Goldzieher J W, Dozier T S
Am J Obstet Gynecol. 1975 Dec 15;123(8):878-914. doi: 10.1016/0002-9378(75)90866-2.
The relationship between oral contraceptive usage and thromboembolism is controversial. Since thromboembolism is often undiagnosed, both clinically and at routine autopsy, most epidemiologic analyses rest or a very uncertain factual base. There are increases in blood coagulation factors in oral contraceptive users similar to, but less than, those seen in pregnancy, which is not associated with increased thromboembolism. Hematologists emphasize that these changes do not define a "hypercoagulable" state, and they do not define or predict the occurrence of thrombosis. Intrinsic vascular wall changes, unrelated to drug use, may play a role in sporadic cases of thromboembolism. When the incidence of thromboembolism in very large Phase III trials of conventional oral contraceptives is compared to that in other populations (patients admitted to the hospital, women who visit a physician, pregnant women, or users of nonestrogenic oral contraceptives), no difference is seen. Epidemiologic studies by the "case-control" ("trohoc") method consistently show an increase "relative risk" associated with oral contraceptive use in subjects with "idiopathic" thromboembolism but no increased risk in thromboembolism patients as a whole or in those with predisposing factors. This retrospective epidemiologic technique, its particular applications, and the inferences drawn are open to serious criticism, as are studies claiming a relationship between estrogen dose and thromboembolism incidence. An Australian prospective survey found no increased risk among users, and a large British study which initially reported an increased risk is currently undergoing recalculation. The only controlled clinical experiment (with random assignment of subjects to vaginal versus high-estrogen contraceptives) showed no increased incidence in the drug-treated group. Statistical associations derived from "trohoc" studies do not establish causal relationships; moreover, their risk estimates are in conflict with the findings of large Phase III clinical surveys including subjects using estrogen-free contraceptives, with at least one prospective clinical survey, and with a randomized, controlled clinical trial. The data relating estrogen dosage to thromboembolism incidence are ambiguous, at best. Thus, the claim of a causal relationship between oral contraceptive steroids and thromboembolism does not appear to be firmly founded, and the belief that predisposing factors increase the risk to contraceptive users is equally insubstantial.
口服避孕药的使用与血栓栓塞之间的关系存在争议。由于血栓栓塞在临床和常规尸检中常常未被诊断出来，大多数流行病学分析基于一个非常不确定的事实基础。口服避孕药使用者的凝血因子会增加，这与孕期相似，但程度较轻，而孕期与血栓栓塞增加并无关联。血液学家强调，这些变化并不意味着处于“高凝”状态，也无法界定或预测血栓形成的发生。与药物使用无关的血管壁内在变化，可能在散发性血栓栓塞病例中起作用。当将传统口服避孕药的大型III期试验中的血栓栓塞发生率与其他人群（住院患者、就诊女性、孕妇或非雌激素口服避孕药使用者）的发生率进行比较时，未发现差异。采用“病例对照”（“病例对照”的反向拼写）方法进行的流行病学研究一致表明，在患有“特发性”血栓栓塞的受试者中，口服避孕药的使用会增加“相对风险”，但在整个血栓栓塞患者群体或有易感因素的患者中，风险并未增加。这种回顾性流行病学技术、其具体应用以及得出的推论都受到了严厉批评，声称雌激素剂量与血栓栓塞发生率之间存在关系的研究也是如此。一项澳大利亚的前瞻性调查发现使用者中风险并未增加，而一项最初报告风险增加的大型英国研究目前正在重新计算。唯一的对照临床试验（将受试者随机分配使用阴道避孕药与高雌激素避孕药）显示，药物治疗组的发生率并未增加。从“病例对照”研究得出的统计关联并不能确立因果关系；此外，它们的风险估计与包括使用无雌激素避孕药的受试者在内的大型III期临床调查结果、至少一项前瞻性临床调查结果以及一项随机对照临床试验结果相冲突。关于雌激素剂量与血栓栓塞发生率的数据充其量也是模糊不清的。因此，口服避孕药类固醇与血栓栓塞之间存在因果关系的说法似乎缺乏确凿依据，认为易感因素会增加避孕药使用者风险的观点同样站不住脚。
