phenprocoumon and Abortion--Spontaneous

Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques.. We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion.. We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians.. An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.

Topics: Abortion, Spontaneous; Anticoagulants; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Logistic Models; Models, Statistical; Pharmacovigilance; Phenprocoumon; Pregnancy; Risk Assessment

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 [OR

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Abortion, Therapeutic; Adult; Anticoagulants; Birth Weight; Blood Coagulation; Drug Administration Schedule; Drug Substitution; Female; Humans; Infant, Newborn; Logistic Models; Odds Ratio; Phenprocoumon; Pregnancy; Pregnancy Trimester, First; Premature Birth; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vitamin K; Young Adult

A 23-year-old woman had received a mechanical bileaflet mitral valve prosthesis because of severe mitral valve insufficiency caused by an acute bacterial endocarditis with vegetations. One year after the operation the patient suffered on two miscarriages under oral anticoagulation by phenprocoumon. Present, she was referred to our center with the question of conversion to low molecular weight heparine because of continued yearning for a baby.. At admission the woman was in good general and nutritional condition. Echocardiography showed a regular prosthetic function. Blood analysis, electrolyte parameters and enzyme values were normal, further laboratory investigations revealed a factor-V-Leiden-mutation. A chromosomal analysis detected no aberrations.. The oral anticoagulation by phenprocoumon was switched to subcutaneous low molecular weight heparine in therapeutical dosage. Anti-factor-Xa-activity was controlled at regular intervals. Further pregnancy was uneventful for both, mother and child. A healthy infant was born by caesarean section at 40 (th) week of gestation.. Treatment with anticoagulation by phenprocoumon is indispensable for mechanical heart valve protheses. Conversion to low molecular weight heparine is possible in patients who insistent request to conceive. The anticoagulation by low molecular weight heparine avoids teratogenic effects during pregnancy because the placenta is impermeable to that heparin. Furthermore, prophylaxis of thromoses by low molecular weight heparine is probably in almost the same manner as by phenprocoumon.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Anticoagulants; Endocarditis, Bacterial; Factor V; Female; Heart Valve Prosthesis; Heparin, Low-Molecular-Weight; Heterozygote; Humans; Mitral Valve; Mitral Valve Insufficiency; Phenprocoumon; Pregnancy; Pregnancy Complications, Cardiovascular; Thrombosis; Young Adult

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Abortion, Spontaneous; Acenocoumarol; Adverse Drug Reaction Reporting Systems; Anticoagulants; Birth Weight; Female; Fetal Diseases; Gestational Age; Humans; Phenindione; Phenprocoumon; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Premature Birth; Prospective Studies; Vitamin K; Warfarin