Third-generation OCs don’t increase VTE risk

A just-released study indicates that "third-generation" pills — combined oral contraceptives (OCs) with a gestodene or desogestrel progestin component — do not put women at increased risk of developing clots in the veins.1

The new research may put to rest epidemiological questions that have surrounded OC progestins and venous thromboembolism (VTE) risk, says Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center in Jacksonville and director of menopause and gynecology services at the Medicus Women’s Diagnostic Center, also in Jacksonville.

"Whether formulated with newer or older progestins, all combination OCs increase the risk of thromboembolism," he says. "From an absolute perspective, this elevated risk is small indeed; nonetheless, this observation underscores the importance of not prescribing combination OCs to high-risk women, particularly those with a prior history, unless they are chronically anticoagulated."

Pills with a gestodene or desogestrel component have been the focus of multiple investigations in the aftermath of what has been termed the British "pill scare." (See Contraceptive Technology Update, January 1996, p. 6, for details on the 1995 pill scare that arose following a warning from Britain’s Committee on the Safety of Medicines.) Concern over use of the pills arose from findings that indicated up to a twofold increase in risk of venous clotting compared with older combined formulations.2-4

No pills in the United States contain gestodene; only two contain desogestrel: Ortho-Cept from Ortho-McNeil Pharmaceuticals in Raritan, NJ, and Desogen from Organon in West Orange, NJ. Although the Food and Drug Administration was quick to issue a statement following the British alert to affirm the safety of desogestrel pills, use of such OCs fell in the United States.

Ortho-Cept dropped from its leading position in the 1995 CTU Contraception Survey to fifth place in 1996, with Desogen falling from sixth place in 1995 to ninth place in 1996. Ortho-Cept remained at fifth place as a first-choice pill for a 21-year-old nonsmoker in CTU’s 2000 Contraception Survey; Desogen was not among the top nine pills named in the survey. (For complete results of the survey, see CTU, September 2000, pp. 101-114.)

Several subsequent studies have found no risk difference between the older and newer pills,5-9 while others have shown an increased risk.10-12 After weighing the evidence, Britain’s Medicines Commission, a government advisory body, issued a national statement in April 1999 saying doctors can prescribe the third-generation pills as a first-line form of contraception. The government again affirmed the safety of the pills after publication of a Danish study showing an increased risk of VTE in users of the third-generation pills.12 (For full study results, see CTU, December 1999, p. 140.)

A look at the new study

The new study examines the incidence of venous clots in British women in the three years before and after the 1995 pill scare, when use of third-generation OCs fell from 54% to 14% in women ages 15 to 49 who take combined pills. Researchers analyzed information from the General Practice Research Database, which pulled data from 304 general practices throughout Great Britain. Women who were at risk of clots for other reasons were not included in the study.

The results show that although the use of third-generation OCs fell during the period after 1995, the rates of venous clots among women taking the pill did not change significantly. Therefore, the findings are not compatible with the assertion that third-generation OCs are associated with a twofold increase in risk of VTE compared with older progestins, the authors conclude.

Most of the studies have been case-control investigations, which are fairly fragile, observes Richard Farmer, MRCGP, FFPHM, PhD, professor at the postgraduate medical school of the University of Surrey in Guildford and lead author of the new analysis. "You have to be sure that the controls you identify genuinely represent the population," he notes. "And they are even more fragile when you are talking about the sort of very low frequency as [is associated] with VTE."

Farmer says only three studies — none of which was adjusted for duration of use — have shown an increased risk with the third-generation pills.2,3,4 The new study can be classified as an intervention study, because the entire pattern of OC use had changed, he says. "If there was genuinely an increase in risk in the so-called third-generation pills, you would expect there to be a fall, and there wasn’t a fall. I think that there is very strong evidence to support the notion that there are no differences between the different types of pills."


1. Farmer RDT, Williams TJ, Simpson EL, et al. Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: Analysis of General Practice Research Database. BMJ 2000; 321:477-479.

2. World Health Organisation Collaborative Study on Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: Results of international multicentre case- control study. Lancet 1995; 346:1,575-1,582.

3. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995; 346:1,589-1,593.

4. Spitzer WO, Lewis MA, Heinemann LAJ, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: An international case-control study. BMJ 1996; 312:83-88.

5. Suissa S, Blais L, Spitzer WO, et al. First­time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998; 57:61­65.

6. Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: A case­control study. Contraception 1998; 57:291­301.

7. Lewis MA, MacRae KD, Kuhl­Habichl D, et al. The differential risk of oral contraceptives: The impact of full exposure history. Hum Reprod 1999; 14:1,493­1,499.

8. Farmer RDT, Lawrenson RA, Thompson CR, et al. Population­based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349:83­88.

9. Farmer RDT, Lawrenson RA, Todd J­C, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000; 49:580­590.

10. Parkin L, Skegg DCG, Wilson M, et al. Oral contraceptives and fatal pulmonary embolism. Lancet 2000; 355:2,133­ 2,134.

11. Bloemenkamp KW, Rosendaal FR, Buller HR, et al. Risk of venous thrombosis with use of current low­dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Int Med 1999; 159:65­70.

12. Mellemkjaer L, Sorenson HT, Dreyer L, et al. Admission for and mortality from primary venous thromboembolism in women of fertile age in Denmark, 1977­95. BMJ 1999; 319:820­821.