The New England Journal of Medicine

Original Article
Volume 345:1787-1793

December 20, 2001

Number 25


Oral Contraceptives and the Risk of Myocardial Infarction
Bea C. Tanis, M.D., Maurice A.A.J. van den Bosch, M.D., Jeanet M. Kemmeren,
Ph.D., Volkert Manger Cats, M.D., Frans M. Helmerhorst, M.D., Ale Algra,
M.D., Yolanda van der Graaf, M.D., and Frits R. Rosendaal, M.D.

ABSTRACT
Background An association between the use of oral contraceptives and the
risk of myocardial infarction has been found in some, but not all, studies.
We investigated this association, according to the type of progestagen
included in third-generation (i.e., desogestrel or gestodene) and
second-generation (i.e., levonorgestrel) oral contraceptives, the dose of
estrogen, and the presence or absence of prothrombotic mutations.
Methods In a nationwide, population-based, case–control study, we identified
and enrolled 248 women 18 through 49 years of age who had had a first
myocardial infarction between 1990 and 1995 and 925 control women who had
not had a myocardial infarction and who were matched for age, calendar year
of the index event, and area of residence. Subjects supplied information on
oral-contraceptive use and major cardiovascular risk factors. An analysis
for factor V Leiden and the G20210A mutation in the prothrombin gene was
conducted in 217 patients and 763 controls.
Results The odds ratio for myocardial infarction among women who used any
type of combined oral contraceptive, as compared with nonusers, was 2.0 (95
percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5
(95 percent confidence interval, 1.5 to 4.1) among women who used
second-generation oral contraceptives and 1.3 (95 percent confidence
interval, 0.7 to 2.5) among those who used third-generation oral
contraceptives. Among women who used oral contraceptives, the odds ratio was
2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a
prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5)
for those with a mutation.
Conclusions The risk of myocardial infarction was increased among women who
used second-generation oral contraceptives. The results with respect to the
use of third-generation oral contraceptives were inconclusive but suggested
that the risk was lower than the risk associated with second-generation oral
contraceptives. The risk of myocardial infarction was similar among women
who used oral contraceptives whether or not they had a prothrombotic
mutation.
  _____

The first report of coronary thrombosis associated with the use of oral
contraceptives appeared in 1963. 1
<http://content.nejm.org/cgi/content/full/345/25/#R1>  Later studies
established the use of oral contraceptives as a risk factor for venous as
well as arterial thrombosis. 2
<http://content.nejm.org/cgi/content/full/345/25/#R2> , 3
<http://content.nejm.org/cgi/content/full/345/25/#R3> , 4
<http://content.nejm.org/cgi/content/full/345/25/#R4> , 5
<http://content.nejm.org/cgi/content/full/345/25/#R5> , 6
<http://content.nejm.org/cgi/content/full/345/25/#R6> , 7
<http://content.nejm.org/cgi/content/full/345/25/#R7>  Various modifications
were made in an attempt to lower these risks, including a reduction in the
estrogen dose and changes in the progestagen compound. Oral contraceptives
containing an estrogen and the progestagen desogestrel or gestodene,
available since the 1980s, are associated with at least a doubling of the
risk of venous thrombosis as compared with other combined oral
contraceptives. 8 <http://content.nejm.org/cgi/content/full/345/25/#R8> , 9
<http://content.nejm.org/cgi/content/full/345/25/#R9> , 10
<http://content.nejm.org/cgi/content/full/345/25/#R10> , 11
<http://content.nejm.org/cgi/content/full/345/25/#R11> , 12
<http://content.nejm.org/cgi/content/full/345/25/#R12>  It has been
suggested that these third-generation contraceptives protect against
myocardial infarction by having a favorable effect on the lipid profile, 13
<http://content.nejm.org/cgi/content/full/345/25/#R13> , 14
<http://content.nejm.org/cgi/content/full/345/25/#R14> , 15
<http://content.nejm.org/cgi/content/full/345/25/#R15>  because studies
showed that women who used these types had a slight increase in the level of
high-density lipoprotein cholesterol. 15
<http://content.nejm.org/cgi/content/full/345/25/#R15> , 16
<http://content.nejm.org/cgi/content/full/345/25/#R16>  Only a few studies
of the association between oral contraceptives and myocardial infarction
have included a direct comparison of third- and second-generation
progestagens, and the results have been contradictory. 17
<http://content.nejm.org/cgi/content/full/345/25/#R17> , 18
<http://content.nejm.org/cgi/content/full/345/25/#R18> , 19
<http://content.nejm.org/cgi/content/full/345/25/#R19> , 20
<http://content.nejm.org/cgi/content/full/345/25/#R20> , 21
<http://content.nejm.org/cgi/content/full/345/25/#R21>  We investigated
whether the use of low-dose combined oral contraceptives affects the risk of
myocardial infarction. We assessed the effect of the type of progestagen
included in the oral contraceptive (levonorgestrel as compared with
gestodene or desogestrel), the dose of estrogen, and the presence of the
G1691A mutation in the factor V gene (factor V Leiden) and the G20210A
mutation in the prothrombin gene, which have been associated with myocardial
infarction in young women 22
<http://content.nejm.org/cgi/content/full/345/25/#R22> , 23
<http://content.nejm.org/cgi/content/full/345/25/#R23>  as well as with a
particularly high risk of venous thrombosis in women who use oral
contraceptives. 24 <http://content.nejm.org/cgi/content/full/345/25/#R24>
Methods
Study Design
The Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO)
study is a population-based case–control study of the relation of arterial
disease to the use of oral contraceptives among women 18 to 49 years of age
in the Netherlands. The study protocol was approved by the ethics committees
of the participating hospitals (see the Appendix). Oral informed consent was
obtained from all participants.
Identification of Women with Myocardial Infarction
Eligible patients were women 18 to 49 years of age who were hospitalized for
a first myocardial infarction between January 1990 and October 1995.
Myocardial infarction was defined by the presence of symptoms, elevated
cardiac-enzyme levels, and electrocardiographic changes. 25
<http://content.nejm.org/cgi/content/full/345/25/#R25>  The patients were
identified through a search of computerized hospital data bases for
International Classification of Diseases, 9th Revision, Clinical
Modification codes for acute myocardial infarction. Of the 321 women who
were admitted to the 16 participating centers during this period, 29 (9
percent) were excluded: 19 died during admission, 9 died between discharge
and the start of the study, and 1 was unable to participate. The medical
records of all patients were reviewed by one investigator. Of the 292
remaining patients, 21 could not be located and 23 declined to participate
(response rate, 85 percent).
Control Women
The study was designed to investigate three types of arterial disease:
myocardial infarction, ischemic stroke, and peripheral arterial disease; the
results for each type are reported separately. We identified and recruited
one large control group through random-digit dialing. 26
<http://content.nejm.org/cgi/content/full/345/25/#R26>  In this method,
private telephone numbers randomly generated by a computer are dialed until
someone answers or at least seven attempts have been made at various times
of the day and the week, including the weekend. We reached someone at 98
percent of the numbers after a total of 15,725 telephone calls. Once it was
ascertained that a household included a woman who was eligible for the
study, she was asked to participate. We recruited control women from the six
geographic areas where the patients lived, and using questionnaires, we
assigned each an index year corresponding to the one of the six years (1990
to 1995) in which the patients had had an index event. Therefore, a control
woman randomly received one of six questionnaires concerning one of the
index years. All questions elicited information about either the index date
(in the case of questions about the body-mass index, menopausal status,
level of education, and family history), the year before the index date (in
the case of questions about a history of hypertension, diabetes,
hypercholesterolemia, alcohol use, and smoking), or the month before the
index date (in the case of questions about the use of oral contraceptives).
The index date was the date of the myocardial infarction in the patients and
midyear in the controls. To minimize age differences between the patients
and the controls, control women in the older age groups were oversampled by
increasing the age limit of eligibility criteria during recruitment. The
control group therefore was a population sample stratified according to age
(in five-year categories), area of residence, and calendar year.
Eligible controls were women 18 to 49 years of age who had no history of
coronary, cerebral, or peripheral arterial disease. A total of 1259 eligible
women were reached by random-digit dialing, 925 of whom agreed to
participate and returned the questionnaire (73 percent).
Data Collection
The standardized questionnaire that was mailed to patients and controls
included questions about demographics, use of oral contraceptives,
reproductive history, height and weight, and the presence or absence of a
history of hypertension, diabetes, hypercholesterolemia, and cigarette
smoking and a family history of cardiovascular disease. Color photographs of
all oral-contraceptive pills marketed in the Netherlands during the study
period were included to help women recall the formulations they might have
used. Oral contraceptives were divided into four groups according to the
type of progestagens included: first-generation formulations containing
lynestrenol or norethindrone, second-generation formulations containing
levonorgestrel, third-generation formulations containing desogestrel or
gestodene, and oral contraceptives containing an estrogen and other
progestagens (cyproterone or norgestimate) or a progestagen alone. We also
classified oral contraceptives according to the dose of estrogen. Women were
categorized according to their use of oral contraceptives (never, former, or
current). The level of education was categorized as primary school or less,
secondary school, or higher education or university. Obesity was defined as
a body-mass index (the weight in kilograms divided by the square of the
height in meters) of at least 27.3. 23
<http://content.nejm.org/cgi/content/full/345/25/#R23>  Women were
classified as having hypertension, diabetes, or hypercholesterolemia when
they reported that the condition had been diagnosed by a physician or that
they had been taking medication for the condition before the index date.
Smoking status was categorized as never, former, or current. Current smokers
were those who reported smoking in the year before the index date. Alcohol
use was categorized as none, 1 to 15 drinks per week, and more than 15
drinks per week. A family history of cardiovascular disease was defined as
the occurrence of myocardial infarction, stroke, or peripheral arterial
disease before the age of 60 years in one or more first-degree relatives.
Samples of venous blood or buccal swabs were obtained from 217 patients (88
percent) and 763 controls (82 percent) who consented to undergo DNA analysis
for factor V Leiden and the G20210A mutation in the prothrombin gene. The
polymerase chain reaction was used for the analysis. 27
<http://content.nejm.org/cgi/content/full/345/25/#R27> , 28
<http://content.nejm.org/cgi/content/full/345/25/#R28>
Statistical Analysis
We used unconditional logistic-regression analyses to calculate odds ratios
for the relation between the use of oral contraceptives and myocardial
infarction, and we derived confidence intervals from the model. We adjusted
for the three stratification factors — age (in five-year categories), area
of residence, and calendar year — and for putative confounding factors
(smoking status; presence or absence of hypercholesterolemia, diabetes,
hypertension, obesity, and a family history of cardiovascular disease; level
of education; and alcohol intake). To exclude an effect of the dose of
estrogen in the analyses that were focused on the type of progestagen
included in the oral contraceptive, we excluded women who used formulations
other than those containing 30 µg of ethinyl estradiol: 28 women (13
patients and 15 controls) used second-generation oral contraceptives
containing 50 µg of ethinyl estradiol, 67 women (13 patients and 54
controls) used triphasic second-generation oral contraceptives, 3 women (all
controls) used triphasic third-generation oral contraceptives, 18 women (2
patients and 16 controls) used third-generation oral contraceptives
containing 20 µg of ethinyl estradiol, and in 6 women (1 patient and 5
controls) the dose of ethinyl estradiol was unknown. In a further effort to
minimize the possibility of confounding, in particular by the presence of
preexisting disease, we repeated the analysis after excluding women with
major cardiovascular risk factors. We also directly investigated whether
confounding was present, in particular prescription bias, by analyzing risk
factors and oral-contraceptive use in the control women. Analyses of the
dose of ethinyl estradiol were restricted to women who used oral
contraceptives containing 50 µg of ethinyl estradiol and 150 µg of
levonorgestrel or 30 µg of ethinyl estradiol and 125 µg of levonorgestrel.
Finally, we assessed the effect of combinations of risk factors: the use of
oral contraceptives and conventional risk factors (current smoking,
hypercholesterolemia, diabetes, and hypertension), as well as factor V
Leiden and the G20210A mutation in the prothrombin gene.
Results
Table 1 <http://content.nejm.org/cgi/content/full/345/25/#T1>  shows the
characteristics of the 248 women who had had a myocardial infarction and the
925 control women. Patients ranged in age from 24 to 49 years (mean, 43),
and controls ranged in age from 18 to 49 years (mean, 38). Patients had a
higher prevalence than controls of major risk factors for cardiovascular
disease, such as hypertension (24 percent vs. 6 percent),
hypercholesterolemia (11 percent vs. 3 percent), diabetes (6 percent vs. 1
percent), and current smoking (84 percent vs. 43 percent). Patients also had
a lower level of education than controls (11 percent vs. 27 percent with
post–secondary-school education).


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Table 1. Characteristics of 248 Women with a First Myocardial Infarction and
925 Control Women.

The risk of myocardial infarction among users of any type of oral
contraceptive was twice that of nonusers (95 percent confidence interval,
1.5 to 2.8), after adjustment for age, calendar year, and area of residence
( Table 2 <http://content.nejm.org/cgi/content/full/345/25/#T2> ).
Additional adjustment for putative confounding factors increased the odds
ratio in most age categories, and the overall risk remained doubled ( Table
2 <http://content.nejm.org/cgi/content/full/345/25/#T2> ). Women with no
conventional risk factors (hypertension, hypercholesterolemia, diabetes, or
smoking) who used oral contraceptives had a relative risk of myocardial
infarction of 3.1 (95 percent confidence interval, 1.0 to 9.2). The duration
of oral-contraceptive use did not differ significantly between patients and
controls (median, 10 years).


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Table 2. Odds Ratios for Myocardial Infarction among Women Who Used Any Type
of Oral Contraceptive, According to Age.

Second-generation oral contraceptives containing levonorgestrel were used by
24 percent of the patients and 19 percent of the controls ( Table 3
<http://content.nejm.org/cgi/content/full/345/25/#T3> ). Third-generation
oral contraceptives containing desogestrel or gestodene were used by 8
percent of the patients and 12 percent of the controls. The odds ratio for
myocardial infarction was 2.8 (95 percent confidence interval, 1.3 to 6.3)
for women who used first-generation contraceptives, as compared with those
who had not used oral contraceptives; 2.4 (95 percent confidence interval,
1.6 to 3.6) for women who had used second-generation contraceptives; and 1.3
(95 percent confidence interval, 0.8 to 2.3) for women who had used
third-generation contraceptives ( Table 3
<http://content.nejm.org/cgi/content/full/345/25/#T3> ). When we restricted
this analysis to users of second-generation oral contraceptives (37 patients
and 94 controls) and third-generation oral contraceptives (18 patients and
91 controls) that contained 30 µg of ethinyl estradiol, the odds ratios did
not change substantially: 2.7 for users of second-generation oral
contraceptives (95 percent confidence interval, 1.6 to 4.3) and 1.6 for
users of third-generation oral contraceptives (95 percent confidence
interval, 0.9 to 2.9). A direct comparison of oral contraceptives containing
30 µg of ethinyl estradiol and levonorgestrel, desogestrel, or gestodene
revealed an odds ratio for myocardial infarction of 0.5 (95 percent
confidence interval, 0.2 to 1.1) for third-generation as compared with
second-generation oral contraceptives (after adjustment for stratification
variables). The odds ratios were similar for third-generation brands
containing desogestrel or gestodene. Further adjustment for confounding did
not affect these estimates ( Table 3
<http://content.nejm.org/cgi/content/full/345/25/#T3> ).


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Table 3. Odds Ratios for Myocardial Infarction in Relation to the Type of
Progestagen Included in the Oral Contraceptive.

In an analysis that was restricted to the 41 patients and 104 controls who
had used contraceptives with a second-generation progestagen, as compared
with those who had not used oral contraceptives, the risk of myocardial
infarction was similar for oral contraceptives with different doses of
estrogen. The odds ratio was 2.0 (95 percent confidence interval, 0.6 to
7.3) for brands containing 50 µg of ethinyl estradiol with levonorgestrel
and 2.6 (95 percent confidence interval, 1.6 to 4.2) for brands containing
30 µg of ethinyl estradiol with levonorgestrel. A direct comparison of oral
contraceptives containing levonorgestrel and ethinyl estradiol revealed an
odds ratio of 1.7 (95 percent confidence interval, 0.4 to 7.9) for all
brands that contained less than 50 µg of ethinyl estradiol as compared with
brands that contained 50 µg of ethinyl estradiol or more.
We analyzed the effect of other cardiovascular risk factors in women who
used oral contraceptives, as compared with the reference category of women
who had not used oral contraceptives and who did not have the given risk
factor ( Table 4 <http://content.nejm.org/cgi/content/full/345/25/#T4> ).
The adjusted odds ratios for myocardial infarction among women who had not
used oral contraceptives were 7.9 (95 percent confidence interval, 4.9 to
12.9) for those who smoked, 5.1 (95 percent confidence interval, 2.9 to 8.8)
for those with hypertension, 3.3 (95 percent confidence interval, 1.6 to
6.8) for those with hypercholesterolemia, 4.2 (95 percent confidence
interval, 1.6 to 10.9) for those with diabetes, and 3.4 (95 percent
confidence interval, 2.2 to 5.3) for those who were obese. Among women who
had used oral contraceptives, the risk of myocardial infarction was highest
among those who smoked (odds ratio, 13.6), those who had diabetes (odds
ratio, 17.4), and those who had hypercholesterolemia (odds ratio, 24.7).


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Table 4. Odds Ratios for Myocardial Infarction in Relation to the Use of
Oral Contraceptives and to the Presence or Absence of Cardiovascular Risk
Factors.

Factor V Leiden or a G20210A mutation in the prothrombin gene was present in
18 of 214 patients (8 percent) and 58 of 760 controls (8 percent). Two
control women carried both mutations. The odds ratio for myocardial
infarction among women with a prothrombotic mutation was 1.1 (95 percent
confidence interval, 0.6 to 1.9), as compared with women without a mutation.
In the subgroup of smokers the presence of one of these mutations increased
the risk of myocardial infarction by 1.6 (95 percent confidence interval,
0.8 to 3.3). Among women younger than 35 years of age who had a
prothrombotic mutation, the odds ratio was 1.6 (95 percent confidence
interval, 0.4 to 5.8), and among those who were at least 35 years old it was
0.9 (95 percent confidence interval, 0.5 to 1.7). The use of oral
contraceptives doubled the risk of myocardial infarction among women without
a prothrombotic mutation (odds ratio, 2.1; 95 percent confidence interval,
1.5 to 3.0) and among women with a prothrombotic mutation (odds ratio, 1.9;
95 percent confidence interval, 0.6 to 5.5).
Discussion
In this case–control study we found that the use of currently available
combined oral contraceptives increased the overall risk of a first
myocardial infarction. As compared with nonusers, women who used first- and
second-generation oral contraceptives had a significantly increased risk,
but the results were inconclusive for women who used third-generation oral
contraceptives. The risk was increased in all age groups except for the
small group of women who were 18 to 24 years old, and there were no
significant differences in the odds ratios between the age categories or
between the doses of estrogen. The risks were highest among users of oral
contraceptives who smoked, who had diabetes mellitus, or who had
hypercholesterolemia, but they were not affected by the presence of factor V
Leiden or the G20210A mutation in the prothrombin gene.
The use of second-generation oral contraceptives increased the risk of
myocardial infarction by a factor of 2.5. The use of third-generation oral
contraceptives did not increase the risk significantly (odds ratio, 1.3).
The direct comparison of second- and third-generation oral contraceptives
suggested that the use of third-generation agents was associated with a
lower risk of myocardial infarction, but the confidence interval was wide
and therefore a definite conclusion could not be reached.
Five studies, including ours, have directly compared the effect of the use
of second- and third-generation oral contraceptives on the risk of
myocardial infarction, 17
<http://content.nejm.org/cgi/content/full/345/25/#R17> , 18
<http://content.nejm.org/cgi/content/full/345/25/#R18> , 19
<http://content.nejm.org/cgi/content/full/345/25/#R19> , 20
<http://content.nejm.org/cgi/content/full/345/25/#R20> , 21
<http://content.nejm.org/cgi/content/full/345/25/#R21>  with reported odds
ratios that ranged from 0.3 18
<http://content.nejm.org/cgi/content/full/345/25/#R18>  to 1.8. 21
<http://content.nejm.org/cgi/content/full/345/25/#R21>  Only the study by
Dunn et al. 21 <http://content.nejm.org/cgi/content/full/345/25/#R21>  and
our study were designed to assess whether the use of third-generation oral
contraceptives has a different effect on the risk of myocardial infarction
than does the use of second-generation agents and included a sufficient
number of women who used third-generation oral contraceptives to allow
conclusions to be drawn. Dunn et al. suggested that the risk is higher with
third-generation than with second-generation oral contraceptives (odds
ratio, 1.8; 95 percent confidence interval, 0.7 to 4.8), whereas we found
the reverse (odds ratio, 0.5; 95 percent confidence interval, 0.2 to 1.1).
As can be seen from the confidence interval, the study by Dunn et al. also
did not permit a definite conclusion to be reached.
Our study was designed as a nationwide, population-based, case–control
study, with patients recruited from all eight academic centers in the
Netherlands and eight surrounding hospitals. One of the strengths of our
study is that the use of both second- and third-generation oral
contraceptives is widespread in the Netherlands, thus providing a large
population of potential study subjects. In the evaluation of our results, we
also need to address the possibility of bias. Because all patients with
known myocardial infarction were hospitalized and the patients were selected
entirely on the basis of the discharge diagnosis, selection bias is
improbable. The rate of nonresponse was fairly low and was unlikely to have
been associated with the use of oral contraceptives or the type of agent
used. Information bias was unlikely, because the women were not told about
the primary objective of the study and the questionnaire elicited
information about many issues. The subjects' recall was optimized by the
inclusion in the questionnaire of color photographs of all available oral
contraceptives. 29 <http://content.nejm.org/cgi/content/full/345/25/#R29>
However, the possibility of recall bias cannot be excluded. Patients who
died after a myocardial infarction were not included in the study, but it is
unlikely that the use of oral contraceptives would be a specific
contributing factor to the case fatality rate.
Selective prescription following screening for risk factors may affect the
risks associated with the use of oral contraceptives. We therefore
investigated risk-factor status according to the use of oral contraceptives
in the control women and found little difference in the prevalence of
cardiovascular risk factors between those who used oral contraceptives and
those who did not ( Table 5
<http://content.nejm.org/cgi/content/full/345/25/#T5> ). There were small
differences in the incidence of hypercholesterolemia and diabetes and in
body-mass index, which were in part explained by the younger age of
oral-contraceptive users. To minimize the likelihood of confounding, we also
conducted an analysis restricted to women with no cardiovascular risk
factors and still found that women who used oral contraceptives had a risk
of myocardial infarction that was three times the risk among nonusers.


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Table 5. Prevalence of Risk Factors for Cardiovascular Events in Control
Women, According to Their Use of Oral Contraceptives.

Although the risk of myocardial infarction in users of oral contraceptives
is small in absolute terms, it has an important effect on women's health,
since 35 to 45 percent of women of reproductive age use oral contraceptives.
30 <http://content.nejm.org/cgi/content/full/345/25/#R30>  Because all
combined oral contraceptives are equally effective means of birth control,
the issue of safety is paramount. Since the absolute risk of myocardial
infarction is highly age-dependent, the risk associated with the use of oral
contraceptives will have the greatest effect in older women. A large number
of women who were 35 years of age or older still used oral contraceptives
(26 percent). This finding, however, may be specific to the Netherlands (the
rate is 24 percent in national statistics). 30
<http://content.nejm.org/cgi/content/full/345/25/#R30>  Before prescribing
oral contraceptives, clinicians should screen women for conventional risk
factors for cardiovascular events, and they should remember that the most
important advice they can give these women remains to quit smoking.
<http://weeklybriefings.org/feature.asp?strXmlDoc=3452501>
Supported by a grant (97-063) from the Netherlands Heart Foundation. Dr.
Helmerhorst has supervised research studies sponsored by multiple
pharmaceutical companies that manufacture oral-contraceptive agents.
We are indebted to Dr. Bruno Stricker for advice during the planning of the
study, to Dr. Jan Vandenbroucke and Dr. Tim Farley for critical reading of
and advice on the analysis and writing, to Annemieke van Dam for her work in
contacting patients and controls as well as for general data management, to
Esther van Lunteren and Marjon de Boer for their assistance in recruiting
controls, to Tineke Krommenhoek-van Es for the DNA analyses, to Dr. Hans Vos
for supervision, and to all the women who participated in this project.

Source Information
From the Thrombosis and Hemostasis Research Center, Department of Hematology
(B.C.T., F.R.R.), and the Departments of Cardiology (V.M.C.), Obstetrics,
Gynecology, and Reproductive Medicine (F.M.H.), and Clinical Epidemiology
(F.R.R.), Leiden University Medical Center, Leiden; and the Julius Center
for General Practice and Patient-Oriented Research (M.A.A.J.B., J.M.K.,
A.A., Y.G.) and the Department of Neurology (A.A.), University Medical
Center, Utrecht — both in the Netherlands.
Address reprint requests to Dr. Rosendaal at the Department of Clinical
Epidemiology, Leiden University Medical Center, Bldg. 1, C9-P, P.O. Box
9600, 2300 RC Leiden, the Netherlands, or at [log in to unmask]
<mailto:[log in to unmask]> .
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Appendix
The following investigators and centers in the Netherlands participated in
the study: Leiden University Medical Center, Leiden — E.E. van der Wall;
Sint Antonius Hospital, Nieuwegein — N.M. van Hemel; Academic Medical
Center, Amsterdam — R.J.G. Peters; Rijnstate Hospital, Arnhem — H.A. Bosker;
Medical Center Haaglanden, Westeinde Hospital, The Hague — J. Kolf;
University Medical Center, Nijmegen–St. Radboud — F.W.A. Verheugt; Leyenburg
Hospital, The Hague — B.J.M. Delemarre; University Medical Center,
Rotterdam–Dijkzigt — F.A.M. Jonkman; Academic Hospital, Maastricht — F.
Vermeer; Rijnland Hospital, Leiderdorp — C. van Rees; Medical Center Free
University, Amsterdam — O. Kamp; University Medical Center, Utrecht — E.O.
Robles de Medina (deceased); Academic Hospital, Groningen — M. van den Berg;
Bronovo Hospital, The Hague — P.R.M. van Dijkman; Sint Franciscus Hospital,
Rotterdam — A. Schelling; and Diaconessenhuis Leiden — S.A.G.J. Witteveen.




Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.