Oral Contraception and the Risk of Thromboembolism
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For four decades the oral contraceptive pill has remained popular with young women because of its convenience and effectiveness. There have, however, been continuing concerns about adverse effects. In the 1960s the risk of venous thromboembolism was linked to the dose of estrogen, which was consequently reduced. Later the risks of arterial disease were linked to progestogen dose, which was also reduced.
In 1995, three case-control studies linked the risk of venous thromboembolism, not to dose, but to the type of progestogen. Newer ‘third-generation’ progestogens appeared to carry a higher risk than older formulations. Although the contraceptive pill was already known to increase the risk of venous thromboembolism 3- to 6-fold, and the risks in the three studies were within this range, the public perception was that a new risk had been discovered. In the UK there were two consequences — a rapid change in prescribing patterns and a sharp increase in the abortion rate.
Critics suggested that the studies may have been affected by confounding — e.g. by a ‘new user’ effect and differential prescribing. Views became very polarised. Between 1995 and 2001 second- and third-generation formulations were compared in 16 studies. Thirteen found that third-generation pills carried a higher risk of venous thromboembolism.
Editorials and reviews recommended second-generation pills as the first choice for new users but official advice was that third-generation pills could still be prescribed, provided the risks were explained. Rates of thrombosis, per 100 000 women, are five for nonusers, 15 with second-generation pills and 25 for third-generation pills. The increase in mortality rates is around 1 to 2 per million.
Drug-industry sponsored studies tended to find lower risks than independent studies and it was assumed that sponsorship produces bias, conscious or unconscious. It is also possible that some ‘independent’ researchers, motivated by antipathy to multinational pharmaceutical companies, are biased in the opposite way.
Compared with the energy put into this debate, other aspects of pill prescribing remain under-researched. For example, doctors on opposite sides of the Atlantic are given different advice about whether gross obesity (a major risk factor for thromboembolism) is a contraindication to oral contraception.
Women in developing countries continue to die of pregnancy-related causes and many deaths could be prevented by effective contraception. Rather than bickering, drug manufacturers and academics should be discussing ways of providing the pill to the women who need it most.
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