|
|||||||
|
|
|
|||||
|
|
|||||||
Background Results of recent studies show that the risk
for venous thrombosis is highest during initial oral contraceptive use. This
suggests a subgroup of females who are at immediate risk of thrombosis when
exposed to oral contraceptives.
Objective To determine whether women with inherited clotting defects who use oral contraceptives develop venous thrombosis at an earlier stage than do those without inherited clotting defects.
Methods Analysis of the data from the Leiden Thrombophilia Study, a population-based case-control study with data on duration of oral contraceptive use and recently detected genetic coagulation disorders. Patients had a first episode of objectively proven deep vein thrombosis. Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or prothrombin 20210 A mutation.
Results Risk of developing deep vein thrombosis was greatest in the first 6 months and the first year of oral contraceptive use. Compared with prolonged use, the risk of developing deep vein thrombosis was 3-fold higher in 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 thrombosis in the early periods of use were more often thrombophilic. Among women with thrombophilia, the risk of developing 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 first year of use, it was increased 11-fold (95% CI, 2.1-57.3).
Conclusions Women with inherited clotting defects who use oral contraceptives develop venous thrombosis not only more often but also sooner than do those without inherited clotting defects. Venous thrombosis in the first period of oral contraceptive use might indicate the presence of an inherited clotting defect.
Arch Intern Med. 2000;160:49-52
FULL TEXT BELOW:
RESULTS OF recent studies1-4 show that the risk for venous thrombosis is highest
during the initial period of oral contraceptive use. This confirms a clinical
impression that has not been studied extensively.5-7 It was previously reported3,
8 that factor V Leiden mutation, which leads to resistance to activated protein
C and was found in about 1 of 5 patients with venous thrombosis, displays a
strong interaction with use of oral contraceptives. Other inherited clotting
defects that are themselves risk factors for venous thrombosis, such as protein
C deficiency, protein S deficiency, antithrombin deficiency, and prothrombin
20210 A mutation, might also lead to a high risk of venous thrombosis when combined
with oral contraceptive use.9
A higher risk of venous thrombosis during the first months of oral contraceptive use might be specific to people with genetic risk factors. To test this hypothesis, we analyzed data from the Leiden Thrombophilia Study.10, 11 In the original study, oral contraceptive use led to a 4-fold increased risk of venous thrombosis (6-fold on age adjustment). In the present analysis, with new data on duration of use and recently detected genetic risk factors, we first looked at whether patients with venous thrombosis were more often in their first 6 months or their first year of oral contraceptive use compared with control subjects who also used oral contraceptives. Second, we investigated whether patients who developed venous thrombosis early had hereditary clotting defects more often than those who developed venous thrombosis during prolonged use.
PARTICIPANTS, MATERIALS, AND METHODS
STUDY SETTING
The patients and methods of this study have been described previously.10 We
invited 474 consecutive patients (both sexes; age, <70 years; without a known
malignant disorder) with a first episode of proven deep vein thrombosis (diagnosed
by established objective methods) between January 1, 1988, and December 31,
1992. Patients had been selected from the medical files of 3 anticoagulation
clinics in the Netherlands, which monitor anticoagulant treatment in all patients
within well-defined geographic areas. Each patient with thrombosis invited 1
age- and sex-matched control subject (a friend or acquaintance; if not possible,
volunteering partners of patients were age- and sex-matched to serve as controls);
age matching was within 5-year bands. After anticoagulant drug treatment was
discontinued for at least 3 months, patients underwent a structured interview
about risk factors for venous thrombosis and collection of blood samples. Controls
were seen around the time of enrollment of the patients and underwent the same
interview and blood sample collection.
In the present analysis, we selected premenopausal females, aged 15 to 49 years, who at the time of their thrombosis (or the corresponding date in the control group, their index date [see the next section]) were not pregnant or in the puerperium, did not have a recent miscarriage, and were not using injectable progestogens. Data about use of oral contraceptives at the thrombosis or index date were available from 155 patients and 169 controls.
TIME WINDOW ASSESSMENT
Information on the duration of oral contraceptive use was newly abstracted from
the interview data and supplemented with data from hospital discharge letters
and original investigation records (for patients and controls). We analyzed
all periods of oral contraceptive use (different types) and compared first-ever
use with prolonged use. For the present analysis, we checked whether the date
of venous thrombosis was in the first 6 months or in the first year of oral
contraceptive use for patients. For controls, we used their index date, ie,
the date of venous thrombosis of their corresponding patient in the original
study. This ensures that use of oral contraceptives among the controls reflects
the same calendar years as patients. We ascertained whether this index date
was within the first 6 months or the first year of oral contraceptive use of
the control. In this way, we could verify whether patients who used oral contraceptives
were more often in their early periods of pill use compared with controls who
used oral contraceptives. When a participant who had used oral contraceptives
at the time of thrombosis or the index date had temporarily stopped using them
in the year before this date, this renewed use was not counted as first use
because there had been previous exposure to oral contraceptives; such use was
categorized as "prolonged" because the participant had already had
her first exposure to oral contraceptives more than 1 year before the thrombosis
or index date (n = 12). This categorization will, if anything, lower the effect
of early use in our data.
GENETIC RISK FACTORS
Blood samples were collected from all participants, and plasma samples were
stored at -70°C. High-molecular-weight DNA was isolated from leukocytes
and stored at 4°C. Presence of the mutant factor V Leiden gene, protein
C deficiency, protein S deficiency, antithrombin deficiency, and prothrombin
20210 A mutation11-14 was determined by technicians who did not know if the
sample was from a patient or control, or from an oral contraceptive user or
nonuser. Criteria for diagnosing clotting deficiencies were used as described
previously.11-13
STATISTICAL ANALYSIS
Because of the age cutoff value and other restrictions in this analysis (see
the "Study Setting" subsection), we had to break the original one-to-one
matching. However, we stratified for age in the analysis because of confounding
by age: new oral contraceptive users are often young, and long-term users are
mostly older. Lack of adjustment for age will lead to underestimation of the
effect of new use because older persons have a higher risk of venous thrombosis.
Because age matching was in 5-year bands, an analysis that stratifies for age
takes potential confounding and the effect of matching into account.
First, we restricted analysis to patients and controls who had been using oral contraceptives (at the thrombosis or index date) to investigate the effect of duration of oral contraceptive use. We analyzed whether patients who used oral contraceptives had their venous thrombosis more often during the first 6 months or first year of oral contraceptive use compared with the index date of the controls by estimating the odds ratio (OR) (95% confidence interval [CI]) of being in an early time window of use.
Second, we restricted analysis to patients who used oral contraceptives to investigate whether patients who had developed venous thrombosis in the early periods of use more often had thrombophilia compared with those who developed venous thrombosis during prolonged use, also by calculating the OR. Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or prothrombin 20210 A mutation.
Multivariate analysis by unconditional logistic regression was used to adjust for possible confounders, eg, age, family history of venous thrombosis, and history of pregnancy. Age was entered into the models as a continuous variable (in years) after assessing that using a categorized dummy variable model led only to trivial differences for the estimators of interest. Family history and history of pregnancy were entered as dichotomous variables.
RESULTS
Of 155 premenopausal patients with deep vein thrombosis (age, 15-49 years), 109 used oral contraceptives at the time of thrombosis. Of 169 controls, 65 used contraceptives at their index date. On average, patients who were using oral contraceptives were slightly older than controls using oral contraceptives (age [mean SD], 32.2 9.6 vs 29.8 8.9 years); long-term users were older than short-term users (age [mean SD], 32.1 9.1 vs 24.4 9.6 years at the cutoff point of 1 year of use). Stratification of oral contraceptive use by duration of use is shown in Table 1. The date of venous thrombosis was more often in the first 6 months or first year of use than was the corresponding index date of the controls. Age-adjusted OR (95% CI) of oral contraceptive use, compared with longer use, for females using oral contraceptives up to 6 months was 3.0 (95% CI, 0.6-14.8). When 1 year was taken as a cutoff point, the age-adjusted OR for use shorter than 1 year became 1.9 (95% CI, 0.6-6.1). Further adjustment for history of pregnancy or positive family history did not change the estimations. Prolonged users (ie, >1 year of use) had an age-adjusted 5-fold increase in risk relative to nonusers of oral contraceptives (data not shown). In the original study,8 the age-adjusted OR of oral contraceptive use (all times together) was 6-fold.
Of 109 oral contraceptive–using patients, 37 were thrombophilic: 5 had a protein C deficiency, 3 had a protein S deficiency, 2 had an antithrombin deficiency, 25 had the factor V Leiden mutation, and 4 had the prothrombin 20210 A mutation (2 had both the factor V Leiden and prothrombin 20210 A mutations). Of 65 oral contraceptive–using controls, 10 were thrombophilic: 5 had a protein S deficiency, 2 had the factor V Leiden mutation, and 3 had the prothrombin 20210 A mutation. Table 2 shows that, among patients who developed venous thrombosis during early use, thrombophilia was more often present than among those who developed venous thrombosis during prolonged use. The age-adjusted OR for coagulation defects was 18.5 (95% CI, 1.9-175.7) for use up to 6 months. For the cutoff point of 1 year, the OR was 11.0 (95% CI, 2.1-57.3).
Four patients who developed deep vein thrombosis in the first year of use took preparations containing monophasic ethinyl estradiol and desogestrel (30 µg), and 2 used ethinyl estradiol- and levonorgestrel-containing oral contraceptives (30 µg); among controls, these numbers were 1 and 2, respectively. Although these numbers are too small to arrive at stable conclusions, they support those in the literature15-17 about difference in venous thrombosis risk for different types of contraceptives. They also indicate that the "starter effect" does not explain the difference between different types of contraceptives.17
COMMENT
In this case-control study, we first confirm the high risk of venous thrombosis during the early stages of oral contraceptive use. Second, we find that the high risk in the first 6 months and first year of use can be explained in part by the presence of inherited coagulation defects.
Several potential biases that are often believed to exist in case-control studies do not apply to studies of genetic risk factors. For genetic risk factors, it is not important that they are assessed only after diseases develop because they do not change. Moreover, the most important genetic risk factors for venous thrombosis, factor V Leiden and factor II mutations, were not yet discovered at the time of data collection. Even their clinical manifestation (venous thrombosis) cannot have affected any prescription of oral contraceptives because we only studied first venous thrombosis. Assessment of the time windows was performed retroactively on existing data, but without knowledge of the participants' genetic status. Finally, patients came from a routine care situation wherein all patients from a certain geographic area are given care; patients were consecutively included on meeting the study and analysis requirements. The CIs in our study remain large—despite the fact that we started with ample numbers of patients and controls—as a consequence of looking at narrow time windows with specific genetic risk factors.
Earlier studies5-7, 18, 19 on duration of oral contraceptive use described that the association between oral contraceptive use and venous thrombosis was unrelated to duration of use. Earlier negative findings might be explained by the use of different cutoff points, with larger time windows. From our study results, we conclude that risk of oral contraceptive use is higher during the first year of use, especially during the first 6 months of use. However, females who use oral contraceptives longer than 1 year are still at risk of developing venous thrombosis; their age-adjusted risk was still 5-fold higher compared with nonusers (data not shown). These results are similar to those of the World Health Organization study1 and the Transnational Study,2 in which women who had used oral contraceptives for the first time were compared with those who had never used them; a 10-fold increased risk during the first year of use was found, which declined to a 2-fold increase in subsequent years.20, 21 Once use of an oral contraceptive is discontinued, risk of venous thrombosis disappears within about 3 months; there is no elevated risk among past users.1, 7, 19, 22, 23
Among patients who developed deep vein thrombosis within 1 year of starting use of oral contraceptives, most inherited clotting defects were found. Risk of developing deep vein thrombosis during the first year of oral contraceptive use was 11-fold for patients with thrombosis. An explanation for the higher risk is that these patients already have 1 inherited risk factor, of which the effect is augmented by oral contraceptives. The exact nature of the biochemical interaction is unknown, although there are interesting leads about the role of acquired activated protein C resistance.24-28
From the results of this study and others,1-4 we conclude that duration of oral contraceptive use affects the association between oral contraceptives and venous thrombosis: the relative risk is highest in first-ever users. Furthermore, we find that this starter effect is explained in part by the presence of inherited clotting defects: females with inherited clotting defects are more likely to develop venous thrombosis during oral contraceptive use in the first year of use. Together with the overall interaction between oral contraceptive use and inherited clotting defects,8, 9 this implies that females with inherited clotting defects who use oral contraceptives develop venous thrombosis not only more often but also sooner. However, the inherited clotting defects explain only part of the starter effect. When females continue using oral contraceptives, their risk of developing venous thrombosis does not disappear, and it also is present in those without clotting defects. Also, the starter effect cannot explain differences between different contraceptives in observational studies.17
It is uncertain whether routine screening for genetic clotting disorders before starting oral contraceptive use is useful or feasible, even when there is a family history of inherited thrombophilia in a first-degree relative.29, 30 Still, taking a careful family history and providing information to patients about signs and symptoms of venous thromboembolism might well be in order. When a female develops venous thrombosis during the first year of oral contraceptive use, this could be an indication that she has an inherited clotting defect.
Author/Article Information
From the Departments of Obstetrics, Gynecology, and Reproductive Medicine (Drs
Bloemenkamp and Helmerhorst) and Clinical Epidemiology (Drs Rosendaal and Vandenbroucke),
and the Thrombosis and Hemostasis Research Center (Dr Rosendaal), University
Hospital Leiden, Leiden, the Netherlands.
Reprints: Jan P. Vandenbroucke, MD, Department of Clinical Epidemiology, Leiden
University Medical Center, Bldg 1-CO-P, PO Box 9600, 2300 RC Leiden, the Netherlands
(e-mail: vdbroucke@mail.medfac.leidenuniv.nl).
Accepted for publication April 13, 1999.
The original study was supported by grant 89.063 from the Netherlands Heart Foundation, The Hague, the Netherlands.
We thank all the patients who took part in this study; T. Koster, the investigator of the original study; Felix J. M. van der Meer, MD, PhD (Anticoagulation Clinic Leiden, Leiden, the Netherlands), Louise P. Colly, MD, PhD (Anticoagulation Clinic Amsterdam, Amsterdam, the Netherlands), and Pieter H. Trienekens, PhD (Anticoagulation Clinic Rotterdam, Rotterdam, the Netherlands) for their cooperation; Ank Schreijer for secretarial and administrative support; Thea Visser for laboratory assistance; and Pieter A. van der Velden, PhD, for DNA analysis.
REFERENCES
1.
Venous thromboembolic disease and combined oral contraceptives: results of international
multi centre case-control study: World Health Organization Collaborative Study
of Cardiovascular Disease and Steroid Hormone Contraception.
Lancet.
1995;346:1575-1582.
MEDLINE
2.
Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD.
Third-generation oral contraceptives and risk of venous thromboembolic disorders:
an international case-control study.
BMJ.
1996;312:83-88.
MEDLINE
3.
Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP.
Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated
with oral contraceptives containing third-generation progestogen.
Lancet.
1995;346:1593-1596.
MEDLINE
4.
Poulter NR, Farley TMM, Chang CL, Marmot MG, Meirik O.
Safety of combined oral contraceptive pills [authors' reply].
Lancet.
1996;347:547.
5.
Vessey MP, Doll R.
Investigation of relation between use of oral contraceptives and thromboembolic
disease.
BMJ.
1968;2:199-205.
MEDLINE
6.
Vessey MP, Doll R.
Investigation of relation between use of oral contraceptives and thromboembolic
disease: a further report.
BMJ.
1969;2:651-657.
MEDLINE
7.
Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE.
Thromboembolism and oral contraceptives: an epidemiologic case-control study.
Am J Epidemiol.
1969;90:365-380.
MEDLINE
8.
Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR.
Increased risk of venous thrombosis in oral-contraceptive users who are carriers
of factor V Leiden mutation.
Lancet.
1994;344:1453-1457.
MEDLINE
9.
Pabinger I, Schneider B.
Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein
S-deficiency taking oral contraceptive medication: the GTH Study Group on Natural
Inhibitors.
Thromb Haemost.
1994;71:548-552.
MEDLINE
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:
Leiden Thrombophilia Study.
Lancet.
1993;342:1503-1506.
MEDLINE
11.
Koster T, Rosendaal FR, Brit E, et al.
Protein C deficiency in a controlled series of unselected outpatients: an infrequent
but clear risk factor for venous thrombosis (Leiden Thrombophilia Study).
Blood.
1995;85:2756-2761.
MEDLINE
12.
Bertina RM, Koeleman RPC, Koster T, et al.
Mutation in blood coagulation factor V associated with resistance to activated
protein C.
Nature.
1994;369:64-67.
MEDLINE
13.
Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH.
High risk of thrombosis in patients homozygous for factor V Leiden.
Blood.
1995;85:1504-1508.
MEDLINE
14.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM.
A common genetic variation in the 3'-untranslated region of the prothrombin
gene is associated with elevated plasma prothrombin levels and an increase in
venous thrombosis.
Blood.
1996;88:3698-3703.
MEDLINE
15.
Hannaford P.
Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific
Group.
Geneva, Switzerland: World Health Organization; 1998. WHO Technical Report Series,
No. 877.
16.
Bloemenkamp KWM, Rosendaal FR, Büller HR, Helmerhorst FM, Colly LP, Vandenbroucke
JP.
Risk of venous thrombosis with use of current low-dose oral contraceptives is
not explained by diagnostic suspicion and referral bias.
Arch Intern Med.
1999;159:65-70.
ABSTRACT | FULL TEXT | PDF | MEDLINE
17.
Walker AM.
Newer oral contraceptives and the risk of venous thromboembolism.
Contraception.
1998;57:169-181.
MEDLINE
18.
Shapiro S.
Oral contraceptives and venous thromboembolic disease, surgically confirmed
gall-bladder disease, and breast tumours: report from the Boston Collaborative
Drug Surveillance Programme.
Lancet.
1973;1:1399-1404.
MEDLINE
19.
Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S.
Venous thromboembolism in relation to oral contraceptive use.
Obstet Gynecol.
1987;69:91-95.
MEDLINE
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.
Contraception.
1997;56:141-146.
MEDLINE
21.
Farley TM, Meirik O, Marmot MG, Chang CL, Poulter NR.
Oral contraceptives and risk of venous thromboembolism: impact of duration of
use.
Contraception.
1998;57:61-65.
MEDLINE
22.
WHO Collaborative Study.
Cardiovascular disease and the use of oral contraceptives.
Bull World Health Organ.
1989;67:417-423.
MEDLINE
23.
Oral contraceptives, venous thrombosis and varicose veins: Royal College of
General Practitioners' Oral Contraception Study.
J R Coll Gen Pract.
1978;28:393-399.
MEDLINE
24.
Henkens CMA, Bom VJJ, Seinen AJ, van der Meer J.
Sensitivity to activated protein C: influence of oral contraceptives and sex.
Thromb Haemost.
1995;73:402-404.
MEDLINE
25.
Østerud B, Robertsen R, Svang GB, Thijssen F.
Resistance to activated protein C is reduced in women using oral contraceptives.
Blood Coagul Fibrinolysis.
1994;5:853-854.
MEDLINE
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.
MEDLINE
27.
Bokarewa MI, Falk G, Sten-Linder M, Egberg N, Blomback M, Bremme K.
Thrombotic risk factors and oral contraception.
J Lab Clin Med.
1995;126:294-298.
MEDLINE
28.
Rosing J, Tans G, Nicolaes GAF, et al.
Oral contraceptives and venous thrombosis: different sensitivities to activated
protein C in women using second- and third-generation oral contraceptives.
Br J Haematol.
1997;97:233-238.
MEDLINE
29.
Briët E, van der Meer FJ, Rosendaal FR, Houwing-Duistermaat JJ, van Houwelingen
HC.
The family history and inherited thrombophilia.
Br J Haematol.
1994;87:348-352.
MEDLINE
30.
Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR.
Factor V Leiden: should we screen oral contraceptive users and pregnant women?
BMJ.
1996;313:1127-1130.
MEDLINE
|
|
|
|