J Wesseling

Growth until puberty after in utero exposure to coumarins

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the childs skeletal development.

Adherence to a guideline for coumarins in pregnancy

Objective: To asses the adherence in daily clinical practice to a guideline for anticoagulation during pregnancy.Methods: The Dutch anticoagulation clinics developed a pregnancy guideline for anticoagulant therapy in order to avoid foetal exposure to coumarins between the 6th and 9th week of gestation. Anticoagulation was studied in 282 prospectively-registered pregnant women, who were treated by 26 different anticoagulation clinics.Results: The guideline was adhered to in 93% of treated women. Conforming to the guideline, the majority of patients commenced anticoagulation with heparin in the first trimester (n = 81) or started treatment from the second trimester onwards (n = 168). At the time of conception, 31 anticoagulated women were on coumarin treatment. In 13 of these patients (42%), coumarins were withdrawn before the 6th gestational week. In two pregnant women coumarin therapy started unintentionally during the first trimester of gestation.Conclusion: The present study shows that the guideline under study is useful in daily clinical practice. A careful instruction of women of child-bearing age who need medication remains important.

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.