Statins and Congenital Malformations

Scott Yee

Introduction

• Statins are the most commonly used class of drug used to treat hyperlipidemia

• Considered contraindicated in pregnancy based on animal studies.

• FDA data on effects in utero exposure on fetal development in humans are few.

• Important to understand statin’s effects in utero:• ½ of all pregnancies in US are unintended• Preclinical studies suggest statins can prevent Pre-

eclampsia.

Introduction

• Statins are HMG-CoA Reductase inhibitors • Inhibit conversion of

HMG-CoA to Mevalonate

• Lipophilic medication

• Category X drug due to animal studies

Cohort Inclusions

• Drawn from Medicaid Analytic eXtract

• Data 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

Cohort Exclusions

• Pregnancies the mother used known teratogenic drugs• Lithium, antineoplastic, retinoids, thalidomide

• Pregnancies in which the infant was diagnosed with chromosomal abnormalities.

Statins

• Claims based on one or more claims for a dispensed statin from LMP through 90 of pregnancy.

• Simavastatin, Lovastatin, Pravastatin, Fluvastatin, Atorvastin, Cerviastatin, Rosuvastatin

Measured Outcomes

• Presence of Congenital malformations• Diagnosis of one or more organ specific

malformations• CNS, 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.

Covariates

• Maternal Demographics• Age at delivery, race, geographic region, year of delivery

• Comorbid 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 drug

• Obstetric Characters • Multiparity and multiple gestations

• Drugs dispense to mother (other than statins)• 3 moths before LMP • Baseline period • Drug prescriptions and physician visits

Covariates

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't’t 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

Subgroup and Sensitivity analyses

• Two 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 trimester

• Two or more statin dispensing during the 1st trimester

Results

• Primary cohort 886,996 pregnancies

• 1152 women filled a prescription for statin drugs during the first trimester.

Risk and Relative Risk

Malformations

Sensitivity and Subgroups

Discussion

• Found no significant association between maternal Use of statins in the first trimester and risk for congenital malformations

• The importance of this finding is 2 fold:1. Increase amount of women in reproductive

age that need statins

2. Potential for statins to aid in the treatment of pre-eclampsia

Discussion

• Weakness• Assumption that a statin is dispensed it is

taken. However, this cannot be verified. • Cannot exclude the possibility that statins

have long term affects.

Question

• Which of the following is NOT a reason for Statin’s presumed association with fetal malformations?

A. The lipophilic nature of some statins

B. Animal Models showed tetratagenic effects

C. Data from the FDA shows tetragenic effects

D. Statins causes defects in astrocyte migration

Question

• Which of the following can be a benefit with statin use in a pregnant women?

A. Statins maybe beneficial for fetuses that have hyperlipidemia

B. Statins maybe beneficial for pregnant women that have pre-eclampsia

C. Statins have been shown to decrease miscarriage rates.

D. Statins have no benefits to the mother or child

Question

• Which of the following is NOT a known teratogenic drug during the first trimester?

A. Lithium

B. Retinoids

C. Insulin

D. Thalidomid

Bibliography

• 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.