Oral Contraceptives Found to Increase Sharply Risk of Heart Attacks, Especially AmongWomen 40 or Older and SmokersSource: Family Planning Perspectives, Vol. 7, No. 4 (Jul. - Aug., 1975), pp. 145-147Published by: Guttmacher InstituteStable URL: http://www.jstor.org/stable/2133885 .

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Covering the key meetings, conferences, journals and special reports of interest to and use for program workers and researchers in the family planning and population fields

Following Year-Long Moratorium, DHEW Will Again Fund Live Fetal Research Projects; New Regulations Approved The Department of Health, Education and Welfare has lifted its year-long mora- torium on live fetal research and ap- proved new regulations governing DHEW-supported research that involves the fetus, the pregnant woman and the products of in vitro fertilization. The new regulations became final August 8 upon publication in the Federal Register. With few exceptions, the new regulations follow the recommendations made two months earlier by the National Commis- sion for the Protection of Human Sub- jects, which were published with the new rules. The rules reject the views expressed by antiabortion groups that no fetal re- search related to abortion can be lawful since, they allege, a fetus cannot give con- sent, and a woman planning an abortion has abrogated any right she may have to consent to the study of her fetus. The new DHEW rule states that a woman "need not be presumed to lack interest in her fetus even when she has decided to termi- nate her pregnancy; thus, she may validly be asked for consent for research involv- ing the fetus." The rules ban experiments that "of themselves would terminate the

heartbeat or respiration of a fetus," or that would artificially maintain the vital fuinctions of a nonviable fetus, except "to develop new methods for enabling fetuses to survive to the point of viability."

As a "guideline" for determining viabil- ity, the DHEW Secretary said that "an es- timated gestational age of 20 weeks or more and a body weight of 500 grams" may indicate that a live fetus is viable. Al- though the National Commission had found no instance in which an infant had survived who was of less than 24 weeks' gestational age and weighed less than 600 grams, it had also recommended restrict- ing nontherapeutic research to fetuses at the lower gestational age and body weight limits to ensure against the possibility of mistaken gestational age, and consequent harm to an infant that may be born live and survive past birth.

Reference

1. Department of Health, Education and Wel- fare, Office of the Secretary, "Protection of Human Subjects: Fetuses, Pregnant Women and In Vitro Fertilization," Federal Register, 40:33525, Aug. 8, 1975.

Fetal research has made possible safer delivery of babies, safer labor for mothers. Photo above shows electronic monitoring of fetus's vital functions.

Oral Contraceptives Found to In crease Sharply Risk of Heart Attacks, Especially Among Women 40 or Older and Smokers The U.S. Food and Drug Administration is drawing up new labeling to alert physi- cians to research findings from Britain associating use of the oral contraceptive with increased risk of heart attack, espe- cially among women more than 40 years of age and among women who already have conditions that predispose them to heart attacks (see Table 1).' The reports agree that heart attacks are rare events among women of reproductive age, and that when they occur they are often asso- ciated with such risk factors as hyperten- sion, obesity, smoking, diabetes and high cholesterol levels, as well as with oral con-

traceptives. (According to the National Heart and Lung Institute, heart attacks are such rare events among U.S. women under 35 years of age that it is virtually impossible to estimate a rate of occur- rence. Among women aged 35-39, the rate is an estimated 5 per 100,000 a year and among women aged 35-44 it is about 35 per 100,000.2)

A retrospective study on nonfatal myo- cardial infarctions (damage to the heart muscle from a blocked artery), reported by J. I. Mann, M. P. Vessey, M. Thoro- good and R. Doll in the British Medical Journal, involved 63 women treated for

infarctions in various British hospitals between 1968 and 1972, and 174 matched controls.3 The latter were selected from among women discharged from the same hospitals following treatment for unre-

Table 1. Annual rate of hospital admissions for nonfatal myocardial infarction and an- nual rate of fatal myocardial infarction per 100,000 married women who never used the pill compared with current pill users, by age

Age Nonfatal rate Fatal rate Non- Users Non- Users users users

30-39 2.1 5.6 1.9 5.4 40-44 9.9 56.9 11.7 54.7 Source: See references 3 and 5.

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DKS6ST lated ailments. All of the women were married and were less than 45 years of age. Information on socioeconomic status, number of children and medical history was obtained by means of interviews and mailed questionnaires, and the medical history elicited data on the risk factors. This information was supplemented, when necessary, with data obtained from physicians. The investigators found that "the relative risk [ratio of pill users to con- trols] of admission for myocardial infarc- tion in women who had been using oral contraceptives in the previous month compared with that in women who had never used them is estimated. . . to be 4.5 to 1 ."

In addition, such risk factors as ciga- rette smoking, hypertension, toxemia and obesity were found more often among the heart attack group than among the con- trols. Cigarette smoking was not only re- ported more often by the heart attack pa- tients than by the controls, but more of the former were moderately heavy or heavy smokers. In comparison with non- smokers, the investigators reported, the relative risk increased from 1.2 to 1 in women smoking fewer than 15 cigarettes a day, to 4.1 to 1 in women smoking 15-24 a day, and it increased steeply to 11.3 to 1 in women smoking 25 or more a day. While most of the other risk factors had only a slight effect on the relative risk of heart attack associated with pill use, ciga- rette smoking had a marked effect: When the figures were standardized for cigarette smoking (excluding other risk factors), the relative risk for pill users (as compared with never-users) was found to be reduced from 4.5 to 1 to just 3.2 to 1.

Few women who had experienced a myocardial infarction had only one risk factor, however. Most had two or more, the study found, of the following: a type of high blood cholesterol, hypertension, obesity, smoking more than 15 cigarettes a day, diabetes and pill use. Women with one risk factor were more than four times as likely to have an infarction than wom- en with no risk factors; those with two risk factors had 10.5 times the risk; and wom- en with three or morefactors had 78 times the risk.

"The strong suggestion that the com- bined effect of risk factors is synergistic

may have important practical implica- tions for the use of oral contraceptives," the investigators pointed out. "The appre- ciable increase in relative risk in women with more than one risk factor for myo- cardial infarction suggests that other methods of contraception should be con- sidered in such cases."

These findings confirm a previous smaller study (reported by M. F. Oliver in the British Medical Journal) of 31 women under 45 years of age who were admitted between 1964 and 1972 to the coronary care unit of the Royal Infirmary in Edin- burgh, Scotland, with myocardial infarc- tion.4 Sixteen, or 52 percent, were pill users. However, the investigator ob- served, "Only two of these 16 women had no major risk factor and nine of the 16 had two or more major risk factors.... This suggests that oral contraceptives in- crease the risk of myocardial infarction only in those women who already have a high risk for the development of [heart disease]." He concluded: "It is not sug- gested that oral contraceptives alone in- crease the risk of myocardial infarction."

Fatal Heart Attacks

A parallel study to that of nonfatal heart attack, reported by Mann and W. H. W. Inman in the British Medical Journal, found that the annual rate of fatal myo- cardial infarction per 100,000 women was similar to the rate of nonfatal infarctions, as Table 1 shows.5 "It seems . . . that the risk of death from myocardial infarction was increased about 2.8 times in current users of oral contraceptives aged 30-39 years and about 4.7 times in women aged 40-44 years," the investigators noted. "In absolute terms," they found, there was "an excess of 3.5 [pill-attributable] deaths per 100,000 users [aged 30-39] yearly . . . and 43 per 100,000 users yearly" among women aged 40-44. (The 1973 mortality rate from acute myocardial infarction among U.S. women aged 35-44 was 12 per 100,000, according to the American Heart Association, while it was less than two per 100,000 among women younger than 35 years of age.6)

The histories of 153 women under 50 years of age who had died in 1973 of myo- cardial infarction were compared with those of 196 living controls selected from the records of the general practitioners who had treated the deceased women. All were matched for marital status and for approximate age.

The investigators found that more than

twice as many of the deceased had been pill users within a month of their death than were the controls (21.4 percent com- pared with 10.5 percent). Among the women under 40 years of age, 44.7 per- cent of the deceased had been users, com- pared with 22.4 percent of the controls; among women iged 40-44, 15.4 percent of the cases had been users, compared with 3.8 percent of controls. The propor- tions of former users were not appreciably different among cases and controls in both age groups. The investigators also ex- amined duration of pill use, and found that the myocardial infarction victims "had been using the preparations on aver- age for longer than the control women." Overall, 70 percent of the pill users among the fatal heart attack victims had been taking oral contraceptives for more than two years, compared with 42 per- cent of the pill users among the controls. A possible confounding effect by other risk factors such as diabetes and hyperten- sion was looked for, but none was found, the investigators reported.

"These results suggest that there is an increased risk of death from myocardial infarction in women using oral contracep- tives," Mann and Inman concluded. They pointed out, however, that

an investigation of this type can provide little evidence of the mech- anism by which oral contraceptives give rise to a risk.... The fact that the patients with infarction had been using them longer on average than the control patients may sug- gest that their use contributes to the atherogenic processes [arteriosclero- sis]. It must be noted, however, that current use of oral contraceptives was more important than use at some time in the past. Moreover, 83 percent of the necropsy reports on women who had been using oral contraceptives at the time of death mentioned a thrombus in the coro- nary arteries, whereas only 55 per- cent of the reports on patients who had not been using the preparations mentioned this finding. . . . These two observations . .. weigh in favor of the hypothesis that a thrombotic tendency rather than increased atheroma explains, at least to some extent, the increased risk attributed to the use of these drugs.

In an editorial in the New England Jour- nal of Medicine reviewing the myocardial infarction reports, Samuel Shapiro of the

146 Family Planning Perspectives

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Boston University Medical Center empha- sized the importance of the risk factors, noting that "the findings strongly suggest that in women below the age of 45 years, oral contraceptives act synergistically with other risk factors, rather than simply additively, to produce myocardial infarc- tion."7 He urged further studies to con- firm the association, including a multi- center case-control study to produce num- bers large enough to yield precise quanti- tative evaluation of the synergism. He called the estimated excess incidence rate of 3.5 per 100,000 users per year, each, of fatal and nonfatal myocardial infarction among women aged 30-39 "reassuring," but said that "for women over the age of 40 . . . it is a matter of opinion whether the risk [about 45 fatal and 45 nonfatal infarctions per 100,000 users per year] can be considered acceptably low."

Synergism Found Also for Stroke Another recent study pinpoints the extent to which predisposing factors such as hypertension, smoking and migraine headache increase the risk of strokes among pill users. The researchers point out, however, that their data are based on relative risks only; the "absolute risk of incidence of thrombotic stroke per year in young women taking oral contraceptives

has been estimated to be 1/10,000." The Collaborative Group for the Study

of Stroke in Young Women matched 598 women aged 15-44 who were discharged from 91 U.S. hospitals after being treated for stroke with two control groups of the same age and race. One control group was selected from among other hospital patients, the other from among the stroke patients' neighbors. Among the Collabo- rative Group's findings, published in the Journal of the American Medical Associa- tion, are the following:8 * Among pill users, hypertension in- creases the risk of developing thrombotic stroke (caused by a blood clot) as well as hemorrhagic stroke (caused by a rupture of a blood vessel). The relative risk of thrombotic stroke rose from 3.1 to 1 among pill users with normal blood pres- sure readings to 8.9 to 1 among those with moderately high blood pressure, and to 13.6 to 1 among those with severe hyper- tension. (Among nonusers of the pill, the relative risk increased from 1.3 to 1 among those with mild hypertension to 6.9 to 1 among those with severe hyper- tension.) The study suggests that the hy- pertension itself is the major risk factor. * Pill users and nonusers run approxi- mately the same risk of hemorrhagic stroke if they never smoked cigarettes. But while former and current smokers who do

not use the pill have about twice the risk of developing hemorrhagic stroke as non- smokers, pill users who smoke have about five times the risk of nonsmokers. * The combination of migraine and cur- rent use of the oral contraceptive pro- duced a significant rise in the risk for thrombotic (but not hemorrhagic) stroke.

References

1. Food and Drug Administration, July 25, 1975, personal communication.

2. T. Gordon, National Heart and Lung Insti- tute, July 31, 1975, personal communication.

3. J. I. Mann, M. P. Vessey, M. Thorogood and R. Doll, "Myocardial Infarction in Young Women with Special Reference to Oral Contraceptive Practice," British Medical Journal, 2:241, 1975.

4. M. F. Oliver, "Ischaemic Heart Disease in Young Women," British Medical Journal, 4:253, 1974.

5. J. I. Mann and W. H. W. Inman, "Oral Con- traceptives and Death from Myocardial Infarc- tion," British Medical Journal, 2:245, 1975.

6. W. Mellinger, American Heart Association, July 30, 1975, personal communication.

7. S. Shapiro, "Oral Contraceptives and Myo- cardial Infarction," editorial, New England Jour- nal of Medicine, 293:195, 1975.

8. Collaborative Group for the Study of Stroke in Young Women, "Oral Contraceptives and Stroke in Young Women: Associated Risk Factors," Jour- nal of the American Medical Association, 231: 718, 1975.

Very Young or Old Maternal Age and Close Pregnancy Spacing Are Key Factors in Mortality of Mothers, Infants

Although pregnancy and its outcome are influenced by all the circumstances of life -cultural practice, genetic disposition, nutrition, health, hygiene, housing, med- ical care and maternal competence-ma- ternal age is a central variable influencing pregnancy outcome. Thus, while socio- economic factors influence the level of risk to both mother and child, these risks vary with maternal age whatever the overall level of health care. This is the conclusion drawn by Dorothy Nortman of The Popu- lation Council, following analysis of more than 60 studies from all parts of the world relating maternal age to various aspects of pregnancy and child development. '

Acknowledging the importance of ma- ternal age (and child spacing) on preg- nancy outcome, another factor-mater- nal nutrition-was emphasized by Colum- bia University investigators, Samuel M. Wishik and Newton S. Lichtblau.' Nort- man pointed out that women in their early twenties generally run the lowest

risk of maternal mortality, fetal mortal- ity, stillbirths and birth defects. Maternal mortality, for example, is lowest when a woman is 22 or 23 years old, regardless of the prevailing mortality level in the coun- try in which she lives. Thus, although a woman bearing a child at the optimum age in a country with poor medical care is likely to run a greater risk of death than an older woman in a country with excel- lent medical care, her chances of dying would be three times as great if she were in her late thirties rather than in her early twenties. In high-mortality countries, poor health care is a major and age a lesser factor contributing to maternal death.

Maternal mortality also varies with birth order, as well as with age. For first and second births, the optimum age is under 20 years; for the third child, it is between 20 and 24; for the fourth and fifth, it is between 25 and 29; and it is be- tween 30 and 34 for higher-order births. This pattern attests "to the importance of

adequate spacing between births." A similar pattern holds true for fetal

mortality, stillbirths, neonatal mortality, perinatal mortality and infant mortality, although with some variation. For first births, the risk of fetal loss is lowest at age 18, rising to 23 for second births, 25 for the third birth and 26 for the fourth. The risk varies with gestational age as well (being higher for gestations under 12 weeks, and decreasing as the fetus ma- tures); but, in general, "the fetus of a younger woman has a much better chance of survival than that of an older woman." Similarly, stillbirths-or late fetal deaths -are less likely when the mother is in her twenties, with the optimum ages of 24 for second births and 26 for higher-order births. For the first birth, however, it appears that the younger the mother, the lower the risk of stillbirth.

Perinatal mortality includes stillbirths and deaths within the first week of life. The major factors in early infant deaths are prematurity and fetal deformity. Thus, Nortman says, "perinatal mortality, like fetal mortality, is heavily weighted

Volume 7, Number 4, July/August 1975 147

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