[Contraceptive agents and risk of thrombosis]

Abstract

In the late sixties and seventies, publications of the Royal College of General Practitioners in England reported that in women using oral contraceptiva the incidence of venous thromboembolism is increased by two to four fold. Moreover, it was demonstrated, that these alterations in coagulation were induced by ethinylestradiol in a dose dependent manner. Following these findings, its dosage was lowered from more than 100 micrograms to 20-30 micrograms per day. More recently, the role of gestagens in inducing thrombosis has also been debated. Different authors observed an increased risk for venous thromboembolism in women using third generation pills containing gestoden or desogestrel compared with users of second generation levonorgestrel contraceptiva. These reports have generated a lot of concern and fear in the patients as well as doctors and have led to a drastic fall in the use of oral contraceptives. Due to the unavailability of safe contraceptive alternatives, the number of women experiencing unwanted pregnancy and its complications increased significantly. Indeed, direct proof for the role of gestagens in inducing thromboembolism is still lacking as the protocol designs of these studies do not allow us to infer whether the effects are due to the gestagens or to confounding variables. Hence, the discussions were beneficial for clinicians to remember the importance of checking the patient for individual and family risks for thrombosis before handling out a pill prescription.

PIP: The pathophysiological basis of blood coagulation includes hemostatic causes and thrombophilia (protein C deficiency, protein S deficiency, APC resistance, plasminogen deficiency, antithrombin III deficiency, hyperhomocystinemia, lupus anticoagulans and anticardiolipin antibodies). The effect of female sexual steroids on coagulation has been observed: ethinyl estradiol produced an increased risk of thromboembolism. Also, there was a pronounced increase of fibrin division products among users of higher EE doses. The effect of gestagens on coagulation was found to be contradictory. The risk of thrombosis as related to oral contraceptives (OCs) was investigated in several studies. Desogestrel and gestoden-containing OCs produced a higher incidence of thrombosis than levonorgestrel-containing pills. A WHO multinational case-control study was carried out in 21 centers and 17 countries during 1989-93, including a total of 1143 cases and 2998 controls. The risk of thrombosis was 2-3 times higher among women using gestoden or desogestrel-containing OCs than those using LNG-containing OCs. Similarly, there was a 1.58 increased risk according to a case-control study using data from England and Germany. A 1995 study of 700 medical practices in Great Britain involving 238,130 women showed increased risk for gestoden (1.8) and desogestrel (1.9). Another 1995 study used the data of 697,000 women from 398 practices in England and registered 116 cases of thromboembolism. There was a risk three times higher for all ovulation inhibitors among cases compared to controls, as well as a pregnancy risk 5.9 times higher. Nonetheless, no definitive conclusion can be drawn from all of these epidemiological studies, which could challenge the prevailing view on contraceptive behavior.