Judy Bernbaum

Early Intervention in Low Birth Weight Premature Infants: Results at 18 Years of Age for the Infant Health and Development Program

OBJECTIVE. To assess whether improvements in cognitive and behavioral development seen in preschool educational programs persist, we compared those in a multisite randomized trial of such a program over the first 3 years of life (INT) to those with follow-up only (FUO) at 18 months of age. METHODS. This was a prospective follow-up of the Infant Health and Development Program at 8 sites heterogeneous for sociodemographic characteristics. Originally 985 children were randomized to the INT (n = 377) or FUO (n = 608) groups within 2 birth weight strata: heavier low birth weight (HLBW; 2001–2499 g) and lighter low birth weight (LLBW; ≤2000 g). Primary outcome measures were the Peabody Picture Vocabulary Test (PPVT-III), reading and mathematics subscales of the Woodcock-Johnson Tests of Achievement, youth self-report on the Total Behavior Problem Index, and high-risk behaviors on the Youth Risk Behavior Surveillance System (YRBSS). Secondary outcomes included Weschler full-scale IQ, caregiver report on the Total Behavior Problem Index, and caregiver and youth self-reported physical health using the Medical Outcome Study measure. Assessors were masked as to study status. RESULTS. We assessed 636 youths at 18 years (64.6% of the 985, 72% of whom had not died or refused at prior assessments). After adjusting for cohort attrition, differences favoring the INT group were seen on the Woodcock-Johnson Tests of Achievement in math (5.1 points), YRBSS (−0.7 points), and the PPVT-III (3.8 points) in the HLBW youth. In the LLBW youth, the Woodcock-Johnson Tests of Achievement in reading was higher in the FUO than INT group (4.2). CONCLUSIONS. The findings in the HLBW INT group provide support for preschool education to make long-term changes in a diverse group of children who are at developmental risk. The lack of observable benefit in the LLBW group raises questions about the biological and educational factors that foster or inhibit sustained effects of early educational intervention.

Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery

BACKGROUND There has been increasing recognition of adverse neurodevelopmental sequelae in some children after repair of congenital heart defects. Even among children with the same cardiac defect, significant interindividual variation exists in developmental outcome. Polymorphisms of apolipoprotein E have been identified as a risk factor for worse neurologic recovery after central nervous system injury. METHODS A single-institution prospective study of patients <or=6 months of age undergoing cardiopulmonary bypass for repair of congenital heart defects was undertaken to evaluate the association between apolipoprotein E genotype and postoperative neurodevelopmental dysfunction. Developmental outcomes were evaluated at 1 year of age by using the Bayley Scales of Infant Development. RESULTS One-year evaluation was performed in 244 patients. After adjustment for preoperative and postoperative covariates-including gestational age, age at operation, sex, race, socioeconomic status, cardiac defect, and use of deep hypothermic circulatory arrest-the apolipoprotein E epsilon2 allele was associated with a worse neurologic outcome as assessed by the Psychomotor Developmental Index of the Bayley Scales of Infant Development (P =.036). Patients with the apolipoprotein E epsilon2 allele had approximately a 7-point decrease in the Psychomotor Developmental Index. CONCLUSIONS Apolipoprotein E epsilon2 allele carriers had significantly lower Psychomotor Development Index scores at 1 year of age after infant cardiac surgery. The effect was independent of ethnicity, socioeconomic status, cardiac defect, and use of deep hypothermic circulatory arrest. An effect of the apolipoprotein E epsilon4 allele was not detected. Genetic polymorphisms that decrease neuroresiliency and impair neuronal repair after central nervous system injury are important risk factors for neurodevelopmental dysfunction after infant cardiac surgery.

Growth status and growth rates of a varied sample of low birth weight, preterm infants: A longitudinal cohort from birth to three years of age

To obtain follow-up growth data on a large sample of low birth weight, preterm infants, 985 infants were monitored longitudinally in an eight-site collaborative program until 3 years of age, corrected for prematurity. The growth of 608 of these infants was described previously through 1 year of age. In the full sample, 149 infants weighed less than or equal to 1250 gm at birth, 474 between 1250 and 2000 gm, and 362 between 2000 and 2500 gm. Thirty-three percent were white, 53% were black, and 11% were Hispanic. Weight, length, and head circumference were measured at birth and at 40 weeks and 4, 8, 12, 18, 24, 30, and 36 months gestation-corrected age in at least 862 infants each time. Descriptive statistics and estimated growth rates for all growth variables and a body mass index (height in kilograms per square meter), plotted by sex and birth weight group, demonstrated growth patterns lower than published standards for term infants of the same age and sex. These patterns of growth differed by birth weight group. Little catch-up was noted by the 36-month examination for gestation-corrected age for any birth weight group. We conclude that low birth weight, preterm infants have different patterns of growth than term infants during the first 3 years of life, even with plotting corrected for gestational age.

Isoflavones in urine, saliva, and blood of infants: data from a pilot study on the estrogenic activity of soy formula

In the United States, about 25% of infant formula sold is based on soy protein, which is an important source of estrogenic isoflavones in the human food supply. Nevertheless, few studies report isoflavone levels in infants. We did a partly cross-sectional and partly longitudinal pilot study to examine childrens exposure to isoflavones from different feeding methods. A total of 166 full-term infants between birth and 1 year of age were recruited into soy formula, cow milk formula, or breast milk regimens according to their feeding histories. A total of 381 urine, 361 saliva, and 88 blood samples were collected at 382 visits. We used automated online solid-phase extraction coupled to high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) for measuring three isoflavones (daidzein, genistein, and equol) in urine, and used similar LC/MS/MS techniques for saliva and blood spots. Concentrations of daidzein and genistein were undetectable in most blood or saliva samples from children fed breast milk or cow milk formula. The proportion of non-detectable values was somewhat lower in urine than in the other matrices. Concentrations of equol were detectable only in a few urine samples. For both daidzein and genistein, urine contained the highest median concentrations, followed by blood and then saliva. Urinary concentrations of genistein and daidzein were about 500 times higher in the soy formula-fed infants than in the cow milk formula-fed infants. The correlations between matrices for either analyte were strikingly lower than the correlation between the two analytes in any single matrix. We did not find significant correlations between isoflavone concentrations and the levels of certain hormones in children fed soy formula. Our results, based on much larger numbers of infants, strongly confirm previous reports, but whether phytoestrogens in soy formula are biologically active in infants is still an open question. We plan further longitudinal studies focusing on physical and developmental findings reflecting the effects of estrogen exposure.

Growth patterns of low birth weight preterm infants: A longitudinal analysis of a large, varied sample

To obtain growth data on a large sample of low birth weight preterm infants, we monitored 608 infants longitudinally in an eight-site collaborative program. Ninety-nine infants weighed less than or equal to 1250 gm at birth, 289 between 1250 and 2000 gm, and 220 infants between 2000 and 2500 gm. Thirty-four percent were white, 52% black, and 14% Hispanic. Weight, height, and head circumference were measured at birth and at 40 weeks and 4, 8, and 12 months of gestation-corrected age on at least 553 infants each time. Descriptive statistics for all growth variables and a body mass index (kilograms per square meter), plotted by sex and birth weight group, demonstrated growth patterns lower than published standards for term infants of the same age and sex. These patterns of growth differed by birth weight group. No catch-up growth was noted by the 12-month examination (gestation-corrected age) for any birth weight group. We conclude that low birth weight preterm infants have different patterns of growth than term infants during the first year of life, even with plotting corrected for gestational age.

Predictors of impaired neurodevelopmental outcomes at one year of age after infant cardiac surgery

OBJECTIVE For most newborns, congenital heart defects (CHD) appear to be isolated anomalies and the brain is presumed to have normal developmental potential. Most studies of neurodevelopmental outcomes have focused on operative management strategies. METHODS Infants with complex CHD and no identified syndromes other than 22q11 microdeletions enrolled in a study of apolipoprotein E (APOE) polymorphisms and developmental outcome were evaluated at one year of age; including genetic evaluation and the Bayley Scales of Infant Development-II [mental (MDI) and psychomotor developmental indices (PDI)]. RESULTS Five hundred and fifty infants enrolled and 359 (20 with 22q11) of 501 survivors (72%) returned. Mean MDI was 90+/-15 and PDI was 78+/-18. Genetic syndromes not identified at birth were confirmed in 28 (8.1%) and suspected in 51 (15.0%). By multivariable analysis, suspected/confirmed genetic syndromes and APOE varepsilon2 allele predicted lower MDI and PDI, all p<0.04. Lower birth weight (p<0.001) and preoperative intubation (p=0.012) predicted lower MDI. Higher hematocrit during the initial operation was associated with higher MDI (p=0.007). Longer postoperative length of stay was predictive of lower PDI (p=0.002). Additional operations with cardiopulmonary bypass were associated with lower MDI and PDI (both p<0.002), but use of deep hypothermic circulatory arrest was not. CONCLUSIONS Patient factors (birth weight and preoperative status) are significant determinants of neurodevelopmental outcomes as opposed to operative management strategies. In this cohort, genetic syndromes unsuspected at birth were surprisingly common and correlate with poor neurodevelopmental outcomes. Without multiple congenital anomalies, syndromes may be missed in infancy. Genetic evaluation should be considered in all infants with CHD.

Effect of neonatal caloric deprivation on head growth and 1-year developmental status in preterm infants

The effects of neonatal illness and caloric intake on head growth velocity and on 1-year developmental outcome were studied in 73 appropriate (AGA) and small for gestational age (SGA) premature infants of (mean +/- SD) 30 +/- 2 weeks gestation who received intensive care during the neonatal period. Head growth from birth to 1 year of corrected age was characterized by a triphasic curve initiated by a period of growth arrest or suboptimal growth followed by a period of catch-up growth and terminated by a period of growth along standard curves. Head growth arrest or suboptimal head growth were directly related to the duration of the initial period of caloric deprivation (less than 85 kcal/kg/day) and to the duration of mechanical ventilation. Catch-up head growth was influenced by the duration of the preceding period of caloric deprivation in all infants and by the caloric intake during that phase only in SGA infants; catch-up growth was unrelated to the duration of mechanical ventilation. Head growth along standard curves occurred in all infants by 3 months of corrected age and persisted up to 1 year of corrected age. Infants calorically deprived the longest (AGA 4 to 6 weeks, SGA 2 to 3 weeks) had head growth along standards at curves below -1 SD on the growth chart; all other groups had this phase of head growth at curves between the mean and -1 SD. Infants calorically deprived for more than 4 weeks had developmental scores below normal ranges by 1 year of corrected age.

Response of preterm infants to diphtheria-tetanus-pertussis immunizations*

To establish guidelines for the routine use of diphtheria, tetanus, and pertussis (DTP) vaccine in preterm infants, we quantitated antibody responses of preterm infants to DTP and determined the nature and extent of side effects. Twenty-five preterm infants were immunized with 0.5 ml DTP vaccine at routine intervals. Term infants served as controls. Immediately before each immunization and 2 months after the third, DTP-specific antibodies were quantitated. Clinical side effects were determined by parental report. After the second immunization, 100% of preterm infants had evidence of specific antibody production against diphtheria, tetanus, and pertussis. The incidence of side effects was low, but irritability was significantly more common in preterm infants after the second immunization. These observations suggest that the initiation of primary immunization with DTP in preterm infants need not be delayed beyond 2 months of age.

Apolipoprotein E Genotype Modifies the Risk of Behavior Problems After Infant Cardiac Surgery

OBJECTIVE: The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. METHODS: A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. RESULTS: Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE ε2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P = .009). In each case, the ε4 allele was associated with a better outcome. APOE ε2 carriers had impaired social skills, compared with ε4 carriers (P = .009). CONCLUSIONS: For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE ε2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns.

Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program.

PURPOSE The purpose of the study was to evaluate the neurodevelopmental outcome in infants with congenital diaphragmatic hernia (CDH). METHODS Between June 2004 and September 2007, 41 CDH survivors were prospectively enrolled in an interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development II (prior 2006, n = 9), the Bayley Scales of Infant Development III (after 2006, n = 27), or the Wechsler Preschool and Primary Scale of Intelligence III (children older than 4 years, n = 5). Scores were grouped as average, mildly delayed, and severely delayed by standard deviation intervals (115-85, 71-84, <70), and mixed if average and mildly delayed in either cognitive or language. RESULTS Median age at last assessment was 24 months (range, 6-62). Average, mixed, mildly delayed, and severely delayed scores for neurocognitive and language skills were found in 49%, 19%, 17%, and 15%, respectively. Psychomotor scores were normal, mildly delayed, and severely delayed in 46%, 23%, and 31%, respectively. Autism was present in 7%. Abnormal muscle tonicity was found in 51% (49% hypotonic, 2% hypertonic). Multivariate risk factors for borderline or delayed neurodevelopmental, neurocognitive, and/or psychomotor outcome were intrathoracic liver position (P = .02), presence of a right-sided CDH (P = .02), extracorporeal membrane oxygenation need (P < .001), Gore-Tex patch repair (P = .02), O(2) requirement at 30 days of life (P < .01), and hypotonicity (P < .01). CONCLUSIONS The prospective evaluation in an interdisciplinary follow-up program uncovered striking morbidities in neurodevelopmental status in approximately half of the CDH infants. The most common neurologic sequelae are neuromuscular hypotonicity and psychomotor dysfunction. Patient-specific factors are important determinants of adverse neurologic outcome.