Elsevier

The Lancet

Volume 349, Issue 9045, 11 January 1997, Pages 83-88
The Lancet

Articles
Population-based study of risk of venous thromboembolism associated with various oral contraceptives

https://doi.org/10.1016/S0140-6736(96)07496-XGet rights and content

Summary

Background

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.

Methods

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 μg ethinyloestradiol and desogestrel compared with the 30 μg product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.

Introduction

Four papers, published since December, 1995, reported a slightly increased risk of venous thromboembolism (VTE) in women who used combined oral contraceptives (OCs) containing third-generation progestagens (desogestrel and gestodene) compared with women who used OCs containing second-generation progestagens (mainly levonorgestrel).1, 2, 3, 4 These findings were unexpected because previous studies had suggested that the risk of VTE was associated only with the dose of oestrogens in combined OCs.5, 6, 7 Most of the investigators interpreted their findings cautiously and did not claim to have shown a causal relation between the type of progestagen and risk of VTE. Nevertheless, action was taken by some licensing authorities before the publication of the reports.

The UK Committee on Safety of Medicines recommended that the use of OCs containing third-generation progestagens be restricted.8 Since then, the findings of these four studies have been scrutinised, and other investigators have suggested that confounding, bias, or both, may account for some of the apparent differences in incidence of VTE.9, 10, 11, 12, 13 Our population-based study used a UK general-practitioner database to re-examine the association between different types of combined OCs and risk of VTE.

Section snippets

Methods

There were two parts to this study: a cohort analysis, in which we estimated and compared the incidence rates of VTE among users of the most commonly prescribed OC preparations; and a case-control study, in which we calculated the odds ratio of VTE associated with use of different types of OCs, after adjustment for potential confounding variables.

For both parts of the study we used computer records of patients from 143 general practices in the UK that used the Meditel system for patients'

Results

491 908 women were included in the study, and there were a total of 234 899 woman-years of exposure to steroid contraceptives. The numbers of woman-years of exposure to each of the major types of steroid contraceptives are given in table 1. Of the 234 899 woman-years of exposure to OCs, 108 842 (46·3%) were exposure to third-generation progestagens. The mean ages of users of each type of steroid contraceptive are also shown in table 1. Women prescribed OCs containing third-generation

Cohort investigation

We estimated that the absolute risk of VTE (pulmonary embolism and deep-venous thrombosis) among women exposed to any combined OC was 4·1 per 10 000 woman-years. This finding accords with those of most previous studies: Gerstman et al17 reported an incidence rate of 4·2 per 10 000 woman-years among users of OCs containing less than 50 μg oestrogen; Vessey and colleagues6 found an incidence rate of 4·3; and Farmer and Preston's study18 reported an incidence rate of 3·0. By contrast, Jick and

Conclusions

The WHO1 and Transnational studies3 cautioned that their findings could have been affected by bias and confounding. Indeed, Lewis and colleagues' study9 confirmed that the so-called healthy-user effect19 could result in an increased incidence of VTE among users of third-generation OCs. Our study accords with the view that bias and confounding have substantial effects on the results of investigations of the risk of VTE associated with different types of OCs. The findings from our cohort study

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