Statins and Congenital Malformations: Cohort Study
Statins and Congenital Malformations: Cohort Study
In this cohort of 886,996 pregnancies among Medicaid beneficiaries, we found no significant association between maternal use of statins in the first trimester and risk for congenital malformations either overall or for any of the organ specific malformations examined after accounting for confounding variables. The upper bound of the confidence interval from our primary analysis implies our findings would be consistent with no more than a 37% increase in the overall risk of congenital malformations. Our findings therefore suggest that statins are not likely to be major teratogens.
These results have several important implications. Firstly, there are increasing numbers of women of reproductive age with potential indications for statins for the primary and secondary prevention of cardiovascular disease. Some have argued for avoiding these drugs in young women who are not using effective contraception, because of concerns about the possibility of inadvertent use during pregnancy. Our findings suggest such concerns may not be warranted. Secondly, based on the potential for statins to interfere with some of the pathologic mechanisms underlying pre-eclampsia, there is growing interest in their potential use in preventing this pregnancy complication. If effective for this indication, statins may become more frequently used in pregnancy, and our findings bolster confidence that these drugs can be used in this clinical context without undue concern about teratogenesis. Finally, our results, combined with the results of earlier observational studies, suggest the need for a critical reappraisal of the US Food and Drug Administration and other regulator's classification of these drugs as absolutely contraindicated in pregnancy.
Our study has several important strengths. Firstly, Medicaid Analytic eXtract is one of the largest and most comprehensive databases of its kind. With 886 996 completed pregnancies included in the study cohort and 1152 women using statins during the first trimester, our study allows for more precise estimates of the risk of malformations associated with statin use than previous studies examining this association. Furthermore, the database contains detailed information on patient characteristics, including maternal demographic characteristics, medical and obstetrical conditions, and healthcare utilization, as well as information on drug use, which can serve as a marker for the presence of comorbid conditions and their severity. The capture of these covariates allows detailed assessment and adjustment of conditions that might confound the association between statin users and non-users. Additionally, information on statin use in the database derives from claims collected in a prospective manner for filled prescriptions, so that our findings are not susceptible to recall bias, a problem that has afflicted studies of drug induced teratogenesis in the past.
Our study is also subject to certain limitations inherent in its design. Because Medicaid Analytic eXtract is based on healthcare utilization data, we relied on physician coding to define the presence of a malformation. However, our group has previously validated certain specific malformations in Medicaid Analytic eXtract by chart review and found that when two or more codes are recorded in the claims, the diagnosis has a high positive predictive value. Though requiring two diagnostic codes may result in high specificity for the outcome at the cost of some sensitivity, when an outcome is defined with high specificity and non-differential sensitivity, results from an observational study will yield unbiased estimates of relative risk. The validity of our outcome definition is given additional credence by our ability to reproduce the known associations between pre-existing diabetes and both overall malformations and certain organ specific malformations (see Supplementary Table S4 ). Also, when we performed a probabilistic assessment of outcome misclassification across a range of conservative estimates for sensitivity and specificity of the outcome, the risk estimate for statin use increased only slightly, suggesting our null findings are robust to any realistic degree of outcome misclassification. Our database lacks robust capture of certain potential confounders, such as body mass index. However, given the direction of the associations, additional adjustment for body mass index or other similar risk factors would, if anything, tend to attenuate the relative risk further. In addition, based on the requirements of the data use agreement intended to protect patient privacy, we cannot disclose counts on fewer than 11 malformations. Finally, our definition of statin use is based on a dispensed statin during the first trimester. While it is likely a reasonable assumption that if a statin is dispensed, it is taken, this cannot be empirically verified. In an effort to further increase the specificity of our exposure definition, we performed a sensitivity analysis in which we defined statin use on the basis of two dispensings during the first trimester; after stratification based on the high dimensional propensity scores, the risk estimate from this analysis was also close to the null (relative risk 1.20).
An additional limitation is that the database only includes information on live births. However, a sensitivity analysis suggests that termination rates for the indication of fetal malformation would need to be unrealistically different between women who did or did not use statins to substantially shift the risk estimate (see Supplementary Appendix 1). Yet, while we can conclude that statins do not significantly increase the overall risk of malformations, we cannot exclude the possibility that they confer risk of rare, specific malformations that could not be identified in this analysis, or that individual statins are associated with specific risks. Nor can we comment on any long term effects on the fetus of in utero exposure to statins. In our sensitivity analysis in which we required a full year of eligibility and follow-up of the infants, the risk estimate for the association between statin use and congenital malformations was statistically significant. Whether this is a chance finding in the setting of multiple sensitivity analyses or a real association cannot be determined. Notably, the effect estimate attenuates and the statistically significant increase is no longer present when we stratify on the high dimensional propensity scores (see Supplementary Table S2 ). Finally, our cohort was drawn from Medicaid beneficiaries. Though the results should be generalizable to other populations, even if they are not this group is of intrinsic interest as Medicaid provides coverage for nearly half of all deliveries in the United States.
Our analysis did not find a significant teratogenic effect from use of statins in the first trimester. Our findings suggest that inadvertent use during the first trimester may not be as worrisome as the FDA's class X (contraindicated for use in pregnancy) designation suggests. However, more information about the long term effects of in utero exposure to statins and about the effect on other neonatal outcomes, as well as replication of our findings in other large datasets with well measured information on statin use, confounders, and outcomes, are needed before statin use during pregnancy can be considered safe.
Discussion
In this cohort of 886,996 pregnancies among Medicaid beneficiaries, we found no significant association between maternal use of statins in the first trimester and risk for congenital malformations either overall or for any of the organ specific malformations examined after accounting for confounding variables. The upper bound of the confidence interval from our primary analysis implies our findings would be consistent with no more than a 37% increase in the overall risk of congenital malformations. Our findings therefore suggest that statins are not likely to be major teratogens.
These results have several important implications. Firstly, there are increasing numbers of women of reproductive age with potential indications for statins for the primary and secondary prevention of cardiovascular disease. Some have argued for avoiding these drugs in young women who are not using effective contraception, because of concerns about the possibility of inadvertent use during pregnancy. Our findings suggest such concerns may not be warranted. Secondly, based on the potential for statins to interfere with some of the pathologic mechanisms underlying pre-eclampsia, there is growing interest in their potential use in preventing this pregnancy complication. If effective for this indication, statins may become more frequently used in pregnancy, and our findings bolster confidence that these drugs can be used in this clinical context without undue concern about teratogenesis. Finally, our results, combined with the results of earlier observational studies, suggest the need for a critical reappraisal of the US Food and Drug Administration and other regulator's classification of these drugs as absolutely contraindicated in pregnancy.
Strengths and Limitations of This Study
Our study has several important strengths. Firstly, Medicaid Analytic eXtract is one of the largest and most comprehensive databases of its kind. With 886 996 completed pregnancies included in the study cohort and 1152 women using statins during the first trimester, our study allows for more precise estimates of the risk of malformations associated with statin use than previous studies examining this association. Furthermore, the database contains detailed information on patient characteristics, including maternal demographic characteristics, medical and obstetrical conditions, and healthcare utilization, as well as information on drug use, which can serve as a marker for the presence of comorbid conditions and their severity. The capture of these covariates allows detailed assessment and adjustment of conditions that might confound the association between statin users and non-users. Additionally, information on statin use in the database derives from claims collected in a prospective manner for filled prescriptions, so that our findings are not susceptible to recall bias, a problem that has afflicted studies of drug induced teratogenesis in the past.
Our study is also subject to certain limitations inherent in its design. Because Medicaid Analytic eXtract is based on healthcare utilization data, we relied on physician coding to define the presence of a malformation. However, our group has previously validated certain specific malformations in Medicaid Analytic eXtract by chart review and found that when two or more codes are recorded in the claims, the diagnosis has a high positive predictive value. Though requiring two diagnostic codes may result in high specificity for the outcome at the cost of some sensitivity, when an outcome is defined with high specificity and non-differential sensitivity, results from an observational study will yield unbiased estimates of relative risk. The validity of our outcome definition is given additional credence by our ability to reproduce the known associations between pre-existing diabetes and both overall malformations and certain organ specific malformations (see Supplementary Table S4 ). Also, when we performed a probabilistic assessment of outcome misclassification across a range of conservative estimates for sensitivity and specificity of the outcome, the risk estimate for statin use increased only slightly, suggesting our null findings are robust to any realistic degree of outcome misclassification. Our database lacks robust capture of certain potential confounders, such as body mass index. However, given the direction of the associations, additional adjustment for body mass index or other similar risk factors would, if anything, tend to attenuate the relative risk further. In addition, based on the requirements of the data use agreement intended to protect patient privacy, we cannot disclose counts on fewer than 11 malformations. Finally, our definition of statin use is based on a dispensed statin during the first trimester. While it is likely a reasonable assumption that if a statin is dispensed, it is taken, this cannot be empirically verified. In an effort to further increase the specificity of our exposure definition, we performed a sensitivity analysis in which we defined statin use on the basis of two dispensings during the first trimester; after stratification based on the high dimensional propensity scores, the risk estimate from this analysis was also close to the null (relative risk 1.20).
An additional limitation is that the database only includes information on live births. However, a sensitivity analysis suggests that termination rates for the indication of fetal malformation would need to be unrealistically different between women who did or did not use statins to substantially shift the risk estimate (see Supplementary Appendix 1). Yet, while we can conclude that statins do not significantly increase the overall risk of malformations, we cannot exclude the possibility that they confer risk of rare, specific malformations that could not be identified in this analysis, or that individual statins are associated with specific risks. Nor can we comment on any long term effects on the fetus of in utero exposure to statins. In our sensitivity analysis in which we required a full year of eligibility and follow-up of the infants, the risk estimate for the association between statin use and congenital malformations was statistically significant. Whether this is a chance finding in the setting of multiple sensitivity analyses or a real association cannot be determined. Notably, the effect estimate attenuates and the statistically significant increase is no longer present when we stratify on the high dimensional propensity scores (see Supplementary Table S2 ). Finally, our cohort was drawn from Medicaid beneficiaries. Though the results should be generalizable to other populations, even if they are not this group is of intrinsic interest as Medicaid provides coverage for nearly half of all deliveries in the United States.
Conclusion
Our analysis did not find a significant teratogenic effect from use of statins in the first trimester. Our findings suggest that inadvertent use during the first trimester may not be as worrisome as the FDA's class X (contraindicated for use in pregnancy) designation suggests. However, more information about the long term effects of in utero exposure to statins and about the effect on other neonatal outcomes, as well as replication of our findings in other large datasets with well measured information on statin use, confounders, and outcomes, are needed before statin use during pregnancy can be considered safe.