PREVENTIVE
MEDICINE
5,
15-19(1976)
Overview: Pulmonary Embolism Mortality in Relation to Oral Contraceptive Use1 PHILIP JAMES
ANN
H.
E. SARTWELL, A. TONASCIA,
PAUL
D.
STOLLEY~,
S. TOCKMAN, RUTLEDGE AND DEBRA WERTHEIMER MELVYN
Departments of Epidemiology and Biostatistics The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205
United States mortality trends due to pulmonary embolism during the period 1%0-1972 were analyzed to determine if death trends were consistent with the hypothesis that mortality would be reduced among females with a switch to the lower estrogen oral contraceptives during the end of the 1960sand early 1970s. Data were consistent with this hypothesis, but must be interpreted cautiously.
In 1968 and 1%9, there appeared several reports on the increased mortality rates in the United Kingdom and the United States from conditions related to intravascular thrombosis among females of reproductive age (1, 2, 4). These increases were considered to be a possible result of the introduction of oral contraceptives. For example, Sartwell and Anello, in a report to the Advisory Committee on Obstetrics and Gynecology of the Food and Drug Administration, examined the trends of mortality from thromboembolic conditions in the United States (2). Two time periods were selected: 1956 to 1961, and 1%2 to 1966, the latter coinciding with a sharp rise in the use of oral contraceptives. Over the age span from 15 to 65 years, the mortality increased in both periods and in both sexes; but the increase was generally greater in the second period, and in females. Over the period 1960to 1966, the regression slopes of death rates from thromboembolic conditions and from pulmonary embolism and infarction were generally steeper in white females than in males, although a majority of the differences were not statistically signifcant. (As there were only seven points on which the regressions were determined, the inability to attribute statistical significance to the differences is not surprising.) On the other hand, at ages 15 to 24, the slope of male rates was slightly higher than that for females, and the female slope was greater in the age class 45 to 54; both of these observations must be considered inconsistent with the hypothesis. 1 This work was suppofied by Contract No. NIH-71-2296 with the National Institutes of Health, U.S. Department of Health, Education, and Welfare. * Address reprint requests to Paul D. Stolley, M.D., Associate Professor, Department of Epidemiology, The Johns Hopkins University, School of Hygiene and Public Health, 615 North Wolfe Street, Room 6207, Baltimore, Maryland 21205. 15 Copyright @ 1976by AcademicPress, Inc. AU rights of reproduction in any form reserved.
16
SARTWELL
ET AL..
Six further years’ mortality experience having become available, it seemed worthwhile to examine any further changes in this pattern. The data to be presented are based on mortality rates ascribed to pulmonary embolism and infarction, number 465 in the seventh revision of the International List and number 450 in the eighth. Four 3-year periods were chosen: 1961-1963, 1964-1966, 19671%9, and 1970-1972. The female/male ratio of rates was calculated for each time period and four age groups, separately for whites and other races (see Fig. 1). The ratios for white persons have somewhat greater stability because they are based on larger numbers: the total number of U. S. deaths due to pulmonary embolism among white persons aged 15-54 during 1960-1972 was 11,537, whereas the corresponding figure for nonwhites was 4,410. For age groups 15-24 and 25-34, there is a sharp increase in the ratio in the 1964-1966 period over the preceding period, and then a fall. At ages 354t, such a pattern is not observed, and in age group 45-54, there is no excess of female over male rates. The interpretation of these changes is hazardous. In the authors’ opinion, they are consistent with the view that oral contraceptives have somewhat increased the mortality in females from this condition. If this interpretation is accepted, then it must be further stated that since the 1967-1969 period there have been improvements in the safety of this form of contraception. Two such improvements are known to have occurred. One is the reduction in the amount of estrogen in the pill. In 1965, about two-thirds of oral contraceptive sales in the United States were for formulations containing 100 mcg or more of estrogen. In 1972, this situation had reversed and two-thirds of all sales were for formulations containing less than 100 mcg, and only one-third contained 100 mcg or more (see Fig. 2).
IS-,?4
t5-3
35-11
45-54
M-2.
2.5-34
3.5-1.
45-5.
AGES
FIG. 1. Ratios of female to male death rates from pulmonary embolism and infarct (ICDA #465, 7th rev., and #450,8th rev.) in the United States in four time periods and four age groups, for whites and nonwhites.
CONTRACEPTIVES
AND
PULMONARY
EMBOLISM
17
The other is the greater recognition of the inadvisability of prescribing this form of contraception for women who may be predisposed to venous thrombosis. The latter change has recently been documented by Stolley, Tonascia et al (3). The fact that the female/male ratio remained at 1.5 in the last period for women in the child-bearing period, but never exceeded unity in the 45-54 year age span, may indicate that there is still an appreciable hazard from the oral contraceptives. The yearly death rates for pulmonary embolism and infarction from 1960to 1972 for white females and males of the four age classes are shown on a logarithmic scale in Fig. 3. All the slopes are upward, and the increase in mortality over this 1Zyear interval averaged more than twofold. No adequate explanation for the general rise in mortality from this cause and other components of thromboembolic disease can be offered. There are, of course, some possibilities other than a genuine increase. The rise may, for instance, reflect more frequent diagnosis of pulmonary embolism and infarction from increased use of diagnostic aids such as isotopic lung scanning and pulmonary angiography. It is doubtful this could explain a major part of the increase for two reasons: a large proportion of the deaths occur before there is time to employ these diagnostic aids, and they were not widely available until recently. Data for other thromboembolic conditions were assembled, but were not used in this report because a) it seems unlikely that many deaths resulting from thrombosis would occur that did not have pulmonary embolism as the immediate cause of death, b) because such deaths are very few in number, and c), because the resulting rates were less stable than for pulmonary embolism and infarction. It would have been desirable to study cerebral thrombosis, but a change in coding practices made this impracticable. One should note that even if oral contraceptives are still responsible for some excess mortality from thromboembolic conditions, they may have an overall life-
%
FIG. 2. Estimated annual prescriptions (both new and refdls) of oral contraceptives in the United States (estimates from sales data), 1%5 through 1974, by estrogenic content.
18
SARI-WELL
40 -45-w
FEMALES
--- 35-44 “...... p-34
30
04 o3
ET AL
1
.. . .. . .. .,'.
-45-w ---x2-44
.."'
...... .. 25.3.J .-.-. 15-24
.A..
....... /. .' ..
..i' A'\.
,./'
MALES
FIG.3. Trend of mortality from pulmonary embolism and infarct in white females and males, by year, from l%O to 1972 inclusive (upper panel, females; lower panel, males). NOTE: The rate for males 15-24was less than 0.1 in the years l%O through 1964(plotted on semi-logarithmic scale).
sparing effect, since they have the highest contraceptive use-effectiveness and thereby reduce the risk of the life-threatening complications of pregnancy. Finally, the secular trends in mortality attributed to pulmonary embolism must be interpreted with great caution due to the many uncertainties in diagnosis and certification of cause of death. Furthermore, with newer diagnostic aids such as angiography and lung scanning, it is possible that more cases are being diagnosed in recent years. Nevertheless, it is believed a study of these mortality patterns, particularly the female/male ratios, contributes in a small way to the further understanding of the risks of oral contraceptives and, therefore, a further analysis was worthwhile as a follow-up to the paper of Sartwell and Anello (2) now that the majority of oral contraceptive users had switched to the lower estrogen formulations . ACKNOWLEDGMENTS The authors would like to express their appreciation to the National Center for Health Statistics and to Mr. Frank Osgood and Ms. Barbara Johannsen of IMS America Ltd., for their assistance in this work.
CONTRACEPTIVES
AND
PULMONARY
EMBOLISM
19
REFERENCES 1. Markosh, R., and Seigel, D. Oral contraceptives and mortality trends from thromboembolism in the United States. Amer. J. Pub. He&h 59,418-434 (1%9). 2. Sartwell, P. E., and Anello, C. Trends in mortality from thromboembolic diseases, in “Second Report on the Oral Contraceptives,” by Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, pp. 37-40, Government Printing Oftice, Washington, D. C., 1969. 3. StoUey, P. D., Tonascia, J. A., To&man, M. S., Sartwell, P. E., Rutledge, A. H., and Jacobs, M. P. Thrombosis with low-estrogen oral contraceptives. Amer. J. Epidemiol. 102,197-208 (1975). 4. Vessey, M. P., and Weather& J. A. C. Venous thromboembolic disease and the use of oral contraceptives. Lancer 2, 94-95 (1968).
MEDICINE
5,
15-19(1976)
Overview: Pulmonary Embolism Mortality in Relation to Oral Contraceptive Use1 PHILIP JAMES
ANN
H.
E. SARTWELL, A. TONASCIA,
PAUL
D.
STOLLEY~,
S. TOCKMAN, RUTLEDGE AND DEBRA WERTHEIMER MELVYN
Departments of Epidemiology and Biostatistics The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205
United States mortality trends due to pulmonary embolism during the period 1%0-1972 were analyzed to determine if death trends were consistent with the hypothesis that mortality would be reduced among females with a switch to the lower estrogen oral contraceptives during the end of the 1960sand early 1970s. Data were consistent with this hypothesis, but must be interpreted cautiously.
In 1968 and 1%9, there appeared several reports on the increased mortality rates in the United Kingdom and the United States from conditions related to intravascular thrombosis among females of reproductive age (1, 2, 4). These increases were considered to be a possible result of the introduction of oral contraceptives. For example, Sartwell and Anello, in a report to the Advisory Committee on Obstetrics and Gynecology of the Food and Drug Administration, examined the trends of mortality from thromboembolic conditions in the United States (2). Two time periods were selected: 1956 to 1961, and 1%2 to 1966, the latter coinciding with a sharp rise in the use of oral contraceptives. Over the age span from 15 to 65 years, the mortality increased in both periods and in both sexes; but the increase was generally greater in the second period, and in females. Over the period 1960to 1966, the regression slopes of death rates from thromboembolic conditions and from pulmonary embolism and infarction were generally steeper in white females than in males, although a majority of the differences were not statistically signifcant. (As there were only seven points on which the regressions were determined, the inability to attribute statistical significance to the differences is not surprising.) On the other hand, at ages 15 to 24, the slope of male rates was slightly higher than that for females, and the female slope was greater in the age class 45 to 54; both of these observations must be considered inconsistent with the hypothesis. 1 This work was suppofied by Contract No. NIH-71-2296 with the National Institutes of Health, U.S. Department of Health, Education, and Welfare. * Address reprint requests to Paul D. Stolley, M.D., Associate Professor, Department of Epidemiology, The Johns Hopkins University, School of Hygiene and Public Health, 615 North Wolfe Street, Room 6207, Baltimore, Maryland 21205. 15 Copyright @ 1976by AcademicPress, Inc. AU rights of reproduction in any form reserved.
16
SARTWELL
ET AL..
Six further years’ mortality experience having become available, it seemed worthwhile to examine any further changes in this pattern. The data to be presented are based on mortality rates ascribed to pulmonary embolism and infarction, number 465 in the seventh revision of the International List and number 450 in the eighth. Four 3-year periods were chosen: 1961-1963, 1964-1966, 19671%9, and 1970-1972. The female/male ratio of rates was calculated for each time period and four age groups, separately for whites and other races (see Fig. 1). The ratios for white persons have somewhat greater stability because they are based on larger numbers: the total number of U. S. deaths due to pulmonary embolism among white persons aged 15-54 during 1960-1972 was 11,537, whereas the corresponding figure for nonwhites was 4,410. For age groups 15-24 and 25-34, there is a sharp increase in the ratio in the 1964-1966 period over the preceding period, and then a fall. At ages 354t, such a pattern is not observed, and in age group 45-54, there is no excess of female over male rates. The interpretation of these changes is hazardous. In the authors’ opinion, they are consistent with the view that oral contraceptives have somewhat increased the mortality in females from this condition. If this interpretation is accepted, then it must be further stated that since the 1967-1969 period there have been improvements in the safety of this form of contraception. Two such improvements are known to have occurred. One is the reduction in the amount of estrogen in the pill. In 1965, about two-thirds of oral contraceptive sales in the United States were for formulations containing 100 mcg or more of estrogen. In 1972, this situation had reversed and two-thirds of all sales were for formulations containing less than 100 mcg, and only one-third contained 100 mcg or more (see Fig. 2).
IS-,?4
t5-3
35-11
45-54
M-2.
2.5-34
3.5-1.
45-5.
AGES
FIG. 1. Ratios of female to male death rates from pulmonary embolism and infarct (ICDA #465, 7th rev., and #450,8th rev.) in the United States in four time periods and four age groups, for whites and nonwhites.
CONTRACEPTIVES
AND
PULMONARY
EMBOLISM
17
The other is the greater recognition of the inadvisability of prescribing this form of contraception for women who may be predisposed to venous thrombosis. The latter change has recently been documented by Stolley, Tonascia et al (3). The fact that the female/male ratio remained at 1.5 in the last period for women in the child-bearing period, but never exceeded unity in the 45-54 year age span, may indicate that there is still an appreciable hazard from the oral contraceptives. The yearly death rates for pulmonary embolism and infarction from 1960to 1972 for white females and males of the four age classes are shown on a logarithmic scale in Fig. 3. All the slopes are upward, and the increase in mortality over this 1Zyear interval averaged more than twofold. No adequate explanation for the general rise in mortality from this cause and other components of thromboembolic disease can be offered. There are, of course, some possibilities other than a genuine increase. The rise may, for instance, reflect more frequent diagnosis of pulmonary embolism and infarction from increased use of diagnostic aids such as isotopic lung scanning and pulmonary angiography. It is doubtful this could explain a major part of the increase for two reasons: a large proportion of the deaths occur before there is time to employ these diagnostic aids, and they were not widely available until recently. Data for other thromboembolic conditions were assembled, but were not used in this report because a) it seems unlikely that many deaths resulting from thrombosis would occur that did not have pulmonary embolism as the immediate cause of death, b) because such deaths are very few in number, and c), because the resulting rates were less stable than for pulmonary embolism and infarction. It would have been desirable to study cerebral thrombosis, but a change in coding practices made this impracticable. One should note that even if oral contraceptives are still responsible for some excess mortality from thromboembolic conditions, they may have an overall life-
%
FIG. 2. Estimated annual prescriptions (both new and refdls) of oral contraceptives in the United States (estimates from sales data), 1%5 through 1974, by estrogenic content.
18
SARI-WELL
40 -45-w
FEMALES
--- 35-44 “...... p-34
30
04 o3
ET AL
1
.. . .. . .. .,'.
-45-w ---x2-44
.."'
...... .. 25.3.J .-.-. 15-24
.A..
....... /. .' ..
..i' A'\.
,./'
MALES
FIG.3. Trend of mortality from pulmonary embolism and infarct in white females and males, by year, from l%O to 1972 inclusive (upper panel, females; lower panel, males). NOTE: The rate for males 15-24was less than 0.1 in the years l%O through 1964(plotted on semi-logarithmic scale).
sparing effect, since they have the highest contraceptive use-effectiveness and thereby reduce the risk of the life-threatening complications of pregnancy. Finally, the secular trends in mortality attributed to pulmonary embolism must be interpreted with great caution due to the many uncertainties in diagnosis and certification of cause of death. Furthermore, with newer diagnostic aids such as angiography and lung scanning, it is possible that more cases are being diagnosed in recent years. Nevertheless, it is believed a study of these mortality patterns, particularly the female/male ratios, contributes in a small way to the further understanding of the risks of oral contraceptives and, therefore, a further analysis was worthwhile as a follow-up to the paper of Sartwell and Anello (2) now that the majority of oral contraceptive users had switched to the lower estrogen formulations . ACKNOWLEDGMENTS The authors would like to express their appreciation to the National Center for Health Statistics and to Mr. Frank Osgood and Ms. Barbara Johannsen of IMS America Ltd., for their assistance in this work.
CONTRACEPTIVES
AND
PULMONARY
EMBOLISM
19
REFERENCES 1. Markosh, R., and Seigel, D. Oral contraceptives and mortality trends from thromboembolism in the United States. Amer. J. Pub. He&h 59,418-434 (1%9). 2. Sartwell, P. E., and Anello, C. Trends in mortality from thromboembolic diseases, in “Second Report on the Oral Contraceptives,” by Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, pp. 37-40, Government Printing Oftice, Washington, D. C., 1969. 3. StoUey, P. D., Tonascia, J. A., To&man, M. S., Sartwell, P. E., Rutledge, A. H., and Jacobs, M. P. Thrombosis with low-estrogen oral contraceptives. Amer. J. Epidemiol. 102,197-208 (1975). 4. Vessey, M. P., and Weather& J. A. C. Venous thromboembolic disease and the use of oral contraceptives. Lancer 2, 94-95 (1968).
