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.

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.

In utero exposure to coumarins and cognition at 8 to 14 years old.

OBJECTIVE: To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. BACKGROUND: Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. METHODS: The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. RESULTS: No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). CONCLUSION: Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy.

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).

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.

Effects of biological and social factors on the cognitive development of very low birth weight children.

OBJECTIVE: To investigate the effects of biological and social factors on the cognitive development of very low birth weight children, a longitudinal follow-up study was conducted from birth to 3.6 years of age. METHODOLOGY: The study group consisted of a cohort of 79 surviving high-risk, very low birth weight infants. Neonatal cerebral ultrasonographic findings and a neurological score were used as indicators of biological risk. A sociodemographic risk score and the Home Observation for Measurement of the Environment inventory were used as indicators of social risk. Cognitive development was assessed at ages 1 and 2 years by the Mental scale of the Bayley Scales of Infant Development and at age 3.6 years by the Kaufman Assessment Battery for Children. RESULTS: The mean mental index at 1 year of age was 96 (SD 19), at 2 years of age 86 (SD 26), and at 3.6 years of age for intelligence 87 (SD 13) and for achievement 86 (SD 14). In a stepwise multiple regression analysis of biological as well as social factors, the neurological score alone was the best predictor for cognitive development at 1 year of age, explaining 46% of the variance. From 2 years of age onward, the best predictors for cognitive development were the neurological score together with the home environment, explaining 46% of the variance for the Mental Developmental Index at age 2, 34% for intelligence, and 56% for achievement at age 3.6. CONCLUSIONS: Children at high biological risk were able to catch up on their cognitive delay in a highly stimulating home environment. Children at low as well as high biological risk in a less stimulating home environment showed a decline in cognitive development. For these children, early intervention programs might be important in the prevention of cognitive disabilities.

Visual functions in relation with neonatal cerebral ultrasound, neurology and cognitive development in very-low-birthweight children.

In order to determine the relationship between visual functions and neonatal cerebral ultrasound, neurological examinations and cognitive development, a prospective longitudinal study was conducted in 69 high-risk very-low-birthweight children. Visual development was studied at 1 and 2.6 years of corrected age by assessment of visual acuity, binocular visual fields, optokinetic nystagmus and strabismus. Visual impairments were found in 33% at age 1 and in 28% at age 2.6. Visual impairments were related to intraparenchymal damage, as detected by neonatal cerebral ultrasound, as well as to abnormal neurological examinations and lower mean developmental indices. A stepwise multiple regression analysis with neonatal cerebral ultrasound as the dependent variable and visual functions at ages 1 and 2.6 and neurological examinations at ages 1 and 2 as independent variables, however, demonstrated that standardized neurological examinations were better markers of neonatal cerebral damage than visual functions. In cognitive development at ages 1 and 2, the neurological examination at age 1 was the most important variable. In cognitive development at age 3.6, visual functions at age 2.6 were more important. Early visual impairments might thus influence later cognitive development. The effectiveness of appropriate early intervention strategies to stimulate visual and cognitive development in infants with less severe visual impairments should be subject to further study.

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.