What data supported the removal of the pregnancy contraindication from statin labeling?
Cardiovascular disease is a common cause of maternal mortality during pregnancy.1 It affects approximately 1 to 2% of all pregnancies in the United States, and accounts for an estimated 15.5% of maternal deaths. Dyslipidemia is a major risk factor for cardiovascular disease.2 Normal physiologic changes during pregnancy often lead to increases in low-density lipoprotein (LDL) and triglyceride levels; these changes serve to support nervous system development in the fetus and produce extra energy stores.3 However, LDL and triglyceride levels typically do not exceed 250 mg/dL in a healthy pregnancy. Patients with pre-existing lipid disorders may demonstrate pathological exaggerations in these physiologic changes, leading to exacerbations of lipid disorders and potential pregnancy complications. Even in the absence of preexisting atherosclerotic cardiovascular disease (ASCVD), dyslipidemia during pregnancy (particularly hypertriglyceridemia) has been associated with adverse maternal and fetal outcomes, including preterm birth, gestational diabetes, and hypertensive disorders of pregnancy. Dyslipidemia has also been identified as an independent risk factor for myocardial infarction during pregnancy.
In order to mitigate the risk of maternal and fetal complications, managing dyslipidemia during pregnancy is important, particularly for patients with preexisting ASCVD, severe hypertriglyceridemia, and/or familial hypercholesterolemia.3,4 Diet and lifestyle interventions are a mainstay of lipid management in pregnancy.2,3 Unfortunately, the pharmacologic options for dyslipidemia management in pregnancy are limited. Bile acid sequestrants are generally considered safe for use in pregnancy, as they are not systemically absorbed.1,3-5 However, these agents can increase triglyceride levels, and their LDL-lowering effects tend to be modest, particularly in patients with very high LDL levels or familial hypercholesterolemia.3 Omega-3 fatty acids with or without fibrates may be used during the second trimester to control triglyceride levels in patients at risk for pancreatitis (eg, triglycerides >500 mg/dL).3,4,6 Data are lacking to support the safety of many other lipid-lowering agents in pregnancy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, icosapent ethyl, and bempedoic acid.3
Statins, the mainstay of pharmacologic therapy for hyperlipidemia, have historically been contraindicated for use in pregnancy.3,7 The original developmental toxicity studies for the first statin drug, lovastatin, indicated that lovastatin was associated with an increased risk of fetal abnormalities (primarily skeletal defects) in rats when given at supratherapeutic doses.8 Additionally, there was concern that lowering cholesterol during pregnancy could be detrimental to the developing fetus, as cholesterol is required for cell membrane development and steroidogenesis. Based on these concerns, lovastatin was approved with a contraindication for use in pregnancy. Although developmental toxicity studies for subsequent statin drugs did not demonstrate an increased risk of fetal abnormality, all drugs in the statin class received the same pregnancy contraindication. Current guidelines for cholesterol management recommend that women who plan to become pregnant discontinue statin use 1 to 2 months prior to attempting pregnancy; if a woman becomes pregnant while on a statin, the statin should be discontinued as soon as the pregnancy is discovered.7
On July 20, 2021, the U.S. Food and Drug Administration (FDA) requested that the contraindication against use in pregnancy be removed from the labeling for all statin drugs.9 In the announcement, the FDA stated that a contraindication in all pregnant women is not appropriate, because the benefits of statin use may outweigh the risks for a small group of pregnant patients who are at very high risk for serious or potentially fatal cardiovascular events (eg, patients with homozygous familial hypercholesterolemia, patients with previous heart attack or stroke). The FDA states that most patients should still discontinue statin therapy during pregnancy; however, the labeling revision is intended to give healthcare providers more freedom to consider the therapeutic needs of the individual patient when prescribing lipid-lowering therapy. The revision is also intended to reassure healthcare providers and patients that unintentional statin exposure during pregnancy is unlikely to result in harm to the fetus.
Evidence for the safety of statins in pregnancy
The FDA based this labeling change on data from multiple prospective and retrospective observational cohort studies, as well as data from case series.9 The largest studies examining statin use in pregnancy are summarized in the Table below.10-16 In most studies, the rate of congenital malformation was not significantly increased with maternal exposure to statins during the first trimester of pregnancy.12-16 One large study by Lee et al identified a higher risk of congenital cardiac abnormalities (specifically ventricular septal defects) in pregnancies with first trimester statin exposure; this risk remained significant even after adjustment for confounders and propensity score matching.10 However, the factors used for propensity score matching were not clearly described in this study, and it is possible that residual confounders may have contributed to this result. A larger study by Bateman et al did not identify an increased rate of any congenital abnormalities, including cardiac abnormalities.12 In this study, numerous important confounders were accounted for with propensity score matching, including maternal age, comorbid conditions, alcohol/tobacco use, and concomitant drug use.
Some studies also examined the risk of miscarriage or spontaneous abortion.11,13,14,16 A study by McGrogan et al found that statin exposure during the first trimester was associated with an increased risk of spontaneous abortion, even after adjusting for confounders.11 However, the authors of the study note that residual confounding may remain, since the type and severity of diabetes was not accounted for in the analysis and diabetes is known to influence the rate of miscarriage. Other studies did not find an increased rate of spontaneous abortion among statin-exposed patients.13,14,16
Two recent meta-analyses have summarized the effects of statin use on fetal development and pregnancy outcomes.17,18 One meta-analysis of 9 studies found no significant association between statin therapy and stillbirth (odds ratio [OR], 1.30; 95% confidence interval [CI], 0.56 to 3.20; p=0.54).17 However, statin therapy was significantly associated with an increased risk of spontaneous abortion in this analysis (OR, 1.36; 95% CI, 1.10 to 1.68; p=0.004). Another meta-analysis of 6 studies did not find a significant association between statin exposure and birth defects (OR, 1.48; 95% CI, 0.90 to 2.42; p=0.509).18 In subgroup analyses, statin exposure was not associated with significantly increased risks of cardiac abnormalities (OR, 2.53; 95% CI, 0.81 to 7.93; p=0.112) or other congenital abnormalities (OR, 1.19; 95% CI, 0.70 to 2.03; p=0.509).
|Table. Overview of observational studies examining the safety of statin use in pregnancy. 10-16|
|Study design and duration||Subjects||Comparison Groups||Results||Conclusions and Limitations
Retrospective cohort study using data from the Kaiser Permanente Southern California Region
January 1, 2003 to December 31, 2014
|N=379,238 pregnancies in patients enrolled in the Kaiser Permanente Health Plan for 1 year prior to delivery||Statin exposure during the first trimester, defined by a statin prescription that was filled between the patient’s estimated conception date and day 84 of pregnancy (n=280 overall; n=279 in the matched cohort)|
Matched control pregnancies without statin exposure (n=378,958 overall; n=1,160 in the matched cohort)
Factors used in propensity score matching not described
Characteristics used for adjusted OR calculation were maternal age, race, and maternal medical history (hypertension, hyperlipidemia, coronary artery disease, heart failure, stroke, diabetes, congenital heart disease, arrhythmia, and chronic renal insufficiency)
|Congenital cardiac abnormalities were present in 5% of all statin-exposed pregnancies and 1.4% of all non-exposed pregnancies|
In the full study cohort, the adjusted OR for congenital cardiac abnormalities with statin exposure vs. no exposure was 2.1 (95% CI, 1.2 to 3.6; p=0.009); after propensity score matching, the OR for congenital cardiac abnormalities with statin exposure was 2.5 (95% CI, 1.3 to 4.9; p=0.008)
Risk of ventricular septal defect was significantly higher in statin-exposed pregnancies: adjusted OR in the full cohort, 3.3 (95% CI, 1.8 to 6; p<0.001); OR after propensity score matching, 4.7 (95% CI, 2 to 10.8; p<0.001)
No significant association was observed between statin exposure and atrial septal defect, conotruncal defect, single ventricle physiology, or patent ductus arteriosus after adjustment for maternal characteristics
|Statin exposure during the first trimester was associated with ventricular septal defect.
Limitations include the unclear methods used to perform propensity score matching and the use of prescription dispensing as verification of statin medication use.
Retrospective cohort study using data from the General Practice Research Database (UK)
January 1, 1992 to March 31, 2009
|N=2,924 pregnancies in women aged 10 to 49 years||Pregnancies where a statin prescription had been issued within 3 months before pregnancy start date and/or during the first trimester of pregnancy (n=281)|
Matched control pregnancies with no statin prescriptions issued (n=2,643)
Matching based on maternal age, presence of diabetes mellitus, and presence of hypertension
|The proportion of pregnancies ending in delivery was 54.45% in the statin-exposed cohort and 62.81% in the cohort that was not exposed|
Spontaneous abortion rates were 25.27% in the statin-exposed cohort and 20.81% in the unexposed cohort
Adjusted HR for spontaneous pregnancy loss with statin exposure was 1.64 (95% CI, 1.1 to 2.46)
|Statin exposure was associated with an increased risk of spontaneous pregnancy loss.
Residual confounding may have influenced results; type and severity of diabetes were not accounted for in the analysis.
Misclassification is possible, as prescriptions issued by practitioners may not have been dispensed or taken by patients.
Cohort study using data from the Medicaid Analytic eXtract database
2000 to 2007
|N=886,996 completed pregnancies linked to liveborn infants of women aged 12 to 55 years enrolled in Medicaid||Statin use during the first trimester, defined as 1 or more claims for a dispensed statin from the last menstrual period through day 90 of pregnancy (n=1,152 in full cohort; n=1,109 in the propensity-matched cohort)|
No statin use during the first trimester (n=885,844 in full cohort; n=3,327 in the propensity-matched cohort)
Patients were matched based on a number of confounding factors, including maternal demographics (age at delivery, race, geographic region, year of delivery), comorbid conditions (including diabetes, dyslipidemia, hypertension, chronic renal disease, obesity), alcohol/tobacco use, obstetric characteristics/conditions (multiparity, multiple gestations), and drugs dispensed to the mother
|Congenital malformations occurred in 6.34% of statin-exposed pregnancies and 3.55% of unexposed pregnancies|
In the propensity score stratified analysis, the RR for congenital malformations with statin exposure was 1.07 (95% CI, 0.85 to 1.37)
Statin exposure was not associated with an increased risk of any organ-specific malformation (CNS malformation, cardiac malformation, respiratory malformation, GI malformation, GU malformation, musculoskeletal malformation, or cleft lip/palate) after adjustment for confounding through propensity score stratification
|After propensity score matching and adjustment for confounders, statin exposure was not associated with an increased risk of congenital malformations.
Limitations include a reliance on physician coding to define the presence of a malformation, inclusion of live births only, inability to control for certain confounders (eg, BMI), and use of prescription dispensing as verification of statin medication use.
Multicenter prospective observational study
1990 to 2009
|N=498 patients seeking advice about medication exposure during the first trimester of pregnancy from a European Network of Teratology Information Services center||Statin exposure (n=249)|
Exposure to a non-statin drug known to be nonteratogenic (n=249)
Patients were matched based on a propensity score incorporating center, maternal age, alcohol and smoking habits, number of previous elective pregnancy terminations and miscarriages, and gestational age at time of entry
|Rate of major birth defects was not different between statin-exposed patients (4.1%) and control patients (2.7%; OR, 1.5; 95% CI, 0.5 to 4.5; p=0.43)|
Miscarriage rates were 14.5% among statin-exposed patients and 7.6% among controls; however, after adjustment for confounding, risk of miscarriage was not increased among statin-exposed patients (HR, 1.36; 95% CI, 0.63 to 2.93; p=0.432)
Median gestational age at birth and birthweight did not differ significantly between exposed and unexposed patients
|The risk of major birth defects was not increased among patients who were exposed to statins during the first trimester of pregnancy.
Limitations include the relatively small sample size, reliance on self-reporting to determine drug exposure, and the potential for residual confounding due to incomplete documentation of factors such as maternal disease or treatment indication.
Prospective cohort study
1998 to 2005
|N=128 women who were pregnant or planning a pregnancy who contacted the teratogen information service at a single hospital for safety concerns||Statin exposure in the first trimester (n=64)|
Exposure to a non-statin drug known to be nonteratogenic (n=64)
Patients were matched based on maternal age, gravidity, parity, previous spontaneous abortions, smoking/alcohol use, and gestational age at time of contact
|Major birth defects occurred in 2.2% of patients in the statin group and 1.9% of patients in the control group (p=0.93)|
Spontaneous abortions occurred in 21.9% of patients in the statin cohort and 17.2% of patients in the control cohort (p=0.50)
Gestational age at birth and birthweight were lower in the statin cohort (38.4 weeks vs. 39.3 weeks; p=0.04 and 3.14 kg vs. 3.45 kg; p=0.01, respectively)
|Statin exposure during the first trimester was not associated with an increased risk of major birth defects or spontaneous abortion.
Limitations include the relatively small sample size and the higher number of women with diabetes enrolled in the statin cohort.
Registry study using data from 3 databases in Quebec
January 1, 1997 to June 30, 2003
|N=288 women aged 15 to 45 years who had filled a prescription for a statin, fibrate, or nicotinic acid in the year before or during pregnancy||Group A: patients who filled prescriptions for statins only, before and during the first trimester of pregnancy (n=153)|
Group B: patients who filled prescriptions for fibrates or nicotinic acid only, before and during the first trimester of pregnancy (n=29)
Group C: patients who had filled prescriptions for statins only in the period between 1 year before conception and 1 month before conception, and who did not have any filled prescriptions for any lipid-lowering medication in the period between 1 month before conception and the end of pregnancy (n=106)
|Congenital anomalies were observed in 4.69% of births in Group A, 21.43% of births in Group B, and 10.45% of births in Group C|
Adjusted OR for risk of congenital anomalies in Group A vs. Group C was 0.36 (95% CI, 0.06 to 2.18)
Adjusted OR for risk of congenital anomalies in Group A vs. Group B was 0.79 (95% CI, 0.10 to 6.02)
|The risk of congenital anomaly was not significantly greater among patients exposed to statins in the first trimester of pregnancy.
Limitations include the relatively small sample size, the lack of information available on certain confounding variables (eg, smoking), and use of prescription dispensing as verification of statin medication use.
Study of data reported to the Merck pharmacovigilance database
Through December 31, 2002
|N=477 patients exposed to lovastatin or simvastatin during pregnancy||Exposure to simvastatin or lovastatin reported prospectively (before pregnancy outcome was known; n=386) or retrospectively (after pregnancy outcome was known; n=91)||Among the 225 prospectively-reported exposures with pregnancy outcome data, spontaneous abortions occurred in 18 patients, fetal death occurred in 4 cases, and congenital anomalies occurred in 6 cases|
Rates of these outcomes were similar to background rates reported in the literature
Retrospective reports included 13 reports of congenital anomalies; no specific pattern of anomalies was identified in either the prospective or retrospective reports
|Exposure to simvastatin or lovastatin during pregnancy was not associated with a higher rate of congenital abnormalities vs. the general population.
Limitations include the lack of a contemporaneous control group, lack of outcome availability for over 40% of the prospectively-reported cases, and potential for incomplete data due to reliance on spontaneous reports from physicians.
|Abbreviations: BMI=body mass index; CI=confidence interval; CNS=central nervous system; GI=gastrointestinal; GU=genitourinary; HR=hazard ratio; OR=odds ratio; RR=relative risk; UK=United Kingdom.|
After reviewing data from observational studies and case series, the FDA concluded that statins have limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during human embryofetal development.9 As a result, the FDA requested the removal of the pregnancy contraindication from statin labeling. However, while most studies showed no increased risk of birth defects with statin exposure in the first trimester, data regarding the risk of spontaneous abortion with statin exposure in the first trimester are less clear. Further studies are necessary to determine whether statins are associated with an increased risk of spontaneous abortion when administered during the first trimester of pregnancy. Available studies focused on the risks associated with statin exposure during the first trimester of pregnancy (eg, accidental exposure before pregnancy was recognized). Therefore, the effects of statins given during the second or third trimester remain unknown. For most patients, stopping statin therapy during pregnancy is still appropriate; treatment of hyperlipidemia during pregnancy is generally not necessary, given the chronic nature of cardiovascular disease. However, for some patients (eg, those at very high risk for cardiovascular events and/or those with familial hypercholesterolemia), the benefits of continuing statin therapy during pregnancy may outweigh the risks.
- Halpern DG, Weinberg CR, Pinnelas R, Mehta-Lee S, Economy KE, Valente AM. Use of medication for cardiovascular disease during pregnancy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(4):457-476. doi:10.1016/j.jacc.2018.10.075
- Liberis A, Petousis S, Tsikouras P. Lipid disorders in pregnancy. Curr Pharm Des. 2021;27(36):3804-3807. doi:10.2174/1381612827666210421103245
- Thobani A, Hassen L, Mehta LS, Agarwala A. Management of hypercholesterolemia in pregnant women with atherosclerotic cardiovascular disease. Curr Atheroscler Rep. 2021;23(10):58. doi:10.1007/s11883-021-00957-w
- Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: a scientific statement from the American Heart Association. Circulation. 2020;141(23):e884-e903. doi:10.1161/cir.0000000000000772
- Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(14):1785-1822. doi:10.1016/j.jacc.2017.07.745
- Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-122.e121. doi:10.1016/j.jacl.2015.09.002
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003
- Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81. doi:10.1161/atv.0000000000000073
- FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins. U.S. Food and Drug Administration. Published July 20, 2021. Updated August 30, 2021. Accessed November 23, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy
- Lee MS, Hekimian A, Doctorian T, Duan L. Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect. Int J Cardiol. 2018;269:111-113. doi:10.1016/j.ijcard.2018.07.002
- McGrogan A, Snowball J, Charlton RA. Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss. Pharmacoepidemiol Drug Saf. 2017;26(7):843-852. doi:10.1002/pds.4176
- Bateman BT, Hernandez-Diaz S, Fischer MA, et al. Statins and congenital malformations: cohort study. BMJ. 2015;350:h1035. doi:10.1136/bmj.h1035
- Winterfeld U, Allignol A, Panchaud A, et al. Pregnancy outcome following maternal exposure to statins: a multicentre prospective study. BJOG. 2013;120(4):463-471. doi:10.1111/1471-0528.12066
- Taguchi N, Rubin ET, Hosokawa A, et al. Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol. 2008;26(2):175-177. doi:10.1016/j.reprotox.2008.06.009
- Ofori B, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol. 2007;64(4):496-509. doi:10.1111/j.1365-2125.2007.02905.x
- Pollack PS, Shields KE, Burnett DM, Osborne MJ, Cunningham ML, Stepanavage ME. Pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res A Clin Mol Teratol. 2005;73(11):888-896. doi:10.1002/bdra.20181
- Vahedian-Azimi A, Bianconi V, Makvandi S, et al. A systematic review and meta-analysis on the effects of statins on pregnancy outcomes. Atherosclerosis. 2021;336:1-11. doi:10.1016/j.atherosclerosis.2021.09.010
- Vahedian-Azimi A, Makvandi S, Banach M, Reiner Ž, Sahebkar A. Fetal toxicity associated with statins: a systematic review and meta-analysis. Atherosclerosis. 2021;327:59-67. doi:10.1016/j.atherosclerosis.2021.05.006
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of November 16, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.