DES (DIETHYLSTILBESTROL) CHILDREN

The scientific world was shocked by the 1971 discovery of the devastating effects in young women of a drug, diethylstilbestrol (DES), taken by their mothers twenty years earlier. The story of DES, from its discovery and widespread marketing without adequate testing or proof of efficacy, to the banning of its use by pregnant women, provides a good example of the serious harm that can result from inadequately protective regulation of new drugs and technologies.

Historical Development

In 1938, Sir E. Charles Dodd formulated DES, the first orally active, synthetic estrogen. This (nonsteroidal) estrogen, estimated to be five times as potent as estradiol, was very inexpensive and simple to synthesize. Because it was not patented, the developing pharmaceutical industry quickly began worldwide production; it was ultimately marketed under more than two hundred brand names for a wide range of indications. DES underwent very limited toxicological testing, a fate common to pharmaceutical products at that time.

Experiments with high doses of DES in women threatening to abort were conducted a few years later. The use of DES for prevention of miscarriage was promoted by the work of Drs. Olive and George Smith, who conducted multiple (uncontrolled) trials of DES for use in pregnancy throughout the 1940s. Despite limited evidence of safety or efficacy, the drug was deemed effective for this purpose and safe for mother and fetus. In 1947, DES obtained market approval in the United States for use in pregnancy in cases of threatened abortion and hormonal inadequacy.

Following the first poorly supported claims of the effectiveness of DES for the prevention of miscarriage, several studies were carried out to assess its efficacy, with mixed results. As these studies became more rigorous, support for the use of DES declined. In 1953, W.J. Dieckmann and colleagues demonstrated the lack of efficacy when DES was compared to a placebo in a randomized trial of pregnant women. Although the authors concluded that DES was ineffective, the drug continued to be prescribed even to women without previous pregnancy problems or evidence of threatened pregnancy. A reanalysis of Dieckmann's data in 1978, which showed that DES actually increased the risk of miscarriage, noted that had the data been properly analyzed in 1953, nearly twenty years of unnecessary exposure to DES could have been avoided.

The dangers of DES were not discovered, however, until 1971. Dr. A.L. Herbst and colleagues identified seven cases of a rare vaginal cancer (vaginal clear cell adenocarcinoma) in a single hospital. Using a case-control study they linked this rare cancer to the young women's prenatal exposure to DES. The results were so overwhelming that the Food and Drug Administration (FDA), in its November 1971 bulletin, declared that DES was contraindicated for use in pregnancy. Subsequent data demonstrated DES to be teratogenic as well as carcinogenic, and showed extensive damage to the reproductive systems of both men and women who had been exposed prenatally.

Elsewhere in the world, DES continued to be sold to pregnant women, in some countries into the 1980s. The fact that DES was prescribed for so long after its lack of efficacy had been demonstrated and dangers recognized illustrates a massive drug system failure.

In fact, it was not the lack of efficacy that triggered the end of marketing of DES for use in pregnancy, but a fortuitous accident. The cancer that DES caused in young women is extremely rare. It is estimated to have occurred in less than one in a thousand exposed daughters. If the cancer cases originally detected by Herbst and his colleagues had been diagnosed in several different medical centers, rather than at a single hospital (Massachusetts General Hospital, where DES use had been high as the site of the Smiths early experiments, the dangers of DES might well have gone unrecognized. Thus, this cancer, its link to DES, and other consequences of DES exposure might well have gone undetected.

DES Case Lessons

The DES story demonstrates that long-term and hidden effects of hormonal exposure may result from prenatal exposure, and that such consequences may be devastating. Could the mishap have been prevented? Where did science, society, and technology fail?

First, no long-term toxicity tests were ever carried out. Ironically, Dodds, the discoverer of DES, wrote in 1965, "I suppose we have to be very thankful that [DES] did prove to be such a non-toxic substance," referring to the minimal testing it underwent before marketing. Six years later the dangers of DES were identified.

Second, DES was put on the market without adequate proof of efficacy. Adequate pre-market testing would have shown that DES was never effective for the prevention of miscarriage. Therefore, a properly conducted and analyzed clinical trial might have avoided the entire episode. This accident is less likely in the early twenty-first century for pharmaceuticals, where thorough toxicity testing and evidence of efficacy are required prior to marketing.

Third, the widespread use of DES was furthered by the faith, prevalent at the time, in the advances of science and human abilities to control nature. DES was believed to be safe and effective, and both "modern and scientific." Its use became fashionable and there was pressure on physicians from peers and patients to prescribe DES. In the Netherlands, for example, the use of DES was aided by endorsement of the Queen's gynecologist.

Pharmaceutical retailers and advertising promoted the effectiveness and safety of DES to doctors and consumers. In fact, some manufacturers promoted it as a panacea for use in all pregnancies. The eagerness of the pharmaceutical companies to sell this profitable, unpatented product was compounded by the failure of medical and regulatory agencies to react rapidly to the emerging evidence.

Even prior to marketing for use in pregnancy, DES was a known animal carcinogen, a suspect human carcinogen, and a drug that had been shown to produce observable changes in the offspring of women exposed in pregnancy. Moreover, after DES was proven to be ineffective for use in pregnancy in 1953, a review of its risks and benefits should have resulted in immediate contraindication of this use. Had DES been withdrawn for use in pregnancy at that time, the unnecessary and tragic exposure of millions of mothers, sons, and daughters could have been avoided.

Regulatory authorities are also more alert in the early 2000s to reporting of adverse drug reactions and more inclined to take action than they were in the 1960s and 1970s. However, it should be remembered that regulation of non-pharmaceuticals is far from rigorous, and prenatal exposure to non-pharmaceuticals may also convey serious risk. The DES lesson can serve to raise consciousness about the dangers of inadequately identifying those risks.

DOLORES IBARRETA
SHANNA H. SWAN

SEE ALSO Abortion;Drugs;Medical Ethics.

BIBLIOGRAPHY

Giusti, Ruthann M.; Kumiko Iwamoto; and Elizabeth E. Hatch. (1995). "Diethylstilbestrol Revisited: A Review of the Long Term Health Effects." Annals of Internal Medicine 122: 778–788.

Ibarreta, Dolores, and Shanna H. Swan. (2002). "The DES story: Long-term consequences of prenatal exposure." In The Precautionary Principle in the 20th Century: Late Lessons From Early Warnings, ed. Poul Harremoës, David Gee, Malcolm MacGarvin, et al. London: Earthscan.

Swan, Shanna H. (2001). "Long term human effects of prenatal exposure to diethylstilbestrol." In Hormones and Endocrine Disruptors in Food and Water: Possible Impact onHuman Health, ed. Anna-Maria M. Andersson, Kenneth N. Grigor, Eva Rajpert de Meyts, et al. Copenhagen: Munksgaard.

INTERNET RESOURCE

National Cancer Institute. (1999). "DES Research Update 1999: Current Knowledge, Future Directions." Available from http://planning.cancer.gov/whealth/DES/.