Bert C.L. Touwen

Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development

Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs)) are widespread environmental contaminants which are neurotoxic in animals. Perinatal exposure to PCBs, PCDDs, and PCDFs occurs prenatally via the placenta and postnatally via breast milk. To investigate whether such an exposure affects the neonatal neurological condition, the neurological optimality of 418 Dutch newborns was evaluated with the Prechtl neurological examination. Half of the infants were breast-fed, the other half were formula-fed, representing a relatively high against a relatively low postnatally exposed group, respectively. As an index of prenatal exposure, four non-planar PCBs in cord and maternal plasma were used. These PCB levels were not related to neurological function. As measures of combined pre- and early neonatal exposure, 17 dioxin congeners, three planar, and 23 non-planar PCB congeners were determined in human milk in the second week after delivery. Higher levels of PCBs, PCDDs, and PCDFs in breast milk were related to reduced neonatal neurological optimality. Higher levels of planar PCBs in breast milk were associated with a higher incidence of hypotonia. This study confirms previous reports about the neurotoxic effects of these compounds on the developing brain of newborn infants.

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Neurological condition in 18-month-old children perinatally exposed to polychlorinated biphenyls and dioxins

The neurological optimality of 418 Dutch children was evaluated at the age of 18 months, in order to determine whether prenatal and breast milk mediated exposure to polychlorinated biphenyls (PCBs) and dioxins affected neurological development. Half of the infants were breast-fed, the other half were formula-fed. PCB concentrations in cord and maternal plasma were used as a measure of prenatal exposure to PCBs. To measure postnatal exposure, PCB and dioxin congeners were determined in human milk and in formula milk. After adjusting for covariates, transplacental PCB exposure was negatively related to the neurological condition at 18 months. Although greater amounts of PCBs and dioxins are transferred via nursing than via placental passage, an effect of lactational exposure to PCBs and dioxins could not be detected. We even found a beneficial effect of breast-feeding on the fluency of movements. We conclude that transplacental PCB passage has a small negative effect on the neurological condition in 18-month-old toddlers.

OBSTETRICAL CONDITION AND NEONATAL NEUROLOGICAL MORBIDITY - AN ANALYSIS WITH THE HELP OF THE OPTIMALITY CONCEPT

In order to increase understanding of the origin of neonatal neurological morbidity, the relationship between the obstetrical and neonatal neurological conditions was studied in a 3-year cohort containing 3162 singleton infants. The infants were neurologically examined at term age according to the technique described by Prechtl. Obstetrical data were documented extensively. Prechtls optimality concept was applied in the analysis. A statistically significant relationship was found between the obstetrical and neonatal neurological optimality scores. There was no sex difference in the obstetrical optimality, whereas there was in the neurological optimality, to the advantage of the girls. It could be shown that obstetrical conditions such as acidemia, preterm birth and intrauterine growth retardation have a stronger relationship to neurological morbidity when the accompanying obstetrical optimality is lower. In obstetrical practice the application of the optimality concept to obstetrical and neurological data is a helpful complementary refinement.

PERINATAL RISK FACTORS AND MINOR NEUROLOGICAL DYSFUNCTION: SIGNIFICANCE FOR BEHAVIOUR AND SCHOOL ACHIEVEMENT AT NINE YEARS

A prospective study was carried out on 133 neurologically deviant infants, 205 with mild abnormalities and 230 normal newborns to compare behavioural and cognitive development with neonatal and nine‐year‐old neurological condition. Overtly handicapped children were excluded. Major determinants of school failure were the severity of minor neurological dysfunction (MND) and social class. Main risk factors for distractable and clumsy behaviour were MND classification and male sex; for troublesome behaviour male sex and interval complicatons after two years of age; and for timid behaviour, family adversity. Definite neonatal neurological deviancy contributed both directly and by its association with MND to problems in behaviour and scholastic abilities. Mild neonatal neurological abnormalities and adverse obstetrical events contributed only indirectly to behavioural and learning problems. Preterm birth (<34 weeks) was the sole obstetric variable directly related to some of the outcome variables. The difference between home and school perception of the childrens behaviour is emphasized.

Antiepileptic medication in pregnancy: Late effects on the children's central nervous system development

In a follow-up study long-term effects of antenatal exposure to two anticonvulsant drugs, phenobarbital and carbamazepine on central nervous system development were evaluated. Children aged 6 to 13 years of epileptic mothers who used phenobarbital (n = 13), carbamazepine (n = 12), phenobarbital plus carbamazepine (n = 12), or no medication (n = 24) during pregnancy were studied. None of the mothers had seizures during pregnancy. A control group carefully matched for confounding variables was selected of children of nonepileptic mothers (n = 61). Minor and major congenital anomalies appeared to be more related to mothers epilepsy than to maternal medication. There were no neurologic differences between the groups. Exposure to phenobarbital was associated with smaller head circumference. An accompanying negative effect of phenobarbital on cognitive development was suggested. Further research on this intriguing phenomenon seems warranted.

Neurological condition in 42-month-old children in relation to pre- and postnatal exposure to polychlorinated biphenyls and dioxins.

Adverse neurological effects of exposure to PCBs have been found up to 18 months of age. Now we report on the effect of pre- and postnatal exposure to PCBs and dioxins on the neurological condition at 42 months of age. For this purpose, PCB levels were determined in cord and maternal plasma, and used as a measure of prenatal exposure. Breast milk was analyzed for PCBs and dioxins. In addition, PCBs were determined in plasma sampled from the child at 42 months of age. We evaluated the neurological condition of 394 children using the Touwen/Hempel method. After adjustment for covariates, neither prenatal PCB exposure nor postnatal exposure to PCBs and dioxins was found to be related to the neurological condition at 42 months of age.

Development of postural adjustments during reaching in infants with CP

The development of postural adjustments during reaching movements was longitudinally studied in seven infants with cerebral palsy (CP) between 4 and 18 months of age. Five infants developed spastic hemiplegia, one spastic tetraplegia, and one spastic tetraplegia with athetosis. Each assessment consisted of a simultaneous recording of video data and surface EMGs of arm, neck, trunk, and leg muscles during reaching in various lying and sitting positions. The basic organization of postural adjustments of the children developing spastic CP was intact. Their main problem was a deficient capacity to modulate the postural adjustments to task‐specific constraints ‐ a deficit which was attributed to a combination of an impaired motor coordination and deficits in sensory integration. The child with spastic‐dyskinetic CP showed distinct abnormalities in the basic organization of postural adjustments.

VARIABILITY AND STEREOTYPY OF SPONTANEOUS MOTILITY AS A PREDICTOR OF NEUROLOGICAL DEVELOPMENT OF PRETERM INFANTS

Observations of the variability stereotypy ratio of spontaneous motility in a group of 47 preterm infants showed that stereotyped motor activity was related to the neurological diagnosis at term age. A minority of the neurologically deviant infants at term recovered during infancy. The presence or absence of intra‐uterine growth retardation and an accumulation of obnoxious antenatal, perinatal and postnatal events seemed to affect outcome, particularly in the presence of extensive and permanent ultrasound findings. A normal neurological condition at term indicates a high probability of normal development.

OBSTETRICAL-NEONATAL NEUROLOGICAL RELATIONSHIP - A REPLICATION STUDY

A study concerning the relationship between neonatal neurological abnormality and 3 parameters of pre- and perinatal condition in a birth cohort of 1507 infants was replicated in a second cohort of 1655 infants. The 3 parameters chosen were preterm birth, intrauterine growth retardation and neonatal acidemia. The neurological examination in the second cohort was carried out by other examiners than in the first cohort. The incidence of neurological abnormality was again found to be raised in all 3 categories and again least in the acidemic subgroup. Also the finding could be confirmed that only in about half of the neurologically abnormal infants could the 3 parameters have exerted any effect at all, which implies the necessity of further analysis. This replication study shows that neurological examination in the newborn period is a reliable tool for the evaluation of the condition of infants with respect to their pre- and perinatal history.