title: Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment.
abstract: The aim of this observational cohort study was to specify the risk of the vitamin K antagonist (VKA) phenprocoumon during first trimester of pregnancy, in particular to estimate the risk of birth defects and spontaneous fetal loss. Four hundred eight pregnancies with phenprocoumon exposure were compared to 1,642 pregnancies neither exposed to VKA nor to other major teratogens or fetotoxicants. There was no typical warfarin embryopathy in our exposed cohort. However, the overall rate of major birth defects was significantly increased (7.4 % vs 2.3 %; adjusted odds ratio [ORadj] 2.14; 95 % confidence interval [CI] 1.4-3.4). With early cessation until five completed gestational weeks the birth defect risk was similar to the comparison cohort (2.4 % vs 2.3 %; ORadj1.07; 95 % CI 0.2-3.6). With treatment duration exceeding seven gestational weeks the rate of major birth defects increased up to five-fold (10.8 % vs 2.3 %; ORadj5.18; 95 % CI 2.0-11.6). The overall risk of spontaneous abortion (SAB) was 38.0 % vs 17.5 % in the comparison cohort (adjusted hazard ratio [HRadj] 2.9; 95 % CI 2.2-3.9). The treatment duration had a significant effect on the hazard of SAB (HRadj1.12; 95 % CI 1.01-1.25 per each additional exposure week). Phenprocoumon and other VKA carry an embryotoxic risk. This risk seems to be time-dependent with a steep risk increase for birth defects and also for fetal loss after week 5. If maternal disease permits, VKA therapy should be switched to safer alternatives such as heparins immediately after early recognition of pregnancy.
authors.affiliation: Eleanor Hüttel, Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie, Charité - Universitätsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany, Tel.: +49 30 450 525 702, Fax: + 49 30 450 525 902, E-mail: eleanor.huettel@charite.de.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Hüttel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Padberg
authors.forename: Reinhard
authors.initials: R
authors.lastname: Meister
authors.forename: Evelin
authors.initials: E
authors.lastname: Beck
authors.forename: Christof
authors.initials: C
authors.lastname: Schaefer
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000175:diagnosis / Q000209:etiology*; D000022:Abortion, Spontaneous / Q000139:chemically induced* / Q000175:diagnosis; D000032:Abortion, Therapeutic; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001724:Birth Weight; D001777:Blood Coagulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D016015:Logistic Models; D016017:Odds Ratio; D010644:Phenprocoumon / Q000008:administration & dosage* / Q000009:adverse effects; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood; D047928:Premature Birth / Q000139:chemically induced; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D010644:Phenprocoumon
keywords: Time-dependence; congenital malformation; observational cohort study; spontaneous abortion; thrombosis prophylaxis