Clinical pharmacology consultation and outcomes associated with pregnancy exposure to pregnancy-contraindicated therapy

Abstract

Background: Although the FDA removed its pregnancy letter designations (A, B, C, D and X) for being overly simplistic and not effectively communicating the risk of drugs during pregnancy, they are still in use by most physicians. It is recognized that the FDA and similar drug classifications are insufficient to address the complexity of weighing the benefits of treatment against the possible risk of drug exposure to a category X medication (contraindicated in pregnancy due to known risks). We conducted a study to assess outcomes and maternal characteristics associated with pregnancy exposure to FDA X drugs or drugs classified as contraindicated in pregnancy, and the strength of association between both the clinical pharmacologists' risk assessment and the FDA risk categorization, and adverse pregnancy outcomes. Methods: We retrospectively reviewed records of 1773 patients consecutively referred to the clinical pharmacology outpatient clinic for pregnancy-related drug exposures (2000-2014). Out of 243 women taking an FDA- X categorized drug during the first or second trimester of pregnancy, documented outcomes were available for 134 women. Clinical pharmacologists' risk assessments were reviewed in relation to FDA drug categorization and available pregnancy outcomes. Results: In pregnancy with available outcomes, the most frequently FDA-X prescribed therapies were as follows: oral contraceptives (54%), paroxetin, medroxiprogesterone, retinoids, warfarin, methotrexate, statins, ribavirin, uliprostal-acetate and radioactive iodine. The exposure occured in most women during the first trimester of pregnancy (88%). Normal fetal outcomes were reported in 95/134(71%), spontaneous abortions in 9/134 (7%), artificial abortions in 21/134(16%), stillbirth in 1/134(1%), and malformations in 4/9 (4%) pregnancies. The drugs involved in reported congenital malformations were in all cases oral contraceptives and medroxyprogesterone. Clinical pharmacologists' risk estimation was in agreement with the FDA risk categorization in only 18% of consulted women with high risk drug exposure. Clinical pharmacologists' risk assessment confirming high risk drug exposure had a better positive predictive value for adverse pregnancy outcome than the FDA categorization. Conclusions: Additional evaluation beyond pregnancy risk classifications of drugs is important, and clinical pharmacologists are ideally placed to consult on risk estimation and how to proceed with a pregnancy following drug exposure to high risk drugs.