Modified-Checklist for Autism in Toddlers (M-CHAT) in Extremely Low Gestational Age Newborns

OBJECTIVE To test the hypothesis that children born preterm are more likely to screen positive on the M-CHAT for an autism spectrum disorder. STUDY DESIGN We compared the M-CHAT positive rate of those with cerebral palsy, cognitive impairment, and vision and hearing impairments to those without such deficits. RESULTS Relative to children who could walk, the odds for screening positive on the M-CHAT were increased 23-fold for those unable to sit or stand independently and more than 7-fold for those requiring assistance to walk. Compared with children without a diagnosis of cerebral palsy, those with quadriparesis were 13 times more likely to screen positive, and those with hemiparesis were 4 times more likely to screen positive. Children with major vision or hearing impairments were 8 times more likely to screen positive than those without such impairments. Relative to those with a Mental Development Index (MDI) of >70, the odds for screening positive were increased 13-fold for those with an MDI of <55 and more than 4-fold for those with an MDI of 55 to 69. CONCLUSIONS Major motor, cognitive, visual, and hearing impairments appear to account for more than half of the positive M-CHAT screens in extremely low gestational age newborns. Even after those with such impairments were eliminated, 10% of children--nearly double the expected rate--screened positive.

Neonatal Cranial Ultrasound Lesions and Developmental Delays at 2 Years of Age Among Extremely Low Gestational Age Children

BACKGROUND. Studies of the relationship between ultrasound images from preterm newborns and developmental delay most often are based on small samples defined by birth weight and exclude infants not testable with standardized assessments. METHODS. We evaluated associations between ultrasound-defined lesions of the brain and developmental delays at 24 months’ corrected age in 1017 children born before the 28th postmenstrual week. Brain ultrasound scans were read for concordance on 4 lesions: intraventricular hemorrhage, moderate/severe ventriculomegaly, white matter echodense/hyperechoic lesions, and white matter echodense/hypoechoic lesions and 2 diagnoses–periventricular leukomalacia and periventricular hemorrhagic infarction. Certified examiners, who were not aware of the infants’ ultrasound findings, administered the Bayley Scales of Infant Development-Second Edition. Children with an impairment (eg., blindness) that precluded testing with the Bayley Scales and those for whom >2 test items were omitted were classified using the Vineland Adaptive Behavior Scales Motor Skills Domain instead of the Psychomotor Development Index and the Adaptive Behavior Composite instead of the Mental Development Index. RESULTS. Fully 26% of all of the children had delayed mental development (ie, Mental Development Index < 70), and 31% had delayed psychomotor development (ie, Psychomotor Development Index < 70). Ultrasound abnormalities were more strongly associated with low Psychomotor Development Index than with low Mental Development Index. Children without cranial ultrasound abnormality had the lowest probability (23% and 26%) of delayed mental or psychomotor development. Moderate/severe ventriculomegaly was associated with a more than fourfold increase in the risk of psychomotor delay and an almost threefold increase in the risk of mental delay. Echolucency was the next best predictor of delayed mental and psychomotor development. The probability of low scores varied with the number of zones involved and with the location of echolucency. At particularly high risk were infants with bilateral cerebellar hemorrhage, co-occurring ventriculomegaly and echolucency bilateral echolucency, or echolucency located posteriorly. CONCLUSIONS. Focal white matter damage, as characterized by echolucent/hypoechoic lesion, and diffuse damage, as suggested by late ventriculomegaly, are associated with delayed mental and psychomotor development.

Effect of sustained pharmacologic vitamin E levels on incidence and severity of retinopathy of prematurity: A controlled clinical trial

The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication. Acute ROP data were collected on 755 infants. Logistic regression analysis, with control for immaturity, oxygen exposure, and other illness risk factors, showed a decrease in incidence of ROP in vitamin E-treated infants (p = 0.003, all infants; p = 0.035, infants weighing less than or equal to 1500 gm at birth). Among the 424 infants weighing less than or equal to 1500 gm at birth, the age at enrollment influenced treatment effect (age day 0 to 1, p = 0.006 (n = 288) vs age day 2 to 5, p greater than 0.1 (n = 136]. Overall, 77.6% of infants with ROP had mild disease. Moderate to severe ROP was confined to infants weighing greater than or equal to 1500 gm at birth (25 given placebo, 25 given vitamin E), with progression to severe disease in nine placebo-treated versus three vitamin E-treated infants (p = 0.048). The incidence of severe ROP per se was not significantly decreased (all birth weights, p = 0.086; less than or equal to 1500 gm birth weight, p = 0.080); the sample size was too small, however, to assess this end point adequately. An increased incidence of sepsis and late-onset necrotizing enterocolitis was found among vitamin E-treated infants weighing less than or equal to 1500 gm at birth who received study medication for greater than or equal to 8 days (p = 0.006). Because most ROP is mild in degree and regresses completely, the risk/benefit ratio of pharmacologic prophylaxis for ROP is unfavorable. Treatment of moderate and severe ROP with vitamin E above physiologic serum levels (greater than 3 mg/dl) appears promising and should be further investigated. The interpretation of cicatricial outcome was confounded by the small number of patients involved and by subsequent treatment of severe ROP in placebo-treated infants with vitamin E.

Follow-up of a Randomized, Placebo-Controlled Trial of Dexamethasone to Decrease the Duration of Ventilator Dependency in Very Low Birth Weight Infants: Neurodevelopmental Outcomes at 4 to 11 Years of Age

OBJECTIVE. High doses of dexamethasone reduce the risk of chronic lung disease among premature infants but may increase the risk of developmental impairments. The objective of this study was to compare developmental outcomes beyond infancy for children who, as neonates, participated in a randomized trial of dexamethasone. PATIENTS AND METHODS. One hundred eighteen children with birth weights <1500 g were randomly assigned at 15 to 25 days of life to a 42-day tapering course of dexamethasone or placebo. All 95 survivors were assessed by using standardized measures of developmental outcome at least once at or beyond 1 year of age, and 84 were examined at 4 to 11 years. For this follow-up study, the outcome of primary interest was death or major neurodevelopmental impairment, which was defined as cerebral palsy, cognitive impairment, or blindness. RESULTS. On the basis of each childs most recent follow-up, the rates of major neurodevelopmental impairments were 40% for the dexamethasone group and 20% for the placebo group. The higher impairment rate for the dexamethasone group was mainly attributed to a higher prevalence of cerebral palsy. Rates of the composite outcome of death or major neurodevelopmental impairment were 47% and 41%, respectively. CONCLUSION. A 42-day tapering course of dexamethasone, which was shown previously to decrease the risk of chronic lung disease in very low birth weight infants, does not increase the risk of the composite outcome of death or major neurodevelopmental impairment.

OUTCOME AT 4 TO 5 YEARS OF ÂGE IN CHILDREN RECOVERED FROM NEONATAL CHRONIC LUNG DISEASE

Outcomes were compared for 31 very‐low‐birthweight children recovered from chronic lung disease and 31 very‐low‐birthweight controls. All children had been free of major abnormalities on neonatal cranial ultrasonography. At 4 to 5 years of age, children were examined by a pediatrician and tested by a psychologist who administered the Wechsler Preschool and Primary Scale of Intelligence‐Revised. Despite similar medical outcomes, the children who had had neonatal chronic lung disease had lower Full‐scale IQs (median 83 vs 87) and Performance IQs (79 vs 90). Median Verbal IQ was similar in the two groups (85 vs.87). A higher proportion of children who had had chronic lung disease had Full‐scale IQ<70 (8/31 [26%] vs 1/31 [3%]) and Performance IQ<70 (8/31 [26%] vs 0/31). These effects persisted after adjustment for confounding factors.

Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study

BackgroundIt is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.MethodsStudy infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.ResultsSurvival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.ConclusionThe probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990s in this regionally based sample of ELGANs.

Comparison of the Bayley Scales of Infant Development-Second Edition and the Bayley Scales of Infant Development with Premature Infants

The Bayley Scales of Infant Development-Second Edition (BSID-II) and Bayley Scales of Infant Development (BSID) were administered concurrently to 49 high-risk, preterm infants. Results suggested that scores from the two tests were correlated very highly. As expected, mean scores on the BSID-II were lower than on the BSID. Classification of infants as “normal,” “borderline,” and “abnormal” on each test resulted in excellent agreement for mental development scores, but only fair agreement for psychomotor scores. Findings were interpreted as adding support to the clinical validity of the BSID-II, and implications of lower scores on the BSID II were discussed.

Agreement Between Bayley Scales Second and Third Edition Assessments of Very Low-Birth-Weight Infants

Results. Mean participant age was 9.9 years; 50.1% (n = 6751) were female. The prevalence of ADHD, GDM, and low SEP was 4.9% (n=660), 2.3% (n=280), and 25.5% (n=3420), respectively. Both maternal GDM and low SEP were significantly related to ADHD (Table). Multivariate regression modeling indicated that not only GDM (OR, 1.91; 95% CI, 1.21-3.01) and low SEP (OR, 2.04; 95% CI, 1.56-2.68) but also perinatal health problems, maternal smoking during pregnancy, and atopic eczema are independent risk factors for ADHD, whereas fully breastfeeding appears to be protective (irrespective of the duration of breastfeeding; data not shown). Further analyses indicated the presence of additive interaction between maternal GDM and SEP on the risk of ADHD (observed OR for middle-class children exposed to GDM: 3.47; expected OR: 2.93; observed OR for lower-class children exposed to GDM: 3.68; expected OR: 3.56).

Follow-up Care for Infants With Chronic Lung Disease: A Randomized Comparison of Community- and Center-Based Models

OBJECTIVES. Premature infants with chronic lung disease benefit from comprehensive care, which typically is based in tertiary medical centers. When such centers are not easily accessible, alternative models of care are needed. The purpose of this work was to compare community-based follow-up, provided via telephone contacts, to traditional center-based follow-up of premature infants with chronic lung disease. PATIENTS AND METHODS. After discharge from neonatal intensive care, 150 premature infants with chronic lung disease were randomly assigned to either community-based (n = 75) or center-based (n = 75) follow-up. In community-based follow-up, a nurse specialist maintained telephone contact with the infants primary caregiver and health care providers. Center-based follow-up consisted of visits to a medical center–based multidisciplinary clinic staffed by a neonatologist, a nurse specialist, and a social worker. The outcomes of interest were Bayley Scales of Infant Development mental developmental index and psychomotor developmental index, Vineland Adaptive Behavioral Composite, and growth delay (weight for length <5th percentile) at 1-year adjusted age and respiratory rehospitalizations through 1-year adjusted age. RESULTS. In each randomization group, 73 infants survived, and 69 were evaluated at 1-year adjusted age. The median mental development index (corrected for gestational age) was 90 for both groups. The median psychomotor developmental index was 82 for the center-based group and 81 for the community-based group. The median Vineland Adaptive Behavioral Composite was 100 and 102 for the center-based and community-based groups, respectively. In the center-based and community-based groups, respectively, the proportions with growth delay were 13% and 26%, and the proportions rehospitalized for respiratory illness were 33% and 29%. CONCLUSIONS. Infants randomly assigned to community-based, as compared with those randomly assigned to center-based follow-up, had similar developmental and health outcomes. The former approach might be a preferred alternative for families in rural settings or families for whom access to a tertiary care medical center is difficult.