Higher Risk of Venous Thrombosis
During Early Use of Oral Contraceptives
in Women With Inherited Clotting Defects
Kitty W. M. Bloemenkamp, MD; Frits R. Rosendaal, MD; Frans M. Helmerhorst, MD; Jan P. Vandenbroucke, MD
Results of recent studies show that the risk
greatest in the first 6 months and the first year of oral
for venous thrombosis is highest during initial oral con-
contraceptive use. Compared with prolonged use, the risk
traceptive use. This suggests a subgroup of females who
of developing deep vein thrombosis was 3-fold higher in
are at immediate risk of thrombosis when exposed to oral
the first 6 months of use (95% confidence interval [CI],
0.6-14.8) and 2-fold higher in the first year of use (95%CI, 0.6-6.1). Patients who developed venous thrombo-
To determine whether women with inher-
sis in the early periods of use were more often thrombo-
ited clotting defects who use oral contraceptives de-
philic. Among women with thrombophilia, the risk of de-
velop venous thrombosis at an earlier stage than do those
veloping deep vein thrombosis during the first 6 months
of oral contraceptive use (compared with prolonged use)was increased 19-fold (95% CI, 1.9-175.7), and in the
Analysis of the data from the Leiden Throm-
first year of use, it was increased 11-fold (95% CI, 2.1-
bophilia Study, a population-based case-control study with
data on duration of oral contraceptive use and recentlydetected genetic coagulation disorders. Patients had a first
Women with inherited clotting defects who
episode of objectively proven deep vein thrombosis. Pa-
use oral contraceptives develop venous thrombosis not
tients and controls were considered thrombophilic when
only more often but also sooner than do those without
they had protein C deficiency, protein S deficiency, an-
inherited clotting defects. Venous thrombosis in the first
tithrombin deficiency, factor V Leiden mutation, or pro-
period of oral contraceptive use might indicate the pres-
ence of an inherited clotting defect.
Risk of developing deep vein thrombosis was
during the first months of oral contracep-
tive use might be specific to people with ge-
netic risk factors. To test this hypothesis,
bophilia Study.10,11 In the original study, oral
that has not been studied extensively.5-7 It
contraceptive use led to a 4-fold increased
adjustment). In the present analysis, with
found in about 1 of 5 patients with venous
detected genetic risk factors, we first looked
thrombosis, displays a strong interaction
with use of oral contraceptives. Other in-
sis were more often in their first 6 months
or their first year of oral contraceptive use
selves risk factors for venous thrombosis,
such as protein C deficiency, protein S de-
Research Center(Dr Rosendaal), University
also lead to a high risk of venous throm-
tary clotting defects more often than those
2000 American Medical Association. All rights reserved.
had been previous exposure to oral contraceptives; such
use was categorized as “prolonged” because the partici-pant had already had her first exposure to oral contracep-tives more than 1 year before the thrombosis or index date
(n = 12). This categorization will, if anything, lower the ef-fect of early use in our data.
The patients and methods of this study have been de-scribed previously.10 We invited 474 consecutive patients
GENETIC RISK FACTORS
(both sexes; age, Ͻ70 years; without a known malignant dis-order) with a first episode of proven deep vein thrombosis
Blood samples were collected from all participants, and
(diagnosed by established objective methods) between Janu-
plasma samples were stored at −70°C. High-molecular-
ary 1, 1988, and December 31, 1992. Patients had been se-
weight DNA was isolated from leukocytes and stored at 4°C.
lected from the medical files of 3 anticoagulation clinics in
Presence of the mutant factor V Leiden gene, protein C de-
the Netherlands, which monitor anticoagulant treatment in
ficiency, protein S deficiency, antithrombin deficiency, and
all patients within well-defined geographic areas. Each pa-
prothrombin 20210 A mutation11-14 was determined by tech-
tient with thrombosis invited 1 age- and sex-matched con-
nicians who did not know if the sample was from a patient
trol subject (a friend or acquaintance; if not possible, vol-
or control, or from an oral contraceptive user or nonuser.
unteering partners of patients were age- and sex-matched
Criteria for diagnosing clotting deficiencies were used as
to serve as controls); age matching was within 5-year bands.
After anticoagulant drug treatment was discontinued for atleast 3 months, patients underwent a structured interview
about risk factors for venous thrombosis and collection ofblood samples. Controls were seen around the time of en-
Because of the age cutoff value and other restrictions in this
rollment of the patients and underwent the same interview
analysis (see the “Study Setting” subsection), we had to break
the original one-to-one matching. However, we stratified for
In the present analysis, we selected premenopausal fe-
age in the analysis because of confounding by age: new oral
males, aged 15 to 49 years, who at the time of their throm-
contraceptive users are often young, and long-term users are
bosis (or the corresponding date in the control group, their
mostly older. Lack of adjustment for age will lead to under-
index date [see the next section]) were not pregnant or in
estimation of the effect of new use because older persons have
the puerperium, did not have a recent miscarriage, and were
a higher risk of venous thrombosis. Because age matching was
not using injectable progestogens. Data about use of oral
in 5-year bands, an analysis that stratifies for age takes po-
contraceptives at the thrombosis or index date were avail-
tential confounding and the effect of matching into account.
able from 155 patients and 169 controls.
First, we restricted analysis to patients and controls
who had been using oral contraceptives (at the thrombo-
TIME WINDOW ASSESSMENT
sis or index date) to investigate the effect of duration of oralcontraceptive use. We analyzed whether patients who used
Information on the duration of oral contraceptive use was
oral contraceptives had their venous thrombosis more of-
newly abstracted from the interview data and supple-
ten during the first 6 months or first year of oral contra-
mented with data from hospital discharge letters and origi-
ceptive use compared with the index date of the controls
nal investigation records (for patients and controls). We
by estimating the odds ratio (OR) (95% confidence inter-
analyzed all periods of oral contraceptive use (different
val [CI]) of being in an early time window of use.
types) and compared first-ever use with prolonged use. For
Second, we restricted analysis to patients who used oral
the present analysis, we checked whether the date of ve-
contraceptives to investigate whether patients who had de-
nous thrombosis was in the first 6 months or in the first
veloped venous thrombosis in the early periods of use more
year of oral contraceptive use for patients. For controls, we
often had thrombophilia compared with those who devel-
used their index date, ie, the date of venous thrombosis of
oped venous thrombosis during prolonged use, also by cal-
their corresponding patient in the original study. This en-
culating the OR. Patients and controls were considered
sures that use of oral contraceptives among the controls
thrombophilic when they had protein C deficiency, pro-
reflects the same calendar years as patients. We ascer-
tein S deficiency, antithrombin deficiency, factor V Leiden
tained whether this index date was within the first 6 months
mutation, or prothrombin 20210 A mutation.
or the first year of oral contraceptive use of the control. In
Multivariate analysis by unconditional logistic regres-
this way, we could verify whether patients who used oral
sion was used to adjust for possible confounders, eg, age,
contraceptives were more often in their early periods of pill
family history of venous thrombosis, and history of preg-
use compared with controls who used oral contracep-
nancy. Age was entered into the models as a continuous
tives. When a participant who had used oral contracep-
variable (in years) after assessing that using a categorized
tives at the time of thrombosis or the index date had tem-
dummy variable model led only to trivial differences for
porarily stopped using them in the year before this date,
the estimators of interest. Family history and history of preg-
this renewed use was not counted as first use because there
nancy were entered as dichotomous variables.
the time of thrombosis. Of 169 controls, 65 used con-traceptives at their index date. On average, patients who
Of 155 premenopausal patients with deep vein throm-
were using oral contraceptives were slightly older than
bosis (age, 15-49 years), 109 used oral contraceptives at
controls using oral contraceptives (age [mean ± SD],
2000 American Medical Association. All rights reserved.
32.2 ± 9.6 vs 29.8 ± 8.9 years); long-term users were olderthan short-term users (age [mean ± SD], 32.1 ± 9.1 vs
Table 1. Patients and Controls Using Oral Contraceptives at
24.4 ± 9.6 years at the cutoff point of 1 year of use). Strati-
the Thrombosis or Index Data According to Duration of Use
fication of oral contraceptive use by duration of use is
shown in Table 1
. The date of venous thrombosis was
cof Use, mo
more often in the first 6 months or first year of use thanwas the corresponding index date of the controls. Age-
adjusted OR (95% CI) of oral contraceptive use, com-
pared with longer use, for females using oral contracep-
tives up to 6 months was 3.0 (95% CI, 0.6-14.8). When1 year was taken as a cutoff point, the age-adjusted ORfor use shorter than 1 year became 1.9 (95% CI, 0.6-6.1). Further adjustment for history of pregnancy or posi-
Table 2. Patients With or Without Inherited Clotting Defects
According to Duration of Oral Contraceptive Use
tive family history did not change the estimations. Pro-longed users (ie, Ͼ1 year of use) had an age-adjusted
5-fold increase in risk relative to nonusers of oral con-
traceptives (data not shown). In the original study,8 the
age-adjusted OR of oral contraceptive use (all times to-
of Use, mo
Of 109 oral contraceptive–using patients, 37 were
thrombophilic: 5 had a protein C deficiency, 3 had a pro-
tein S deficiency, 2 had an antithrombin deficiency, 25had the factor V Leiden mutation, and 4 had the pro-thrombin 20210 A mutation (2 had both the factor V
nous thrombosis) cannot have affected any prescription of
Leiden and prothrombin 20210 A mutations). Of 65 oral
oral contraceptives because we only studied first venous
contraceptive–using controls, 10 were thrombophilic: 5
thrombosis. Assessment of the time windows was per-
had a protein S deficiency, 2 had the factor V Leiden mu-
formed retroactively on existing data, but without knowl-
tation, and 3 had the prothrombin 20210 A mutation.
edge of the participants’ genetic status. Finally, patients came
shows that, among patients who developed
from a routine care situation wherein all patients from a
venous thrombosis during early use, thrombophilia was
certain geographic area are given care; patients were con-
more often present than among those who developed ve-
secutively included on meeting the study and analysis re-
nous thrombosis during prolonged use. The age-
quirements. The CIs in our study remain large—despite
adjusted OR for coagulation defects was 18.5 (95% CI,
the fact that we started with ample numbers of patients and
1.9-175.7) for use up to 6 months. For the cutoff point
controls—as a consequence of looking at narrow time win-
of 1 year, the OR was 11.0 (95% CI, 2.1-57.3).
dows with specific genetic risk factors.
Four patients who developed deep vein thrombo-
Earlier studies5-7,18,19 on duration of oral contracep-
sis in the first year of use took preparations containing
tive use described that the association between oral con-
monophasic ethinyl estradiol and desogestrel (30 µg), and
traceptive use and venous thrombosis was unrelated to
2 used ethinyl estradiol- and levonorgestrel-containing
duration of use. Earlier negative findings might be ex-
oral contraceptives (30 µg); among controls, these num-
plained by the use of different cutoff points, with larger
bers were 1 and 2, respectively. Although these num-
time windows. From our study results, we conclude that
bers are too small to arrive at stable conclusions, they sup-
risk of oral contraceptive use is higher during the first
port those in the literature15-17 about difference in venous
year of use, especially during the first 6 months of use.
thrombosis risk for different types of contraceptives. They
However, females who use oral contraceptives longer than
also indicate that the “starter effect” does not explain the
1 year are still at risk of developing venous thrombosis;
difference between different types of contraceptives.17
their age-adjusted risk was still 5-fold higher comparedwith nonusers (data not shown). These results are simi-
lar to those of the World Health Organization study1 andthe Transnational Study,2 in which women who had used
In this case-control study, we first confirm the high risk
oral contraceptives for the first time were compared with
of venous thrombosis during the early stages of oral con-
those who had never used them; a 10-fold increased risk
traceptive use. Second, we find that the high risk in the
during the first year of use was found, which declined
first 6 months and first year of use can be explained in
to a 2-fold increase in subsequent years.20,21 Once use of
part by the presence of inherited coagulation defects.
an oral contraceptive is discontinued, risk of venous
Several potential biases that are often believed to ex-
thrombosis disappears within about 3 months; there is
ist in case-control studies do not apply to studies of ge-
no elevated risk among past users.1,7,19,22,23
netic risk factors. For genetic risk factors, it is not impor-
Among patients who developed deep vein throm-
tant that they are assessed only after diseases develop because
bosis within 1 year of starting use of oral contracep-
they do not change. Moreover, the most important ge-
tives, most inherited clotting defects were found. Risk
netic risk factors for venous thrombosis, factor V Leiden
of developing deep vein thrombosis during the first year
and factor II mutations, were not yet discovered at the time
of oral contraceptive use was 11-fold for patients with
of data collection. Even their clinical manifestation (ve-
thrombosis. An explanation for the higher risk is that these
2000 American Medical Association. All rights reserved.
patients already have 1 inherited risk factor, of which the
2. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD. Third-
effect is augmented by oral contraceptives. The exact na-
generation oral contraceptives and risk of venous thromboembolic disorders:an international case-control study. BMJ. 1996;312:83-88.
ture of the biochemical interaction is unknown, al-
3. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Buller HR, Vanden-
though there are interesting leads about the role of ac-
broucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein throm-bosis associated with oral contraceptives containing third-generation progesto-
quired activated protein C resistance.24-28
From the results of this study and others,1-4 we con-
4. Poulter NR, Farley TMM, Chang CL, Marmot MG, Meirik O. Safety of combined
clude that duration of oral contraceptive use affects the
oral contraceptive pills [authors’ reply]. Lancet. 1996;347:547.
5. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives
association between oral contraceptives and venous
and thromboembolic disease. BMJ. 1968;2:199-205.
thrombosis: the relative risk is highest in first-ever us-
6. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives
ers. Furthermore, we find that this starter effect is ex-
and thromboembolic disease: a further report. BMJ. 1969;2:651-657.
7. Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE. Thromboembolism and
plained in part by the presence of inherited clotting de-
oral contraceptives: an epidemiologic case-control study. Am J Epidemiol. 1969;
fects: females with inherited clotting defects are more
likely to develop venous thrombosis during oral contra-
8. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR.
Increased risk of venous thrombosis in oral-contraceptive users who are carri-
ceptive use in the first year of use. Together with the over-
ers of factor V Leiden mutation. Lancet. 1994;344:1453-1457.
all interaction between oral contraceptive use and inher-
9. Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrom-
ited clotting defects,8,9 this implies that females with
bin III-, protein C- and protein S-deficiency taking oral contraceptive medica-tion: the GTH Study Group on Natural Inhibitors. Thromb Haemost. 1994;71:
inherited clotting defects who use oral contraceptives de-
velop venous thrombosis not only more often but also
10. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM.
Venous thrombosis due to poor anticoagulant response to activated protein C:
sooner. However, the inherited clotting defects explain
Leiden Thrombophilia Study. Lancet. 1993;342:1503-1506.
only part of the starter effect. When females continue us-
11. Koster T, Rosendaal FR, Brit E, et al. Protein C deficiency in a controlled series
ing oral contraceptives, their risk of developing venous
of unselected outpatients: an infrequent but clear risk factor for venous throm-bosis (Leiden Thrombophilia Study). Blood. 1995;85:2756-2761.
thrombosis does not disappear, and it also is present in
12. Bertina RM, Koeleman RPC, Koster T, et al. Mutation in blood coagulation factor
those without clotting defects. Also, the starter effect can-
V associated with resistance to activated protein C. Nature. 1994;369:64-67.
not explain differences between different contracep-
13. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombo-
sis in patients homozygous for factor V Leiden. Blood. 1995;85:1504-1508.
14. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation
It is uncertain whether routine screening for ge-
in the 3Ј-untranslated region of the prothrombin gene is associated with el-
netic clotting disorders before starting oral contracep-
evated plasma prothrombin levels and an increase in venous thrombosis. Blood.
tive use is useful or feasible, even when there is a family
15. Hannaford P. Cardiovascular Disease and Steroid Hormone Contraception: Re-
history of inherited thrombophilia in a first-degree rela-
port of a WHO Scientific Group. Geneva, Switzerland: World Health Organiza-tion; 1998. WHO Technical Report Series, No. 877.
tive.29,30 Still, taking a careful family history and provid-
16. Bloemenkamp KWM, Rosendaal FR, Bu¨ller HR, Helmerhorst FM, Colly LP, Van-
ing information to patients about signs and symptoms
denbroucke JP. Risk of venous thrombosis with use of current low-dose oral
of venous thromboembolism might well be in order. When
contraceptives is not explained by diagnostic suspicion and referral bias. ArchIntern Med. 1999;159:65-70.
a female develops venous thrombosis during the first year
17. Walker AM. Newer oral contraceptives and the risk of venous thromboembo-
of oral contraceptive use, this could be an indication that
lism. Contraception. 1998;57:169-181.
she has an inherited clotting defect.
18. Shapiro S. Oral contraceptives and venous thromboembolic disease, surgically
confirmed gall-bladder disease, and breast tumours: report from the Boston Col-laborative Drug Surveillance Programme. Lancet. 1973;1:1399-1404.
Accepted for publication April 13, 1999.
19. Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous throm-
The original study was supported by grant 89.063
boembolism in relation to oral contraceptive use. Obstet Gynecol. 1987;69:91-95.
from the Netherlands Heart Foundation, The Hague, the
20. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use
of newer oral contraceptives and the risk of venous thromboembolism. Contra-
We thank all the patients who took part in this study;
21. Farley TM, Meirik O, Marmot MG, Chang CL, Poulter NR. Oral contraceptives and
T. Koster, the investigator of the original study; Felix J. M.
risk of venous thromboembolism: impact of duration of use. Contraception. 1998;
van der Meer, MD, PhD (Anticoagulation Clinic Leiden,
22. WHO Collaborative Study. Cardiovascular disease and the use of oral contra-
Leiden, the Netherlands), Louise P. Colly, MD, PhD (An-
ceptives. Bull World Health Organ. 1989;67:417-423.
ticoagulation Clinic Amsterdam, Amsterdam, the Nether-
23. Oral contraceptives, venous thrombosis and varicose veins: Royal College of
lands), and Pieter H. Trienekens, PhD (Anticoagulation
General Practitioners’ Oral Contraception Study. J R Coll Gen Pract. 1978;28:393-399.
Clinic Rotterdam, Rotterdam, the Netherlands) for their co-
24. Henkens CMA, Bom VJJ, Seinen AJ, van der Meer J. Sensitivity to activated pro-
operation; Ank Schreijer for secretarial and administrative
tein C: influence of oral contraceptives and sex. Thromb Haemost. 1995;73:
support; Thea Visser for laboratory assistance; and Pieter
25. Østerud B, Robertsen R, Svang GB, Thijssen F. Resistance to activated protein C
A. van der Velden, PhD, for DNA analysis.
is reduced in women using oral contraceptives. Blood Coagul Fibrinolysis. 1994;
Reprints: Jan P. Vandenbroucke, MD, Department of
Clinical Epidemiology, Leiden University Medical Center,
26. Olivieri O, Friso S, Manzato F, et al. Resistance to activated protein C in healthy
women taking oral contraceptives. Br J Haematol. 1995;91:465-470.
Bldg 1-CO-P, PO Box 9600, 2300 RC Leiden, the Nether-
27. Bokarewa MI, Falk G, Sten-Linder M, Egberg N, Blomback M, Bremme K. Throm-
lands (e-mail: [email protected]).
botic risk factors and oral contraception. J Lab Clin Med. 1995;126:294-298.
28. Rosing J, Tans G, Nicolaes GAF, et al. Oral contraceptives and venous throm-
bosis: different sensitivities to activated protein C in women using second- and
third-generation oral contraceptives. Br J Haematol. 1997;97:233-238.
29. Brie¨t E, van der Meer FJ, Rosendaal FR, Houwing-Duistermaat JJ, van Houwel-
ingen HC. The family history and inherited thrombophilia. Br J Haematol. 1994;
1. Venous thromboembolic disease and combined oral contraceptives: results of
international multi centre case-control study: World Health Organization Col-
30. Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V
laborative Study of Cardiovascular Disease and Steroid Hormone Contracep-
Leiden: should we screen oral contraceptive users and pregnant women? BMJ.
2000 American Medical Association. All rights reserved.
Patient Travel Questionnaire Please complete this questionnaire and return it as soon as possible. You may need travel vaccinations depending on the country or countries you intend to visit. Asthe vaccines are not immediately effective, please ask about them as soon as you havebooked, ideally at least 4 weeks before travelling. Please fill in this form and hand it in to thereceptionist. Afte
Italy Discovery + Israel Journey PROGRAM ITINERARY We have provided the fol owing sample itinerary to give you an idea of what this travel experience is all about. The actual itinerary may vary slightly. A formal itinerary, including a list of confirmed accommodations wil be sent to you 4-6 weeks prior to the start of the program. DAY #1 / Tuesday / Take Off! • Depar