Statins and Congenital Malformations: Cohort study
IntroductionStatins are the most commonly used class of drug used to treat hyperlipidemiaConsidered contraindicated in pregnancy based on animal studies. FDA data on effects in utero exposure on fetal development in humans are few.Important to understand statins effects in utero: of all pregnancies in US are unintendedPreclinical studies suggest statins can prevent Pre-eclampsia.
Introduction Statins are HMG-CoA Reductase inhibitors Inhibit conversion of HMG-CoA to MevalonateLipophilic medicationCategory X drug due to animal studies
Cohort InclusionsDrawn from Medicaid Analytic eXtractData from 46 States and District of Columbia from 2000-2007.Women ages 12-55 years old with completed pregnancies that were linked to live born infants. Woman that were continuously eligible for Medicaid from three months before the estimated last menstrual period month through one month post partum Medicaid Analytic eXtract is a healthcare database that records demographics and medicaid enrollment information on beneficiaries, claims, including all recorded DX and procedures associated with inpatient admins and outpatient visits, clamisn for all filled out patient drug prescriptions.
4Cohort Exclusions Pregnancies the mother used known teratogenic drugsLithium, antineoplastic, retinoids, thalidomide Pregnancies in which the infant was diagnosed with chromosomal abnormalities. StatinsClaims based on one or more claims for a dispensed statin from LMP through 90 of pregnancy. Simavastatin, Lovastatin, Pravastatin, Fluvastatin, Atorvastin, Cerviastatin, RosuvastatinMeasured OutcomesPresence of Congenital malformationsDiagnosis of one or more organ specific malformationsCNS, eye, ear, face, cardiac, respiratory, cleft palate or lip, GI, GU, musculoskeletal.Presence of international classification of diseases on two or more separate days in the infant inpatient or outpatient records during first three months of life. CovariatesMaternal DemographicsAge at delivery, race, geographic region, year of deliveryComorbid Medical Conditions Baseline period (Last menstrual period through the end of the 1st trimester)Pre-existing diabetes, dyslipidemia, pre-existing HTN, chronic renal disease, obesity and ETOH, tobacco, or illicit drugObstetric Characters Multiparity and multiple gestations Drugs dispense to mother (other than statins)3 moths before LMP Baseline period Drug prescriptions and physician visits
Drugs such as antihypertensives, insulin, oral antidiabetes, teratogenic drugs during the first trimester. 8Covariates
Statistical Analysis Estimated association between statin use and primary outcome stratified on pre-existing DM with Mantel Haenszel method.Propensity score used to measure differences in baseline characteristics of women who did and didn'tt not use statins Logistic regression model that estimated the probability of being dispensed a statin in the 1st trimester based on potential variables. Subgroup and Sensitivity analyses
To asses the robustness of primary findings. Again using stratification by propensity scoreBecause more lipophilic statins have been postulated to have greater teratogenic potential than hydrophilic statins. 11Subgroup and Sensitivity analysesTwo alternative definitions of first trimester statin use:Days supply of statin overlapping 1st trimester based on dispensing 90 days prior to the LMP through the end of the 1st trimesterTwo or more statin dispensing during the 1st trimester To estimate the potentia impact of exposure misclassification12Results Primary cohort 886,996 pregnancies1152 women filled a prescription for statin drugs during the first trimester.
Important baseline differences:Statin users tend to be olderMore often whiteMore prevelance of all of the comorbid conditions consideredPre-existing Diabetes was common in women who filled prescription for statins
96.3% of the exposed pregnancies were retained in the analysis and covariates were balanced. With a standard difference of less than .15 in the frequency of all covariates14
Risk and Relative RiskOver all congeintal malformations were present in 73 or the pregnancies in which statins were used and 31416 in which statins were not used
Typically used in cohort studies. Risk of developing disease in the exposed group divided by risk in the unexposed group (e.g., if 21% of smokers develop lung cancer vs. 1% of nonsmokers, RR = 21/1 = 21). If prevalence is low, RR OR.
But as you can see with the relative risk after stratifying for just diabetes it goes down, and then when you stratify for all the co-morbits it goes way down. Almost to 1. ( a 1 to 1 risk)
Malformations Typically used in cohort studies. Risk of developing disease in the exposed group divided by risk in the unexposed group (e.g., if 21% of smokers develop lung cancer vs. 1% of nonsmokers, RR = 21/1 = 21). If prevalence is low, RR OR.
If the 95% CI for odds ratio or relative risk includes 1, H0 is not rejected.
Sensitivity and SubgroupsExposure based on two dispensings However, after statification based on high demensional propensity scores, the relative risk dropped to 1.2 with CI .81-1.8. In supplemental data
Required full year of infant eligiblity: however after attenuation with stratification relative risk was 1.10 with CI .89-1.36
17DiscussionFound no significant association between maternal Use of statins in the first trimester and risk for congenital malformationsThe importance of this finding is 2 fold:Increase amount of women in reproductive age that need statinsPotential for statins to aid in the treatment of pre-eclampsia
DiscussionWeaknessAssumption that a statin is dispensed it is taken. However, this cannot be verified. Cannot exclude the possibility that statins have long term affects.QuestionWhich of the following is NOT a reason for Statins presumed association with fetal malformations?The lipophilic nature of some statins Animal Models showed tetratagenic effects Data from the FDA shows tetragenic effectsStatins causes defects in astrocyte migrationQuestionWhich of the following can be a benefit with statin use in a pregnant women?Statins maybe beneficial for fetuses that have hyperlipidemia Statins maybe beneficial for pregnant women that have pre-eclampsia Statins have been shown to decrease miscarriage rates. Statins have no benefits to the mother or child QuestionWhich of the following is NOT a known teratogenic drug during the first trimester?LithiumRetinoidsInsulin ThalidomidBibliography BMJ 2015;350:h1035 doi: 10.1136/bmj.h1035 Rosenson, RS. Statins: Actions, side effects, and administration. In: UpToDate, Post, TW (Ed), UpToDate,Waltham, MA, 2014.