Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis

E F W van Vlijmen ¹, S Wiewel-Verschueren ^1 2, T B M Monster ³, K Meijer ¹

PMID: 27121914. DOI: 10.1111/jth.13349

Abstract

Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated.

Summary: Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between ‘mild’ (factor V Leiden and prothrombin-G20210A mutation) and ‘severe’ thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21-8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.

Reference:

J Thromb Haemost. 2016 Jul;14(7):1393-403. doi: 10.1111/jth.13349.Epub 2016 Jun 16.

Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis

Bernardine H Stegeman ¹, Marcos de Bastos, Frits R Rosendaal, A van Hylckama Vlieg, Frans M Helmerhorst, Theo Stijnen, Olaf M Dekkers

PMID: 24030561. PMCID: PMC3771677. DOI: 10.1136/bmj.f5298

Abstract

Objective: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.

Design: Systematic review and network meta-analysis.

Data sources: PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.

Review methods: Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.

Results: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10,000 woman years, in line with previously reported incidences of 1-6 per 10,000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

Conclusion: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.

Reference:

BMJ. 2013 Sep 12;347:f5298. doi: 10.1136/bmj.f5298.

Mechanisms of estrogen-induced venous thromboembolism

Svetlana N Tchaikovski ¹, Jan Rosing

PMID: 20163835. DOI: 10.1016/j.thromres.2010.01.045

Abstract

The use of oral contraceptives (OC) is a well established risk factor for venous thrombosis. It has been known for many years that almost all haemostatic parameters i.e. plasma levels of coagulation factors, anticoagulant proteins and proteins involved in the fibrinolytic pathway change during OC use. The discovery of several risk factors of venous thrombosis in the 1990s shed new light on the association between the effects of OC on the haemostatic system and the increased risk of venous thrombosis. In this review, we summarize the current knowledge on the effects of different kinds of hormonal contraceptives (OC, transdermal contraceptives, vaginal ring and levonorgestrel-releasing intrauterine device) on haemostatic variables and the relationship between the changes of these variables and the risk of venous thrombosis.

Reference:

Thromb Res. 2010 Jul;126(1):5-11. doi: 10.1016/j.thromres.2010.01.045.Epub 2010 Feb 16.

Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

Yana Vinogradova ¹, Carol Coupland ², Julia Hippisley-Cox ²

PMID: 30626577. PMCID: PMC6326068. DOI: 10.1136/bmj.k4810

Erratum in

• Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.

[No authors listed]BMJ. 2019 Jan 15;364:l162. doi: 10.1136/bmj.l162.PMID: 30647094 Free PMC article. No abstract available.

Abstract

Objective: To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy.

Design: Two nested case-control studies.

Setting: UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data.

Participants: 80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls.

Main outcome measures: Venous thromboembolism recorded on general practice, mortality, or hospital records. Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs.

Results: Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).

Conclusions: In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations