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The advent of the Human Genome Project has allowed for increased understanding and sophistication in diagnosis, treatment methods, and overall care planning on the part of healthcare providers for children with genetic disorders. Genetics research dealing with polymorphic changes within a genome has opened the door to awareness of how dormant genetic alleles may become active when coupled with certain environmental insults. Such genetic aberrations may place a child at a higher risk for health disparities when exposed to environmental toxins. It has been posited that such exposure in children with an arylsulfatase-A (ASA) allelic variation is associated with increased risk for neurodevelopmental damage. This initial study contributes to this new field and supports development of finer-tuned methods to prevent ominous outcomes of lead exposure. The purpose of this study was to explore the incidence of children in a representative sample from a Midwest metropolitan city with positive test results for the ASA allelic variation who have been exposed to the environmental toxin lead. In this corollary study of 107 children, part of a parent study on the behavior of African American children prenatally exposed to cocaine, 45% were found to be heterozygous, 11% mutant homozygous, and 44% normal in terms of ASA allele or alleles. Further studies on neurodeficiencies, low-level exposure to environmental toxins, and allelic variations must be conducted before a relation between ASA allelic variance and environmental lead can be determined.

Prenatal exposure to cocaine, alcohol, and cigarettes has been linked to decreased birth weight and length. Unclear, however, is whether growth deficits persist into childhood. Women who were pregnant, African-American, not HIV-positive, and who delivered singleton infants were extensively screened throughout pregnancy for cocaine, alcohol, cigarette, and other illicit drug use. Of the approximately 1100 eligible subjects, 665 families were located at a 7-year postbirth follow-up and 540 participated. After appropriate control for potential confounders and prenatal exposures, prenatal exposure to cocaine, alcohol, and cigarettes each independently predicted birth weight and length. At age 7, prenatal cocaine exposure was significantly related to height deficits after accounting for other prenatal exposures and significant confounders. Children at age 7 exposed to cocaine in utero were up to 1 in. shorter and twice as likely to fall below the 10th percentile in height as the control children after accounting for other significant confounders including other prenatal exposures. Maternal age moderated the relation between prenatal exposures and child growth. Children born to women over 30 and exposed to cocaine were up to 2 in. shorter and four times more likely to have clinically significant height deficits at age 7. Children of older women and exposed to moderate-to-high levels of alcohol prenatally were up to 14 lb lighter and five times more likely to fall below the 10th percentile in weight. Similar growth restriction was not associated with prenatal exposures for children born to younger mothers. These outcomes add to the growing body of literature detailing long-term effects of prenatal drug exposure, suggesting differential effects for cocaine and alcohol, and indicating that maternal age may moderate these effects. Mechanisms for growth restriction and failure of catch-up under conditions of prenatal exposures are presented, suggesting further study of these developmental outcomes.

Reductions in birth weight and length have been independently attributed to prenatal exposure to alcohol, cigarettes and cocaine. While pregnant women often use multiple substances, studies have not consistently controlled for exposure to other agents or other important differences in maternal lifestyle associated with the use of these substances. Despite these difficulties, the preponderance of evidence suggests that prenatal alcohol and cocaine independently reduce birth measurements. This review synthesizes the scientific literature focusing on prenatal exposures and the relationship to child growth. First examined are studies that investigated the link between prenatal exposures and birth weight and length, followed by the effects of these substances on childhood growth. Studies vary in the number of subjects, cohort characteristics, measurement of exposure and control for potential confounders. Differences in sample characteristics and size, as well as degree of statistical control for potential confounders and the examination of moderating characteristics, have led to differing conclusions regarding the long-term effect of prenatal substance exposure on growth. Large-scale, well-designed studies are needed to clearly examine the unique contribution of both varying prenatal exposures and the magnitude and timing of these exposures on childhood growth deficits.

Background: Exposure to violence in childhood has been associated with lower school grades. However, the association between violence exposure and performance on standardized tests (such as IQ or academic achievement) in children is unknown. It is also not known whether violence exposure itself or subsequent symptoms of trauma are primarily responsible for negative outcomes., Objective: To examine the relationship between violence exposure and trauma-related distress and standardized test performance among early school-aged urban children, controlling for important potential confounders., Design: A total of 299 urban first-grade children and their caregivers were evaluated using self-report, interview, and standardized tests., Main Outcome Measures: The child's IQ (Wechsler Preschool and Primary Scale of Intelligence--Revised) and reading ability (Test of Early Reading Ability, second edition) were the outcomes of interest., Results: After controlling for confounders (child's gender, caregiver's IQ, home environment, socioeconomic status, and prenatal exposure to substance abuse) violence exposure was related to the child's IQ (P =.01) and reading ability (P =.045). Trauma-related distress accounted for additional variance in reading ability (P =.01). Using the derived regression equation to estimate effect sizes, a child experiencing both violence exposure and trauma-related distress at or above the 90th percentile would be expected to have a 7.5-point (SD, 0.5) decrement in IQ and a 9.8-point (SD, 0.66) decrement in reading achievement., Conclusion: In this study, exposure to violence and trauma-related distress in young children were associated with substantial decrements in IQ and reading achievement.

In Part I, the initial development of a preliminary tool, the PROBS-14, was reported. The tool was developed and initially tested through a consensus process that tapped the perceptions of early education teachers. Concurrent validity between the PROBS-14 and the Conners' Teacher Rating Scale (CTRS) was established with factor analysis, yielding a hyperactivity-conduct factor, composed of PROBS items and all but two of the CTRS subscales, and a central processing factor, composed of PROBS items and the remaining CTRS scales. The purpose of Part II was to further establish concurrent validity of the PROBS-14 with known pediatric behavior measures (TRF, CTRS) and to ascertain if the PROBS-14 better predicts a cocaine behavioral effect. A sample of 468 African American children with known cocaine exposure (n = 200) and control status (n = 268) were evaluated. Factor analyses produced results similar to those reported in Part I, with PROBS items accounting for problem behavior variance beyond that accounted for by the TRF, and more specific than that accounted for by the CTRS. Additionally, children prenatally exposed to cocaine, particularly those exposed late in pregnancy, differed significantly from controls on the PROBS total, central processing scale, and several PROBS items. The PROBS instrument offers a promising brief measure of child problem behaviors with adequate concurrent and predictive validity, and which outperforms the TRF and CTRS in discriminating prenatal cocaine exposure status.

Objective: Moderate to heavy levels of prenatal alcohol exposure have been associated with alterations in child behavior, but limited data are available on adverse effects after low levels of exposure. The objective of this study was to evaluate the dose-response effect of prenatal alcohol exposure for adverse child behavior outcomes at 6 to 7 years of age., Methods: Beginning in 1986, women attending the urban university-based maternity clinic were routinely screened at their first prenatal visit for alcohol and drug use by trained research assistants from the Fetal Alcohol Research Center. All women reporting alcohol consumption at conception of at least 0.5 oz absolute alcohol/day and a 5% random sample of lower level drinkers and abstainers were invited to participate to be able to identify the associations between alcohol intake and child development. Maternal alcohol, cigarette, and illicit drug use were prospectively assessed during pregnancy and postnatally. The independent variable in this study, prenatal alcohol exposure, was computed as the average absolute alcohol intake (oz) per day across pregnancy. At each prenatal visit, mothers were interviewed about alcohol use during the previous 2 weeks. Quantities and types of alcohol consumed were converted to fluid ounces of absolute alcohol and averaged across visits to generate a summary measure of alcohol exposure throughout pregnancy. Alcohol was initially used as a dichotomous variable comparing children with no prenatal alcohol exposure to children with any exposure. To evaluate the effects of different levels of exposure, the average absolute alcohol intake was relatively arbitrarily categorized into no, low (>0 but <0.3 fl oz of absolute alcohol/day), and moderate/heavy (>/=0.3 fl oz of absolute alcohol/day) for the purpose of this study. Six years later, 665 families were contacted. Ninety-four percent agreed to testing. Exclusions included children who missed multiple test appointments, had major congenital malformations (other than fetal alcohol syndrome), possessed an IQ >2 standard deviations from the sample mean, or had incomplete data. The Achenbach Child Behavior Checklist (CBCL) was used to assess child behavior. The CBCL is a parent questionnaire applicable to children ages 4 to 16 years. It is widely used in the clinical assessment of children's behavior problems and has been extensively used in research. Eight syndrome scales are further grouped into Externalizing or undercontrolled (Aggressive and Delinquent) behavior and Internalizing or overcontrolled (Anxious/Depressed, Somatic Complaints, and Withdrawn) behaviors. Three syndromes (Social, Thought, and Attention Problems) fit neither group. Higher scores are associated with more problem behaviors. Research assistants who were trained and blinded to exposure status independently interviewed the child and caretaker. Data were collected on a broad range of control variables known to influence childhood behavior and/or to be associated with prenatal alcohol exposure. These included perinatal factors of maternal age, education, cigarette, cocaine, and other substances of abuse and the gestational age of the baby. Postnatal factors studied included maternal psychopathology, continuing alcohol and drug use, family structure, socioeconomic status, children's whole blood lead level, and exposure to violence. Data were collected only from black women as there was inadequate representation of other racial groups., Statistical Analyses: Statistical analyses were performed using the SPSS statistical package. Frequency distribution, cross-tabulation, odds ratio, and chi(2) tests were used for analyzing categorical data. Continuous data were analyzed using t tests, analyses of variance (ANOVAs) with posthoc tests, and regression analysis., Results: Testing was available for 501 parent-children dyads. Almost one fourth of the women denied alcohol use during pregnancy. Low levels of alcohol use were reported in 63.8% and moderate/heavy use in 13% of pregnancies. Increasing prenatal alcohol exposure was associated with lower birth weight and gestational age, higher lead levels, higher maternal age, and lower education level, prenatal exposure to cocaine and smoking, custody changes, lower socioeconomic status, and paternal drinking and drug use at the time of pregnancy. Children with any prenatal alcohol exposure were more likely to have higher CBCL scores on Externalizing (Aggressive and Delinquent) and Internalizing (Anxious/Depressed and Withdrawn) syndrome scales and the Total Problem Score. The odds ratio of scoring in the clinical range for Delinquent behavior was 3.2 (1.3-7.6) in children with any prenatal exposure to alcohol compared with nonexposed controls. The threshold dose was evaluated with the 3 prenatal alcohol exposure groups. One-way ANOVA revealed a significant between group difference for Externalizing (Aggressive and Delinquent) and the Total Problem Score. (ABSTRACT TRUNCATED)

Background/purpose: Extracorporeal membrane oxygenation (ECMO) as a treatment of last resort for neonates with persistent pulmonary hypertension of the newborn (PPHN) caused by congenital diaphragmatic hernia (CDH) may be used for preoperative stabilization or postoperative rescue. The aim of this study was to examine the acute and long-term morbidity associated with pre- and postoperative ECMO., Methods: Neonates born with CDH and needing ECMO were classified into 2 groups. Group 1 consisted of neonates placed on ECMO after CDH surgery. Patients in group 2 underwent preoperative ECMO stabilization. Medical records after birth were evaluated. Growth, neuromotor and cognitive development, hearing, and behavior were evaluated. Student t test and chi(2) were used to determine statistical significance between groups., Results: Subjects in group 2 had significantly more days on ECMO and loop diuretics. Alkalosis was induced for a longer duration in group 2. At follow-up 3 to 9 years later, no differences were found between the 2 groups in growth parameters, neuromotor outcome, or behavior. However, in group 1, 2 of 9 children had significant hearing impairment necessitating amplification compared with 6 of 6 subjects in group 2., Conclusions: Neonates with CDH first stabilized on ECMO (group 2) had a higher incidence of hearing loss compared with those needing ECMO postrepair (group 1). The etiology of this finding is not clear. This may be secondary to the prolonged period of hyperventilation or general intensive care that is part of the protocol for neonates who are electively stabilized on ECMO preoperatively. J Pediatr Surg 36:539-544., (Copyright 2001 by W.B. Saunders Company.)

It was hypothesized that prenatal exposure to cocaine and other substances would be related to delayed expressive language development. Speech and language data were available for 458 6-year olds (204 were exposed to cocaine). No significant univariate or multivariate differences by cocaine exposure group were observed. Classification and regression tree modeling was then used to identify language variable composites predictive of cocaine exposure status. Meaningful cut points for two language measures were identified and validated. Children with a type token ratio of less than 0.42 and with fewer than 97 word types were classified into a low language group. Low language children (n = 57) were more likely to be cocaine exposed (63.1%), with cocaine-exposed children 2.4 times more likely to be in the low language group compared with control children after adjustment for covariates. Prenatal cigarette, but not alcohol exposure, was also significantly related to expressive language delays.

Objective: Prenatal cocaine exposure has been associated with alterations in neonatal behavior and more recently a dose-response relationship has been identified. However, few data are available to address the long-term behavioral effects of prenatal exposures in humans. The specific aim of this report is to evaluate the school-age behavior of children prenatally exposed to cocaine., Methods: All black non-human immunodeficiency virus-positive participants in a larger pregnancy outcomes study who delivered singleton live born infants between September 1, 1989 and August 31, 1991 were eligible for study participation. Staff members of the larger study extensively screened study participants during pregnancy for cocaine, alcohol, cigarettes, and other illicit drugs. Prenatal drug exposure was defined by maternal history elicited by structured interviews with maternal and infant drug testing as clinically indicated. Cocaine exposure was considered positive if either history or laboratory results were positive. Six years later, 665 families were contacted; 94% agreed to participate. The child, primary caretaker (parent), and, when available, the biologic mothers were tested in our research facilities. Permission was elicited to obtain blinded teacher assessments of child behavior with the Achenbach Teacher's Report Form (TRF). Drug use since the child's birth was assessed by trained researchers using a structured interview., Results: Complete laboratory and teacher data were available for 499 parent-child dyads, with a final sample size for all analyses of 471 (201 cocaine-exposed) after the elimination of mentally retarded subjects. A comparison of relative Externalizing (Aggressive, Delinquent) to Internalizing (Anxious/Depressed, Withdrawn, Somatic Complaints) behaviors of the offspring was computed for the TRF by taking the difference between the 2 subscales to create an Externalizing-Internalizing Difference (T. M. Achenbach, personal communication, 1998). Univariate comparisons revealed that boys were significantly more likely to score in the clinically significant range on total TRF, Externalizing-Internalizing, and Aggressive Behaviors than were girls. Children prenatally exposed to cocaine had higher Externalizing-Internalizing Differences compared with controls but did not have significantly higher scores on any of the other TRF variables. Additionally, boys prenatally exposed to cocaine were twice as likely as controls to have clinically significant scores for externalizing (25% vs 13%) and delinquent behavior (22% vs 11%). Gender, prenatal exposures (cocaine and alcohol), and postnatal risk factors (custody changes, current drug use in the home, child's report of violence exposure) were all related to problem behaviors. Even after controlling for gender, other prenatal substance exposures, and home environment variables, cocaine-exposed children had higher Externalizing-Internalizing Difference scores. Prenatal exposure to alcohol was associated with higher total score, increased attention problems, and more delinquent behaviors. Prenatal exposure to cigarettes was not significantly related to the total TRF score or any of the TRF subscales. Postnatal factors associated with problem behaviors included both changes in custody status and current drug use in the home. Change in custody status of the cocaine-exposed children, but not of the controls, was related to higher total scores on the TRF and more externalizing and aggressive behaviors. Current drug use in the home was associated with higher scores on the externalizing and aggressive subscales., Conclusions: Results of this study suggest gender-specific behavioral effects related to prenatal cocaine exposure. Prenatal alcohol exposure also had a significant impact on the TRF. Postnatal exposures, including current drug use in the home and the child's report of violence exposure, had an independent effect on teacher-assessed child behavioral problems. (ABSTRACT TRUNCATE

Objectives: The purposes of this study were to report the neurodevelopmental, neurosensory, and functional outcomes of 1151 extremely low birth weight (401-1000 g) survivors cared for in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network, and to identify medical, social, and environmental factors associated with these outcomes., Study Design: A multicenter cohort study in which surviving extremely low birth weight infants born in 1993 and 1994 underwent neurodevelopmental, neurosensory, and functional assessment at 18 to 22 months' corrected age. Data regarding pregnancy and neonatal outcome were collected prospectively. Socioeconomic status and a detailed interim medical history were obtained at the time of the assessment. Logistic regression models were used to identify maternal and neonatal risk factors for poor neurodevelopmental outcome., Results: Of the 1480 infants alive at 18 months of age, 1151 (78%) were evaluated. Study characteristics included a mean birth weight of 796 +/- 135 g, mean gestation (best obstetric dates) 26 +/- 2 weeks, and 47% male. Birth weight distributions of infants included 15 infants at 401 to 500 g; 94 at 501 to 600 g; 208 at 601 to 700 g; 237 at 701 to 800 g; 290 at 801 to 900 g; and 307 at 901 to 1000 g. Twenty-five percent of the children had an abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index <70, 29% had a Psychomotor Developmental Index <70, 9% had vision impairment, and 11% had hearing impairment. Neurologic, developmental, neurosensory, and functional morbidities increased with decreasing birth weight. Factors significantly associated with increased neurodevelopmental morbidity included chronic lung disease, grades 3 to 4 intraventricular hemorrhage/periventricular leukomalacia, steroids for chronic lung disease, necrotizing enterocolitis, and male gender. Factors significantly associated with decreased morbidity included increased birth weight, female gender, higher maternal education, and white race., Conclusion: ELBW infants are at significant risk of neurologic abnormalities, developmental delays, and functional delays at 18 to 22 months' corrected age.

Study Objective: The objective of the study was to describe the epidemiology of neural tube defects (NTD) in the eastern region of Ireland using the EUROCAT register of congenital malformations., Design, Setting and Patients: EUROCAT registries monitor the prevalence of congenital anomalies in defined populations using multiple sources for case ascertainment. All cases of NTD on the Dublin EUROCAT register born between 1980 and 1994 were extracted and analysed. The crude birth prevalence rate for all NTD, spina bifida, anencephaly and encephalocoele were calculated for each year. Parameters measured were: sex ratio, stillbirth rate, proportion of low birth-weight babies (< 2500 g) and the proportion who were premature (< 37 weeks gestation)., Main Results: Of 821 NTD cases, 419 (51.0%) had spina bifida, 322 (39.2%) had anencephaly, 69 (8.4%) had encephalocoele and 11 (1.3%) were iniencephalic. The crude birth prevalence of NTD decreased fourfold from 46.9/10,000 births in 1980 to 11.6/10,000 in 1994. The downward trend ceased during the early 1990's. Younger mothers had significantly higher rates of NTD affected births. Twenty two per cent of NTD cases had additional non-central nervous system anomalies. In 40 cases, there was a previous family history of NTD in siblings. Seasonal effects in birth prevalence were observed. Birth notification was the most frequent mechanism of ascertainment., Conclusion: There was a marked fall in the birth prevalence of NTD during the 15 year period. This change was real and not accounted for by pre-natal screening and diagnostic practises with termination of pregnancy, which is not legally permissible in Ireland. Dietary factors may have had an influence. Rates of NTD in this region are still higher than many other parts of Europe. Primary prevention strategies through increased folic acid intake are necessary to further reduce NTD affected births.

Objective: To identify infants at risk of death and abnormal neurodevelopmental outcome following extracorporeal membrane oxygenation (ECMO) in the neonatal period., Methods: The medical records of 82 neonates treated with ECMO were reviewed to evaluate risk of death. All survivors were followed by neurologic examinations and tested using the Bayley Scales of Infant Development or McCarthy Scale of Children's Abilities, and risk for abnormal neurodevelopmental outcome was assessed., Results: The overall survival was 91% (75 of 82). The mean gestational age and birth weight of nonsurvivors were lower than those of survivors (37 +/- 1 weeks vs 40 +/- 0 weeks; 2734 +/- 230 vs 3325 +/- 69 gm, p < 0.05). Infants who were lost to follow-up (16%) did not differ from those with follow-up in demographic variables or clinical indicators of illness severity. Thirty-five of 63 infants (56%) with follow-up had normal neurodevelopmental outcome. Risk of abnormal outcome was higher in infants requiring assisted ventilation for > or = 15 days (relative risk [RR] 5.5; 95% confidence interval [CI] 2.0 to 14.8), supplemental oxygenation for > or = 22 days (RR 3.1; 95% CI 1.3 to 7.6), and black race (RR 8.9; 95% CI 1.3 to 62.9). None of the neuroimaging studies accurately predicted the neurodevelopmental outcome of these infants., Conclusion: We conclude that ECMO in critically ill infants is associated with good survival. The need for prolonged respiratory support may help in identifying infants at risk for abnormal neurodevelopmental outcome.

The incidence and site of electroencephalogram (EEG) abnormalities and the efficacy of post-ECMO EEG as a predictor of neurodevelopmental outcome was evaluated in survivors of neonatal extracorporeal membrane oxygenation (ECMO). All survivors of neonatal ECMO with an EEG performed prior to their discharge were included if they had at least 12 months of follow-up. The neurodevelopmental outcome was reported as normal, suspect, and abnormal on the basis of neurological examination and the scores on Bayley Scales of Infant Development or McCarthy Scale of Children's Abilities. EEG abnormalities were noted in 31 (70%) of 44 infants. The distribution of EEG abnormalities was not significantly different for right and left hemispheres. The incidence of abnormal neurodevelopmental outcome was similar in infants with a normal or an abnormal EEG (3 of 13 vs. 7 of 31; p = 0.8). EEG abnormalities had no correlation with neurodevelopmental outcome. We conclude that the high incidence of EEG abnormalities and their lack of correlation with neurodevelopmental outcome would suggest that these abnormalities do not represent permanent brain injury and a single EEG performed after decannulation from ECMO is not helpful in identifying infants at risk of subsequent abnormal neurodevelopmental outcome.

Objective: The aim of this study was to evaluate previous teacher reports that children exposed to cocaine prenatally have more problem behaviors., Methods: A historical, prospective design was used. Maternal subjects (n = 116) of 6-year-old singleton, term (>/=36 weeks) children, and the children's first-grade teachers (n = 102) agreed to participate. The child's first-grade teacher, blinded to study design and exposure status, rated the child's behavior with the Conners' Teacher Rating Scales (CTRS) and an investigator-developed scale, the Problem Behavior Scale (PROBS 14), measuring behaviors reported by educators to be specific to cocaine exposure. Mothers were interviewed by telephone regarding demographic and socioeconomic factors., Results: Although the cocaine-exposed group had higher (more problem behaviors) for each of the CTRS subscales, the overall multivariate analysis of variance for the CTRS was not significant. Children exposed to cocaine prenatally had higher scores (more problem behaviors) for 11 of the 14 PROBS items and the overall multivariate analysis of variance relating prenatal cocaine exposure to the PROBS was significant (Wilkes' lambda =.775), even after controlling for gender and prenatal exposure to alcohol and cigarettes., Conclusions: This pilot study supports that teachers blinded to exposure status of early elementary students did rate the cocaine-exposed group as demonstrating significantly more problem behaviors than control children. Although an important first step, postnatal factors that also may influence behavior were not evaluated; hence, causation is not addressed.

Despite media reports and educators' concerns, little substantive data have been published to document or refute the emerging reports that children prenatally exposed to cocaine have serious behavioral problems in school. Recent pilot data from this institution have indeed demonstrated teacher-reported problem behaviors following prenatal cocaine exposure after controlling for the effects of prenatal alcohol use and cigarette exposure. Imperative in the study of prenatal exposure and child outcome is an acknowledgement of the influence of other control factors such as postnatal environment, secondary exposures, and parenting issues. We report preliminary evaluation from a large ongoing historical prospective study of prenatal cocaine exposure on school-age outcomes. The primary aim of this NIDA-funded study is to determine if a relationship exists between prenatal cocaine/alcohol exposures and school behavior and, if so, to determine if the relationship is characterized by a dose-response relationship. A secondary aim evaluates the relationship between prenatal cocaine/alcohol exposures and school achievement. Both relationships will be assessed in a black, urban sample of first grade students using multivariate statistical techniques for confounding as well as mediating and moderating prenatal and postnatal variables. A third aim is to evaluate the relationship between a general standardized classroom behavioral measure and a tool designed to tap the effects thought to be specific to prenatal cocaine exposure. This interdisciplinary research team can address these aims because of the existence of a unique, prospectively collected perinatal Database, funded in part by NIAAA and NICHD. The database includes repeated measures of cocaine, alcohol, and other substances for over 3,500 births since 1986. Information from this database is combined with information from the database of one of the largest public school systems in the nation. The final sample will be composed of over 600 first grade students for whom the independent variables, prenatal cocaine/alcohol exposures, were prospectively assessed and quantified at the university maternity center. After informed consent, the primary dependent variable, school behavior, is assessed, using the PROBS-14 (a teacher consensus developed instrument), the Child Behavior Check List, and the Conners' Teacher Rating Scale. The secondary dependent measure, school achievement, is measured by the Metropolitan Achievement Text and the Test of Early Reading Ability. Control variables, such as the environment and parenting, are measured by several instruments aimed at capturing the child and family ecology since birth. All analyses will be adjusted as appropriate for prospectively gathered control variables such as perinatal risk, neonatal risk, and other prenatal drug and cigarette exposures. Further adjustment will be made for postnatal social risk factors which may influence outcome. Of particular concern are characteristics of the home (adaptation of HOME), parent (depression, stress), and neighborhood (violence exposure). Finally, postnatal exposure to lead and other drugs is being considered.

Objective: In utero passage of meconium may represent a response to hypoxic stress or a normal maturational event. When found during the third trimester, one may be tempted to use its presence as prima facie evidence of fetal lung maturity. The purpose of our study was to determine the frequency of meconium-stained fluid in the third trimester and the incidence of biochemical and physiologic lung immaturity in these fetuses., Methods: Amniotic fluid specimens obtained at our institution from 1991 through 1993 (n = 2,377) were analyzed for maturity and visually inspected for meconium. Perinatal outcome was obtained for intramural deliveries occurring within 3 days of amniotic fluid collection (n = 905). Gestational age was defined as the best obstetric estimate based on menstrual dates, clinical examination, and ultrasound results., Results: Meconium staining was present in 2.7% (n = 64) of specimens. Although meconium-stained specimens were more likely to have mature lecithin-sphingomyelin (L:S) ratios (OR 2.1, 95% confidence interval [CI] = 1.2-3.6) and phosphatidylglycerol (PG) concentrations (OR 3.8, CI 2.2-6.7), 17.2% were immature for both L:S and PG (n = 11, CI = 9.9-28.2%). When analysis was limited to fetuses delivering intramurally within 3 days of amniotic fluid collection, respiratory distress syndrome occurred in 3.0% (CI = 0.5-15%) with meconium-stained fluid., Conclusions: The presence of meconium in amniotic fluid does not guarantee lung maturity. The same consideration of the risks of prematurity must be given to the fetus with meconium-stained fluid as given to the fetus with clear fluid.

A patient with end-stage renal disease and known benign monoclonal gammopathy underwent kidney transplantation at Westchester County Medical Center, Valhalla, NY. After surgery, during routine follow-up, the patient had laboratory evidence of frank multiple myeloma. However, she did not show any clinical signs or symptoms of the disease. Four years later, the patient is asymptomatic and continues to have stable renal function. As a result of our experience, and that of others, we support transplantation as a viable option for patients with multiple myeloma.

Objective: The aim of this study was to evaluate the hypothesis that prenatal cocaine exposure would negatively affect newborn behavior., Methods: A prospective observational study of term infants recruited from the low-risk nursery used a structured, standardized interview to obtain maternal data. Cocaine exposure was determined by radioimmunoassay of the infant's meconium stool. An examiner blinded to the infant's cocaine status administered the Brazelton Neonatal Behavioral Assessment Scales., Results: The sample was composed of 23 exposed and 29 nonexposed infants. On six of the seven Brazelton Neonatal Behavioral Assessment Scale clusters, cocaine-exposed infants performed less well than control infants, with significant differences observed for autonomic stability. In addition, a dose-response relationship was suggested. Significant negative, within-group relationships were evident in the exposed group, indicating poorer performance with increasing meconium cocaine concentration for orientation (r = -.40) and regulation of state (r = -.40). Regression model testing of the influence of meconium cocaine concentration on neurobehavioral outcomes, after controlling for significant confounders, identified a significant independent, negative effect of meconium cocaine concentration on two clusters-motor and regulation of state., Conclusion: In otherwise healthy full-term infants, prenatal cocaine exposure identified by quantitative analysis of cocaine concentration in meconium had a significant, independent negative association with motor and regulation of state that remained after controlling for other significant confounders. A dose-response relationship was evident.

Objective: To determine whether gestational age is a significant determinant of neonatal outcome, irrespective of biochemical lung maturity. The effects of specimen source and clarity on the reliability of biochemical tests for predicting respiratory distress syndrome are also evaluated., Study Design: Perinatal outcome was analyzed for 904 neonates undergoing amniotic fluid maturity studies within three days of delivery from 1991 to 1993. The relationships of gestational age and biochemical maturity to neonatal outcome were examined using multivariate analysis of covariance. Test reliability was evaluated using log-linear analysis of multiway frequency tables., Results: Gestational age was a better predictor of neonatal outcome than biochemical lung maturity. Gestational age significantly correlated with every measure of outcome except intraventricular hemorrhage and jaundice. Test reliability was not significantly influenced by specimen source or clarity., Conclusion: Results obtained using contaminated amniotic fluid are reliable when the proper technique is used. Irrespective of biochemical maturity, neonatal outcome is significantly related to gestational age. Gestational age, and not just biochemical maturity, should be considered when timing delivery.

Objective: To evaluate the effect of antenatal phenobarbital (PB) therapy on neurodevelopmental outcome at 36 months., Design: Prospective, randomized, controlled trial., Setting: Single-institution study. SUBJECT AND INTERVENTIONS: Children born to women who participated in the study evaluating the effect of antenatal phenobarbital (PB) on neonatal intracranial hemorrhage were prospectively followed to 3 years of age., Outcome Measures: Physical growth, neurologic examinations, and developmental testing (McCarthy Scales of Children's Abilities). Comparisons between groups were made on all children and those born to multiple gestations., Results: Forty-one children born to women who received 10 mg/kg PB before delivery and 55 children in the control group were evaluated. Three children, all in the control group, had growth parameters (height, weight, and head circumference) below the fifth percentile. The McCarthy General Cognitive Index (standard, 100 +/- 16) was 93 +/- 20 in the PB group and 85 +/- 18 in the control group. The subscores tended to be higher in the PB group than in the control group, with higher quantitative scores in the PB group (44 +/- 11 vs 39 +/- 8). Neurologic deficits were noted in 2 of 41 in the PB group and in 6 of 55 in the control group., Conclusions: Infants born to women who received antenatal PB therapy had similar neurodevelopmental outcomes as infants born to women who did not receive PB. No adverse effects of PB exposure were detected.

To determine whether children with language delays are more likely to have been exposed to cocaine in utero than children with normal language development, a case-control study was undertaken. Based on routine office screening in our primary-care clinic over a 1-year period, we identified 29 consecutive children, aged 24 to 48 months, as language-delayed. They were compared with an approximate 2:1 match of children without language delay who had been seen in the clinic on the same days and who were of similar age. There was more reported cocaine use during pregnancy (six of 29, 21%) among the language-delayed children than among the controls (five of 71, 7%). This difference is statistically significant (P < 0.05, chi 2 = 3.92; odds ratio = 3.4 +/- 2.2). Discriminant analysis revealed that both cocaine and nicotine exposure were associated with delayed language development--with an unexpected negative, i.e., an antagonistic, protective, interactive effect (F[3,96] = 4.66, R2 = 12.7%, P < .005); neither gender nor caretaker contributed to language development in this sample. These results suggest that children with language delay detected in a clinical setting are more likely to have been exposed in utero to cocaine than children with normal language development. Prenatal cocaine exposure should be a risk factor in monitoring development in children.

Objective: To determine the incidence and site of single photon emission computed tomography scan (SPECT) abnormalities in survivors of neonatal extracorporeal membrane oxygenation and to evaluate the efficacy of SPECT scan as a predictor of neurodevelopmental outcome in these infants., Setting: Tertiary care neonatal intensive care unit in Detroit, MI., Patient Population: Survivors of neonatal extracorporeal membrane oxygenation who had a SPECT scan of the brain performed after decannulation and before their discharge from the neonatal intensive care unit were included if they had at least 12 months of follow-up in our developmental assessment clinic., Outcome Measures: The neurological outcome was reported as normal, suspect, and abnormal on the basis of neurological examination and developmental milestones. The developmental outcome was assessed by Bayley mental development index or McCarthy general cognitive index scores., Results: A total of 59 patients met study criteria. SPECT scan abnormalities were noted in 45 (76%) infants. Global hypoperfusion was the most frequent abnormality followed closely by bilateral focal perfusion defects. The distribution of perfusion abnormalities was not significantly different for right and left hemispheres. Among 14 infants with normal SPECT scans, 13 infants had normal neurological outcome and all had a normal developmental outcome. Of the 45 infants with an abnormal SPECT scan, 7 infants had an abnormal neurological outcomes and 4 infants had an abnormal developmental outcome. SPECT scan abnormalities had no significant correlation with neurodevelopmental outcome of these infants., Conclusion: Although a normal SPECT scan was more likely to predict a normal neurodevelopmental outcome, an abnormal SPECT scan did not predict an abnormal outcome in these infants.

Hypokalemia induced by the use of diuretics is common. Those at risk include the elderly, women, patients with edematous states, and patients in whom higher doses and/or the more potent agents are used. Prevention should include a low-salt diet rich in potassium, magnesium, and chloride (either through foods enriched with these elements or through potassium chloride supplements) and use of low doses of short-acting diuretics in the treatment of mild to moderate hypertension. The subgroup of hypertensive patients in whom hypokalemia develops despite these recommendations may benefit from a change to the potassium-sparing diuretic spironolactone or substitution of diuretics with alternative first-line drugs.

Seven term neonates with encephalopathy resulting from asphyxia and/or intracranial hemorrhage underwent invasive monitoring of intracranial pressure through the epidural or intracerebral space. The average age (in hours) at insertion of the monitor was 27 h in the 3 neonates with asphyxia and 70 h in the 4 neonates with hemorrhage. Intracranial hypertension was noted in 6 neonates. The management of the hypertension included hyperventilation followed by mannitol for pressures that were sustained above 20 mmHg and pentobarbital for pressures above 30 mmHg. The duration of the hypertension varied in 5 neonates from 4 to 72 h, while in the remaining neonates, the pressure remained elevated until death at 70 h. All 4 survivors with intracranial hemorrhage have minimal neuromotor deficits on follow up and 2 survivors with asphyxia have cognitive deficits and are microcephalic. From this small series, it appears that in the management of term neonates with intracranial hemorrhage, monitoring of intracranial pressure should be considered.

The influence of delayed renal graft function on long-term allograft outcome remains uncertain. All 495 cyclosporine treated cadaver donor renal transplants within a single center were analyzed with respect to dialysis dependence in the early posttransplant period. When compared with immediate allograft function, dialysis dependence for more than one week posttransplant was associated with prolonged cold ischemia time (27 +/- 11 vs 32 +/- 12 hours), cytotoxic antibodies > 30% (14% vs 25%), black race (29% vs 41%), increased incidence of acute rejection in the first year posttransplant (31% vs 67%) and inferior 1-year (85% vs 52%) and 5-year (68% vs 33%) graft survival among primary transplants. No adverse effect however was noted on renal function in long-term survivors.

150 episodes of allograft dysfunction in 128 renal transplant recipients, 77 due to acute rejection, 32 secondary to acute-on-chronic rejection, 33 due to either prerenal factors, acute tubular necrosis, or ciclosporin A nephrotoxicity, and 8 secondary to multiple causes, were evaluated by fine-needle aspiration biopsy (FNAB), Doppler ultrasound (DUS), and radionuclide scintigraphy (RS), each performed within a 24-hour period and prior to any specific therapeutic intervention. Tests were interpreted by appropriate specialists in a large transplant center without access to clinical information. The final diagnosis was based primarily upon response to therapeutic maneuvers with histological (core biopsy) confirmation in 123 episodes. RS was the most sensitive (70%) test for the diagnosis of acute rejection during the early posttransplant period, exceeding both FNAB (52%) and DUS (43%). The predictive accuracy of either FNAB, DUS, RS, or core biopsy in the detection of a steroid-responsive component to acute rejection when superimposed upon chronic rejection was low at approximately 50%. When the underlying cause of renal dysfunction was either prerenal, acute tubular necrosis, or ciclosporin A nephrotoxicity, FNAB, DUS, and RS each gave an erroneous diagnosis of acute rejection in about 50% of the episodes. Cost analysis revealed that core biopsy was the most expensive test, but only 9% more than RS, with FNAB the least costly. In conclusion, the lack of ideal sensitivity and specificity combined with the expense of present-day FNAB, DUS, RS, and core biopsy in the diagnosis of a therapeutically reversible component to acute-on-chronic rejection and of FNAB, DUS, and RS in the diagnosis of acute rejection during the early posttransplant period should prompt research into ways to improve their diagnostic yield or alternate modalities.

A complex case of trisomy 21-related pulmonary hypoplasia with polyhydramnios and hydrops fetalis is described. The value of antenatal surveillance and genetic counselling is emphasized.

The clinical course of HIV seropositive renal allograft recipients is ill defined. Thus, a retrospective analysis of mortality, morbidity and graft survival was performed in two groups of HIV-positive patients. Group 1 (nine patients), seropositive for an indefinite period of time prior to transplantation (eight i.v. drug abusers, one homosexual), all lost their grafts after a mean period of 23 +/- 11 months from chronic rejection (six), complicated by focal glomerular sclerosis and nephrotic syndrome in three cases, sepsis (two) and death with a functioning graft (one). Four patients died, two from sepsis, one from Kaposi's sarcoma and one from fluid overload. Of the remaining five patients, all on hemodialysis, one had AIDS and four were asymptomatic after a mean period of 44 months following graft failure. Prolonged hospitalizations for both infections and acute rejection were common. Group 2 (six patients) seroconverted in the perioperative period, and two had functioning allografts at 78 and 100 months post-transplant. Causes of allograft loss, patient death and infection-related complications were similar to those of group 1, but acute rejection was rare. In conclusion, HIV infection in renal allograft recipients was associated with poor allograft survival due mainly to rejection, mostly chronic, often complicated by glomerular sclerosis and nephrotic syndrome. Infectious complications requiring hospitalization were also increased.

The present analysis was undertaken to evaluate the influence of primary allograft nephrectomies on the early function, incidence of rejection, and short-term graft survival of subsequent renal retransplants. Among 95 consecutive cyclosporine treated retransplant recipients, 52 were retransplanted without primary allograft nephrectomy; 35 had removal of their primary grafts prior to retransplantation for fever and graft tenderness (30 patients) and persistent hematuria (5 patients); and 8 patients had an elective primary graft nephrectomy at the time of retransplantation. Demographic characteristics and immunosuppressive regimens were otherwise similar in all three groups. Nephrectomy of the primary allograft prior to retransplantation was associated with a significant subsequent rise in preformed cytotoxic antibody levels (57% having PRA greater than 30% compared with 33% in those with retention of primary grafts), a significantly higher incidence of delayed graft function among retransplants (63% compared with 30% in those who did not undergo primary allograft nephrectomy) and a trend toward decreased allograft survival in the subgroup who lost their primary allografts in the first year posttransplant. The incidence of acute rejection and 3-year posttransplant renal function in retransplants were not, however, influenced by nephrectomy of the primary allograft.

A single center experience of 514 ciclosporin-treated renal allografts which survived longer than 1 year was reviewed in order to analyze the causes of renal allograft loss beyond the 1st year post-transplantation and the contribution of selected parameters to long-term survival. 83 grafts were lost between 1 and 5 years with the most common causes of graft loss being chronic rejection (54%), death (14%), noncompliance (13%) and sepsis (11%). Actuarial 5-year graft survival rates, decaying from 100% at 1 year, of living related and cadaveric grafts were 88.6 and 79.5%, respectively. Parameters with a substantial influence on long-term survival included the quality of early graft function and incidence of acute rejection in the 1st year post-transplantation. A marker for long-term survival (> 5 years) was a significantly lower serum creatinine (177 mumol/l; < or = 2 mg/dl) at 1 year. We conclude that chronic rejection is responsible for the majority of late graft losses in the ciclosporin era as in the earlier azathioprine period.

A single center experience of 160 cyclosporine-treated renal allografts that survived longer than 1 year was reviewed in an attempt to analyze the contribution of selected parameters to long-term survival. Sixty-one grafts were lost between 1 and 5 years, with the remaining functioning for longer than 5 years. Parameters with a significant influence on long-term survival included both quality of early graft function, with 13% of long-term survivors having delayed function, compared to 52% among the short-term survival group, and the incidence of acute rejection in the first year posttransplant (31% in long-term survivors compared to 63% in the short-term survival group). A marker for long-term survival (greater than 5 years) was a lower serum creatinine at 1 year (1.9 +/- 0.1 mg/dl, compared with 2.6 +/- 0.2 mg/dl in the short-term survival group). Recipient race, original renal disease, number of transplants and/or transfusions, panel reactive antibodies, and human leukocyte antigens matching did not appear to influence long-term outcome.

Background: Glucose reacts nonenzymatically with proteins in vivo, chemically forming covalently attached glucose-addition products and cross-links between proteins. The excessive accumulation of rearranged late-glucose-addition products, or advanced glycosylation end products (AGEs), is believed to contribute to the chronic complications of diabetes mellitus., Methods: To elucidate the relation of AGEs to diabetic complications, we used a radioreceptor assay to measure serum and tissue AGEs in diabetic (Types I and Type II) and nondiabetic patients with different levels of renal function. Serum AGEs were measured as a low-molecular-weight (less than or equal to 10 kd) peptide fraction and a high-molecular-weight (greater than 10 kd) protein fraction., Results: The mean (+/- SD) AGE content of samples of arterial-wall collagen from 9 diabetic patients was significantly higher than that of samples from 18 nondiabetic patients (14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE units per milligram, P less than 0.001). Moreover, diabetic patients with end-stage renal disease had almost twice as much AGE in tissue as diabetic patients without renal disease (21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE units per milligram, P less than 0.001). The AGE levels in both serum fractions were elevated in the patients with diabetes, and the levels of AGE peptides correlated directly with serum creatinine (P less than 0.001) and inversely with creatinine clearance (P less than 0.005), suggesting that levels of AGE peptides increased with the severity of diabetic nephropathy. In six patients with diabetes who required hemodialysis, the levels of AGE peptides were five times higher than in eight normal subjects (82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE units per milliliter, P less than 0.001). In another group of diabetic patients the mean serum creatinine level, which decreased by 75 percent during a session of hemodialysis, whereas the level of AGE peptides decreased by only 24 percent. Serum levels of AGE peptides were normal in two patients with normal serum creatinine levels after renal transplantation., Conclusions: AGEs accumulate at a faster-than-normal rate in arteries and the circulation of patients with diabetes; the increase in circulating AGE peptides parallels the severity of renal functional impairment in diabetic nephropathy.

The effects of maleic acid on renal phosphate (Pi) transport were examined by clearance and brush-border membrane vesicle (BBMV) transport studies. In normal rats, maleic acid 50 mg.kg body wt-1.h-1 increased the phosphaturia (P less than 0.001). Intraperitoneal administration of a similar dose of maleic acid decreased the BBMV uptake of Pi but not glucose. In rats fed a low-phosphate diet (0.03%), the maleic acid-induced phosphaturia was blunted, but the inhibitory effect on the BBMV transport of Pi persisted. In chronic parathyroidectomized rats fed a low-phosphate diet, where the filtered load of Pi was higher than in the previous groups, the phosphaturia was abolished, but the inhibition of the BBMV transport of Pi was sustained. Both the in vitro incubation of BBMVV and in vivo administration of maleic acid were associated with a competitive inhibition of Pi transport. These studies indicate that the maleic acid-induced phosphaturia is expressed at the apical membrane entry step of Pi, and the enhanced distal tubular reabsorption accounts for the lack of phosphaturia in dietary Pi deprivation.

Objective: To study the incidence, outcome, and possible etiopathogenic factors involved in posttransplantation diabetes mellitus in cyclosporine-treated black renal allograft recipients., Research Design and Methods: One hundred thirty-eight nondiabetic black renal transplant recipients whose grafts survived greater than 1 yr were studied retrospectively., Results: Twenty-eight (20.3%) patients developed posttransplantation diabetes mellitus, 46 and 75% were diagnosed by 6- and 12-mo posttransplantation, respectively, and 46% were insulin dependent. Diabetes was more frequently encountered in older recipients and recipients of cadaveric kidneys but was independent of sex, number of transplants, incidence of acute rejection, percentage of body weight gain, steroid or cyclosporine dose, and use of beta-blockers and/or diuretics. Renal function was similar in the diabetic group compared with the control group. Actuarial 5-yr graft survival was 82% in the diabetic cohort compared with 78% in the control group, with chronic rejection accounting for all graft losses within the diabetic group., Conclusions: Twenty percent of black cyclosporine-treated renal allograft recipients developed diabetes mellitus in the posttransplantation period. However, its presence did not appear to influence intermediate-term graft or patient survival.

In an attempt to analyze the influence of race on renal allograft outcome among insulin-dependent diabetic uremics, all 109 cyclosporine treated transplants were studied. Black recipients were noted to have inferior 1 year survival for both living related and cadaver donor grafts when compared with both whites and Hispanics (67% and 43% vs. 92% and 84%, 100% and 80%, respectively, p less than 0.01). Nonimmunologic causes accounted for 69% of graft losses among blacks, compared with 39% and 33% in whites and Hispanics, respectively. Among long-term survivors, however, renal function remained relatively stable among all racial groups. This differing trend among black diabetic recipients suggests the need for aggressive cardiac workups before transplantation, and judicious immunosuppression in the posttransplant period.

A worldwide shortage of cadaveric donors has led to the increased utilization of elderly living donors, with controversial results. In an attempt to assess the effect of donor age on graft survival and subsequent renal function, we analyzed our clinical results in 276 consecutive recipients of living related renal transplants spanning both the cyclosporine and the azathioprine eras, of whom a total of 44 recipients received kidneys from donors over 55 years old. All recipients were otherwise similar in age, race, haplotype mismatch, number of retransplants, and number of pretransplant transfusions, apart from an increased number of diabetics among the CsA-treated recipients of elderly kidneys (38% vs. 14%). The cumulative patient and graft survival rates at 1 and 5 years were independent of donor age whether CsA or AZA was utilized. Nor was the incidence of rejection or infection significantly different in the older donor group when compared with the younger cohort. Short-term and intermediate-term renal function, as assessed by serum creatinine, was however poorer but stable in the older donor group when compared with the younger one. The mean serum creatinine levels at 1 year in the CsA- and AZA-treated recipients of kidneys from older donors were 2.4 and 2.0 mg/dl, respectively, compared with 1.6 and 1.4 mg/dl, respectively, when the donor age was less than 55 years (P less than 0.001). Since renal function at the end of the first posttransplant year is considered a determinant of long-term graft survival, this is a cause for concern, but in view of the universal shortage of organs and the negligible morbidity to donors, renal transplantation from elderly living donors remains an acceptable practice.