Oral Contraceptives and Venous Thromboembolism<BR> Consensus Opinion from an International Workshop held in Berlin, Germany in December 2009

Abstract

Background and purpose of the workshopConcern about the venous thromboembolism (VTE) risk of new hormonal contraceptive options shortly after their entry into the market has triggered a number of 'pill scares', each of which resulted in panic stopping of the formulations in question and a spike in unplanned pregnancies, yet with no subsequent reduction in VTE rates among women of reproductive age.Perhaps the best example of a recent pill scare that resulted in enormous harm from a public health perspective was the 'third-generation pill scare' that occurred in many countries in Europe and around the world in 1995. At that time the new third-generation pills were promoted as being less androgenic and as possibly having fewer adverse effects on cardiovascular and metabolic parameters and thereby potentially being safer than existing pills.Shortly after the introduction of these third-generation pills, reports of a possible increased risk of VTE began to appear. Such reports brought the progestogen component of these pills under scrutiny and inevitably a phenomenon known as 'stimulated reporting' occurred. Physicians with patients on these new pills were more likely to send their patients for assessment of any leg pain or swelling and more likely to report any VTE episodes to regulatory authorities because of heightened awareness of the possible risk. What followed was an international pill scare when regulatory authorities in a number of countries issued alerts about the possible increased risk of VTE with thirdgeneration pills. Panic stopping of pills by millions of women resulted in an abrupt and alarming rise in unplanned pregnancy as evidenced by sudden increases in deliveries and abortions, 1-3 each with their attendant increased risks of VTE.The history of this unfortunate episode is well documented. After class action lawsuits and lengthy trials, at which experts in epidemiology debated the findings, there emerged an awareness that studies examining VTE risks, in particular, required an understanding of the epidemiology of VTE and the possible biases that might systematically result in findings which diverged from the 'truth'. 4,5 The precise effects of different hormonal contraceptives on the haemostatic system continue to be studied and debated 6,7 but because compelling data for an increased risk have not been demonstrated the lawsuits were ultimately thrown out 8 and third-generation pills remain on the market and are widely prescribed today. 9 In 2009, anecdotal reports of VTE episodes in women using an ethinylestradiol/drospirenone (EE/DRSP)-based oral contraceptive (Yasmin ® ) were followed by publications with conflicting findings about the risk of VTE with this product. This led the manufacturer to invite experts in gynaecology, reproductive endocrinology, haematology and epidemiology to a workshop to critically review these recent publications to understand the reasons for divergent results and to produce a consensus statement about the likely comparative risk of this new formulation and other mar...

Contraception in women over 40 years of age

“…19 Among women of reproductive age, the risk of venous thromboembolism among those who use estrogen-containing contraceptives is double that among nonusers (8-10 per 10 000 woman-years v. 4-5 per 10 000 woman-years). 20 However, pregnancy and the immediate postpartum period is associated with 3 times the risk of venous thromboembolism compared with the use of estrogen-containing contraceptives. 21 Recent studies of estrogen-containing contraceptives and venous thromboembolism are consistent in several findings.…”

“…26 All studies we found of estrogen-containing contraceptive use and risk of venous thromboembolism included women of all reproductive ages (up to age 59 in one study 24 ), consistently noting age to be an independent risk factor. [19][20][21][22][23] Although arterial events are less common than venous thromboembolism in women of reproductive age, the sequelae of stroke and myocardial infarction may be more devastating than those of venous thromboembolism. A large Danish cohort study found that women aged 45-49 years had 20 times the risk of stroke and 100 times the risk of myocardial infarction as women aged [15][16][17][18][19].…”

Contraception and Venous Thromboembolism: Risk Factors and Clinical Considerations

“…The MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) study found that the risk of venous thrombosis was 5-fold increased during pregnancy (OR, 4.6; 95% CI, 2.7 -7.8) and 60-fold increased during the first 3 months after delivery compared with non-pregnant women (OR, 60.1; 95% CI, 26.5 -135.9) [14]. Translated into women years, per 10,000 women 29 events would occur in pregnancy and over 300 in the postpartum period [15].…”

“…Combined hormonal contraceptives (CHCs), whether pill, patch, or vaginal ring, are known risk factors for VTE [15] [67] [68]. With the introduction of the sub-50 μg estrogen combined oral contraceptives there was a fall in VTE risk compared to older higher dose formulations and because of this the risk of VTE has been largely attributed to the procoagulant effects of estrogen.…”

“…Comparing levonorgestrel to other progestins Lidegaard reported a Relative Risk for desogestrel of 2.2 (95% CI, 1.7 -3.0), gestodene of 2.1 (95% CI, 1.6 -2.8), drospirenone 2.1 (95% CI, 1.6 -2.8) [39]. These studies have been criticized for significant methodological deficiencies [15] [71] [72]. Several higher quality prospective cohort studies have shown no differences in VTE risk between products based on progestin formulation [70] [75].…”