Considerations for contraception in women with cardiovascular disorders

Considerations for contraception in women with cardiovascular disorders Jay M. Sullivan, MD: and Rogerio A. Lobo, MDb Memphis, Tennessee, and Los Angeles, California Women with hypertension, angina pectoris, or mitral valve prolapse require special considerations when selecting an appropriate method of contraception. All three effective, reversible options (oral contraceptives, intrauterine devices, or progestin implants) carry some degree of added risk for these patient populations. However, pregnancy itself presents certain risks and, in the event of contraceptive failure, certain women with these disorders are at increased risk of developing serious cardiovascular sequelae that affect both mother and fetus. These negative effects can carry far into the neonatal period. This article describes the risk/benefit profiles of the currently available contraceptive options relative to their potential impact in these compromised women. (AM J OBSTET GYNECOL 1993; 168:2006-11.)

Key words: Angina pectoris, contraception, hypertension, mitral valve prolapse, preeclampsia

Premenopausal women are at lower risk for coronary heart disease (CHD) than men of the same age with similar levels of blood pressure, serum cholesterol, and cigarette smoking. Mter menopause, women's risk of CHD equals that of men. I A growing body of evidence indicates that estrogen is responsible for lower rates of CHD in premenopausal women. 2 The impact of sex hormones on lipids and the implications of contraception for women with dyslipidemias have been discussed elsewhere.' Three additional cardiovascular disorders that pose significant challenges in contraception selection are hypertension, mitral valve prolapse (MVP), and angina pectoris. This article focuses on the relationships of these disorders with the m~or forms of effective, reversible contraception: oral contraceptives (OCs), intrauterine devices (IUDs), and progestin implants. Contraception concerns for women with cardiovascular problems arise from two sources: the extra load imposed on the system by pregnancy should contraception fail, and the potential occurrence of adverse circulatory effects resulting from the contraception method selected (e.g., exogenous steroids used in OC preparations). The demands of the growing fetus translate into many cardiovascular changes for the mother, including an almost 50% increase in blood volume and cardiac output and a significant increase in extravascular ftuid. 4 . 5 Whereas a healthy woman may have no

From the Division of Cardiovascular Disease, University of Tennessee College of Medicine, a and the Department of Obstetrics and Gynecology, University of Southern California School of Medicine. b Reprint requests: Rogerio A. Lobo, MD, University of Southern California School of Medicine, Women's Hospital, Room 1M2, 1240 N. Mission Rd., Los Angeles, CA 90033. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/0/47503

2006

difficulty dealing with these demands, women who have cardiovascular disorders may not do as well. In women of reproductive age who have cardiovascular disease, incremental risk that can be avoided or controlled deserves careful scrutiny. Because of the significant additional burdens that pregnancy imposes on the circulatory system, the decision to attempt pregnancy in such patients is of tremendous consequence. Depending on the severity of their disease, some women opt for sterilization or abortion as viable alternatives to pregnancy. Others choose reversible contraception to avoid childbearing altogether or to postpone it until their cardiovascular risks are minimized. No method of fertility control is without some risk, but some carry minimal risks while also providing benefits. All clinical recommendations for contraception selection must be considered in the context of the patient's cardiovascular risk profile. Hypertension

Approximately one of four Americans has high blood pressure (systolic blood pressure ~ 140 mm Hg or diastolic blood pressure ~ 90 mm Hg). It is well known that the prevalence of hypertension increases with age and that there are clear racial differences in the incidence of hypertension. It is also clear that premenopausal women have a lower incidence of hypertension than do postmenopausal women. Nevertheless, premenopausal women can be hypertensive, and this is an important factor in selecting a contraceptive method. Table I shows the Joint National Committee V criteria for classifYing degrees of hypertension. 6 Hypertension is clearly linked to target organ damage, resulting in myocardial infarction (MI), stroke, heart and kidney failure, or other visceral damage. Severe hypertension

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Table I. Joint National Committee V hypertension criteria: Adult patient classification and follow-up Blood pressure range (mm Hg) Systolic

< 130 130-139 140-159 160-179 180-209 >210

I

Time limit for follow-up (after firstoccasion measurement)

Diastolic

Classification

<85 85-89 90-99 100-109

Normal blood pressure High-normal blood pressure Stage I mild hypertension Stage II moderate hypertension Stage III severe hypertension Stage IV (very severe)

110-;;:: 119

> 120

2 yr

1 yr 2mo 1 mo 1 wk Immediate

Data from the 1993 report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure, Arch Intern Med 1993; 153:154-83,

can rapidly precipitate such catastrophic illness, However, there is a growing appreciation that chronic mild hypertension predisposes to serious illness through slow target organ damage and may cause gradual destruction of organs such as the kidney with a virtual absence of symptoms while the damage is far progressed. Interestingly, hypertension-induced organ damage is generally less severe in women than in men at a given level of blood pressure. 7 Fortunately, most hypertensive patients who are treated by the obstetrician (or other primary care physician) will respond to standard treatment protocols for hypertension. Obviously the first preference is to manage hypertension through such hygienic measures as weight reduction, exercise, and restriction of salt and alcohol. With all of its other health detriments, cigarette smoking also exacerbates the blood vessel damage caused by hypertension and should obviously be eliminated (especially in women contemplating pregnancy). Compliance with hygienic measures is often not optimal and for patients in whom these hygienic measures fail to obtain satisfactory control, pharmacologic therapy is indicated. Reduction of blood pressure with drugs reduces morbidity and mortality; the most dramatic reductions in risk are seen in patients with diastolic blood pressure greater than 104 mm Hg. The largest body of evidence for these observations has accumulated for diuretics and j3-blockers, although a vast body of literature also supports the use of angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as firstline treatment for hypertension. The Joint National Committee has recently reviewed its guidelines for pharmacologic therapy. Diuretics, j3-blockers, angiotension-converting enzyme inhibitors, calcium blockers, a-blockers and (3-blockers are acceptable for first-line therapy; however, diuretics or (3-blockers are preferred because these agents have been shown to reduce morbidity and mortality in placebo-controlled, large-scale clinical trials. In general the woman's physician should feel confident in working with the patient to control hyperten-

sion with hygienic measures and, failing these, with the pharmacologic strategy with which they are most familiar and comfortable. Should the patient's hypertension appear refractory to such measures, consultation with or referral to an internist or cardiologist with special expertise in the management of hypertension should be considered. Hypertension in pregnancy. Hypertensive women who become pregnant incur several major risks. Even if the mother appears to be in satisfactory health, the placenta and therefore the fetal circulation can undergo ischemic or target organ damage as a result of compromised maternal circulation. There is an increased risk of 20% to 30% that superimposed preeclampsia may develop during pregnancy. Uncontrolled hypertensive pregnant women can also experience an increase in abruptio placentae, disseminating intravascular coagulation, acute tubular necrosis, and renal· cortical necrosis; these complications vary from 0.4% to 10%. Although these complications are far from insignificant, maternal morbidity is low as a result of expert prenatal care and has decreased from the 3% to 6% figure quoted for severe hypertension in 1950. The mother's prognosis is clearly better in the absence of kidney disease. However, fetal mortality is substantial because of a premature delivery rate of 25% to 30% and a rate of intrauterine growth retardation between 10% and 15%.8 Lowering blood pressure is beneficial in reducing both fetal and maternal mortality in pregnant women with chronic (essential) hypertension. Methyldopa, hydralazine, and (3-blockers have all been used successfully to control hypertension in pregnant women. There is also a growing acceptance of the use of calcium channel blockers. Animal studies have shown an increase of fetal mortality associated with the use of ACE inhibitors, and these agents probably should be avoided during pregnancy. 6 Contraceptive choices for the hypertensive patient

OCs. Epidemiologic data suggest that OCs induce a small increase in the incidence of hypertension (Fig. 1).9

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10

8 % Cases

June 1993 Am J Obstet Gynecol

FfA Current DC users o Nonusers

6 4 2

15-24

25-34 35-44 Age (Y)

45-60

Fig. 1. Impact of OCs on systolic (2: 140 mm Hg) and diastolic (2: 90 mm Hg) blood pressure. (Data from Beller FK. Ebert C. Obstet Gynecol Surv 1985;40:425-36.)

Both low- and high-dose OCs may induce changes in blood pressure. However, because blood pressure increases are generally quite small and because women experience a lesser degree of target organ damage than men in the same cohort, this mild effect of OCs is generally believed to be of little clinical significance. Less frequently, the degree of blood pressure elevation induced by OC therapy can be severe. A possible mechanism for the OC-induced increase in blood pressure might be an exaggerated response of renin substrate to pharmacologic estrogen, resulting in elevated plasma renin levels. 6 However, OC-induced hypertension cannot be explained by this mechanism alone because similar elevations in renin substrate have been noted in normotensive and hypertensive OC users. II Exploration of this information may help shed light on one or more unique susceptibility factors at work among hypertensive women. For example, certain women may be susceptible to increased blood pressure when taking OCs because of the possible existence of a specific moiety of angiotension that, when exposed to estrogen, causes an increase in blood pressure. One aspect of hypertension in women warranting specific attention is that hypertension combined with cigarette smoking and the use of OCs causes a substantial increase in risk for CHD; as a result either OCs or smoking should be discontinued, preferably smoking. Aside from this important caveat. however, OCs do not invariably present a substantial risk to hypertensive women. It is not yet clear whether the pharmacologic control of hypertension significantly reduces the cardiovascular risk to women who smoke and use OCs. Lowdose OC preparations usually can be used safely in nonsmoking, younger hypertensive patients whose blood pressure is well controlled by medication. 12 Fre-

quent monitoring of blood pressure is extremely important nevertheless. Among women with a history of hypertension who were not not taking antihypertensive drugs, one study has shown that whereas most women remain normotensive, 8.2% stopped OC use because of recurrence of hypertension. 13 In addition, OCs are not contraindicated in women with a history of pregnancy-induced hypertension. Alternatives for women who are older, who smoke, or who have hypertension that is difficult to control are progestin-only formulations or the IUD. There is no evidence that current doses of progestins adversely effect blood pressure. Both implants and depot injections do not affect blood pressure and are good alternatives.

Mitral valve prolapse MVP affects approximately 15 million Americans. It is defined as a displacement of the mitral leaflets in a posterior and superior direction relative to their normal position in systole. MVP appears to be genetically transmitted in most cases. Thirty to fifty percent of firstdegree relatives of patients with MVP also have the condition. 14, 15 Expression of the genome is governed by age and gender. Of concern here is that more women than men have MVP and that prolapse rarely occurs until the childbearing years of adolescence and early adulthood. In the past, MVP in women was believed to be associated with panic attacks. However, recent research has failed to demonstrate a correlation between the two conditions. 16 The natural history of MVP is completely benign in most cases. However, 1 in 6000 MVP patients per year experiences systemic embolization, which should be considered when prescribing exogenous steroids for such patients. Contraceptive failure in women with MVP may have less dire consequences than hypertension because of the benign nature of this condition. The main risk is that of bacterial endocarditis in patients with structural abnormality of the mitral valve, which can lead to chordal rupture, increased mitral insufficiency, and congestive heart failure. I?

Contraceptive choices for women with MVP Des. Because of the typically benign clinical manifestations of MVP, the condition generally poses little risk on pregnancy. However, the small incidence (1/6000) of those who experience systemic embolization is of concern when considering use of OCs. Whereas most women do not have symptoms, one study found that patients with MVP who experienced cerebrovascular insufficiency while taking OCs showed a reduction in platelet survival time. 18 Another study suggested that among patients with MVP who had recovered from

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stroke, platelet survival time was significantly shortened (Fig. 2).19 Thus it appears that coagulation problems may occur in only a subset of patients with MVP, which makes them more vulnerable to thromboembolism when they receive oes. Some stroke victims who use oes also show increased levels of J3-thromboglobulin and decreased levels of antithrombin III, which indicates that oe use, MVP, and abnormal coagulation physiology is a potentially dangerous combination. In general, oes can be safely used by women with MVP as long as they are without symptoms other than anxiety. At present, oe use among MVP patients is limited to those with an echocardiographically confirmed diagnosis but no mitral regurgitation. Specifically, oes should not be used by patients who smoke or by women who have symptoms. In women who have experienced thrombotic complications, it may be advisable to perform coagulation screening. If abnormalities are discovered in blood clotting factors, other methods of contraception should be considered. IUDs. The IUD can often be safely used by women with MVP. Whereas there is a slight risk for systemic infection (which if undetected and uncontrolled can lead to infective endocarditis in patients with mitral regurgitation caused by mitral valve prolapse), such infections are quite rare, generally occur within a few weeks of placement of the device, and can usually be detected before the infection reaches the bloodstream?O Appropriate antibiotics should be used at the time of insertion if mitral regurgitation is present. The IUD does not appear to influence thrombus formation. 21 Progestins do not adversely effect coagulation parameters. Evidence indicates that fibrinolytic activity may be increased with progestins. Therefore long-acting progestins such as in implants and depot injections are safe to use and may even be beneficial.

Angina/coronary artery disease Approximately one-half million deaths occur per year among the 1.5 million persons who experience MI. 22 In terms of gender differences, slightly more women than men die from cardiovascular disease each year. Symptoms start approximately 10 years later in women than in men, and deaths occur approximately 20 years later. The goals of management are to prolong life and improve its quality by slowing or reversing the atherosclerotic process. Angina pectoris is a symptom that is most often caused by myocardial ischemia, which means an imbalance of myocardial oxygen demand and supply. This condition is usually the result of coronary artery disease, which, in turn, is usually caused by gradually progressive atherosclerosis. Although the most frequent cause of angina is coronary atherosclerosis, it can also be

2009

5 4 Platelet survival time (t Y2) Days

31-

I

$, ~

0

-8-

2

(p
8

1-

(n=26)

Thromboembolism

No Thromboembolism

Fig. 2. Platelet survival time in patients with MVP. (Modified from Steele P, Weily H, Rainwater J, Vogel R. Platelet survival time and thromboembolism in patients with mitral valve prolapse. Circulation 1979;60:43-5. Reproduced with permission from Circulation. Copyright 1979, American Heart Association.) 1.6 1.4 1.2

Plaque Area (mm2)

1.0 0.8

..!..

0.6

-•I

·

0.4 0.2 0

Males

Control Females

Intravaginal Ring

Oral Contraceptive

Fig. 3. Coronary artery plaque area in four experimental groups. (Modified from Adams MR, et al. Ferti! Steril 1987; 47:1010-18. Reproduced with permission of the publisher, The American Fertility Society.)

caused by coronary spasm, microvascular dysregulation, or syndrome X (i.e., normal coronary angiography, positive treadmill tests, and abnormal thallium scans). Physicians of such patients should be aware of the acute symptoms of myocardial ischemia and recall that such patients are also at increased risk of ischemia of other vital organs. Often the patient has concomitant hypertension, and thus the earlier comments on hypertension should be recalled at this juncture. Hypertensive patients, particularly those with left ventricular hypertrophy, have diminished coronary flow reserve, that is, impaired ability to increase myocardial blood flow when needed, which leads to an imbalance of supply and demand and causes angina without atherosclerosis.

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Table II. Cardiovascular deaths in OC and IUD users in Finland*: Relative risks for developing pulmonary embolism, coronary heart disease, or cerebrovascular accident Condition developed

OC users

Pulmonary embolism Coronary heart disease Cerebrovascular accident

0.2 (p < 0.01) 0.7 (p < 0.03)

Modified from Hirvonen E, Idanpaan-HeikkilaJ. AM] *After excluding patients with risk factors.

1.2

OBSTET GYNECOL

Patients with "true" angina (suggested by severe STsegment depression and thallium perfusion abnormalities during a cardiac stress test) clearly pose a special set of clinical challenges because they are at high risk of experiencing MI should they become pregnant. Two thirds of pregnant women who undergo acute MI during the third trimester die. If delivery occurs within 2 weeks of MI, mortality increases precipitously. Mortality of the fetus of a women who sustains an MI during pregnancy depends on the condition of the mother after MI. Overall there appears to be a death rate of 34% for the infants of mothers who experienced MI. 23 This risk certainly makes contraception a logical clinical recommendation, but any superimposed risks of the contraceptive choice must be clearly identified. Contraceptive choices for women with angina caused by coronary atherosclerosis Des. Because of the association of angina and MI with atherosclerosis, it is appropriate to comment on what is known about the effects of OCs on the atherosclerotic process. OCs do not appear to stimulate the atherosclerotic process. They may in fact inhibit plaque formation. One study of women less than 50 years of age who had experienced an MI found that the incidence of angiographically confirmed coronary atherosclerosis in non-OC users was roughly double that of OC users (79% vs 36%, respectively)!4 This finding suggests that MI in OC users is not generally caused by atherosclerosis. Not surprisingly, OC users in whom atherosclerosis developed had significantly higher incidences of hypertension (100%), glucose intolerance (60%), or elevated cholesterol (53%) compared with the nonatherosclerotic group of OC users (0%, 7%, and 11%, respectively), which demonstrates the importance of additive risk factors. Only the rate of smoking was similar in both groups, which emphasizes the power of this risk factor for MI. Previous data have shown that smoking and OC use results in decreases in prostacyclin release, which may help explain the hazards associated with this combination. 25 Concerns about negative cardiovascular effects associated with the use of estrogen and progestin in OCs originated at a time when the steroid dose was much higher than that used in modern, low-dose ( < 50 J.Lg of estrogen) preparations. Increased risk of thrombosis

IUD users

o

0.6 (NS) 1.2 (NS)

1990;163:281-4.

leading to myocardial infarction or stroke has not been demonstrated for low-dose preparations in the absence of other risk factors. Interestingly, one study has demonstrated that OC use may actually be protective against stroke and CHD (Table 1I).2l Supporting this finding are animal studies that show a decrease in expected atherosclerotic plaque size with various combinations of contraceptive steroids (Fig. 3).26 Even in the setting of decreased high-density lipoprotein cholesterol concentrations, monkeys who were fed a high-fat diet were protected from atherosclerosis. The current view is that a direct effect on the vessel by ethinyl estradiol is protective against atherosclerosis, even when high-density lipoprotein cholesterol levels are lowered by progestational agents. In summary, the risk of OCs in relationship to ischemic heart disease is that of thrombosis, not atherosclerosis. The former risk has been reduced by the use of one of the current low-dose OCs, unless a woman has thrombogenic risk factors. When contemplating use of OCs in women with known angina who may have atherosclerosis, it is important to keep in mind the impact of additive risk factors. Low-dose OCs that have a minimal metabolic impact may be used safely in currently asymptomatic women who have a history of angina and who have no additional risk factors. However, for women with previous MI, OCs should not be used and other nonsteroidal methods should be chosen. Chest pain should be evaluated in women. This symptom can be caused by coronary atherosclerosis or other, less threatening pathophysiologic processes. In the absence of atherosclerotic CVD and significant risk factors, OC use is not contraindicated. IUDs and long-acting progestins. IUDs do not modify the endocrine milieu. In the context of cardiovascular risk, IUDs can be associated with an increased risk of salpingitis at the time of insertion. In addition, the pain of insertion may include a vasovagal response that may be of concern in a woman with severe heart disease. Nevertheless, with these small risks in mind, the IUD is an alternative method for women with CHD. However, if they are receiving anticoagulation therapy, increased blood loss may be problematic. Progestin implants and depo-medroxyprogesterone

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acetate appear to be quite safe and effective. The metabolic impact of these progestins appears to be small and the overall impact should not be different from the metabolic effects of low-dose OCs. Conclusion

The systemic impact of low-dose OCs is generally quite minimal. However, in the presence of cardiovascular risk factors (particularly cigarette smoking), they may engender some added risk for thromboembolism. Current OC use alone has little effect on end organ damage in hypertensive women. However, some data indicate that OCs in combination with risk factors such as smoking and previous MI may lead to higher MI mortality. Therefore, for patients with well-controlled hypertension who do not smoke and who have no previous history of MI, OCs are acceptable. The potential antiatherosclerotic effect of OCs makes them reasonable options in cases of angina where no other risk factors pertain. Similarly, women with MVP can use OCs unless they have had episodes of thromboembolism or have other risk factors such as smoking. It may be advisable to screen women with symptoms who have MVP for the presence of abnormal hematologic parameters. In general the IUD and long-acting progestins are safe methods for women with cardiovascular disease. Risk of infertility with the IUD is viewed as being small and the overall metabolic impact of the long-acting progestins is similarly of no major consequence. Although contraceptive choices are sometimes difficult in high-risk individuals with medical illnesses, it must be remembered that the risk of pregnancy is often much greater than the risks associated with contraceptive use. Not discussed specifically is the option of either male or female sterilization. This is obviously an important option for women who have completed their families. REFERENCES 1. Kannel WB, Dawber 'fR, McGee DL. Perspectives on systolic hypertension: the Framingham study. Circulation 1980;61: 1179-82. 2. Knopp RH. Cardiovascular effects of endogenous and exogenous sex hormones over a woman's lifetime. AM J OBSTET GYNECOL 1988;158:1630-43. 3. Knopp RH, LaRosa JC, Burkman RT. Contraception and dyslipidemia. AM J OBSTET GYNECOL 1993; 168: 1994-2005. 4. Pitkin RM, Perl off JK, Koos BJ, Beall MH. Pregnancy and congenital heart disease. Ann Intern Med 1990; 112:44554. 5. Cowles T, Gonik B. Mitral valve prolapse in pregnancy. Semin Perinatol 1990; 14:34-41.

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6. The 1993 report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1993;153: 154-83. 7. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. AmJ Med 1984;76:4-12. 8. Sibai BM, Anderson GD. Intensive management of severe hypertension in the fIrst trimester. Obstet Gynecol 1986; 67:517-22. 9. Beller FK, Ebert C. Effects of oral contraceptives on blood coagulation: a review. Obstet Gynecol Surv 1985;40:42536. 10. Shionoiri H, Eggena P, Barrett JD, et al. An increase in high-molecular weight renin substrate associated with estrogenic hypertension. Biochem Med 1983;29:14-22. 11. Eggena P, Barrett JD, Shionoiri H, et al. In: Sambhi MP, ed. Heterogenicity of renin and renin substrate. New York: Elsevier, 1981. 12. Speroff L, Darney PD. A clinical guide for contraception. Baltimore: Williams & Wilkins, 1992. 13. Tsai CC, Williamson HO, Kirkland BH, Braun JO, Lam CF. Low-dose oral contraception and blood pressure in women with a past history of elevated blood pressure. AM J OBSTET GVNECOL 1985;151:28-32. 14. Scheele W, Allen HW, Krauss R, et al. Familial prevalence and genetic transmission of mitral valve prolapse. Circulation 1977;5-6(1). 15. Weiss AN, Mimbs JW, Ludbrook PA, et al. Echocardiographic detection of mitral valve prolapse: exclusion of false positive diagnosis and determination of inheritance. Circulation 1975;52:1091-6. 16. Devereux RB, Kramer-Fox R, Brown WI', et al. Relation between clinical features of the mitral valve prolapse syndrome and echocardiographically documented mitral valve prolapse. J Am Coil Cardiol 1986;8:763-72. 17. Oakley CM. Pregnancy in heart disease: pre-existing heart disease. In: Douglas PS, ed. Heart disease in women. Cardiovascular clinics. Philadelphia: FA Davis Co, 1989: 70. 18. Elam MB, Viar M, Ratts TE, Chesney CM. Mitral valve prolapse in women with oral contraceptive-related cerebrovascular insufficiency. Arch Intern Med 1986; 146:73-7. 19. Steele P, Weily H, Rainwater J, Vogel R. Platelet survival time and thromboembolism in patients with mitral valve prolapse. Circulation 1979;60:43-5. 20. Grimes DA. The intrauterine device, pelvic inflammatory disease, and infertility: the confusion between hypothesis and knowledge. Fertil Steril 1992;58:670-3. 21. Hirvonen E, Idanpaan-Heikkila J. Cardiovascular death among women under 40 years of age using low-estrogen oral contraceptives and intrauterine devices in Finland from 1975 to 1984. AM J OBSTET GYNECOL 1990; 163:281-4. 22. American Heart Association. 1992 Heart facts. Dallas: American Heart Association National Center, 1991. 23. Hankins GD, Wendal GD Jr, Leveno KJ, Stoneham J. Myocardial infarction during pregnancy: a review. Obstet Gynecol 1985;65: 139-46. 24. Engel HJ, Engel E, Lichtlen PR. Coronary atherosclerosis and myocardial infarction in young women-role of oral contraceptives. Eur HeartJ 1983;4:1-6. 25. Mileikowsky GN, Nadler JL, Huey F, et al. Evidence that smoking alters prostacyclin formation and platelet aggregation in women who use oral contraceptives. AM J OBSTET GYNECOL 1988;159:1547. 26. Adams MR, Clarkson TB, Koritnik DR, Nash HA. Contraceptive steroids and coronary artery atherosclerosis In cynomolgus macaques. Fertil Steril 1987;47:1010-18.