Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception
The composition and use of oral contraceptives (OCs) have changed since their cardiovascular side-effects were established 20 years ago. This report describes the risk of idiopathic venous thromboembolic (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) in association with current use of combined OCs among 1143 cases aged 20-44 and 2998 age-matched controls, as evaluated in a hospital-based, case-control study in 21 centres in Africa, Asia, Europe, and Latin America. OC use was associated with an increased risk of VTE in Europe (odds ratio 4.15 [95% CI 3.09-5.57]) and in non-European ("developing") countries (3.25 [2.59-4.08]). Risk estimates were generally higher for DVT than for PE but no consistent trend by certainty of diagnosis (definite, probable, possible) was found. Increased risk was apparent within 4 months of starting OCs, was unaffected by duration of current episode of OC use, and had disappeared within 3 months of stopping OCs. Relative risk estimates of VTE associated with OC use were unaffected by age of user, by history of hypertension (excluding hypertension in pregnancy), or in any consistent way by smoking. However, in both groups of countries increased body mass index (BMI) was an independent risk factor for VTE, and OC-associated odds ratios were higher among those with a BMI above 25 kg/m2 than among those with smaller BMIs. OC-associated risk estimates were high among women in Europe with a history of hypertension in pregnancy. Odds ratios associated with the use of OCs containing a third-generation progestagen were higher than those observed with progestagens of the first (norethindrone type) and second (norgestrel group) generation. Odds ratios associated with first and second generation progestagens tended to be lower, though not significantly, when used in combination with low (< 50 micrograms oestrogen) rather than higher oestrogen doses. This study confirms an association between OC use and VTE in Europe and the developing countries, although overall risk estimates associated with use were lower than demonstrated in most previous studies of non-fatal idiopathic VTE.
combined oral contraceptive venous thromboembolism WHO international study, oral contraceptive VTE risk multinational case control study, combined OC deep vein thrombosis pulmonary embolism risk, body mass index oral contraceptive thromboembolism interaction, oral contraceptive duration use VTE risk onset cessation, third generation progestagen first second generation thrombosis comparison, estrogen dose oral contraceptive venous thromboembolism risk, developing countries oral contraceptive cardiovascular risk, WHO collaborative study steroid hormone contraception 1995, hypertension pregnancy history oral contraceptive VTE risk
PMID 7500748 7500748 DOI 10.1016/s0140-6736(95)91926-0 10.1016/s0140-6736(95)91926-0 No Authors Listed et al. 1995, No Authors Listed 1995
Cite this article
No Authors Listed (1995). Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet (London, England), 346(8990), 1575-1582. https://doi.org/10.1016/s0140-6736(95)91926-0
No Authors Listed. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995;346(8990):1575-1582. doi:10.1016/s0140-6736(95)91926-0
No Authors Listed. "Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception." Lancet (London, England), vol. 346, no. 8990, 1995, pp. 1575-1582.
In a national case-control study of fatal pulmonary embolism in New Zealand women of childbearing age, we estimated that current users of combined oral contraceptives had a relative risk of 9.6 (95% CI 3.1-29.1). From national distribution data, the absolute risk of death from pulmonary embolism in current users was estimated to be 10.5 per million woman-years.
Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. Findings: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. Interpretation: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.
A multinational hospital-based case-control study of the risk of venous thromboembolic disease associated with combined oral contraceptives (OCs) done in 1989-93 prompted a separate inquiry comparing the risk of venous thromboembolism (VTE) associated with low oestrogen (< 35 micrograms ethinyloestradiol) OCs containing levonorgestrel with risks in low oestrogen preparations containing the third-generation progestagens desogestrel or gestodene. This analysis of data from 9 countries, involved 769 cases and 1979 age matched hospital controls and, in one centre, 246 community controls matched on age and general practice. 137 cases and 203 controls were current users of levonorgestrel (odds ratio [OR with 95% confidence interval] 3.5 [2.6-4.7]), with non-users as the reference; 35 cases and 28 controls were current users of desogestrel (9.1 [4.9-17.0]), and 36 cases and 28 controls were current users of gestodene (9.1 [4.9-16.7]). The ratios of these risks, compared with levonorgestrel, were 2.6 (1.4-4.8) for both products separately. Risk estimates adjusted for body mass index (BMI) were 3.4, 7.3, and 10.2 for levonorgestrel, desogestrel, and gestodene, respectively, compared with non-users, and 2.2 and 3.0 for desogestrel and gestodene, respectively, compared with levonorgestrel. 48 (68%) cases and 48 (86%) controls exposed to desogestrel or gestodene were from the UK (Oxford region). In this centre risk estimates compared with non-users, adjusted for BMI, were 2.6, 5.3, and 5.7 for levonorgestrel, desogestrel, and gestodene, respectively. Current users of low oestrogen dose combined OCs containing desogestrel or gestodene appear to be at higher risk of VTE than users of combined OCs containing levonorgestrel. The possibility that these unexpected results on a secondary study objective are due to chance, bias, or residual confounding cannot be excluded entirely and the results need to be confirmed by independent studies. They are at variance with the apparently more favourable metabolic effects of the newer progestagens. Whether the new progestagens are associated with lower risk of arterial disease (stroke and myocardial infarction) must be evaluated further.
Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.