Int J Gynaecol Obstet 16: 466- 4 72, 1979

Oral Contraceptive Hypertension and Thromboembolism W. B. Kannel Framingham H eart Study of the National H eart, Lung and Blood Institute, Framingham, Massachusetts, USA

ABSTRACT Kannel WB (Framingham Heart Study of the National Heart, Lung and Blood Institute, Framingham, MA, USA). Oral contraceptive hypertension and thromboembolism. Intj Gynaecol Obstet 16: 466- 472, 1979 Oral contraceptives (OCs) are a highly effective and widely accepted means of avoiding pregnancy, but they also worsen the major atherogenic cardiovascular risk factors to some degree in all women. Some OC users may suffer severe hypertensive episodes or massive hypertriglyceridemia with pancreatitis. Mild or severe adverse effects could eventually have serious consequences beyond the childbearing years. OC use would appear imprudent for women with a history of hypertension, gestational hypertension and a family history of hypertension. Special care is needed with blacks, diabetics and women with renal disease. OCs may also affect blood clotting, fibrinolysis and platelet adhesiveness. Also, histochemical and anatomical changes in blood vessels have been noted. Both may precipitate thromboembolic events while the OC user is still at the childbearing age and may also contribute to accelerated atherogenesis in subsequent years. There is a need for more specific guidelines for monitoring women on OCs for a worsening of their cardiovascular risk profile and changes in blood coagulation. Indications and contraindications for OC use in relation to the hazard of thromboembolic sequelae need to be more explicitly defined.

INTRODUCTION Oral contraceptives (OCs) are a highly effective and widely accepted means of avoiding pregnancy, and they have reduced fertility levels in all socioeconomic and ethnic groups. Despite widespread publicity about the hazards of OCs beginning in 1962, their use continues to increase in married women and sexually active unmarried adolescents. It also is estimated that abandonment of the pill for other methods would result in the need for 1- 7 million additional abortions annually. Hypertension, hyperlipidemia and impaired glu-

lnt J Gynaecol Obstet 16

cose tolerance are the major atherogenic risk factors for cardiovascular disease (CVD) (28, 42). OCs worsen the major atherogenic cardiovascular (CV) risk factors to some degree in all women. Although they may remain within normal limits, the whole distributions of these risk factors are shifted upward . In addition, some susceptible women exhibit a marked change and may suffer severe hypertensive episodes, massive hypertriglyceridemia with pancreatitis or overt diabetes. Either the mild or severe adverse effects on risk factors could eventually have serious consequences beyond the childbearing years.

HYPERTENSION OC hypertension went unnoticed, despite the widespread use of the pill by millions of women for about a decade. It was noted to occur in previously normotensive women and to aggravate existing hypertension and also to return to normal when the medication was discontinued (35, 69). In the ensuing ten years, the pressor potential of OCs has been abundantly confirmed (8, 17, 34, 53, 57, 61, 67, 68) . In addition to promoting frank hypertension in some women, OCs also elevate pressure within the nonhypertensive range in practically all women (13, 34, 48, 57, 68). The average increase noted has been variously estimated, and varies with age with greater differences among older women (13, 68) . Although seemingly innocuous, this shift in the whole distribution of blood pressure (BP) has ominous longterm implications because, for each 10 mm Hg increment in pressure, an estimated 30% increase in CVD incidence was noted in the Framingham Study (42). It has been estimated that 5% of OC users will develop frank hypertension within five years, an incidence 2.6 times greater than that in nonusers ( 13, 29, 48, 50). Some susceptible women have a marked change and may suffer severe hypertensive episodes including malignant hypertension ( 19).

OC hypertension and thromboembolism

The mechanism may entail volume and vasoconstrictive effects of estrogen-induced increase in renin substrate (35, 53, 55). The increase in renin substrate results in elevation of plasma angiotensin-2 which may cause both vasoconstrictive hypertension (through increased peripheral resistance) and also elevated BPs through fluid retention. Vasoconstriction decreases renal blood flow and activates aldosterone synthesis, causing increased sodium reabsorption (29). Although estrogen is the probable culprit, synthetic progestogens (by their conversion to estrogen) may also be involved (29). Once established, OC hypertension may take 3-6 months to disappear, and the renin-aldosterone system will continue to show abnormalities for 2-3 months. The hypertensive effect may increase with the duration of OC use (Table I). OC use would appear imprudent for women with a history of hypertension, toxemia of pregnancy, gestational hypertension and a family history of hypertension. Special care is needed with blacks, diabetics and women with renal disease.

Table I. Incidence of OC"-induced hypertension according to duration of useb.

8

b

Years of OC Use

Rate Per 1000 WomanYears

1 2 3

3.83 8.93 15.22

OCs contained 50 mg of estrogen. . Source: Royal College of General Practitioners (50).

467

EFFECTS ON BLOOD LIPIDS OCs affect the serum lipids, particularly the triglyceride and very low-density lipoprotein (VLDL) (Table II) (14, 44). Although changed, the lipids generally remain within usual limits (Table III), but pronounced hypertriglyceridemia can occur (44, 71). On rare occasions, hyperlipemic crises may be precipitated even with pancreatitis (3, 11 , 16, 21, 44, 71) . These extreme responses appear to be more likely in those predisposed by diabetes or preexisting type 4 VLDL abnormality. OC-induced hypertriglyceridemia appears to result from enhanced VLDL production stimulated by estrogen ( 1, 20, 49) . The plasma triglycerides rise more than would be expected from the size of the VLDL increase. Overproduction is indicated by increased triglyceride turnover rates (21, 31, 49). There is also a change in the apolipoprotein composition of VLDL (23). Progestogens, on the other hand, tend to increase the rate of clearance of triglyceride from plasma ( 15, 31). In considering the lipid aberrations which accompany OC administration, it is important to recognize that pregnancy is also accompanied by an increased triglyceride level (33, 51), and an elevation of serum total cholesterol is also common (45). Although there is no demonstrated independent contribution of triglyceride per se to atherogenesis, marked rises in triglyceride or VLDL on OC administration cannot be viewed with equanimity. OCs also appear to raise the serum total cholesterol and low-density lipoprotein (LDL), particu-

Table II. Differences in plasma lipids between OC users and nonusers, aged 20-39 (data from The Framingham Offspring Study}. Difference o/o Difference Plasma Lipids8

Unadjusted

Adjusted

Unadjusted

Adjustedb

4.6 -2.2 2.8 4.0 31.2

5.3 -1.0 3.5 3.8 22.5

2.5 -3.9 2.5 28.0 51.0

2.9 NS NS 26.0 37.0

Total cholesterol HDL-cholesterol LDL-cholesterol VLDL-cholesterol Triglycerides 8

b

HDL = high-density lipoprotein, LDL = low-density lipoprotein and VLDL = very /ow-density lipoprotein. Adjusted for: other lipids, age, skin folds, cigarettes, blood pressure, uric acid, blood urea nitrogen, bilirubin and hemoglobin.

Table Ill. Plasma lipid values in OC users and nonusers, aged 20-39 (data from The Framingham Offspring Study). Mean Lipid Valuesa

LDL

Triglyceride

VLDL-Cholesterol

Cholesterol

HDL-Cholesterol

111 114

61 93

14 18

182 186

56 54

/ow-density lipoprotein, VLDL

=

OC Use Nonusers Users a

LDL

=

very /ow-density lipoprotein and HDL

=

high-density Jopoprotein.

lntj Gynaecol Obstet / 6

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Kannel

larl y in young women, but not to the same degree as they affect triglyceride. Estrogen-containing OCs may secondarily raise the serum total cholesterol by elevat ing the VLDL and high-density lipoprotein (HDL) cholesterol-containing lipoprotein fractions (12). A particular fraction of HDL and its apolipoprotein composition may be specifically increased. However, the changes in HDL reported are rather inconsistent, and the atherogenic potential of these changes is currently unknown. Type 5 hyperlipoproteinemia may be induced by OC use in women with type 4 abnormalities. This may a lso occur with ethanol intake in OC users (12). On the other hand, OC use (estrogen) may improve a type 3 d ys lipoproteinemia (20). As in the case for hypertension, OCs can unmask an occult inborn error of lipid metabolism or shift the entire population distribution of lipids upward (2, 70) . OC-induced lipid changes can also complicate the diagnosis of the various hyperlipidemias. The co mbined effect of the modest increases in BP and serum cholesterol produced has ominous implications for coronary incidence.

DIABETES Effects of OCs on glucose tolerance are less consistently demonstrated (46, 54, 56). Induced carbohydrate intolerance in women is important because diabetes exerts a greater influence, as regards CV sequelae, in women than in men (42). Development of overt di abetes can, in women, erase their rel a tive immunity to CV mortality compared to that of men (42). Prospective studies have shown that abnormal glucose tolerance is not uncommon in OC users (46, 56). Glucose tolerance curves of a diabetic type may occur in a bout 15%- 20% of OC users (46, 54). Although the long-term implications of these changes are not known, they are a cause for some apprehension. An elevated triglyceride level a nd impaired glucose tolerance due to insulin resistance often go together. It would appear th at the nortestosterone derivatives in certain OCs can, in particul ar, cause deterioration of glucose tolerance, and synt hetic estrogen potentiates this. Abnormal glucose tolerance is more co.mmonly evoked when OCs are prescribed for subjects with a positive family history of di a betes (56) . It is unclear whether OCs increase the risk of persistent diabetes.

COMBINED ATHEROGENIC EFFECTS Although the shifts in BP, blood lipid levels and glucose tolerance mi ght appear to be minor from a

lntj Gynaecol Obstet 16

clinical standpoint, from an epidemiologic point of view the shifts in the entire distribution of the major atherogenic traits in a substantial portion of the female population have ominous implications. Multi variate analysis has shown that shifts of this degree within the population, as an aggregate, would have rather substantial effects on the incidence of CVD (42). Risk mounts precipitously in proportion to the dose of atherogenic traits, and combinations of marginal abnormalities of multiple traits can result in a substantial escalation of risk. OC-induced changes in risk factors could have different implications from these which occur spontaneously, but we cannot assume this to be the case.

INTRAVASCULAR COAGULATION In addition to worsening atherogenic traits, OCs may affect blood clotting, fibrinolysis and platelet adhesiveness (6, 24). The increased risk of thromboembolic CV catastrophies in an OC user of childbearing age has been shown to be independent of the coexisting CV risk factors. This unique effect may well be its influence on intravascular coagulation a nd on the histochemistry and anatomy of the blood vessels. A large number of aberrations in the process of blood coagulation have been noted including: an increased platelet stickiness, possible elevation of platelet counts, a rise in prothrombin and increases in factors 7, 8, 9 and lO (6, 24). Depression in a ntithrombin 3, which is responsible for 70% of the plasm a antithrombin activity, has also been noted (6, 24), as has a reduction in fibrinolytic activity in the walls of superficial veins. Thus, estrogen increases the tendency of the blood to clot and of platelets to aggregate and, at the same time, inhibits fibrinol ys is. These changes could be ominous in persons with a compromised circulation or with multiple atherogenic traits. They have been noted to revert to pretreatment levels within nine months of discontinuing OCs.

VASCULAR EFFECTS Increases in the amount of vascular muscle, a decrease in collagen, fragmentation of reticulum, a marked loss of mucopolysaccharides and loss of elastic tissue have all been induced in animals on administration of OC hormones (9, 10, 36, 37). Inflammatory lesions which resemble polyarteritis nodosa have also been produced (9). Structural and histochemical vascular changes have also been noted at postmortem in women on

OC hypertension and thromboembolism

OCs who died unexpectedly of thromboembolic disease. Atherosclerosis was not a common finding in these cases (41, 43). Other changes, similar to those noted in animals, were found in the vascular intimae of these young victims of OC use. Venous stasis may predispose to venous thrombosis in the lower extremities as a consequence of estrogen-induced decrease in vascular smooth muscle tone. Pooled serum from OC users promotes proliferation of arterial smooth muscle cells in culture, a phenomenon which is a prominent feature of atherogenesis. Although primarily responsible for the vascular catastrophies occurring during the childbearing age, the vascular and clotting aberrations may also contribute to an accelerated atherogenesis to become clinically manifest beyond the reproductive stage of life.

CARDIOVASCULAR HAZARDS Left uncontrolled, the adverse effect ofOC use on atherogenic traits, on clotting and on the blood vessels themselves threatens to eradicate the normal female advantage over men in CV mortality. Thus far, trends in overall mortality and in CV mortality show nothing alarming (65). In fact, mortality has been declining since 1968 in women as well as men, despite widespread use of OCs. Nevertheless, prospective studies now corroborate retrospective reports of a substantially increased risk of thromboembolic disease (4, 7, 22, 25, 30, 47). Serious cardiac and vascular side effects indude thrombophlebitis in the legs, pulmonary emboli, strokes and coronary attacks (32, 38, 40, 41, 52, 54, 62- 64). While women are still at the childbearing age, OC use is associated with a four- to 11-fold increased risk of coronary and circulatory disease (5, 25, 62). Venous thromboembolic disease is 4- 9 times as common as judged from data on hospitalizations, development of pulmonary embolism and postsurgical thromboembolic complications (5, 18, 25, 62, 63, 66) . Strokes and coronary attacks have increased about fourfold (50). The data connecting strokes and OC use in the reproductive age span of women are not entirely consistent, although most reports show a positive correlation. The association of OC use with coronary attacks is more consistently reported (38- 40). There is about a threefold excess risk overall. The absolute risk i~creases with age, but, except for fatal attacks, the relative risk seems constant. At any age, the risk is greater in OC users and varies widely depending on associated CV risk factors. Smoking, in particular,

469

has a distinctly pernicious synergistic effect. Women who use OCs and also smoke have over a threefold greater chance of death from coronary attacks or other circulatory disorders than OC users who do not smoke (Table IV). Those who both smoke and use OCs have ten times the mortality from coronary and circulatory disorders of those who neither smoke nor use OCs. This reaches significant proportions beyond age 35 when the risk exceeds that of childbearing and delivery. Since about 30%-40% of OC users also smoke and OC users are more likely to smoke than those who do not use the pill, this is a serious problem . Although the relative risk ofOCs is substantial, the absolute risk during the childbearing age is small compared to the risk of mortality of 22/100 000 for unwanted pregnancy and childbirth, even excluding illegal abortions (4, 26, 38, 40). In older women (4044 years) who also smoke, the risk of mortality exceeds that of pregnancy and other birth control methods. In heavy smokers (> 15 cigarettes/ day) the risk is about three times that of childbirth (22, 27, 30, 32, 58-60). Even for nonsmokers over 40 years of age, the risk of OCs is higher than for other methods, but this risk is relatively low and lower than that of childbirth . In addition to cigarettes, ethanol may be dangerous since it tends to aggravate OC-induced hypertriglyceridemia. Although the elevated level of CV risk factors appears to be reversible on discontinuing OCs, it is not likely that the accelerated atherogenesis promoted over decades of OC use is as readily reversed.

PREVENTIVE IMPLICATIONS Women have long enjoyed a relative immunity to CVD compared to men. The lag in incidence for CVD in general is about ten years (42). For myocardial infarction and for sudden death, in particular, the female advantage is 20 years. This female advantage is not entirely a consequence of a lesser exposure to CV risk factors. For any level or combination of risk factors , women have a distinct advantage over men (42) . However, the risk in women Table IV. Death rates for OC users according to cigarette smoking status8 • Death Rate per 100 000 Age (years) 30-34 35-39 40-44

Nonsmokers

2

Smokers (>15 cigarettes/day)

4

16 23

7

83

• Source: A. K. Jain, The Population Council.

lnt J Gynaecol Obstet 16

470

Kannel

is still related to the same risk factors as in men, to the same degree on a relative scale, comparing those with and without the risk factor in each sex. A few conditions are capable of obliterating this female advantage: diabetes, familial hypercholesterolemia, the menopause and advanced age. On undergoing the menopause, women in the Framingham Study escalated their risk three times that of those who continue premenopausal at the same age. One might assume that the use of estrogen would counteract this loss of immunity. However, the opposite appears to apply. Now there is a new threat to this female resistance to CVD which may not become apparent for decades to come. Disquieting reports continue to appear heralding adverse effects of OCs on the major CV risk factors, on blood coagulation and on the blood vessels themselves. These have been accompanied by thromboembolic events during the childbearing age. With an already substantial and apparently still growing percentage of the female population likely to be taking OCs for most of their reproductive lives, it is conceivable that we may be headed for an escalation of female CV morbidity and mortality. No contraceptive known at the present time is accompanied by a death rate comparable to that of pregnancy itself. However, there is a need for more specific guidelines for monitoring women on OCs for worsening of their CV risk profile and for changes in blood coagulation. Indications and contraindications for OC use in relation to the hazard of thromboembolic sequelae need to be more explicitly defined. Women taking OCs should be made aware of the risks involved, so that they will recognize the need for periodic surveillance and more readily accept alternative contraceptives if contraindications exist or occur during OC use. OCs should not be prescribed casually. Once they are prescribed, the woman's BP, blood lipids and glucose tolerance should be periodically checked, even if there is no history of abnormality. If a worsening of the CV risk profile occurs, the OCs should be discontinued. OC use would appear imprudent for women with a history of hypertension, toxemia and excessive weight gain with the menses. Special care is needed with blacks, diabetics and the obese. Women who will not give up smoking should not receive OCs. In view of the dose-related effect, preparations with the lowest effective dose of estrogen should be used. Because of enhanced clotting, OCs should be discontinued before elective surgery and prolonged immobilization or after major trauma. Prescription without automatic refill helps ensure return. for necessary surveillance. lnt j Gynaecol Obstet 16

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OC hyper/ens ion and thromboembolism

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68.

69. 70. 71.

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Address for reprints: W. B. Kannel Framingham Heart Study 118 Lincoln St Framingham, MA 01701 USA

Oral contraceptive hypertension and thromboembolism.

Int J Gynaecol Obstet 16: 466- 4 72, 1979 Oral Contraceptive Hypertension and Thromboembolism W. B. Kannel Framingham H eart Study of the National H...
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