warfarin and Teratogenesis

Coagulability increases during pregnancy, and thromboembolism can easily occur. Venous thromboembolism is a cause of death in pregnant women, but arterial thrombosis such as ischemic stroke in pregnancy is also not uncommon. In pharmacotherapy for thromboembolism in pregnant women, fetal toxicity and teratogenicity must be carefully considered. As anticoagulants in pregnant women, unfractionated heparin and low-molecular-weight heparin are recommended, but warfarin is not recommended since it has a low molecular weight and crosses the placenta. Various types of new oral anticoagulant drugs have been available in Japan since 2011. However, the Japanese package inserts for these anticoagulants advise quite cautious administration in pregnant women. The guidelines on pregnant women include less information about antiplatelet drugs than anticoagulant drugs. Aspirin may cause teratogenicity and fetal toxicity, and perinatal mortality is increased. However, when low doses of aspirin are administered as antiplatelet therapy, the US Food and Drug Administration has assigned pregnancy category C, and treatment is relatively safe. Neurosurgeons and neurologists commonly encounter pregnant women with thromboembolism, such as ischemic stroke. Up-to-date information and correct selection of drugs are necessary in consultation with specialists in perinatal care.

Topics: Aspirin; Contraindications; Cooperative Behavior; Dose-Response Relationship, Drug; Drug Labeling; Female; Fibrinolytic Agents; Guideline Adherence; Heparin; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Interdisciplinary Communication; Japan; Pregnancy; Pregnancy Complications, Hematologic; Stroke; Teratogenesis; Thromboembolism; Warfarin

All vitamin K antagonist active substances used as rodenticides were reclassified in 2016 by the European authorities as active substances "toxic for reproduction", using a "read-across" alternative method based on warfarin, a human vitamin K antagonist drug. Recent study suggested that all vitamin K antagonist active substances are not all teratogenic. Using a neonatal exposure protocol, warfarin evokes skeletal deformities in rats, while bromadiolone, a widely used second-generation anticoagulant rodenticide, failed to cause such effects. Herein, using a rat model we investigated the mechanisms that may explain teratogenicity differences between warfarin and bromadiolone, despite their similar vitamin K antagonist mechanism of action. This study also included coumatetralyl, a first-generation active substance rodenticide. Pharmacokinetic studies were conducted in rats to evaluate a potential difference in the transfer of vitamin K antagonists from mother to fetus. The data clearly demonstrate that warfarin is highly transferred from the mother to the fetus during gestation or lactation. In contrast, bromadiolone transfer from dam to the fetus is modest (5% compared to warfarin). This difference appears to be associated to almost complete uptake of bromadiolone by mother's liver, resulting in very low exposure in plasma and eventually in other peripheric tissues. This study suggests that the pharmacokinetic properties of vitamin K antagonists are not identical and could challenge the classification of such active substances as "toxic for reproduction".

Topics: 4-Hydroxycoumarins; Administration, Oral; Animals; Animals, Newborn; Animals, Suckling; Female; Fetal Development; Liver; Male; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rodenticides; Teratogenesis; Teratogens; Vitamin K; Warfarin

Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans. Instead, significant information can be obtained by the identification and analysis of human genetic syndromes characterized by clinical features overlapping with those observed in drug-induced embryopathies. Until now, genetic phenocopies have been reported for the embryopathies/fetopathies associated with prenatal exposure to warfarin, leflunomide, mycophenolate mofetil, fluconazole, thalidomide and ACE inhibitors. In most cases, genetic phenocopies are caused by mutations in genes encoding for the main targets of teratogens or for proteins belonging to the same molecular pathways. The aim of this paper is to review the proposed teratogenic mechanisms of these drugs, by the analysis of human monogenic disorders and their molecular pathogenesis.

Topics: Abnormalities, Drug-Induced; Angiotensin-Converting Enzyme Inhibitors; Animals; Female; Fetal Diseases; Fetus; Fluconazole; Humans; Isoxazoles; Leflunomide; Mutation; Mycophenolic Acid; Phenotype; Pregnancy; Teratogenesis; Teratogens; Thalidomide; Warfarin