Shaul Harel

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study.

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.

Neurodevelopmental Outcome in Children With Intrauterine Growth Retardation: A 3-Year Follow-Up

The study was designed to detect early clinical predictors of developmental outcome in children with intrauterine growth retardation. Eighty-five children with intrauterine growth retardation were followed up prospectively to 3 years of age, using biometric parameters, perinatal risk questionnaires, and neurodevelopmental evaluations. Forty-two children served as controls. A significant difference in neurodevelopmental score at 3 years of age was noted between the intrauterine growth retardation and control groups (P < .001). In the intrauterine growth retardation group, the clinical parameters that most significantly correlated with outcome were cephalization index (head circumference:birthweight ratio), neonatal risk score, and birthweight. The best predictor of 3-year outcome was the cephalization index (P < .01). The children with intrauterine growth retardation with neonatal complications had significantly lower IQ scores (P < .05) and a poorer neurodevelopmental outcome (P < .01) than those without complications. Children with intrauterine growth retardation are at higher risk for developmental disabilities than are controls, especially in the presence of neonatal complications and a high cephalization index. (J Child Neurol 1999;14:724-727).

Six-Year Follow-Up of Children With Intrauterine Growth Retardation: Long-Term, Prospective Study

This prospective study was designed to characterize the neurodevelopmental and cognitive difficulties specific to children with intrauterine growth retardation and to detect early clinical predictors of these difficulties. Eighty-one children with intrauterine growth retardation were monitored up to 6 to 7 years of age using biometric parameters, perinatal risk questionnaires, and detailed neurodevelopmental and cognitive assessments. Forty-one children served as age-matched, appropriate for gestational age controls. A significant difference in growth parameters (P < .001), neurodevelopmental score (P < .05), and IQ (P < .05) was found between the children with intrauterine growth retardation and controls. A specific profile of difficulties in coordination, lateralization, spatial and graphomotor skills, and abundance of associated movements is typical of the children with intrauterine growth retardation and hints at possible later learning disabilities. The clinical parameters best predicting neurodevelopmental outcome were the neonatal risk score (P < .05) and the weight and height at 6 years of age (P < .05). The children with intrauterine growth retardation with neonatal complications had lower neurodevelopmental scores than the controls but no difference in IQ. Intrauterine growth retardation children diagnosed prenatally had the same neurodevelopmental and IQ scores as those diagnosed at birth, probably due to the careful perinatal and obstetric care provided. Children with intrauterine growth retardation demonstrate a specific profile of neurodevelopmental disabilities at preschool age. Early diagnosis and intervention could probably reduce these difficulties to a minimum. (J Child Neurol 2000;15:781-786).

Significance of microcephaly among children with developmental disabilities.

To assess the clinical impact of microcephaly among children with developmental disabilities, we reviewed the charts of 1393 consecutive patients from birth to 5 years of age referred to our child development center. Comparisons were made between normal and low IQ microcephalic patients and between children with cerebral palsy with and without small head circumference. Microcephaly was detected in 15.4% of patients. Although mental retardation was more common among microcephalic children (P < .001), almost half had normal intelligence. Prematurity (P < .001), perinatal asphyxia (P < .001), small for gestational age (P < .001), respiratory distress syndrome (P < .001), and brain hemorrhage (P < .001) were associated with microcephaly. Hypotonia (P < .001) and spasticity (P < .001) were the most common neurologic findings. Cerebral palsy (P < .001), growth retardation (P < .001), epilepsy (P < .001), and strabismus (P < .001) were the main associated diagnoses found. Mental retardation was significantly more common among microcephalic patients with cerebral palsy than among normocephalic ones (P < .0004). Microcephaly is common among children evaluated for developmental disabilities. Many of these patients have normal or borderline IQ. Of several perinatal conditions associated with later microcephaly, respiratory distress syndrome and intraventricular hemorrhage show the strongest correlation. Mental retardation is not a risk factor for other neurologic complications in microcephalic children. However, in children with cerebral palsy, microcephaly is a risk factor for mental retardation. (J Child Neurol 2002;17:117-122).

Neonatal general movements: an early predictor for neurodevelopmental outcome in infants with intrauterine growth retardation.

Intrauterine growth retardation plays a significant role in neurodevelopmental outcome. The assessment of general movements during the first 20 weeks is a new method for early detection of brain dysfunction. General movements in 31 infants with asymmetric intrauterine growth retardation and their appropriate for gestational age—matched controls were examined. General movements were scored as normal or abnormal by sequential videotape recordings in the writhing (term to 2 weeks), early fidgety (9—11 weeks), and late fidgety (14—16 weeks) periods. Scores were compared between the groups and correlated with neurodevelopmental outcome at 2 years. The incidence of normal general movements was lower in the intrauterine growth retarded infants than in the controls (P < .001). Significant correlations were found between general movement quality and neurodevelopmental scores in the intrauterine growth retarded group. The fidgety movements were the most sensitive and specific for prediction of neurologic outcome. The general movement assessment can, therefore, serve as an additional tool for examining the neurologic status of the preterm and term intrauterine growth retarded infant. (J Child Neurol 2004;19:14—18).

The effect of chronic anticonvulsant therapy on serum lipids and lipoproteins in epileptic children

We measured serum lipids and lipoproteins in 33 epileptic children who were treated with phenobarbital, valproate, and carbamazepine. High-density lipoprotein cholesterol (HDL-c) was significantly higher in the epileptic children than in two control groups: healthy nonepileptic children, and epileptic children before starting anticonvulsant therapy. Our findings indicate that anticonvulsant drugs should be added to the list of substances that affect serum HDL-c.

The cephalization index: A screening device for brain maturity and vulnerability in normal and intrauterine growth retarded newborns*

Predictive estimates of future neurological maldevelopment as a result of vascular induced intrauterine injury are based on the assumption that the body is more affected than the brain resulting in asymmetrical intrauterine growth retarded (IUGR) newborns. The higher the brain:body ratio, the more severe the IUGR process and the greater the risk for the brain to be affected. This prompted us to study in human newborns, a cephalization index based on the ratio of head circumference to body weight to express the degree of brain maturity and possible vulnerability in relation to gestational age. The newborn cephalization index was correlated with neurodevelopment. A trend could be delineated; in the later gestational age, the higher the cephalization index reflecting a greater degree of brain vulnerability, the more severe the clinical pathology; especially the likelihood of cerebral palsy and severe psychomotor retardation. The cephalization index may serve as an additional screening device for high risk intrauterine growth retarded newborns.

Acute Uteroplacental Ischemic Embryo: Lactic Acid Accumulation and Prostaglandin Production in the Fetal Rat Brain

A new experimental model for studying the effects of acute ischemia on brain development in the near‐term fetal rat has been devised. Ischemic conditions are achieved by complete clamping of blood vessels branching from the uterine vasculature into each individual fetus for designated times followed by removal of the clamps to permit reperfusion. Accumulation of lactic acid in the fetal orain depends on the length of the restriction period, reaching a plateau level of 29 μmol/g tissue at about 30 min. It also depends on the reperfusion time. Thus after a period of 15 min of restriction lactate levels show an increase over the next 30‐min reperfusion to a value of 25.5 μmol/g followed by a rapid decrease to normal values by 3 h of reperfusion. Restriction of 15 min followed by reperfusion of 45 min causes an elevation of prostaglandin E2 (PGE2) level from 12.4 ± 0.86 ng/g to 21.1 ± 0.6 ng/g (p < 0.001). This elevation in PGE2 level is less apparent after 20 min of restriction. No effects are seen on the level of PGF2α. Both PGE2 and PGF2α accumulate in vitro in a time‐dependent manner by brain paniculate fraction. In vitro synthesis of both PGE2 and PGF2α is inhibited by indomethacin (100% and 68%, respectively) and AA861 (94% and 76%, respectively). BW755c and nordihydro‐guaiaretic acid do not affect PGE2 formation but enhance PGF2a production by 112% and 152%, respectively. Paniculate fractions from restricted brain produce less PGF2α than control brains (6.38 ± 1.62 versus 11.43 ± 2.2, p < 0.01). The new experimental model should be adequate for studying the consequences of perinatal ischemia on the developing brain.

Clinical characteristics of children referred to a child development center for evaluation of speech, language, and communication disorders

Speech, language, and communication disorders are prominent reasons for referrals to a child development center. From 1984 to 1988, 1,090 preschool children were referred to our child development center, which serves the Tel Aviv metropolitan area. Of all referrals, 432 (41%) were primarily due to speech, language, and communication problems. After exclusion of those with IQ < 50 and those with non-language-related disabilities, 323 children remained. The children were classified into different subtypes of developmental language disorders and autistic spectrum disorders. The main developmental language disorder subtypes were combined expressive-receptive (49%) and expressive (44%). Central processing deficits were less common, occurring in 20 (7%) of the children. Parents of children with developmental language disorders had educational levels similar to those of parents of children referred to the child development center for other causes. However, parents of children with infantile autism had higher educational levels than parents of children with developmental language disorder or parents of children referred for other causes (P < .001). Our results reflect the distribution of language and related problems in an unselected population of preschool children referred to a child development center.

Muscarinic binding sites in the developing rabbit brain: Regional distribution and ontogenesis in the prenatal and early neonatal cerebellum

Several studies are now avarlable on the ontogenesis of the muscariruc binding sites in the developing chrck [l] and rat brain [2] chick retina cells [3] and drs- socrated rat cerebral cell cultures [4]. The postnatal levels of the muscarunc receptor m several regrons of the developmg rat bram were investigated m more detarl [2] and maximum bmdlng actrvity by about 4 weeks postpartum was shown. A similar develop- mental profne has been recently reported for the muscarmrc receptor in that rat hrppocampus forma- tion [5]. As part of our mterest m studying the effects of vascular-induced mtrauterme growth retardation on brain development [6] we have examined the ontog- enesrs of the muscarmrc binding sites m the fetal rabbit bram. Here we report on the concentration of the mus- carmrc receptor m several regions of the prenatal, newborn and adult rabbrt bram. In addition we dem- onstrate that the maximal concentratron of the receptor m the rabbrt cerebellum 1s attamed early rn the neonatal stage.