McFarlane M J, Feinstein A R, Horwitz R I
Am J Med. 1986 Nov;81(5):855-63. doi: 10.1016/0002-9343(86)90358-x.
The association between DES and the development of clear cell vaginal carcinoma may have several alternative explanations rather than a cause- and-effect relation. One important possibility is that susceptibility bias, arising from reasons for use of the drug in a problem pregnancy, is a prime source of the observed effect in the case-control studies. Rather than being a cause of clear cell vaginal carcinoma, exposure to DES would serve as a prognostic "marker" to identify women born of problem pregnancies that increased their risk for development of the disease. Since medical advances in prenatal and perinatal care allowed these problem pregnancies to be carried to the term delivery of a viable child, DES may have been associated with an increased occurrence of clear cell vaginal carcinoma--without causing the disease. Another alternative hypothesis is needed to account for the high rates of reported previous exposure to DES in the case subjects of the two case-control studies. These rates may have been elevated by some form of interviewer bias or recall bias. The relatively high incidence of clear cell vaginal carcinoma that would be expected from the results of these case-control studies has not been observed in cohort studies. No instances of clear cell vaginal carcinoma have thus far been found in suitably assembled cohorts of women exposed to DES in utero. The history of science contains abundant examples of fervently held beliefs about cause- and-effect relations that were later found to be erroneous. The existing evidence of a DES/vaginal cancer relation is currently too weak for the causal role of DES to be regarded as established. To get better evidence, the problems of biased comparison and biased data can be addressed in at least three ways. The first is to carry out an appropriately objective new case-control study, with suitably chosen control subjects; the second is to study the issue of susceptibility bias by getting additional information about the occurrence of problem pregnancies in the mothers of patients with clear cell vaginal carcinoma who were not exposed to DES; the third is to review past tissue specimens from previously diagnosed genital adenocarcinomas, searching for clear cell cancers that may have been unrecognized. Until the suspected biases are addressed and either confirmed or refuted, the relation between DES and clear cell vaginal carcinoma remains a statistical association that is unaccompanied by the quality of evidence required for scientific conclusions.
己烯雌酚（DES）与透明细胞阴道癌发生之间的关联可能有多种解释，而非因果关系。一个重要的可能性是，在问题妊娠中使用该药物的原因所引起的易感性偏倚，是病例对照研究中观察到的效应的主要来源。DES暴露并非透明细胞阴道癌的病因，而是作为一种预后“标志物”，用于识别因问题妊娠出生、患该病风险增加的女性。由于产前和围产期护理的医学进展使这些问题妊娠能够足月分娩出存活婴儿，DES可能与透明细胞阴道癌发生率增加有关——但并非导致该疾病。还需要另一种替代假说来解释两项病例对照研究中病例组报告的既往DES暴露率较高的情况。这些比率可能因某种形式的访谈者偏倚或回忆偏倚而升高。这些病例对照研究结果预期的透明细胞阴道癌相对高发病率在队列研究中并未观察到。迄今为止，在适当组建的子宫内暴露于DES的女性队列中尚未发现透明细胞阴道癌病例。科学史上有大量例子表明，人们曾坚信的因果关系后来被证明是错误的。目前关于DES与阴道癌关系的现有证据太薄弱，无法认定DES的因果作用。为了获得更好的证据，至少可以通过三种方式解决比较偏倚和数据偏倚问题。第一种是进行一项适当客观的新病例对照研究，选择合适的对照对象；第二种是通过获取未暴露于DES的透明细胞阴道癌患者母亲中问题妊娠发生情况的更多信息，研究易感性偏倚问题；第三种是回顾既往诊断的生殖器腺癌的组织标本，寻找可能未被识别的透明细胞癌。在解决并确认或反驳可疑偏倚之前，DES与透明细胞阴道癌之间的关系仍然只是一种统计关联，缺乏科学结论所需的证据质量。
