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Long-Term Consequences of Prenatal Exposure Dolores Ibarreta and Shanna H 84 Late lessons from early warnings: the precautionary principle 1896–2000 8. The DES story: long-term consequences of prenatal exposure Dolores Ibarreta and Shanna H. Swan 8.1. Introduction) secondary characteristics in both males and females. In 1938, Charles Dodds and In 1970, Herbst and colleagues reported an colleagues formulated DES, the first orally unprecedented finding; they had diagnosed active synthetic oestrogen (Dodds et al., a rare vaginal cancer (vaginal clear-cell 1938). This synthetic (non-steroidal) adenocarcinoma) in seven young women, a oestrogen has been estimated to be five times cancer that had never before been seen in as potent as oestradiol, the most potent this age group in this hospital (Herbst and naturally occurring oestrogen in mammals Scully, 1970). The following year, these (Noller and Fish, 1974). DES is inexpensive authors published the startling finding that and simple to synthesise and the developing seven of the eight cases (one more had been pharmaceutical industry quickly began identified), but none of 32 matched controls, worldwide production; DES was marketed had been prenatally exposed to the synthetic under more than 200 brand names. Like oestrogen diethylstilboestrol (DES) (Herbst other pharmaceuticals produced at that time, et al., 1971). Seven months after this DES underwent very limited toxicological publication, the US Food and Drug investigations. It rapidly became popular in a Administration (FDA) withdrew approval for wide variety of treatments, including those use of DES by pregnant women, for whom for menopausal symptoms and prostate this potent synthetic oestrogen had been cancer. Other therapeutic uses were prescribed since 1947 in the mistaken, but suppression of lactation, post-coital widespread, belief that it prevented contraception (morning-after pill) and post- spontaneous abortion (miscarriage). In fact, menopause syndrome (Noller and Fish, this apparently innocent treatment proved to 1974). It was later used as a growth promoter be a time bomb for the infants exposed in chicken, sheep and cattle (Aschbacher, during the first third of pregnancy. The 1976). discovery that DES was a transplacental carcinogen (and was shown after 1971 to also Among the multiple uses of DES was that for be a teratogen — causing birth defects) the prevention of spontaneous abortion occurred only 10 years after the awful (miscarriage). It was believed in the 1940s discovery (James, 1965) that the use of that spontaneous abortion was the result of a thalidomide by women in early pregnancy decrease in oestrogen levels, now recognised caused severe limb reductions. These tragic as a consequence, not a cause (Smith, 1948). lessons forced scientists to abandon their As early as 1941, Karnaky and others began commonly held view of the foetal experimenting with the use of very high environment as a safe place, protected by the doses (100 mg administered intramuscularly placental ‘barrier’, and replace it with an into the cervix daily) in women ‘threatening understanding of the extreme vulnerability to abort’, and deemed the drug effective for of the developing foetus, for whom any this purpose, stating that there were no maternal exposure that occurred during adverse consequences to mother or foetus critical periods had the potential to alter (Karnaky, 1942). The use of DES for development, even long after birth. prevention of miscarriage was further promoted by the work of Olive and George 8.2. Optimistic beginnings Smith, who conducted multiple (uncontrolled) trials of DES for use in Oestrogens are steroid hormones, made pregnancy throughout the 1940s and primarily in the female ovaries and the male published extensively regarding its testes, that act by binding to oestrogen effectiveness (Smith, 1948; Smith et al., receptors. Oestrogens, together with the 1946). other so-called sex hormones (progestins and androgens), are required for the regulation Paradoxically, Charles Dodds, the scientist of reproduction and the development of who first synthesised DES, a discovery for The DES story: long-term consequences of prenatal exposure 85 which he was later knighted, speculated years However, until 1971 there was little evidence later about the minimal testing of new drugs suggesting that maternal use of DES could at that time. Reviewing the history of result in cancer and reproductive stilboestrol (another common term for DES), abnormalities in humans, 20 years after suggested by Dodds himself (Dodds et al., exposure. 1938), he noted that no long-term toxicity tests of this synthetic oestrogen had been The 1971 case-control study of Herbst and conducted. He stated: ‘I suppose we have to colleagues identifying prenatal exposure to be very thankful that it (DES) did prove to be DES as the likely cause of a rare and often such a non-toxic substance.’ (Dodds, 1965) fatal vaginal cancer in young women was Unfortunately, when Dodds wrote this the startling and unprecedented. This case- long-term consequences of DES had not control study was followed within a few been discovered. months by a second, corroborative, case- control study (Greenwald et al., 1971). The 8.3. Tragic consequences relationship between DES use by pregnant women and the occurrence of vaginal clear- Reports that DES increased cancer incidence cell adenocarcinoma is clearly apparent in in laboratory animals appeared as early as Figure 8.1. As can be seen, there is a 1938 (Lacassagne, 1938; Geschickter, 1939; remarkable correspondence between sale of Shimkin and Grady, 1941; Greene and DES (represented here by market sales Brewer, 1941). Since those early reports, figures produced by a large and extensive research has demonstrated an representative US manufacturer during increased incidence of cancer of the litigation) and diagnosis of this cancer 20 mammary glands, cervix and vagina in years later (Melnick et al., 1987). multiple rodent species in response to DES. Market sales of 25 mg DES vs. cases of clear-cell cancer by year of diagnosis Figure 8.1. Source: D. Ibarreta and S. H. Swan 35 Cases 35 30 30 25 25 20 20 Sales 15 15 Million pills Number of cases 10 10 5 5 Year of sale ’45 ’50 ’55 ’60 ’65 ’70 Year of diagnosis ’65 ’70 ’75 ’80 ’85 ’95 86 Late lessons from early warnings: the precautionary principle 1896–2000 This shocking finding finally raised a red flag became more rigorous, the support for the concerning the dangers of DES use by use of DES declined. Finally, in the early pregnant women, as well as providing 1950s, two randomised, placebo-controlled convincing evidence of the potential hazards trials were conducted. The larger of these that exposure of the pregnant woman to trials, conducted by Dieckmann et al. (1953), pharmaceuticals (and other chemicals) pose reported no statistically significant to the foetus. As a result of this study, the differences in adverse pregnancy outcomes FDA released a bulletin in November 1971 when DES was compared to a placebo. The stating that DES use was contraindicated authors concluded (as did the authors of the (must not be used) during pregnancy (US second, smaller trial) that DES was ineffective Department of Health, E. and Welfare, in the prevention of miscarriage and 1971). Tragically, the use of DES by pregnant complications in late pregnancy. In spite of women continued even after 1971 outside this, the drug continued to be prescribed the United States and in some countries was even to women without previous pregnancy reported many years later (Direcks and problems. An advertisement for one of the t’Hoen, 1986). The number of women who DES congeners (DesPlex) read, took DES is known imprecisely, but the ‘Recommended for routine prophylaxis in all National Institutes of Health has estimated pregnancies’ (see Figure 8.2.). that it was used by 4.8 million pregnant women in the United States alone. Total A reanalysis of Dieckmann’s data was exposure (to mothers, sons and daughters) published in 1978, after the long-term worldwide has been estimated to be 10 carcinogenic and teratogenic effects of DES million (see Box 8.1.). were known (Brackbill and Berendes, 1978). The authors reanalysed Dieckmann’s Later studies, including follow-up of a large published data and found that DES actually cohort of DES-exposed women (DESAD increased the risk of the endpoints it was sold cohort, for DES-adenosis) showed that these to prevent. The methods used in the ‘DES daughters’ exhibited a wide range of reanalysis were not new, and had been reproductive tract abnormalities. These available in 1953. As the authors noted, had included epithelial changes (such as vaginal the data been properly analysed in 1953, adenosis) as well as structural changes such nearly 20 years of unnecessary exposure to as cervical stenosis (narrowing of the cervical DES might have been avoided. The fact that opening) and uterine malformations. Unlike this drug was prescribed for two decades after vaginal clear-cell adenocarcinoma, which was its lack of efficacy was clearly demonstrated extremely rare among DES-exposed women, illustrates a massive failure of the system. these abnormalities were common, particularly in women whose mothers had In fact, it was not the lack of efficacy that been prescribed DES in early pregnancy. triggered the end of DES marketing for use These changes, at least some of which were in pregnancy, but a fortuitous accident. If the found to be prevalent even before birth seven cases originally detected by Herbst and (Johnson et al., 1979), resulted in serious colleagues had been diagnosed in several reproductive consequences for those different medical centres, rather than at affected. The risk of all adverse pregnancy Massachusetts General Hospital (where DES outcomes, including ectopic pregnancy use had been high because the Smiths had (embryo attachment outside the uterus), conducted their early experiments on DES spontaneous abortion and premature there), the dangers of DES might well have delivery, were significantly increased (Swan, gone unrecognised. The cancer that DES 1992).
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