Coumarins during pregnancy: long-term effects on growth and development of school-age children.

Anticoagulation during pregnancy is complicated because of potential risks for mother and foetus. Unfractionated or low-molecular-weight heparin is used for most anticoagulant indications. Its efficacy, however, in pregnant women with prosthetic heart valves is questioned, therefore coumarins are preferred for this indication. We studied long-term effects of prenatal coumarin-exposure on growth and on neurological, behavioural and cognitive development in 274 school-age children in comparison with 231 age-matched non-exposed controls. No major abnormalities were found. The exposed children had an increased risk for minor neurological dysfunction and for a low intelligence quotient (IQ below 80). The risk for a combination of two or more (minor) abnormalities was higher for the exposed children, RR = 7.6. We conclude that prenatal exposure to coumarins is associated with an increased risk for disturbances in development in school-age children. However, for the vast majority of children there is no clinical significant effect on growth and long-term development.

How normal is variable, or how variable is normal?

Variability is an important property of the central nervous system, and it shows characteristic changes during infancy and childhood. The large amount of variations in the performance of sensomotor functions in infancy is called indiscriminate or primary variability. During toddling age the child develops the capacity to select adaptive variations, and then automatize them: secondary or adaptive variability. The latter is required for the development of motor skills during later preschool age and school age. The question 'How normal is variable or how variable is normal is a wrong question, as any form of variability must be interpreted according to its extent, type and age adequacy.

Body measurements, neurological and behavioural development in six-year-old children born preterm and/or small-for-gestational-age.

In three groups of low birth weight (LBW) infants: full term, small-for-gestational-age (FT-SGA, N = 142); preterm, appropriate-for-gestational-age (PT-AGA, N = 47); preterm, small-for-gestational-age (PT-SGA, N = 20); and a reference group of FT-AGA infants (N = 185) the relationship between body weight, body length and head circumference and the presence of minor neurological dysfunction (MND) was studied. Non-caucasian and handicapped children were excluded from the analysis. Data were collected on behaviour and school achievement. The parameters of physical growth in the three LBW groups were reduced significantly compared to the FT-AGA group. In both preterms and full-terms body measurements were related to weight at term age; in the preterm groups no relation with gestational age at birth was found. MND was not related to body weight or length. In the group of FT severely growth retarded infants a relation was found between a skull circumference below the third centile and the presence of MND. Body measurements, behaviour at home and at school and school achievement were not related. The significance of severe intrauterine growth retardation for developmental disorders is emphasized. The data suggest a different aetiology and clinical significance of small head size for AGA and SGA born children.

Hypotonia at six years in prematurely-born or small-for-gestational-age children.

A neurological follow up study was done of 143 full-term infants who were small for gestational age based on intrauterine growth retardation and of 49 preterm appropriate-for-gestational-age (PTAGA) infants at the age of 6 years. Findings were compared with those of a reference group of 192 full-term appropriate-for-gestational-age (FTAGA) children. In 11% of the children of both study groups, hypotonia was found without any other neurological deviancy. This type of hypotonia was absent in the reference group, whereas minor neurological dysfunction consisting of hypotonia with other neurological signs was found in all the three groups of children. No relation was found with obstetrical or neonatal variables, including severity of growth retardation and gestational age, or with weight, body height or head circumference at 6 years. The possible interference of preterm birth or intrauterine growth retardation with, and the role of placental mechanisms in, fetal and early postnatal muscle development is discussed.

Is clonidine a behavioural teratogen in the human?

Twenty-two children prenatally exposed to clonidine and no other hypotensive drugs were compared at a mean age of 6.3 +/- 1.6 years to a non-exposed control group, matched for degree of maternal hypertension, sex, birthweight and gestational age. There were no differences in head circumference, neurological findings, school performance and a number of behavioural characteristics except for a marginal excess of hyperactivity and an excess of sleep disturbances in the study group. It is questionable whether the differences represent a direct effect of clonidine on prenatal development but the dose-effect relationship and the fact that the same effects have been found in rats suggest that this may be so.

Implications of a neural network model of early sensori-motor development for the field of developmental neurology.

This paper reports on a neural network model for early sensori-motor development and on the possible implications of this research for our understanding and, eventually, treatment of motor disorders like cerebral palsy. We recapitulate the results we published in detail in a series of papers [1-4]. The neural circuits in the model self-organize on the basis of rhythmic activity spontaneously generated in the model. This indicates the importance of endogenously generated activity in the developing brain. We also show that afferent feed-back from the mechanical part of the model is easily incorporated in the neural part of the model. In this way the model acquires reflex-related properties which have long been demonstrated in man. In the discussion we relate these experimental findings to the variability concept from developmental neurology and show how variable motor performance is important for motor learning. We also discuss possible implications of our modelling effort for movement disorders, specifically spastic cerebral palsy.

The relation between umbilical pH values and neonatal neurological morbidity in full term appropriate-for-dates infants.

The relationship of umbilical cord pH with the neonatal neurological condition was investigated in a group of 805 appropriate-for-dates (AFD) infants, delivered vaginally at term, and in a subgroup of 205 infants born after uncomplicated pregnancy and delivery ('low-risk' group). The results of the neonatal neurological examination were expressed in a neonatal neurological optimality score (NNOS) and in a neurological classification (normal, suspect and abnormal). In both study groups a significant relation between umbilical arterial pH (pHua) and the difference between maternal venous pH and pHua (delta pHm-ua) on the one hand and neurologically suspect infants and NNOS on the other hand, was found. The percentages of explained variance in NNOS, however, were very low (for delta pH, 1 and 4% in the total and low-risk group respectively). Neurological abnormality was not related to acidaemia at birth. Because of the specific relation between maternal and umbilical pH, delta pH is a less reliable indicator of fetal condition in cases of maternal alkalosis or acidosis. The use of a delta pH corrected with the help of a maternal-fetal pH nomogram, however, only slightly improved the relation with neurological morbidity. It is concluded, that in AFD term infants acidaemia at birth is only slightly related to neonatal neurological morbidity.

Minor neurological dysfunction and behavioural development. A report from the Groningen Perinatal Project.

In a follow-up study of 230 children a statistically significant relation was found between the neonatal neurological diagnosis and the presence of minor neurological dysfunctions at the age of 6 years: of 167 normal newborns, 7% turned out to have MND at follow-up versus 21% of 63 (mildly) abnormal neonates. Interval complications occurred especially in the latter group of MND children. Their presence may have hampered recovery. Both follow-up and neonatal neurological diagnoses were in a varying degree related to undesired behaviour as reported by parents and teachers, such as 'clumsy', 'difficult to handle', 'hyperactive', 'irritable' and 'temper tantrums'. However, only to a limited extent the variance of the behaviour was explained by the neurological findings. It was concluded that, although the neurological condition of a child may determine his vulnerability for environmental influence to a certain extent, the contribution of both sex and environment on behavioural development is preponderant.

Minor neurological dysfunction after the onset of puberty: association with perinatal events.

In order to study the hypotheses that puberty is related to a decrease of minor neurological dysfunction (MND) and that persisting MND is associated with perinatal factors, two groups (174 normal, 172 MND) of the Groningen Perinatal Project were followed from 12 to 14 years. At 14 years almost all the children had entered puberty (n = 329) defined as the presence of three or more puberty signs. In the MND group 55% of the children were normal at 14 years and in 45% MND signs were still present, though in a less extensive form. The latter phenomenon was most clear in children who had just begun puberty. The effect of puberty was similar in both sexes. MND which persisted into puberty was related to neonatal neurological deviancy, lower social class, lower obstetrical optimality score and male sex. After differentiation with specific MND clusters, it appeared that fine manipulative disability was associated with neonatal neurological deviancy, with minor physical anomalies and with lower social class; choreiform dyskinesia with asphyxia; hypotonia with constitutionally related factors; and coordination problems with pre-maturity (< 32 weeks).

The recovery rate of neurologically deviant newborns.

1507 newborns were examined neurologically at term; 80 of them were found to be abnormal. These were re-examined at 4 years of age, together with a control group of neonatally normal children. One child in the study group died, 8 were severely handicapped, 10 were mildly abnormal (MND = minor neurological dysfunction). In the control group 6 children turned out to have MND at 4 years. All but one of them had suffered interval complications, mainly before the age of 18 months. The relationships between the follow-up findings and the obstetrical, neonatal neurological and paediatric observations, family history and interval data are discussed. There appears to be a cumulative effect. The parents' reports on behaviour at age 4 suggest differences between the neonatally abnormal and normal groups, especially when MND is present at 4 years.

The effect of intra-uterine breech position on postnatal motor functions of the lower limbs.

The effect of intra-uterine movement restriction on the development of motor functions was studied longitudinally by comparing infants born after uncomplicated breech position (n = 13) with control infants (vertex position, n = 5-10). Before birth, fetal leg posture was studied at regular intervals by means of real time ultrasound observations, and classified as complete (n = 1), inconsistent (n = 6), or incomplete (n = 6) breech position. Limited extension of the hips, preference posture and joint position in percentage of time (each until 12 weeks), withdrawal reflex and magnet response (until 26 weeks) and posture while sitting, standing and walking without support (up to 12-18 months) were assessed longitudinally. The results showed statistically significant, positive relationships between intra-uterine breech position and neonatal limited extension of the hip-joint, between limited extension of the hip-joint and the percentage of time that the hips are in flexion during the first 12 weeks, between this flexion of the hips (in percentage of time) and an abnormally 'flexed' walking pattern at 12-18 months, and finally, between a positive magnet response at 6 months and an abnormal walking pattern at 12-18 months. These findings suggest that intra-uterine movement restriction of the legs can cause long term alterations in the development of motor functions (leg posture, reflexes and posture while walking), possibly mediated by alterations in proprioceptive feedback mechanisms.

Late neurological, cognitive and behavioural sequelae of prenatal exposure to coumarins: a pilot study.

Neurological, cognitive and behavioural development were assessed in a group of 21, 8- to 10-year old children whose mothers took coumarins during pregnancy. Findings were compared with those in a group of 17 control children. The study was performed to test whether it is feasible to carry out a reliable retrospective study of late effects of prenatal exposure to coumarins. This turned out to be the case. In this small pilot study, no statistical significant differences were found between the study and control group, nevertheless a few findings were remarkable. One child showed severe neurological abnormalities, which may be due to prenatal exposure to oral anticoagulants. The children with the lowest scores on the neurological assessment and the lowest IQ-scores, were found in the exposed group. Obviously, the number of children in this study is too small to conclude if there has been definite effects from coumarin, but these results indicate that a large follow-up study is required. In the present paper, we have shown that such a study is feasible.

Neurological outcome in school-age children after in utero exposure to coumarins.

The effect of prenatal exposure to coumarins (acenocoumarol, phenprocoumon) on neurological outcome was assessed in a cohort of 306 children aged 7-15 years. Findings were compared with those in a non-exposed cohort of 267 children, matched for sex, age, and demographic region. We used a neurological examination technique which pays special attention to minor neurological dysfunction (MND). None of the children was found to be neurologically abnormal. However, exposure to coumarins during gestation increases the risk for MND in children of school age, odds ratio (OR) 1.9 (CI(95) 1.1-3.4), predominantly after exposure in the second or third trimester, odds ratio 2.1 (CI(95) 1.2-3.8). We found a dose-response relationship with an odds ratio of 1.2 (CI(95) 1.0-1.5) per mg coumarin derivative prescribed per day. The results suggest that coumarins have an influence on the development of the brain which can lead to mild neurological dysfunctions in children of school age.

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.

Behavioural outcome of school-age children after prenatal exposure to coumarins.

In utero exposure to coumarin derivatives may affect the development of the central nervous system of the child, irrespective of the period of exposure in pregnancy. Little is known about effects on development in the long term. The aim of the present study was to determine whether prenatal exposure to coumarins affects behavioural outcome in children at school age. Behavioural outcome was assessed in a cohort of 305 exposed children, aged 7-15 years. Findings were compared with those in a cohort of 263 non-exposed controls, matched for sex, age, and demographic region. Behaviour was rated by parents and teachers using standardized questionnaires: the Groningen Behaviour Checklist Family situation (GBF) and the Groningen Behaviour Checklist School situation (GBS), respectively. The findings of the GBF were supported by the results of the GBS, filled in by teachers who were blind for the exposure status of the child. In comparison to the non-exposed children, the coumarin-exposed children scored lower on the cluster 'positive task orientation' (GBF P<0.05, GBS P<0.01), they scored higher on 'emotional instability' (GBF P<0.001, GBS P<0.05), and they had more problems on the social clusters (P<0.01). Based on the results of both questionnaires, we conclude that behavioural development may be negatively influenced in school-age children after in utero exposure to coumarins, leading to less favourable task-oriented and social-emotional behaviour. However, the frequency of clinically relevant 'problem behaviour' (GBF) was not increased in relation to coumarin exposure, the odds ratio was 1.2 (CI(95) 0.7-1.8).

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. Prechtl's 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.

Preterm birth, growth retardation and acidemia in relation to neurological abnormality of the newborn.

The Groningen Perinatal Project is a follow-up study relating pre- and perinatal conditions to early and late neurological sequelae. A description is given of the first cohort of 1507 children, examined neurologically during the neonatal period, and of their mothers and their pregnancies. In this preliminary analysis three 'final pathways' are considered, i.e. intrauterine growth retardation, preterm birth and acidemia (pH in umbilical vein below 7.20). Significant relationships were found between the 'final pathways' and the neurological findings. Since, however, these relationships account for only a small part of the variance of the latter, it is concluded that the (cumulative) effect of other antenatal variables must be taken into account as well. Results of analyses to this effect will be reported in forthcoming publications.

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.

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.

The neurological development of prehension: a developmental neurologist's view.

From the developmental neurological point of view prehension is an important function as it involves the total sensorimotor nervous system. In order to make efficient performance possible both postural activity and motility of arms and hands must be coordinated, implying an intricate interplay between tonic and phasic activities. The analysis of the development of the different contributors suggests that they are based on independently developing brain mechanisms. This independency guarantees the variability which is required for adequately adaptive and purposeful functioning. A lack of this ability to vary, i.e. monotonous and stereotyped function resulting from deficient or deficiently coupled brain mechanisms leads to maladaptive and impaired motor function. Identification of the dysfunctioning brain mechanisms may inform treatment strategies.