Oral contraceptives and the risk of venous thromboembolism

Abstract

Oral Contraceptives (OC) were introduced in the 1960s and were a major advance in family planning technology for women. The first pills contained high doses of estrogen and progestin; 4 times more estrogen and 10 times more progestin than today’s OCs (Buttar and Seward, Enovid: the first hormonal birth control pill, 2009; http://​www.​accessdata.​fda.​gov/​scripts/​cder/​drugsatfda/​index.​cfm?​fuseaction=​Search.​DrugDetails). The first cases of cardiovascular events in OC users, including venous thromboembolism (VTE), myocardial infarction and stroke were observed soon after the pills were marketed (Records unit of the Research Advisory Service of the Royal College of General Practitioners 1967; Inman and Vessey, BMJ 2:193–199, 1968; Vessey and Doll, Br Med J 2(5599):199–205, 1968; Vessey and Doll, Br Med J 2(5658):651–657, 1969; Sartwell et al., Am J Epidemiol 90:365–380, 1969; Inman et al., BMJ 2:203–209, 1970). It was thought at that time that the high doses of hormone were responsible (Records unit of the Research Advisory Service of the Royal College of General Practitioners 1967) and consequently lower dose pills with different progestins were introduced with the goal to reduce the CVD risk. This next generation of OCs did lower the risk of CVD, VTE in particular, but more recently discussions around OCs and VTE risk have focused on progestin type after concerns were raised that newer, so called third and fourth generation OCs, might increase the risk of VTE compared to OCs containing the older progestin levonorgestrel (Meade et al., BMJ 280:1157–1161, 1980; Sitruk-Ware, Maturitas 47:277–283, 2004; WHO, Lancet 346:1582–1588, 1995; Jick et al., Lancet 346:1589–1593, 1995; Bloemenkamp et al., Lancet 346:1593–1596, 1995; Lidegaard et al., Contraception 57:291–301, 1998; Farmer et al., Lancet 349:83–88, 1997; Spitzer et al., BMJ 312:83–88, 1996; Jick et al., BMJ 321:1190–1195, 2000; Kemmeren et al., BMJ 323:131–134, 2001). Studies have since found that risks vary according to progestin formulation (Lidegaard et al., BMJ 343:d6423, 2011; Vasilakis-Scaramozza and Jick, Lancet 358:1427–1429, 2001; Seaman et al., Pharmocoepidemiol Drug Saf 13:427–436, 2004; Vasilakis et al., Lancet 254:1610–1611, 1999; Rubig, Climacteric 6:49–53, 2003; Heineman and Dinger, Drug Saf 27:1001–1018, 2004). Below, the history of OC development and its relationship to the risk of VTE is described from the 1960s when the pill was first marketed until the present day, many years and many OC formulations later.