Second Generation Effects Teratogenicity

Diethylstilbestrol was used extensively in pregnancies between 1940 and about 1975, in the belief that it could protect threatened pregnancies and counter the risk of spontaneous abortion. Toward the end of that period, increasingly clear evidence emerged that diethylstilbestrol could have an adverse effect on the second generation that did not become apparent until puberty or adulthood, and perhaps could also appear in the third generation (10). It appears to be the only estrogen with this effect, but it is naturally not excluded that some structurally related nonsteroidal estrogens might carry the same risk, although these have never been used in the same way in pregnancy.

History

Diethylstilbestrol provides several illustrations of how societies cope with the risks of harm from a drug. Under different brand names diethylstilbestrol has been given to a wide range of patients over many years, mostly pregnant women and aging men with prostate cancer. The history of iatrogenic disease as a result of the use of diethylstil-bestrol in pregnant women shows that patients can play an important role in securing legitimacy for research and the publication of data on the harmful effects of a drug.

Diethylstilbestrol was given to pregnant women in many countries, mainly in the 1940s to 1970s, in the mistaken belief that it would prevent miscarriage and provide strong healthy babies (11,12). The application to market diethylstilbestrol in the USA was the first new drug application submitted to the FDA shortly after the 1938 Food, Drugs, and Cosmetics Act had been passed; permission was granted, although diethylstilbestrol had already been identified as a carcinogen in animals (13). Diethylstilbestrol was especially popular in some maternity clinics in North America, serving middle-class and upper-middle class women, and in the Netherlands, where the Queen's gynecologist promoted it. In other countries it was dispensed through public health maternity centers.

In the USA, evidence showing that it was ineffective for its intended purpose appeared by the 1950s. However, conclusions based on animal experiments, as well as a major double-blind, controlled clinical trial (14), remained unheeded, partly because prescribing physicians trusted their collegial loyalty more than data that implicitly threw doubt on their practice.

In 1971, a rare form of aggressive cancer in the vagina of young girls was attributed to the girls' exposure to diethylstilbestrol in utero in a report that was based on a case-control study of eight young women, two of whom had died, at the Massachusetts General Hospital (15). It was already clear from this small study that monitoring young women exposed to diethylstilbestrol would save lives. However, months and even years were to pass before the discovery led to any public action, at different times in different countries. Only after 5 months, when the risk of cancer in patients exposed to diethylstilbestrol was featured at hearings in the US Congress, did the FDA react. The FDA's Administrator then announced that diethylstilbestrol products were to be labelled with a warning that diethylstilbestrol was contraindicated in pregnancy and should not be given to pregnant women because of risk of the cancer in the offspring (16).

Drug regulatory agencies in other countries in which diethylstilbestrol had also been commonly used in pregnancy delayed taking action. In the Netherlands, the first change of labelling to include a warning to physicians that diethylstilbestrol given to pregnant women might harm the fetus was implemented in 1972. A similar change in labelling was introduced in France in 1977. In many other countries, the news that some daughters of women who had taken diethylstilbestrol while pregnant were at risk of developing a potentially lethal cancer was passed over in silence.

In Britain, the medical community was alerted to the risks by an editorial in the British Medical Journal in 1971, but it was only in 1973 that the Committee on Safety of Medicines advised against the use of diethylstilbestrol during pregnancy (17). In Britain, drugs were commonly not labelled with information about their contents, nor with warnings of risk until well into the 1990s; thus, patients were kept in ignorance. No measures have yet been taken in Britain to alert the public to the need for medical surveillance of women who have been exposed to diethylstilbestrol in utero.

It is estimated that in the USA, the Netherlands, and France, diethylstilbestrol was given to over 5.3 million pregnant women, and it is known that it has been given to pregnant women in most parts of the world. Single cases of clear-cell vaginal carcinoma from many countries are known, but systematic studies have not been conducted everywhere.

One in a thousand young women exposed to diethylstil-bestrol before birth have been estimated to be at risk of developing clear-cell vaginal adenocarcinoma (18). Exposure to diethylstilbestrol in utero also has a range of other effects on exposed women, including malformations of the reproductive organs and difficulties in conception and carrying a pregnancy to term. Some of the men exposed to diethylstilbestrol in utero have urogenital malformations and an increased risk of testicular cancer (19).

Most of the women who suspected that they had taken diethylstilbestrol were to learn of the problems from the media, and they had to guess that their daughters might be at risk of developing cancer. When they tried to discover whether they had been given diethylstilbestrol during pregnancy, many of the women found that their obstetricians were not willing to give them access to their own medical records. In a report from a nationwide US survey intended to locate pregnant women who had been given diethylstilbestrol during 1940-72, the investigators complained that at some clinics they had encountered extreme difficulties in getting access to the records (20). Women who have been exposed to diethylstilbestrol sometimes say that never have so many medical files reportedly been lost through fire and inundation, as when they asked for access to records that might document the use of diethylstilbestrol during pregnancy.

Many doctors did not notice or did not heed warnings in the early 1970s about the risks of giving diethylstilbestrol to pregnant women. As late as 1974, according to one writer, some 11000 prescriptions for diethylstilbestrol to be used during pregnancy were written in the USA (21). In 1976, it was observed that diethylstilbestrol was given to unsuspecting pregnant women in several Latin-American countries (21). In other countries, prescribing physicians' responses to reports that linked the use of diethylstilbestrol during pregnancy with cancer risks in their daughters were even slower. The latest documented prescription of diethylstilbestrol in Europe was in Spain in 1983 (22).

The first batches of educational material for physicians, with warnings and advice regarding health care for women who had been exposed to diethylstilbestrol, were distributed in the USA in 1971, in the Netherlands in

1974, and in France in 1989. No such material has been distributed in Britain.

Mothers in the USA who had taken diethylstilbestrol formed an organization, DES Action, to inform the public about the risks and to alert exposed mothers that their daughters needed regular medical examinations, so that potential tumor development would be detected early. Through DES Action they also gave each other mutual support during litigation against the manufacturers and acted politically to ensure that health care would be available for their daughters. DES Action groups outside the USA were formed in Australia, Belgium, Canada, France, Great Britain, Italy, Ireland, and the Netherlands. DES Action was still in the 1990s a prime mover in securing resources for research and follow-up of women who had been exposed to diethylstilbestrol, and in promoting educational programs for those women and for medical professionals.

Initiatives by medical researchers, by DES Action, and by the Public Citizen's Health Research Group secured funding in the USA for medical research on the prevalence of cancer and other effects in the young women who had been exposed in utero, and eventually also the men. The US National Institute for Environmental Health Sciences (NIEHS) has been one of the centers for toxicological studies of the effects of diethylstilbestrol. A substantial amount of research on the effects of diethylstilbestrol— animal experiments as well as epidemiological studies— has produced a valuable body of knowledge about how hormones affect the development of the fetus and prime the individual for disease later in life.

As in the case of thalidomide, the emotional engagement evoked by the harm caused by diethylstilbestrol in pregnancy led to committed action. Some physicians have devoted a major part of their careers to finding out why and how diethylstilbestrol produced adverse effects. The anger over the harm caused by diethylstilbestrol inspired patients to a commitment to prevent further harm by engaging in political action and achieving an effective response from legislators and governmental administrators. Despite the abandonment of diethylstilbestrol in pregnancy for habitual or threatened abortion, its late effects continue to be reported. Essentially, the female offspring of these pregnancies tend to develop vaginal changes (adenosis, with cervical ectropion) when reaching adolescence or adulthood and these can subsequently give rise to a clear-cell adenocarcinoma. Whereas carcinomas are a late and infrequent event, even in exposed subjects, cervical vaginal adenosis is common, the incidence probably being some 30% (23). The estimated tumor risk is only 0.14-1.4 per 1000 diethylstilbestrol-exposed subjects, but since up to 6 million fetuses were exposed to diethyl-stilbestrol between 1940 and 1970 the total number affected in some way may be very high indeed. There is also a high incidence of fertility disturbances among these daughters, and their own pregnancies apparently stand a high chance of not going normally to term (SED-12, 1023)

(24). Analogous changes were found in male offspring

(25). As in the case of thalidomide, an important element in determining cause and effect was the characteristic nature of the defect: the vaginal pathology does occur spontaneously but is highly unusual. A major problem has been the fact that the defect is as a rule only recognizable so many years after birth, by which time the history of the original treatment may be difficult or impossible to reconstruct. Even today the material is not homogeneous and strict statistical analysis of some of the epidemiological data has been claimed to point to a series of shortcomings. This does not undermine the clear conclusion that the drug is indeed responsible for the effects described (26).

Epidemiological studies on the complications of the use of diethylstilbestrol in pregnancy will certainly produce new data as time goes on: most of the data will probably continue to come from the USA and the Netherlands, where diethylstilbestrol was much more widely used to treat habitual or threatened abortion than elsewhere. In France 150 000-200 000 pregnancies were involved; in the Netherlands, with a much smaller population, 180000-380000 pregnant women were treated with diethylstilbestrol up to 1976.

Vaginal adenosis and adenocarcinoma

Second-generation (and possible third-generation) effects of diethylstilbestrol continue to be reported (27,28). Typical is a 1987 update analysing 519 cases of clear-cell carcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago (18); in 60% of all cases the patient's mother could be shown to have used diethylstilbestrol during pregnancy. The median age at diagnosis was 19 years. The authors argued that in view of the relative rarity of the tumors, even in exposed women, one could consider that diethylstilbestrol is not a complete carcinogen and that some other factor is also involved in the pathogenesis of this type of carcinoma. The particular question of third-generation injury has actually been the subject of judicial proceedings in the USA (27,28); on the balance of evidence it seems that it can occur, although the mechanism is not clear.

Evidence has also emerged on long-term survival in young women with a clear-cell adenocarcinoma of the vagina, 20% of whom had been exposed to diethylstil-bestrol and 80% had not (29). The probabilities of survival at 5 and 10 years for diethylstilbestrol-associated cases were 84 and 78% respectively, compared with 69 and 60% for those not associated with diethylstilbestrol. These differences were not due to differences in clinical prognostic factors, but suggest differences in tumor behavior for as yet undetermined reasons.

Although it is more than 30 years since the full extent of the injury to offspring by the ill-advised use of diethylstil-bestrol during pregnancy became clear, details of that injury are still being filled in as the individuals concerned grow older. The picture will continue to develop as long as this generation of individuals lives, and it is even possible that findings in the third generation will throw light on the persisting injury to the family.

Psychological research among "DES daughters'' has shown how traumatic it can be for a woman to learn of her prenatal exposure to diethylstilbestrol, and the extent to which this creates persistent uncertainty about her health; the failure of a physician to provide reliable information and continuing support can severely undermine her faith in health care (30).

Table 1 Outcomes in pregnancies exposed and not exposed to diethylstilbestrol

Outcome

Exposed (%)

Non-exposed (%)

Full-term delivery

64

85

Spontaneous abortion

19

10

Preterm delivery

12

4.1

Ectopic pregnancy

4.2

0.8

Long-term studies of the pregnancy experiences of women exposed to diethylstilbestrol in utero, compared with unexposed women, now include one in the US National Collaborative Diethylstilbestrol Adenosis cohort and one in the Chicago cohort and their respective non-exposed comparison groups. A review of questionnaire replies from 3373 exposed daughters and from controls has confirmed that diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ecto-pic pregnancies (31). The data are shown in Table 1. Second-trimester spontaneous pregnancy losses were much more common in diethylstilbestrol-exposed women.

Other cancers

Long-term data are also accumulating on the actual incidence of genital cancer in women exposed to diethylstilbestrol in utero (32). In the Netherlands, a country in which diethylstilbestrol was used intensively in pregnancy, there is evidence that the risk of cervical cancer in these women is trebled, rather than doubled as was previously supposed (33).

• A diethylstilbestrol-exposed woman developed concurrent primary cancers of both the vagina and the endo-metrium at the age of 39 (34).

However, it is important to bear in mind that cases occur in which there is no history of the mother's having taken diethylstilbestrol during pregnancy. In one such case, HIV/AIDS infection was also a predisposing factor for vaginal carcinoma and this could explain a proportion of new cases that are being reported today (35).

A further follow-up and analysis of 3879 women, taken from two earlier US studies, who had been exposed to diethylstilbestrol during pregnancy has been presented (36). The results showed a modest association between diethylstilbestrol exposure and the risk of breast cancer (RR = 1.27; 95% CI = 1.07, 1.52). The increased risk was not further aggravated by a family history of breast cancer, by use of oral contraceptives, or by HRT. There was no evidence that diethylstilbestrol was associated with a raised risk of ovarian, endometrial, or other hormone-associated cancers.

Sensory systems

A study in the USA has produced some evidence that in people with amblyopia, those who were exposed to diethylstilbestrol before birth may be more likely to develop myopia (37).

Menstrual and vaginal disturbances

The effects of in-utero exposure to diethylstilbestrol on the menstrual cycle have been studied prospectively in 198 women and in 162 unexposed controls (38). A major limitation of this study was the exclusion of women with a severe menstrual abnormality. Exposure to diethylstilbestrol was associated with a statistical significantly lower duration of menstrual bleeding but not with dysmenorrhea. For most women exposed to diethylstilbestrol, any effects on reproductive hormonal function are in all probability minor, if present at all.

Even the classic genital manifestations of diethylstil-bestrol in women who have been exposed to it in fetal life may be overlooked unless one is alert to them; vaginal discharge with ectropion should cause one to enquire as to possible prenatal diethylstilbestrol exposure (39).

Autoimmune disease

During the last 15 years, various additional aspects of the diethylstilbestrol problem have given rise to concern. One emerged in 1988 from a large multicenter epidemiological cohort study established by the US National Cancer Institute (DESAD Project), in which it was found that women exposed in utero to diethyl-stilbestrol had a 50% increased incidence of autoimmune disease (40).

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