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June 18/25, 2019 Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 e1114

CLINICAL STATEMENTS AND GUIDELINES Recommendation 1, implementing a very lowfat diet,S4.5.2-9 and adding fibrates or omega-3 fatty acids for patients with persistently elevated severe hypertriglyceridemia.S4.5.2-15 These are the most reliable pharmacological therapies to reduce triglycerides to a safer level. If a fibrate is necessary in a patient being treated with a statin, it is safer to use fenofibrate than gemfibrozil because of lower risk of severe myopathy.S4.5.2-16 Severe or life-threatening hypertriglyceridemia during pregnancy is best managed in consultation with a lipid specialist.S4.5.2-17

4.5.3 Issues Specific to Women

Recommendations for Issues Specific to Women Referenced studies that support recommendations are summarized in Online Data Supplements 33 to 35.

COR LOE Recommendations

I B-NR 1.  Clinicians should consider conditions specific to women, such as premature menopause (age <40 years) and history of pregnancyassociated disorders (hypertension, preeclampsia, gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries), when discussing lifestyle intervention and the potential for benefit of statin therapy.S4.5.3-1–S4.5.3-6

I C-LD 2.  Women of childbearing age who are treated with statin therapy and are sexually active should be counseled to use a reliable form of contraception.S4.5.3-7–S4.5.3-12

I C-LD 3.  Women of childbearing age with hypercholesterolemia who plan to become pregnant should stop the statin 1 to 2 months before pregnancy is attempted, or if they become pregnant while on a statin, should have the statin stopped as soon as the pregnancy is discovered.S4.5.3-7–S4.5.3-12

Synopsis

Although atherosclerosis typically occurs later in women than in men, CVD remains the leading cause of death in women. Statins clearly reduce ASCVD events in women as well as in men with ASCVD. The 2015 meta-analysis by the CTT Collaboration showed no heterogeneity by gender for the risk of major vascular events with statin therapy in participants with a history of vascular disease.S4.5.3-13 A history of certain pregnancy-related conditions and premature menopause (age <40 years) have been associated with increased ASCVD risk. However, current best practice emphasizes that statins should not be taken during pregnancy. Thus, women of childbearing age who are on statin therapy and are sexually active should use a reliable form of contraception to avoid pregnancy. When pregnancy is planned, stopping statin therapy 1 to 2 months before pregnancy is attempted is suggested as reasonable guidance. When an unplanned pregnancy occurs, statins should be stopped immediately when the preg- nancy is ­discovered. Both cholesterol and triglycerides rise with pregnancy, and those with genetic lipid disorders should consider consulting a clinician with lipid expertise before starting the pregnancy.

Recommendation-Specific Supportive Text

1.	 Several conditions specific to women (eg, hypertensive disorders during pregnancy, preeclampsia, gestational diabetes mellitus, delivering a preterm or low-birth-weight infant,S4.5.3-2–S4.5.3-4 and premature menopause [age <40 years]S4.5.3-5,S4.5.3-6,S4.5.3-14) have been shown to increase ASCVD risk. The present guideline includes preeclampsia and premature menopause (age <40 years) as riskenhancing factors for statin therapy because they appear to increase ASCVD risk in the same range as other risk-enhancing factors. On the other hand, the mechanism or cause of preterm birth is often unknown; therefore, it is difficult to routinely include this condition as a risk-enhancing factor for statin therapy. Furthermore, if gestational diabetes mellitus predisposes a woman to metabolic syndrome or diabetes mellitus, these are already identified as risk-enhancing or major ASCVD risk factors. After pregnancy and throughout the life course of every woman, a thorough pregnancy history should be obtained, and risk factors and risk-enhancing factors should be identified. Interventions should include aggressive lifestyle counseling to reduce ASCVD risk and when appropriate, statin therapy, if ASCVD risk estimation indicates that the potential for benefit from statin therapy outweighs the potential for adverse effects. Decisions should be made in the context of a risk discussion and should take into consideration an informed patient preference. 2.	 All statins are currently contraindicated in pregnant women, primarily as a result of a 2004 series of cases of first-trimester statin exposure reported to the FDA, which showed 20 cases of malformation, including 5 severe defects of the central nervous system and 5 unilateral limb deficiencies.S4.5.3-7 In all cases of adverse birth outcomes, the statin used was lipophilic. No malformation was identified in the 14 infants exposed to pravastatin (hydrophilic). Since this case series, cohort studies of statin exposure in pregnancy did not show an increase in teratogenic risk,S4.5.3-8–S4.5.3-10 and in fact, the safety of pravastatin is under study for the prevention of preeclampsia in high-risk pregnant women.S4.5.3-15 In a meta-analysis of 6 studies of pregnant women exposed to statins, no increased risk of birth defects was observed compared with control subjects. However, there was an increased risk of

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