Sonia Tabacova1, Ruth Little, Yi Tsong, Amarilys Vega, Carole A Kimmel. 1. National Center for Toxicological Research, US Food and Drug Administration, Center for Drug Evaluation and Research, DNDP, HFD-120, 5600 Fishers Lane, Rockville, MD 20857, USA. tabacovas@cder.fda.gov
Abstract
BACKGROUND: Adverse pregnancy outcomes following the use of angiotensin-converting enzyme (ACE) inhibitors, including enalapril, have been reported in descriptive studies. However, no analytical studies on the relationship between the adverse outcomes and enalapril gestational exposures are available. OBJECTIVES: To explore the association between enalapril exposure and adverse outcomes in pregnancy, taking into account other possible risk factors. METHODS: We analyzed a series of all usable cases reported to the FDA between 1986 and 2000 in which enalapril was a suspect drug for the observed adverse outcomes (N = 110). Parameters of exposure and reported outcomes as well as information on potentially confounding variables were systematically abstracted from this series by a single physician. Because exposure to ACE inhibitors after the first trimester of pregnancy had been associated with adverse outcomes in the existing literature, we divided the cases into those exposed in the first trimester only (considered as the baseline group) and cases exposed beyond or after this time. Frequency of reported adverse outcomes in the second group was compared with those in the baseline group; odds ratios were computed, taking account of potentially confounding variables by logistic regression where appropriate. RESULTS: Exposure to enalapril after the first trimester of pregnancy was strongly associated with oligohydramnios and specific adverse outcomes thought to be secondary to reduced amniotic fluid volume (limb deformities, cranial ossification deficits, lung hypoplasia), as well as with neonatal renal failure. The relationship did not change after taking numerous potential confounders into account, including duration of exposure, concomitant drug use, maternal age, concurrent disease, neonatal gender, and gestational age at birth. Such a pattern of abnormalities is considered to be a consequence of the effect of ACE inhibition on fetal renal function that develops after the first trimester. CONCLUSION: The specificity and temporality of the observed adverse manifestations suggest a causal relationship to enalapril exposure.
BACKGROUND: Adverse pregnancy outcomes following the use of angiotensin-converting enzyme (ACE) inhibitors, including enalapril, have been reported in descriptive studies. However, no analytical studies on the relationship between the adverse outcomes and enalapril gestational exposures are available. OBJECTIVES: To explore the association between enalapril exposure and adverse outcomes in pregnancy, taking into account other possible risk factors. METHODS: We analyzed a series of all usable cases reported to the FDA between 1986 and 2000 in which enalapril was a suspect drug for the observed adverse outcomes (N = 110). Parameters of exposure and reported outcomes as well as information on potentially confounding variables were systematically abstracted from this series by a single physician. Because exposure to ACE inhibitors after the first trimester of pregnancy had been associated with adverse outcomes in the existing literature, we divided the cases into those exposed in the first trimester only (considered as the baseline group) and cases exposed beyond or after this time. Frequency of reported adverse outcomes in the second group was compared with those in the baseline group; odds ratios were computed, taking account of potentially confounding variables by logistic regression where appropriate. RESULTS: Exposure to enalapril after the first trimester of pregnancy was strongly associated with oligohydramnios and specific adverse outcomes thought to be secondary to reduced amniotic fluid volume (limb deformities, cranial ossification deficits, lung hypoplasia), as well as with neonatal renal failure. The relationship did not change after taking numerous potential confounders into account, including duration of exposure, concomitant drug use, maternal age, concurrent disease, neonatal gender, and gestational age at birth. Such a pattern of abnormalities is considered to be a consequence of the effect of ACE inhibition on fetal renal function that develops after the first trimester. CONCLUSION: The specificity and temporality of the observed adverse manifestations suggest a causal relationship to enalapril exposure.