What is the teratogenic potential of Warfarin (Coumadin)?

From the Guidelines

Warfarin is highly teratogenic and should be avoided during pregnancy, especially during the first trimester, due to its dose-dependent teratogenic effects, with a risk of fetal loss or embryopathy exceeding 30% when taken in doses >5 mg/d. The teratogenic effects of warfarin are dose dependent, and the rate of warfarin embryopathy is reduced (<3%) but not eliminated if the daily dose of warfarin is ≤5 mg/d 1. Warfarin can cause warfarin embryopathy, characterized by nasal hypoplasia, stippled epiphyses, and limb abnormalities, as well as central nervous system defects including microcephaly and intellectual disability.

Key Considerations

• The critical period for these malformations is between weeks 6-12 of gestation.
• Pregnant women requiring anticoagulation should be switched to low molecular weight heparin (LMWH) such as enoxaparin, which does not cross the placenta and is considered safe during pregnancy 1.
• For women planning pregnancy who are on warfarin, preconception counseling is essential, and they should be transitioned to LMWH before conception or immediately upon pregnancy confirmation.
• The teratogenic effects of warfarin occur because it crosses the placenta and interferes with vitamin K-dependent carboxylation of proteins involved in bone and cartilage formation.
• Additionally, warfarin can cause fetal hemorrhage at any stage of pregnancy and is associated with an increased risk of spontaneous abortion, stillbirth, and preterm birth.

Management Strategies

• If warfarin is taken in doses >5 mg/d during the first trimester of pregnancy, replacing warfarin with dose-adjusted LMWH during the first trimester reduces fetal loss 1.
• After the first trimester, the fetal toxicity of warfarin is substantially lower, so switching back to warfarin for the second and third trimesters results in a reasonable balance between maternal safety and fetal safety 1.
• In regions where LMWH is unavailable or cost-prohibitive, or if anti-Xa levels cannot be monitored, continuous infusion of UFH can be used as an alternative to LMWH during the first trimester for women who require a warfarin dose of >5 mg/d 1.

From the FDA Drug Label

Warfarin sodium tablets are contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy. Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed Mental retardation, blindness, and other central nervous system abnormalities have been reported in association with second and third trimester exposure Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.

Warfarin is teratogenic and its use during pregnancy is associated with a high risk of birth malformations and fetal mortality. The potential risks to the fetus include:

• Embryopathy
• Central nervous system abnormalities
• Urinary tract anomalies
• Cardiac defects
• Congenital heart disease
• Spontaneous abortion
• Stillbirth
• Low birth weight
• Growth retardation 2

From the Research

Warfarin Teratogenicity

• Warfarin, a coumarin compound, crosses the placenta and has the potential to cause teratogenicity, particularly in the first trimester 3, 4.
• The use of warfarin during pregnancy is not recommended during the first trimester and during the perinatal period due to its potential to cause bleeding in the fetus and teratogenicity 3.
• Warfarin embryopathy, a well-defined condition, may occur if warfarin is administered between 6 and 12 weeks' gestation, resulting in impaired fetal synthesis of proteins crucial for bone and cartilage formation 5.
• The risks of warfarin use during pregnancy should be carefully explained to the patient to help avoid medicolegal problems 4.

Alternative Anticoagulants

• Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) do not cross the placenta and are safe for the fetus, making them alternative options for anticoagulation during pregnancy 3, 4, 6.
• LMWH is considered a safe alternative to UFH due to its logistic advantages and lower incidence of osteoporosis and heparin-induced thrombocytopenia 6.
• The use of LMWH during pregnancy has been associated with a low incidence of adverse fetal outcomes, comparable to that seen in the normal population 6.