British Medical Bulletin (1978) VoL 34, No. 2, pp. 137-162
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey &J I Mam regimens have not been reported. Finally, it must be stressed that almost all the published epidemiological investigations have been carried out in wealthy Western countries; it would therefore be quite incorrect to extrapolate the findings to countries such as Africa or India. 1
Oral Contraceptives
a Venous Thrombo-EmboUsm The possibility that oral contraceptives might increase the risk of venous thrombo-embolism was first raised by a case history reported in The Lancet in 1961 (Jordan, 1961). Since that time, thousands of similar case histories have appeared in the medical journals or have been reported to the pharmaceutical manufacturers or to the national bodies responsible for drug safety in different parts of the world1. Evidence for a cause-and-effect relationship, however, has been derived principally from case-control and cohort studies. Table I presents the main features of the published casecontrol studies. These investigations have been reviewed on many previous occasions and do not require detailed consideration here. It may be noted, however, that all the studies indicate an increase in the risk of venous thrombo-embolism in women using oral contraceptives. This increase in risk appears to be greatest (4-11-fold) in studies concerned only with "idiopathic" deep-vein thrombosis or pulmonary embolism. Cohort studies of the relationship between oral contraceptives and venous thrombo-embolism are Tummfl^^d in Table H. In the first of these, almost 10000 Puerto Rkan women seeking birth control advice were allocated at random either to an oral contraceptive (Enovid, 5mg) or to a vaginal contraceptive (Fuertes-de la Haba et al. 1970, 1971). Hospital admissions for venous thrombosis and deaths from any cause occurring among these women were sought by a variety of means. In the second study, 23000 women using oral contraceptives together with a similar number of control subjects using other methods or no method of birth control
M P VESSEY MA MD FFCM J I MANN DM PhD MFCM Department of Social and Community Medicine University of Oxford 1 Oral contraceptives a Venous thrombo-embolism b Stroke c Myocardial infarction and other cardiovascular disease d Conclusion 2 Postmenopausal use of oestrogens References Oral contraceptives have now been in use for almost two decades; throughout most of that period there has been continuing anxiety about their cardiovascular effects. Oestrogens (usually unopposed by progestogens) are also being given increasingly commonly to older women to try to control "menopausal" symptoms and to reduce postmenopausal bone loss. Although most of the anxiety about such therapy centres round endometrial cancer, possible adverse effects on the cardiovascular system must also be considered. In this review, most attention will be concentrated on epidemiological studies of clinical events rather than on the results of laboratory investigations. Furthermore, as far as oral contraceptives are concerned, the findings to be described relate only to preparations containing both an oestrogen and a progestogen; appropriate studies concerning other steroidal
t See Inman, Br. Utd. BtdL 1970,16,248-236.—ED.
TABLE I. Case-control studies of the relationship between oral contraceptives and venous thromboembolism References
Source of data
Royal Cotlen of General PraetWoners. 1967
General practice
Inmta & Vessey, 1968 V « u y * Doll. INS, 19(9 Sartwell et of. 1969
Britain, 1961-66 Deaths in Britain, 1966 Hospital admliriora In Britain, 1964-67 Hospital admissions In
VMMy et of. 1970
USA, 1943-47 Hospital admissions in
ft Westerholm, 1971 • GrMn* & Sartwell, 1972
Britain, 1964-67 Hospital admissions In Sweden, 1964-68 Hospital admissions in
Bosson Collaboi alive Dnif Surveillance Program, 1973 StoOey et a!. 1975
consultations In
USA, 1963-67 Hospital admissions in USA, 1972
Hospital admission In USA, 1970-73
PeJ'Ceiltaje
of cam aJnjOC
Percentage of controls using OC
Retativ* risk, us«rs to nocwaers
72 24
15 21
6 10
3:1 2:1
Fatal Mlopathlc PE Idiopathic deep VT or PE
26 M
16 14
8: 1 6:
/Idiopathic superficial VT \Mlopethlc deep VT or PE Post-operative de«p VT
27 129 30
£2 50 22 41 40
15 15
3: 4: 4: II:
Type of disease studied
/Superficial VT \Other VT or PE
nberof at**
Idlosathk deep VT
84
65
14
Postoperative or posttraumatic deep VT or PE Idiopathic de*p VT
(0
35
17
6:
43
72
20
11:1
Malnlvldlopathtc deep VT
104
57
19
7:1
* Market research data were used for control purposes In this study Abbreviations: OC: oral contraceptives VT: venous thrombosis FT: pulmonary embolism DtSerent methods were used for cocnputltti relative risk In the various studies. The data fhnm In the put cohrnio of the table cannot, thv tfort^ fMcflwiiy o% dcrtvM from the data In the two preceding columns
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FEMALE SEX HORMONES AND THROMBOSIS Epidemiological Aspects
FEMALE SEX HORMONES AND THROMBOSIS M PVessey &J I Mann TABLE II. Cohort studies of the relationship between oral contraceptives and venous thromboembolism (Numbers of cases are In parentheses) Referenc
Source of data
Typo of disease studied
Rate p«r 1000 woman-years In: UnnofOC
Hospital admissions and dtaths in Puerto Rico, 1961-69
Ron! Colltje of General Practitioners, 1974, 1977
Central practice consultations (1968-71) and deaths (1968-76) In Britain
Groundi, 1974
Self-diagnosed disease in Australia, 1969-70 Hospital referrab (1960-75)
r f. 1976; Vasty a al. 1977; Vessey, 1978
and deaths (l96tt-77) In Britain
ridtopathlc VT \FatsjPE fMlopathlc superficial VT I Mlopathlc deep VT 1 "Other" Idlopathic VT LFatal PE "Clots In veins" (I superficial VT) fUiopathlcVT < Post-operative VT* I Fatal PE
1.1:1
0.43 0.00
1.5:1 5.7:1 2.1 :l 0.3:1 0.14 3.01 0X0
6.3:1 2.0:1
* The figures ftven are rates per 1000 surgical operations For abbreviations, see below Table I
four times as many control subjects as oral contraceptive users gave a past history of superficial venous thrombosis; no allowance was made for this difference in the analysis. Fourthly, no data are provided on the disorders other studies have found to be most strongly associated with oral contraceptives, namely deep-vein thrombosis and pulmonary embolism. Fifthly, the diagnosis of "superficial venous thrombosis" depended on the answer given by the patient to the question mentioned earlier; perhaps this is why the incidence of the disorder is so remarkably high. Finally, the British studies are, respectively, about 40 times and 25 times as large as the Australian one. For these reasons, among others, the Australian findings do not weigh heavily against the British ones. In addition to the large-scale cohort studies, mention should be made of an investigation in which the radioactive fibrinogen uptake test was used to diagnose post-operative deep-vein thrombosis (Sagar et al. 1976). It was found that six of 31 young women undergoing emergency abdominal surgery who gave a history of recent oral contraceptive intake developed deep-vein thrombosis in comparison with none of 19 similar patients who had not been using oral contraceptives. Evidence that the oestrogen content of oral contraceptives is an important determinant of the risk of venous thromboembolism was first provided by an analysis of over 1000 reports of thrombo-embolism following the use of oral contraceptives, received by the drug safety committees in the United Kingdom, Sweden and Denmark (Inman et al. 1970). When the different oral contraceptive preparations were grouped according to the dose of the oestrogen component, there was a marked excess of reports associated with those preparations containing a high dose of oestrogen and a marked deficiency associated with those containing a low dose. As a result of this finding, the British Committee on Safety of Drugs issued a recommendation in December 1969 that oral contraceptives containing more than 50 ng oestrogen should not normally be prescribed. This recommendation led to the virtual disappearance of preparations containing a high dose of oestrogen in the United Kingdom from 1970 onwards; prior to that date they hadrepresentedabout 50% of the total sales (Vessey & Tnmnp, 1973). Confirmation of the relationship between thrombo-embolic risk and oestrogen dose was subsequently provided by the Royal College of General Practitioners (1974) and by Stolley et al. (1975).
were brought under observation by 1400 general practitioners throughout Great Britain (Royal College of General Practitioners, 1974,1977). During follow-up, doctors recorded the diagnoses of episodes of illness newly presenting after the date of recruitment together with information about oral contraceptive prescriptions. Mortality data were, of course, also collected. The third study concerned 1370 women using oral contraceptives and 1253 women not doing so observed by 40 Australian general practitioners (Grounds, 1974). During follow-up, each woman was asked: "Have you had any trouble with clots in the veins in the past year?" Those responding positively were considered to have suffered from superficial venous thrombosis. In the fourth study, 17000 women using oral contraceptives, the diaphragm or an intrauterine device were recruited at one or other of 17 large family-planning clinics in different parts of England and Scotland (Vessey et al. 1976; Vessey et al. 1977; Vessey, 1978). Among the data collected during follow-up were details of changes in contraceptive practices, reasons for referral to hospital, and causes of death. From Table U it can be seen that the two British cohort studies (like all the case-control studies) provide strong evidence of an increase in the risk of venous thromboembolism in women using oral contraceptives, although the data are too few for any conclusions to be drawn about fatal pulmonary embolism. The Puerto Rican study does not support the British findings, but the numbers of women affected are small and the data are hard to interpret because Fuertes-de la Haba and his colleagues have never provided any information about the extent to which women in the oral contraceptive group switched to other methods of contraception and the extent to which women in the control group later adopted "the pill". It should also be borne in mind that oral contraceptives might have different effects in Puerto Rican women from those in Caucasian women. The Australian study, however, appears to indicate that oral contraceptives protect against superficial venous thrombosis. How is this to be explained? Close examination of the report of the Australian study reveals a number of serious shortcomings in design and analysis; these have been well summarized by Sartwell (1976). First, it was planned to have two control subjects per oral contraceptive user, but the study ended up with fewer of the former than the latter. Secondly, the drop-out rate in the second (and last) year of the study was over 30%. Thirdly, 158
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Fuertes-de la Habs et al. 1770, 1971
Relative risk, users to non-users
Non-users of OC
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey&J I Mam
b Stroke The processes that have led to the establishment of stroke as a rare adverse reaction to oral contraceptives have followed a pattern similar to those just described for venous thromboembolism. Thefirstpublished report, which appeared in 1962, concerned a lesion of the left parietal region that was thought to be a consequence of cortical venous thrombosis (Lorentz, 1962). Other reports then followed in quick succession, almost all relating to arterial rather than to venous thromboses. Important additional evidence for an association has come from physicians who have reviewed their total clinical experience over a period of time rather than singling out particular case histories for special consideration (Masi &
TABLE III. Case-control studies of the relationship between oral contraceptives (OC) and stroke References
Source of data
1 nman & Vesser,
Deaths in Britain, 1966
Vessev » Doll. 1968, 1969 Sartwell et al. 1969
Hospital admissions In Britain. 1964-67 Hospital admissions In USA, 1963-67 Hospital admissions In USA, 1969-71
Collaborative Uroup...l97J*
Type of disease studied
Number of of cases
Percentage of cases using O C
Percentage of controls using O C
Fatal idlopathic throm-
10
50
15
—
Mlopathlc thrombotic stroke Idiopathlc "Intracranlal vascular lesion" fAny thrombotk stroke \ A n y haemorrhagic stroke
19
58
18
6:1
13
62
8
140 195
42 23
10 13
Relative risk. users to non-usen
__ 9:1 2:1 .
* The data for "neighbourhood" controls have been ftven In this table Different methods ware used for computinf relative risks In the various studies. The data. (Ivan In tha last column of the table cannot, therefore, necessarily be derived from the data In tha two preceding columns
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Dugdale, 1970). One of the most impressive series of this type is that reported by Bickerstaff (1975) from the British Midland Centre for Neurosurgery and Neurology. During the interval 1954-63, 25 women below the age of 45 were" seen at the Centre who fulfilled the criteria necessary for a diagnosis of "cerebral arterial insufficiency". None of these had been taking oral contraceptives and they presented at a regular rate of two to three per year. During the interval 1964-73, as neither the population served by the Centre nor the total number of neurological consultations had altered materially, between 20 and 30 similar cases would have been expected. In fact, 83 were seen. Of these, 21 were not using oral contraceptives, while 62 were doing so. Case-control studies of the relationship between oral contraceptives and stroke are summarized in Table m . Considered together, they suggest that the use of oral contraceptives increases the risk of thrombotic stroke six- to nine-fold and of haemorrhagic stroke twofold. A further report concerning the largest of the studies underlined the importance of hypertension as a risk factor in the development of either thrombotic or haemorrhagic stroke (Collaborative Group for the Study of Stroke in Young Women, 1975). Some evidence was also obtained that cigarette smoking and migraine might be risk factors for one or the other type of stroke. There was little indication of any interaction between oral contraceptive use and other risk factors: it was found, for example, that the relative risk of thrombotic stroke associated with the presence of both oral contraceptive use and severe hypertension (about 14:1) was approximately equal to the product of the relative risks associated with the presence of these two factors separately (about 3:1 and 6:1, respectively). Some information about stroke has also been obtained from cohort studies (Table IV). The data are few, but the evidence that oral contraceptive use is related to an increase in the risk of a variety of different types of stroke is strong. Tnman et al. (1970), in the investigation outlined in section la, found the risk of thrombotic stroke to be positively correlated with the oestrogen content of oral contraceptives. This observation has been neither confirmed nor refuted in other studies. No reliable data are currently available to show whether the risk is related to duration of use of the preparations. Most studies have indicated that the increase in risk is limited to the time during which oral contraceptives are being taken and, perhaps, for a short period thereafter. However, the recent analysis of deaths among women in the Royal College of General Practitioners' oral contraception study suggests that an increased risk of fatal subarachnoid haemorrhage may persist in ex-users of oral contraceptives; four
In the last few years, oral contraceptives containing only 30fig oestrogen have become widely available; indeed, it is estimated that such preparations are now being used by about 40% of women who are taking oral contraceptives. Unfortunately, none of the epidemiological studies shown in Tables I or H provide any direct information about the risks associated with the use of these preparations containing a very low dose of oestrogen. Those studies in which the association between duration of oral contraceptive use and venous thrombo-embolism has been examined have uniformly shown that the risk appears to be constant with time. Furthermore, all studies have indicated that the increased risk occurs only while the preparations are actually in use and, perhaps, for the first week or so after discontinuation. Venous thrombo-embolism tends to occur more commonly in people of blood group A than in those of blood group O. One study has indicated that this difference may be particularly marked when thrombo-embolism is associated with the use of oral contraceptives or with pregnancy (Jick et al. 1969). There is no evidence that venous thrombo-embolism is associated with cigarette smoking either in users or non-users of oral contraceptives (Lawson et al. 1977). Apart from the studies to which reference has already been made, evidence that oral contraceptives are associated with an increased risk of thrombo-embolism has been derived from the analysis of mortality statistics (Beral, 1976) and from studies of the effects of the preparations on Virchow's triad (Poller, 1973; Vessey, 1973). Furthermore, it is also known that oestrogens are a cause of thrombo-embolism when administered to prevent lactation (Daniel et al. 1967) or when used in the treatment of arterial disease (Coronary Drug Project Research Group, 1970) or prostatk cancer (Blackard et al. 1970).
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey d JI Mam TABLE IV. Cohort studies of the relationship between oral contraceptives (OC) and stroke (Numbers of cues are In parentheses) Refa
Sou re* of data
Type of d i m s * studied
Deaths In Puerto Rico. 1*61-69
Royal College of General Practitioners, 1974, 1977
General practice consultations (1968-72) and deaths (1968-76) In Britain
Vessey et of. 1976; Vesaey et al. 1977
Hospital referrabf 1968-75) and deaths (1968-77) In Britain
Non-users of OC
Any fatal stroke Any thrombotlc stroke Any haemorrhagic stroke Any "other stroke" Fatal subarechnold
0X5 0.20 0X7 O2I | 0X9
0.10 ( 0.00 ( 0.04 0X6 (
Other fatal stroke Any thrombotlc stroke Any haemorrhagic stroke Any "other stroke" Any fatal stroke
0.03 0.14 0X9 0J3 0X4
deaths occurred among such subjects, representing a mortality rate of 0.16 per 1000 woman-years of observation.
3.5:1
0X0 (
the study but this proportion was thought to be greater than might have been expected. Since there was no difference in the prevalence of major risk factors for ischaemic heart disease between those women taking oral contraceptives and those not doing so, Radford & Oliver concluded that the preparations increased the risk of myocardial infarction only in those already predisposed to the disease. The hypothesis that the effect of oral contraceptives might be different in women with and without other risk factors for vascular disease was pursued in subsequent investigations. Mann et al. (1975) and Mann et al. (1976a) found a fourfold increase in the risk of non-fatal myocardial infarction amongst users of oral contraceptives considered as a group (Table V). In women with no predisposing factors for the disease, however, oral contraceptives appeared to increase the risk only twofold, while among women in whom cigarette smoking was the only predisposing factor the corresponding increase in risk was fivefold. Although the case series collected by Mann and his colleagues was the largest reported to date, the numbers were still too few to enable the relationship between oral contraceptives and other combinations of risk factors to be estimated. However, Table VI shows the proportions of patients and controls known to have had various numbers of risk factors. The risk estimates derived from these data suggest that the combined effect of the factors is synergistic. In comparison with patients not known to have any risk factors, the relative risk increased from 4:1 in women with one factor to 20:1 in
c Myocardial Infarction and Other Cardiovascular Disease The suggestion that oral contraceptives might also be associated with myocardial infarction was the subject of a series of case reports which started to appear shortly after those linV ing the use of the preparations with venous thromboembolism and stroke (Boyce et al. 1963). In the first controlled study, Inman & Vessey (1968) found that women who had died from coronary thrombosis in the absence of predisposing factors had been using oral contraceptives about twice as often as might have been expected from the experience of the control group (Table V). On the other hand, an uncontrolled Danish study of fatal myocardial infarction suggested that oral contraceptive use before death was no different from that in the general population of the same age (Fischer & Mosbech, 1970). Vessey & Doll (1968,1969) in a further case-control study were able to identify only 17 women with non-fatal myocardial infarction; they confined their attention, however, to idiopathic disease and with so few cases no definite conclusions could be drawn (Table V). Oliver (1970) and Radford & Oliver (1973) reported a personal case series admitted to hospital in Edinburgh during the years 1964-72. Fifty-two per cent of the 31 patients had been using oral contraceptives at the time of admission. No control subjects were included in TABLE V.
Relative risk. sars to non-users
Case-control studies of the relationship between oral contraceptives (OC) and myocardial infarction (Ml)
References
Inman & Vessey, 1968 Vessey & Doll, 1968, 1969 Mann et al. 1975; Mann et of. 1976a
Source of data
Deaths In Britain, 1966 Hospital admissions in Britain, 1964-67 Hospital admissions In Britain, 1968-72
Mann A Inman, 1975; Mann et d. 1976b
Deaths in Britain, 1973
Jldcet ol. 1978
Hospital admissions In USA, 1975
Type of disease studied
Number of of case*
Percentage of cases uslnf O C
Percentage of controls using OC
Relative risk, lers to non-users
Fatal Idiopathic M l *
69
26
13
2.1
tdlopathk M l *
17
12
12
1:1
72 12 43
28 17
8 10 8
4:1 2:1 5:1
47
45
22
3:1
rAny Ml I Idiopathic Mtt 1 Ml In smokers with no I other risk factors f A n y Ml In patients aged I < 4 0 years "1 Any Ml In patients aged L 4O-44yeers Idiopathic M l *
106 26
30
17 77
7
3:1
24
14:1
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Fucrtes-de b Haba et d. 1970
Rate per 1000 w o m a n - r a n in: Users of O C
* Excluding those cases and controls with known risk factors for Ml and also those with other chronic disease t Excluding those cases and cootrob who were smokers, hypertensive, diabetic or byperilpaemic i Excluding those cases and controls who gave a history of a predisposing Illness, who were postmenopausal or where the patient or her husband had been sterilized Different methods were used for computing relative risk In the various studies. The data given In the last column of the table cannot, therefore, necessarily be derived from'the data in the two preceding columns
160
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FEMALE SEX HORMONES AND THROMBOSIS MP Vessey &J I Mam TABLE VI. Risk factors in myocardial infarction (Ml) and control patients (Percentages are In parentheses)
N o risk factor O n * risk factor Current orml contraceptive us* Type II hyperflpoprotelna*ral* Diabetes d f a r e t t e unoklnf (15 or more daily) Hypertension or pre-edamptk t a n t m l i Two rUk factors T h r M or more rfalc facton
Total
Ml patients
Control
14 (I&9)
128 (
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey &J I Mam regimens have not been reported. Finally, it must be stressed that almost all the published epidemiological investigations have been carried out in wealthy Western countries; it would therefore be quite incorrect to extrapolate the findings to countries such as Africa or India. 1
Oral Contraceptives
a Venous Thrombo-EmboUsm The possibility that oral contraceptives might increase the risk of venous thrombo-embolism was first raised by a case history reported in The Lancet in 1961 (Jordan, 1961). Since that time, thousands of similar case histories have appeared in the medical journals or have been reported to the pharmaceutical manufacturers or to the national bodies responsible for drug safety in different parts of the world1. Evidence for a cause-and-effect relationship, however, has been derived principally from case-control and cohort studies. Table I presents the main features of the published casecontrol studies. These investigations have been reviewed on many previous occasions and do not require detailed consideration here. It may be noted, however, that all the studies indicate an increase in the risk of venous thrombo-embolism in women using oral contraceptives. This increase in risk appears to be greatest (4-11-fold) in studies concerned only with "idiopathic" deep-vein thrombosis or pulmonary embolism. Cohort studies of the relationship between oral contraceptives and venous thrombo-embolism are Tummfl^^d in Table H. In the first of these, almost 10000 Puerto Rkan women seeking birth control advice were allocated at random either to an oral contraceptive (Enovid, 5mg) or to a vaginal contraceptive (Fuertes-de la Haba et al. 1970, 1971). Hospital admissions for venous thrombosis and deaths from any cause occurring among these women were sought by a variety of means. In the second study, 23000 women using oral contraceptives together with a similar number of control subjects using other methods or no method of birth control
M P VESSEY MA MD FFCM J I MANN DM PhD MFCM Department of Social and Community Medicine University of Oxford 1 Oral contraceptives a Venous thrombo-embolism b Stroke c Myocardial infarction and other cardiovascular disease d Conclusion 2 Postmenopausal use of oestrogens References Oral contraceptives have now been in use for almost two decades; throughout most of that period there has been continuing anxiety about their cardiovascular effects. Oestrogens (usually unopposed by progestogens) are also being given increasingly commonly to older women to try to control "menopausal" symptoms and to reduce postmenopausal bone loss. Although most of the anxiety about such therapy centres round endometrial cancer, possible adverse effects on the cardiovascular system must also be considered. In this review, most attention will be concentrated on epidemiological studies of clinical events rather than on the results of laboratory investigations. Furthermore, as far as oral contraceptives are concerned, the findings to be described relate only to preparations containing both an oestrogen and a progestogen; appropriate studies concerning other steroidal
t See Inman, Br. Utd. BtdL 1970,16,248-236.—ED.
TABLE I. Case-control studies of the relationship between oral contraceptives and venous thromboembolism References
Source of data
Royal Cotlen of General PraetWoners. 1967
General practice
Inmta & Vessey, 1968 V « u y * Doll. INS, 19(9 Sartwell et of. 1969
Britain, 1961-66 Deaths in Britain, 1966 Hospital admliriora In Britain, 1964-67 Hospital admissions In
VMMy et of. 1970
USA, 1943-47 Hospital admissions in
ft Westerholm, 1971 • GrMn* & Sartwell, 1972
Britain, 1964-67 Hospital admissions In Sweden, 1964-68 Hospital admissions in
Bosson Collaboi alive Dnif Surveillance Program, 1973 StoOey et a!. 1975
consultations In
USA, 1963-67 Hospital admissions in USA, 1972
Hospital admission In USA, 1970-73
PeJ'Ceiltaje
of cam aJnjOC
Percentage of controls using OC
Retativ* risk, us«rs to nocwaers
72 24
15 21
6 10
3:1 2:1
Fatal Mlopathlc PE Idiopathic deep VT or PE
26 M
16 14
8: 1 6:
/Idiopathic superficial VT \Mlopethlc deep VT or PE Post-operative de«p VT
27 129 30
£2 50 22 41 40
15 15
3: 4: 4: II:
Type of disease studied
/Superficial VT \Other VT or PE
nberof at**
Idlosathk deep VT
84
65
14
Postoperative or posttraumatic deep VT or PE Idiopathic de*p VT
(0
35
17
6:
43
72
20
11:1
Malnlvldlopathtc deep VT
104
57
19
7:1
* Market research data were used for control purposes In this study Abbreviations: OC: oral contraceptives VT: venous thrombosis FT: pulmonary embolism DtSerent methods were used for cocnputltti relative risk In the various studies. The data fhnm In the put cohrnio of the table cannot, thv tfort^ fMcflwiiy o% dcrtvM from the data In the two preceding columns
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FEMALE SEX HORMONES AND THROMBOSIS Epidemiological Aspects
FEMALE SEX HORMONES AND THROMBOSIS M PVessey &J I Mann TABLE II. Cohort studies of the relationship between oral contraceptives and venous thromboembolism (Numbers of cases are In parentheses) Referenc
Source of data
Typo of disease studied
Rate p«r 1000 woman-years In: UnnofOC
Hospital admissions and dtaths in Puerto Rico, 1961-69
Ron! Colltje of General Practitioners, 1974, 1977
Central practice consultations (1968-71) and deaths (1968-76) In Britain
Groundi, 1974
Self-diagnosed disease in Australia, 1969-70 Hospital referrab (1960-75)
r f. 1976; Vasty a al. 1977; Vessey, 1978
and deaths (l96tt-77) In Britain
ridtopathlc VT \FatsjPE fMlopathlc superficial VT I Mlopathlc deep VT 1 "Other" Idlopathic VT LFatal PE "Clots In veins" (I superficial VT) fUiopathlcVT < Post-operative VT* I Fatal PE
1.1:1
0.43 0.00
1.5:1 5.7:1 2.1 :l 0.3:1 0.14 3.01 0X0
6.3:1 2.0:1
* The figures ftven are rates per 1000 surgical operations For abbreviations, see below Table I
four times as many control subjects as oral contraceptive users gave a past history of superficial venous thrombosis; no allowance was made for this difference in the analysis. Fourthly, no data are provided on the disorders other studies have found to be most strongly associated with oral contraceptives, namely deep-vein thrombosis and pulmonary embolism. Fifthly, the diagnosis of "superficial venous thrombosis" depended on the answer given by the patient to the question mentioned earlier; perhaps this is why the incidence of the disorder is so remarkably high. Finally, the British studies are, respectively, about 40 times and 25 times as large as the Australian one. For these reasons, among others, the Australian findings do not weigh heavily against the British ones. In addition to the large-scale cohort studies, mention should be made of an investigation in which the radioactive fibrinogen uptake test was used to diagnose post-operative deep-vein thrombosis (Sagar et al. 1976). It was found that six of 31 young women undergoing emergency abdominal surgery who gave a history of recent oral contraceptive intake developed deep-vein thrombosis in comparison with none of 19 similar patients who had not been using oral contraceptives. Evidence that the oestrogen content of oral contraceptives is an important determinant of the risk of venous thromboembolism was first provided by an analysis of over 1000 reports of thrombo-embolism following the use of oral contraceptives, received by the drug safety committees in the United Kingdom, Sweden and Denmark (Inman et al. 1970). When the different oral contraceptive preparations were grouped according to the dose of the oestrogen component, there was a marked excess of reports associated with those preparations containing a high dose of oestrogen and a marked deficiency associated with those containing a low dose. As a result of this finding, the British Committee on Safety of Drugs issued a recommendation in December 1969 that oral contraceptives containing more than 50 ng oestrogen should not normally be prescribed. This recommendation led to the virtual disappearance of preparations containing a high dose of oestrogen in the United Kingdom from 1970 onwards; prior to that date they hadrepresentedabout 50% of the total sales (Vessey & Tnmnp, 1973). Confirmation of the relationship between thrombo-embolic risk and oestrogen dose was subsequently provided by the Royal College of General Practitioners (1974) and by Stolley et al. (1975).
were brought under observation by 1400 general practitioners throughout Great Britain (Royal College of General Practitioners, 1974,1977). During follow-up, doctors recorded the diagnoses of episodes of illness newly presenting after the date of recruitment together with information about oral contraceptive prescriptions. Mortality data were, of course, also collected. The third study concerned 1370 women using oral contraceptives and 1253 women not doing so observed by 40 Australian general practitioners (Grounds, 1974). During follow-up, each woman was asked: "Have you had any trouble with clots in the veins in the past year?" Those responding positively were considered to have suffered from superficial venous thrombosis. In the fourth study, 17000 women using oral contraceptives, the diaphragm or an intrauterine device were recruited at one or other of 17 large family-planning clinics in different parts of England and Scotland (Vessey et al. 1976; Vessey et al. 1977; Vessey, 1978). Among the data collected during follow-up were details of changes in contraceptive practices, reasons for referral to hospital, and causes of death. From Table U it can be seen that the two British cohort studies (like all the case-control studies) provide strong evidence of an increase in the risk of venous thromboembolism in women using oral contraceptives, although the data are too few for any conclusions to be drawn about fatal pulmonary embolism. The Puerto Rican study does not support the British findings, but the numbers of women affected are small and the data are hard to interpret because Fuertes-de la Haba and his colleagues have never provided any information about the extent to which women in the oral contraceptive group switched to other methods of contraception and the extent to which women in the control group later adopted "the pill". It should also be borne in mind that oral contraceptives might have different effects in Puerto Rican women from those in Caucasian women. The Australian study, however, appears to indicate that oral contraceptives protect against superficial venous thrombosis. How is this to be explained? Close examination of the report of the Australian study reveals a number of serious shortcomings in design and analysis; these have been well summarized by Sartwell (1976). First, it was planned to have two control subjects per oral contraceptive user, but the study ended up with fewer of the former than the latter. Secondly, the drop-out rate in the second (and last) year of the study was over 30%. Thirdly, 158
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Fuertes-de la Habs et al. 1770, 1971
Relative risk, users to non-users
Non-users of OC
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey&J I Mam
b Stroke The processes that have led to the establishment of stroke as a rare adverse reaction to oral contraceptives have followed a pattern similar to those just described for venous thromboembolism. Thefirstpublished report, which appeared in 1962, concerned a lesion of the left parietal region that was thought to be a consequence of cortical venous thrombosis (Lorentz, 1962). Other reports then followed in quick succession, almost all relating to arterial rather than to venous thromboses. Important additional evidence for an association has come from physicians who have reviewed their total clinical experience over a period of time rather than singling out particular case histories for special consideration (Masi &
TABLE III. Case-control studies of the relationship between oral contraceptives (OC) and stroke References
Source of data
1 nman & Vesser,
Deaths in Britain, 1966
Vessev » Doll. 1968, 1969 Sartwell et al. 1969
Hospital admissions In Britain. 1964-67 Hospital admissions In USA, 1963-67 Hospital admissions In USA, 1969-71
Collaborative Uroup...l97J*
Type of disease studied
Number of of cases
Percentage of cases using O C
Percentage of controls using O C
Fatal idlopathic throm-
10
50
15
—
Mlopathlc thrombotic stroke Idiopathlc "Intracranlal vascular lesion" fAny thrombotk stroke \ A n y haemorrhagic stroke
19
58
18
6:1
13
62
8
140 195
42 23
10 13
Relative risk. users to non-usen
__ 9:1 2:1 .
* The data for "neighbourhood" controls have been ftven In this table Different methods ware used for computinf relative risks In the various studies. The data. (Ivan In tha last column of the table cannot, therefore, necessarily be derived from the data In tha two preceding columns
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Dugdale, 1970). One of the most impressive series of this type is that reported by Bickerstaff (1975) from the British Midland Centre for Neurosurgery and Neurology. During the interval 1954-63, 25 women below the age of 45 were" seen at the Centre who fulfilled the criteria necessary for a diagnosis of "cerebral arterial insufficiency". None of these had been taking oral contraceptives and they presented at a regular rate of two to three per year. During the interval 1964-73, as neither the population served by the Centre nor the total number of neurological consultations had altered materially, between 20 and 30 similar cases would have been expected. In fact, 83 were seen. Of these, 21 were not using oral contraceptives, while 62 were doing so. Case-control studies of the relationship between oral contraceptives and stroke are summarized in Table m . Considered together, they suggest that the use of oral contraceptives increases the risk of thrombotic stroke six- to nine-fold and of haemorrhagic stroke twofold. A further report concerning the largest of the studies underlined the importance of hypertension as a risk factor in the development of either thrombotic or haemorrhagic stroke (Collaborative Group for the Study of Stroke in Young Women, 1975). Some evidence was also obtained that cigarette smoking and migraine might be risk factors for one or the other type of stroke. There was little indication of any interaction between oral contraceptive use and other risk factors: it was found, for example, that the relative risk of thrombotic stroke associated with the presence of both oral contraceptive use and severe hypertension (about 14:1) was approximately equal to the product of the relative risks associated with the presence of these two factors separately (about 3:1 and 6:1, respectively). Some information about stroke has also been obtained from cohort studies (Table IV). The data are few, but the evidence that oral contraceptive use is related to an increase in the risk of a variety of different types of stroke is strong. Tnman et al. (1970), in the investigation outlined in section la, found the risk of thrombotic stroke to be positively correlated with the oestrogen content of oral contraceptives. This observation has been neither confirmed nor refuted in other studies. No reliable data are currently available to show whether the risk is related to duration of use of the preparations. Most studies have indicated that the increase in risk is limited to the time during which oral contraceptives are being taken and, perhaps, for a short period thereafter. However, the recent analysis of deaths among women in the Royal College of General Practitioners' oral contraception study suggests that an increased risk of fatal subarachnoid haemorrhage may persist in ex-users of oral contraceptives; four
In the last few years, oral contraceptives containing only 30fig oestrogen have become widely available; indeed, it is estimated that such preparations are now being used by about 40% of women who are taking oral contraceptives. Unfortunately, none of the epidemiological studies shown in Tables I or H provide any direct information about the risks associated with the use of these preparations containing a very low dose of oestrogen. Those studies in which the association between duration of oral contraceptive use and venous thrombo-embolism has been examined have uniformly shown that the risk appears to be constant with time. Furthermore, all studies have indicated that the increased risk occurs only while the preparations are actually in use and, perhaps, for the first week or so after discontinuation. Venous thrombo-embolism tends to occur more commonly in people of blood group A than in those of blood group O. One study has indicated that this difference may be particularly marked when thrombo-embolism is associated with the use of oral contraceptives or with pregnancy (Jick et al. 1969). There is no evidence that venous thrombo-embolism is associated with cigarette smoking either in users or non-users of oral contraceptives (Lawson et al. 1977). Apart from the studies to which reference has already been made, evidence that oral contraceptives are associated with an increased risk of thrombo-embolism has been derived from the analysis of mortality statistics (Beral, 1976) and from studies of the effects of the preparations on Virchow's triad (Poller, 1973; Vessey, 1973). Furthermore, it is also known that oestrogens are a cause of thrombo-embolism when administered to prevent lactation (Daniel et al. 1967) or when used in the treatment of arterial disease (Coronary Drug Project Research Group, 1970) or prostatk cancer (Blackard et al. 1970).
FEMALE SEX HORMONES AND THROMBOSIS MP Vessey d JI Mam TABLE IV. Cohort studies of the relationship between oral contraceptives (OC) and stroke (Numbers of cues are In parentheses) Refa
Sou re* of data
Type of d i m s * studied
Deaths In Puerto Rico. 1*61-69
Royal College of General Practitioners, 1974, 1977
General practice consultations (1968-72) and deaths (1968-76) In Britain
Vessey et of. 1976; Vesaey et al. 1977
Hospital referrabf 1968-75) and deaths (1968-77) In Britain
Non-users of OC
Any fatal stroke Any thrombotlc stroke Any haemorrhagic stroke Any "other stroke" Fatal subarechnold
0X5 0.20 0X7 O2I | 0X9
0.10 ( 0.00 ( 0.04 0X6 (
Other fatal stroke Any thrombotlc stroke Any haemorrhagic stroke Any "other stroke" Any fatal stroke
0.03 0.14 0X9 0J3 0X4
deaths occurred among such subjects, representing a mortality rate of 0.16 per 1000 woman-years of observation.
3.5:1
0X0 (
the study but this proportion was thought to be greater than might have been expected. Since there was no difference in the prevalence of major risk factors for ischaemic heart disease between those women taking oral contraceptives and those not doing so, Radford & Oliver concluded that the preparations increased the risk of myocardial infarction only in those already predisposed to the disease. The hypothesis that the effect of oral contraceptives might be different in women with and without other risk factors for vascular disease was pursued in subsequent investigations. Mann et al. (1975) and Mann et al. (1976a) found a fourfold increase in the risk of non-fatal myocardial infarction amongst users of oral contraceptives considered as a group (Table V). In women with no predisposing factors for the disease, however, oral contraceptives appeared to increase the risk only twofold, while among women in whom cigarette smoking was the only predisposing factor the corresponding increase in risk was fivefold. Although the case series collected by Mann and his colleagues was the largest reported to date, the numbers were still too few to enable the relationship between oral contraceptives and other combinations of risk factors to be estimated. However, Table VI shows the proportions of patients and controls known to have had various numbers of risk factors. The risk estimates derived from these data suggest that the combined effect of the factors is synergistic. In comparison with patients not known to have any risk factors, the relative risk increased from 4:1 in women with one factor to 20:1 in
c Myocardial Infarction and Other Cardiovascular Disease The suggestion that oral contraceptives might also be associated with myocardial infarction was the subject of a series of case reports which started to appear shortly after those linV ing the use of the preparations with venous thromboembolism and stroke (Boyce et al. 1963). In the first controlled study, Inman & Vessey (1968) found that women who had died from coronary thrombosis in the absence of predisposing factors had been using oral contraceptives about twice as often as might have been expected from the experience of the control group (Table V). On the other hand, an uncontrolled Danish study of fatal myocardial infarction suggested that oral contraceptive use before death was no different from that in the general population of the same age (Fischer & Mosbech, 1970). Vessey & Doll (1968,1969) in a further case-control study were able to identify only 17 women with non-fatal myocardial infarction; they confined their attention, however, to idiopathic disease and with so few cases no definite conclusions could be drawn (Table V). Oliver (1970) and Radford & Oliver (1973) reported a personal case series admitted to hospital in Edinburgh during the years 1964-72. Fifty-two per cent of the 31 patients had been using oral contraceptives at the time of admission. No control subjects were included in TABLE V.
Relative risk. sars to non-users
Case-control studies of the relationship between oral contraceptives (OC) and myocardial infarction (Ml)
References
Inman & Vessey, 1968 Vessey & Doll, 1968, 1969 Mann et al. 1975; Mann et of. 1976a
Source of data
Deaths In Britain, 1966 Hospital admissions in Britain, 1964-67 Hospital admissions In Britain, 1968-72
Mann A Inman, 1975; Mann et d. 1976b
Deaths in Britain, 1973
Jldcet ol. 1978
Hospital admissions In USA, 1975
Type of disease studied
Number of of case*
Percentage of cases uslnf O C
Percentage of controls using OC
Relative risk, lers to non-users
Fatal Idiopathic M l *
69
26
13
2.1
tdlopathk M l *
17
12
12
1:1
72 12 43
28 17
8 10 8
4:1 2:1 5:1
47
45
22
3:1
rAny Ml I Idiopathic Mtt 1 Ml In smokers with no I other risk factors f A n y Ml In patients aged I < 4 0 years "1 Any Ml In patients aged L 4O-44yeers Idiopathic M l *
106 26
30
17 77
7
3:1
24
14:1
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Fucrtes-de b Haba et d. 1970
Rate per 1000 w o m a n - r a n in: Users of O C
* Excluding those cases and controls with known risk factors for Ml and also those with other chronic disease t Excluding those cases and cootrob who were smokers, hypertensive, diabetic or byperilpaemic i Excluding those cases and controls who gave a history of a predisposing Illness, who were postmenopausal or where the patient or her husband had been sterilized Different methods were used for computing relative risk In the various studies. The data given In the last column of the table cannot, therefore, necessarily be derived from'the data in the two preceding columns
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FEMALE SEX HORMONES AND THROMBOSIS MP Vessey &J I Mam TABLE VI. Risk factors in myocardial infarction (Ml) and control patients (Percentages are In parentheses)
N o risk factor O n * risk factor Current orml contraceptive us* Type II hyperflpoprotelna*ral* Diabetes d f a r e t t e unoklnf (15 or more daily) Hypertension or pre-edamptk t a n t m l i Two rUk factors T h r M or more rfalc facton
Total
Ml patients
Control
14 (I&9)
128 (
