By Jeffrey T. Jensen, MD, MPH, Editor

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for Teva Pharmaceuticals and MicroChips; and is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed.

SYNOPSIS: A meta-analysis of cohort studies supports that women with mild thrombophilias like heterozygote Factor V Leiden mutation can use combined hormonal contraception if other reliable methods are not acceptable.

SOURCE: van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: A systematic review and meta-analysis. J Thromb Haemost 2016;14:1-11. [Epub ahead of print].

Numerous studies have established that combined hormonal contraceptives (CHCs) increase the risk of venous thromboembolism (VTE), and that women with hereditary thrombophilia are at highest risk. Both the World Health Organization (WHO) and CDC Medical Eligibility Criteria for contraception use place hereditary thrombophilias — antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden (FVL) and prothrombin-G20210A (PT) mutation — as Category 4 (unacceptable health risk). To better evaluate the additional risks associated with hereditary thrombophilias in users of CHC, van Vlijmen and coauthors performed a meta-analysis using the MEDLINE and EMBASE databases, identifying 12 case-control and three cohort studies of high quality out of an initial literature search with 2,087 hits. The authors classified the baseline severity of a thrombophilia as “mild” (heterozygous for FVL or prothrombin-G20210A mutation) and “severe” (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of FVL, and PT mutation). The literature focused on combined oral contraceptive (COC) pills, as the use of patches and rings was not widespread.

The results from the cohort studies provided incidence data, and these were calculated with different control groups for the underlying conditions. The incidence of VTE in COC users with mild thrombophilias (FVL Leiden and PT mutation) was 0.49 (95% confidence interval [CI], 0.18-1.07) to 2.0 (0.3-7.2)/100 pill-years compared to 0.19 (95% CI, 0.07-0.41) to 0.0 (0-5.5)/100 pill-years in COC users without these mutations. The incidence of VTE in COC users with severe (homozygous or double heterozygosity) FVL or PT mutations was 0.86 (0.10-3.11)/100 pill-years compared with 0.19 (0.07-0.41) in COC users without these mutations. The highest incidence was seen in COC users with antithrombin, protein C, or protein S deficiency; 4.3 (1.4-9.7) to 4.62 (2.5-7.9)/100-pill years compared to 0.48 (0.1-1.4) to 0.7 (0.0-3.7)/100 pill-years in non-deficient COC users.

The authors used the incidence values from the control populations in each study to calculate the absolute risk (AR) of VTE in women with thrombophilia. This was considerably higher in COC users with severe thrombophilia (4.3 to 4.6/100 pill-years) than in those with mild thrombophilia (0.49 to 2.0/100 pill-years), respectively. Of interest, the differences in absolute risks were higher in the control group of nonthrombophilic COC users used to evaluate the severe conditions (0.48 to 0.7/100 pill-years) compared to the mild conditions (0.19 to 0.0/100 pill-years). However, these control subjects included relatives of the thrombophilic patients with VTE, suggesting that women with a positive family history of VTE remain at high risk independent of a diagnosed thrombophilia.

The authors concluded that these results support the current practice of discouraging COC use in women with severe hereditary thrombophilia. However, they suggested that the additive VTE risk of mild thrombophilia is only modest, and when no other risk factors (such as a positive family history) are present, COCs could be offered if a reliable alternative is not tolerated.

COMMENTARY

Given that estrogen increases the risk of thrombosis, it makes sense for obstetricians and gynecologists to make friends with a hematologist. My local buddy is Tom Deloughery at OHSU. Tom proudly sports a levonorgestrel intrauterine system pin on his lab coat to indicate solidarity with our movement. A great way to solve many problems with coagulopathy.

Like most hematologists, Tom has a mild “allergy” to estrogen. He forwarded this recent manuscript out of the Journal of Thrombosis and Haemostasis for my review. The recommendations in this paper that COC may be safely used in women with mild thrombophilias deserves thorough consideration.

The use of COCs remains high in Europe, despite the high incidence of inherited thrombophilias in the northern European population.1 European women also tend to smoke more than American women, putting them at higher risk.2 The thrombosis controversy with combined hormonal contraception and the differential effects of various progestins remains an active area of debate, compared to the low level of interest among American clinicians. Given this background, these new recommendations seem surprising.

The overall risk of VTE for women without a positive family history, other identifiable risk factors, or known thrombophilia is low. It is well-established that both pregnancy and estrogen-containing contraceptives increase the risk of VTE.3 The risk appears to be related to potent synthetic estrogens like ethinyl estradiol and first-pass effects after oral administration of any estrogen, since transdermal administration of estradiol in postmenopausal women does not increase VTE risk.4

Inherited thrombophilias not only increase the baseline risk of VTE, they also interact with other known risk factors, such as pregnancy and combined hormonal contraception, to further elevate risk.1 For this reason, both the CDC and WHO provide a Category 4 (unacceptable risk) rating for CHC in women carrying a known mutation. Although a personal history of VTE also carries a Category 4 recommendation, a family history of VTE in a first-degree relative is only a Category 2 (advantages generally outweigh risks). Routine testing for known thrombophilias in women with a positive family history is not recommended because of high cost and low yield.5

The new recommendations from the van Vlijmen paper to consider COC use in women with single mutations for FVL or PT go against WHO and CDC guidelines. I recommend caution when recommendations are based on no new data, and simply reflect the results of a meta-analysis. One of the most important clues to bias is the fact that the incidence rates among non-thrombophilic control COC users in the various papers that contributed to the analysis differed, and were highest, in the “severe” thrombosis studies. It is also important to consider the main findings of the study; the presence of a mild thrombophilia increased the risk of VTE in COC users almost six-fold, while a severe thrombophilia increased the risk of VTE more than seven-fold. One would be hard pressed to defend a six-fold increase as insignificant!

An important side note from this paper is that women with a positive family history of VTE in a first-degree relative are at higher risk of VTE than women without a positive proband even if they do not carry the same mutation. This reinforces the importance of positive family history as an important primary risk factor, and, to me, is the most important finding of this paper.

My clinical opinion is to reject the conclusions of van Vlijmen and colleagues, and to continue to follow CDC/WHO recommendations as outlined in the Eligibility Criteria. Although routine testing for known thrombophilias prior to prescription of COCs is not recommended, women with a positive family history deserve careful counseling and consideration of safer alternatives. In all cases, this discussion should be carefully documented.

REFERENCES

  1. Bergendal A, Persson I, Odeberg J, et al. Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol 2014;124:600-609.
  2. Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: Basic pathophysiology. Crit Care Med 2010;38:S3-9.
  3. Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003;1:1371-1380.
  4. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation 2007;115:840-845.
  5. Creinin MD, Lisman R, Strickler RC. Screening for factor V Leiden mutation before prescribing combination oral contraceptives. Fertil Steril 1999;72:646-651.