Cardiovascular disease (CVD) is the leading cause of mortality in women.¹ Serum cholesterol has a long standing association with atherosclerotic cardiovascular disease (ASCVD). Although ASCVD typically presents approximately a decade later in women than in men, there has been uncertainty regarding effectiveness of cholesterol lowering statin therapy in CVD risk reduction in women. The dearth of individual trial-specific data in women has contributed to this ambiguity, which also reflects the underrepresentation of women in clinical trials.² The meta-analysis of individual data from 174,000 participants in 27 randomized trials by the Cholesterol Treatment Trialists' (CTT) Collaboration showed that among people with a history of vascular disease, there were similar effects of statin therapy on reduction of cardiovascular events and mortality in both men and women. Irrespective of gender, secondary prevention in high-risk populations with established CVD benefited from statin therapy as well as the low-risk populations who were being treated for primary prevention of major vascular events.³

According to the updated 2018 ACC/AHA cholesterol guidelines,⁴ certain female-specific risk enhancing conditions should be considered in the evaluation and management of women for primary prevention of ASCVD. In addition to therapeutic lifestyle changes for all patients, risk discussion with statin therapy may be recommended based on the patient's 10 year ASCVD risk based on the presence of "risk enhancers."

In a "borderline risk" woman (10 year ASCVD risk of 5% to <7.5%), if "risk enhancers" (preeclampsia and premature menopause [before 40 years of age]) are present then a risk/benefit discussion regarding moderate intensity statin therapy is recommended (Class IIb indication). In an "intermediate risk" woman (10 year ASCVD risk calculation of >7.5% to <20%) with risk enhancing conditions a moderate intensity statin should be initiated to reduce LDL-C by 30%-49% (Class I indication). Additionally, statin therapy should be carefully planned in women of childbearing age.⁴

Risk Enhancing Conditions
In addition to traditional risk factors of ASCVD, several non-traditional female specific risk conditions have recently emerged. These female specific risk conditions, which include premature menopause and certain pregnancy-related conditions, have been associated with increased long-term risk of ASCVD.^5,6 Premature menopause and preeclampsia appear to similarly increase ASCVD risk compared to other risk enhancers and are the only two female specific risk-enhancer conditions in the recent cholesterol guidelines. The other pregnancy-related conditions (such as gestational diabetes and preterm delivery) are recognized as increasing lifetime CVD risks but were not classified as risk enhancing factors. Pregnancy-related conditions should be assessed in all women during pregnancy and throughout their entire lifetime in order to determine lifetime ASCVD risk. Additionally these women should be counseled on therapeutic lifestyle changes to reduce risk as well and they should have discussions with their health care provider regarding the benefits and risks of statin therapy. Also in women with hypercholesterolemia, elevated lipoprotein (a) (Lp(a)) levels (>50 mg/dL or >125 nmol/L) could be considered a risk-enhancing factor; however, the risk prediction improvement was shown to be minimal in one large clinical trial.^7,8

Menopause and CV Risk
Onset of menopause is associated with increasing CV risk. Menopause alters lipid profiles with increases in total cholesterol and LDL-cholesterol and lower levels of HDL-cholesterol.⁹ Compared to men, women of childbearing age generally are at a lower ASCVD risk; however, those women who undergo early menopause are at an elevated lifetime risk of ASCVD. Data from the Nurses' Health Study showed a shorter duration of reproductive life span (<30 versus >42 years between menarche and menopause) was significantly associated with higher risk of total CVD, coronary heart disease (CHD) and stroke. This association was evident regardless of natural versus surgically induce menopause. Extremely early age at menarche (<10 years) was modestly associated with higher risk of CVD and may be problematic as the age of menarche in the United States continues to decline.¹⁰ Additionally, early age of menopause (<40 years) was associated with higher CVD risk in multivariable analysis.¹¹ Furthermore, a recent meta-analysis also demonstrated early menopause (age <45 years) was associated with increased risk of all-cause mortality, CVD mortality and CHD, but not with stroke risk.¹²

Pregnancy and CV Risk
History of pregnancy-related conditions also affects long-term CVD risks. Gestational hypertension, chronic hypertension and preeclampsia are all hypertensive disorders that can occur during pregnancy. Chronic hypertension is diagnosed in women who develop hypertension prior to 20 weeks of gestation age whereas gestational hypertension is diagnosed in women who develop new onset hypertension after 20 weeks of gestational age. Both conditions can be monitored and treated during pregnancy; however, development of preeclampsia is more likely in those with severe hypertension (>160/110 mmHg). Worldwide, preeclampsia affects 2-8% of all pregnancies and is a major cause of maternal mortality.^13,14 Oxidative stress, caused by placental hypoperfusion and hypoxia due to failure of spiral artery remodeling, can activate a systemic inflammatory response. This leads to endothelial dysfunction and vasoconstriction, which results in systemic hypertension.¹³ In a recent meta-analysis, there was four-fold increase in future heart failure and two-fold increase in CHD, stroke and death secondary to CVD associated in patients with preeclampsia.¹⁵ Additionally women aged 45-55 years with a prior history of preeclampsia have been shown to have accelerated subclinical coronary atherosclerosis.¹⁶

Preterm delivery (<37 weeks' gestation age) occurs in approximately 11% of all pregnancies worldwide and in a large population based study preterm birth was shown to be an independent long term risk factor for CVD mortality.^17,18 A recent meta-analysis demonstrated that women who experienced pre-term birth, regardless of etiology, had a 1.4 to two-fold increased maternal risk of future adverse CVD events, including CVD death, CHD, stroke and CHD death.¹⁹ The etiology for preterm birth is frequently unclear and therefore it cannot be consistently used as a risk enhancer to determine statin favorability. Low birth weight occurs in approximately 8% of all deliveries, the underlying mechanism is unclear and it has been associated with a two-fold increase in maternal CVD moratlity.^5,20

Gestational diabetes occurs in approximately 6% of pregnancies in the US and is associated with the development of subsequent maternal CVD. In one study of young women, those with gestational diabetes had a significantly greater risk of future development of CVD; however, the increased risk was largely attributed to the subsequent development of type 2 diabetes mellitus.²¹ However other studies have shown the increased CVD risk in those with gestational diabetes is independent of the development of type 2 diabetes.^22,23 Nevertheless, gestational diabetes is associated with the subsequent development of metabolic syndrome and diabetes mellitus. Should a woman develop either of these predisposed conditions then she would require statin therapy as metabolic syndrome is an ASCVD risk enhancer and diabetes is a major ASCVD risk factor.

Pregnancy and Statins
Lipid profiles are known to be altered with pregnancy and therefore women with underlying genetic lipid disorders would benefit from lipidology consultation prior to consideration of pregnancy. Statin therapy is contraindicated during pregnancy. The effects of other LDL-C lowering therapies, such as PCSK9 inhibitors, is not well established. Therefore, sexually active women of childbearing age should be counseled on avoidance of pregnancy and need for reliable contraception while on statin therapy. In women with hypercholesterolemia who are planning on getting pregnant, it is recommended to stop statin therapy 1-2 months prior to attempting to get pregnant. Additionally, it is imperative to stop statin therapy as soon as an unplanned pregnancy is realized and should not be restarted until after pregnancy as well as breastfeeding period are completed.

As discussed above, lifelong CVD risk assessment and monitoring in all women should include discussions regarding pregnancy-associated conditions (even if pregnancy was decades prior) and age at menopause. All women should receive aggressive lifestyle counseling and those with elevated ASCVD risk and risk enhancers should have a risk discussion regarding the addition of statin therapy to reduce ASCVD risk.

References

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2. Kim ES, Menon V. Status of women in cardiovascular clinical trials. Arterioscler Thromb Vasc Biol 2009;29:279-83.
3. Cholesterol Treatment Trialists' (CTT) Collaboration, Fulcher J, O'Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397-405.
4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA 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 2018. [Epub ahead of print]
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13. Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V. Pre-eclampsia and future cardiovascular risk among women: a review. J Am Coll Cardiol 2014;63:1815-22.
14. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323-33.
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16. Zoet GA, Benschop L, Boersma E, et al. Prevalence of subclinical coronary artery disease associated by coronary computed tomography angiography in 45- to 55-year-old women with a history of preeclampsia. Circulation 2018;137:877-9.
17. Blencowe H, Cousens S, Chou D, et al. Born too soon: the global epidemiology of 15 million preterm biths. Reprod Health 2013;10:S2.
18. Kessous R, Shoham-Vardi I, Pariente G, Holcberg G, Sheiner E. An association between preterm delivery and long-term maternal cardiovascular morbidity. Am J Obstet Gynecol 2013;209:368.
19. Wu P, Gulati M, Kwok CS, et al. Preterm delivery and future risk of maternal cardiovascular disease: a systematic review and meta-analysis. J Am Heart Assoc 2018;7.
20. Davey Smith G, Hart C, Ferrell C, et al. Birth weight of offspring and mortality in the Renfrew and Paisley study: prospective observational study. BMJ 1997;315:1189-93.
21. Shah BR, Retnakaran R, Booth Gl. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care 2008;31:1668-9.
22. Gunderson EP, Chiang V, Pletcher MJ, et al. History of getstational diabetes mellitus and future risk of atherosclerosis in mid-life: the Coronary Artery Risk Development in Young Adults study. J Am Heart Assoc 2014;3.
23. Retnakaran R, Shah BR. Role of type 2 diabetes in determining retinal, renal, and cardiovascular outcomes in women with previous gestational diabetes mellitus. Diabetes Care 2017;40:101-8.

Keywords: Primary Prevention, Secondary Prevention, Plaque, Atherosclerotic, Cholesterol, Women, Cardiovascular Diseases, Risk, Risk Reduction Behavior, Hypercholesterolemia, Metabolic Syndrome, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diabetes, Gestational, Pre-Eclampsia, Hypertension, Fetal Hypoxia, Pregnancy, Menarche, Menopause, Cholesterol, HDL, Cholesterol, LDL, Lipoprotein(a), Hypercholesterolemia

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