Multistate methodology improves risk assessment under time-varying drug intake-a new view on pregnancy outcomes following coumarin exposure.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Exposure to cox-2 inhibitors (coxibs) during the first trimester and pregnancy outcome: a prospective observational cohort study.

PURPOSE: Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further data on coxibs and their effects on embryogenesis are needed. METHODS: This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January 2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens. RESULTS: The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI 0.34-3.42; OR adjusted 0.96, 95% CI 0.28-3.26). The cumulative incidence of spontaneous abortions was nonsignificantly lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51-1.58; HR adjusted, 0.87; 95% CI, 0.49-1.56). Elective terminations of pregnancies (ETOP), mainly for 'social' reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR, 2.31; 95% CI, 1.26-4.24; HR adjusted 2.12, 95% CI 1.13-3.97). CONCLUSIONS: Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence basis on coxib exposure during pregnancy, well-established alternatives should be preferred.

Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature.

AIMS: Angiotensin-II receptor 1 antagonists (AT1-antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1-antagonist treatment during the second or third trimester of pregnancy. METHODS: Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1-antagonist fetopathy were: oligo-/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death. RESULTS: In 5/29 (17%) prospectively enrolled cases with AT1-antagonist exposure beyond the first trimester oligo-/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo-/anhydramnios was reversible after AT1-antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive. CONCLUSIONS: Our survey suggests that the risk increases with duration of AT1-antagonist treatment into late pregnancy and oligo-/anhydramnios may be reversible after AT1-antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1-antagonist fetopathy. AT1-antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1-antagonist exposure should be considered.