Statins and Congenital Malformations: Cohort Study
Statins and Congenital Malformations: Cohort Study
Objective. To examine the teratogenic potential of statins.
Design. Cohort study.
Setting. United States.
Participants. A cohort of 886,996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.
Methods. We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.
Results. 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.
Conclusions. Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.
Statins are the most commonly used class of drug to treat hyperlipidemia. Since they were first brought to market, statins have been considered contraindicated in pregnancy based on animal data showing teratogenic potential at high doses and concern that they might disrupt cholesterol biosynthesis in the developing fetus. Because of this, use during pregnancy is rare, and data about the effects of in utero exposure on fetal development are scarce in humans. Those data that do exist derive primarily from registries, small cohort studies, and case reports. These studies have been inconsistent in their findings on the teratogenic potential of statins. For example, a review of spontaneous reports of exposure to statins during the first trimester to the US Food and Drug Administration suggested that lipophillic statins may increase the risk of central nervous system and limb anomalies, whereas a case series analysis from the National Birth Defects Prevention Study failed to observe the same distribution of defects. A meta-analysis of the small number of controlled studies (n=6, including a total of 618 women who used statins) failed to find an increase in the risk of birth defects, although the confidence interval was wide (pooled estimate of relative risk 1.15, 95% confidence interval 0.75 to 1.76).
As the prevalence of risk factors for cardiovascular disease, including hypercholesterolemia, diabetes, hypertension, and obesity in women of reproductive age increases and as the indications for statin treatment expand, it is important to understand whether it is safe to use these drugs in patients who may inadvertently become pregnant; about half of all pregnancies in the United States are unintended. This need is also pressing since preclinical studies suggest a possible role for statins in the prevention of pre-eclampsia as a result of their pleiotropic effects on endothelial function and inflammation; human studies (using pravastatin) have begun examining this potential indication.
We undertook an epidemiologic study to assess the association between statin use in the first trimester and the risk of congenital malformations, using data derived from a large cohort of Medicaid beneficiaries.
Abstract and Introduction
Abstract
Objective. To examine the teratogenic potential of statins.
Design. Cohort study.
Setting. United States.
Participants. A cohort of 886,996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.
Methods. We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.
Results. 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.
Conclusions. Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.
Introduction
Statins are the most commonly used class of drug to treat hyperlipidemia. Since they were first brought to market, statins have been considered contraindicated in pregnancy based on animal data showing teratogenic potential at high doses and concern that they might disrupt cholesterol biosynthesis in the developing fetus. Because of this, use during pregnancy is rare, and data about the effects of in utero exposure on fetal development are scarce in humans. Those data that do exist derive primarily from registries, small cohort studies, and case reports. These studies have been inconsistent in their findings on the teratogenic potential of statins. For example, a review of spontaneous reports of exposure to statins during the first trimester to the US Food and Drug Administration suggested that lipophillic statins may increase the risk of central nervous system and limb anomalies, whereas a case series analysis from the National Birth Defects Prevention Study failed to observe the same distribution of defects. A meta-analysis of the small number of controlled studies (n=6, including a total of 618 women who used statins) failed to find an increase in the risk of birth defects, although the confidence interval was wide (pooled estimate of relative risk 1.15, 95% confidence interval 0.75 to 1.76).
As the prevalence of risk factors for cardiovascular disease, including hypercholesterolemia, diabetes, hypertension, and obesity in women of reproductive age increases and as the indications for statin treatment expand, it is important to understand whether it is safe to use these drugs in patients who may inadvertently become pregnant; about half of all pregnancies in the United States are unintended. This need is also pressing since preclinical studies suggest a possible role for statins in the prevention of pre-eclampsia as a result of their pleiotropic effects on endothelial function and inflammation; human studies (using pravastatin) have begun examining this potential indication.
We undertook an epidemiologic study to assess the association between statin use in the first trimester and the risk of congenital malformations, using data derived from a large cohort of Medicaid beneficiaries.
Source...