The story of exposure to diethylstilbestrol (DES) in utero is a classic of medical detection. Of special interest to pediatricians is the recognition of a prolonged latency in the expression of the drug effect and the identification of a group of abnormalities whose full import is unknown. DES was widely administered after World War Il to pregnant women who had histories of miscarriage in the belief that it would prevent or lessen the risk of such adverse outcomes. It is estimated that from one to three million pregnant women in the United States alone received it between 1951 and 1969. Up to four to six million Americans - mothers, daughters, and sons - may have been exposed to DES during pregnancy.
In 1951 -52 a clinical trial was conducted at the University of Chicago by W. J. Dieckmann and his associates to see if the drug was effective in preventing problems in pregnancy. The investigators concluded that it had no effect on the maintenance of pregnancy or on the incidence of abortion, prematurity, postmaturity, perinatal mortality, or toxemia. Yet, despite the demonstration of its ineffectiveness, DES continued to be prescribed and was only gradually abandoned. Comparatively little was prescribed for pregnant women after 1970.
There is tragic irony in the recent finding that the statistics of the Dieckmann study, recalculated today, clearly show that DES significantly increased abortions, neonatal deaths, and premature births. The wide exposure to DES might have been avoided had the data been interpreted correctly.
In 1971, Arthur Herbst and his colleagues at Harvard alerted the scientific community and the public at large with reports establishing a significant association between maternal use of DES in pregnancy and a rare vaginal cancer in daughters born of these pregnancies. In some cases the condition was discovered many years after exposure. In addition to the increased risk of adenocarcinoma of the vagina, Herbst reported a high percentage of noncancerous changes in the epithelium in the vagina and cervix. This report was followed by observations of additional cases. A Registry of Clear-cell Adenocarcinoma of the Genital Tract in Young Females was established, and public concern was manifested in the formation of DES Action Groups to search for exposed daughters so that they might be examined and closely monitored.
Soon afterward, the NICHD issued a request for proposals to evaluate the effects of sex hormones and contraceptive agents on the subsequent development of abnormalities in the offspring. In response, Marluce Bibbo, from the University of Chicago, proposed to trace the subjects of the Dieckmann study and obtain data on their children. The project was begun in 1974 and has continued to the present; Arthur Herbst is currently director. It has provided an unusual opportunity to follow up and compare a large group of subjects and their controls 25 years after an original study. Eighty-three per cent of the original group took part, consisting of 693 women who had received DES and 668 who had received placebos. The offspring, 665 daughters and 615 sons, were similarly divided into DES-exposed subjects and nonexposed controls; all had been found normal at birth.
Initially, the investigation focused on the daughters. Significant differences between the two groups were found. More than 66 per cent of the exposed group had vaginal adenosis, as against 3.6 per cent of the controls; 40 per cent of the exposed group had vaginal or cervical ridges vs. zero per cent of the controls; 6.6 per cent of the exposed group showed dysplastic lesions vs. 1 .3 per cent among the controls.
No case of neoplasia was observed in tissues derived from the gonadal ridge. At present, based on this and other studies, the risk of developing adenocarcinoma can be estimated to be within 1:1,000 to 1:10,000 exposed, less than was previously feared. Follow-up examinations are considered prudent for those daughters who have any nonmalignant abnormalities, because the natural history of adenosis associated with DES is not known. It is generally recommended that daughters exposed in utero be referred to a gynecologist and undergo examination of the cervix and vagina if they are postmenarchal, or before that if there is any unusual bleeding or discharge.
What of the sons? To date, no cancers related to DES exposure have been found, but it is clear that exposure to DES in utero can be followed by anatomic changes in the male reproductive tract. Of the 615 sons, those exposed to DES had a significantly higher incidence of epididymal cysts (64 vs. 15) and abnormalities of the testes (35 vs. 8) than the unexposed controls. One or more abnormalities were found in 97 of the males exposed to DES but in only 23 of the controls.
Differences were also found in average sperm density, total sperm count, and count of motile spermatozoa. The average score was abnormal for the DES group for all parameters of sperm quantity and quality; for the control group it was within normal limits. More severe abnormalities were found in 27 per cent of the men exposed to DES, as against 7 per cent of the controls. In both groups, abnormal semen was most often present among males with genital abnormalities. However, there was a twofold increase in semen abnormalities in males exposed to DES without genital abnormalities. Studies are in progress to determine whether the semen abnormalities are transitory or permanent.
Whether or not the fertility of these men is affected is not known. Their average age is 26, and they belong to a cohort of young men nationally that has delayed marriage and parenthood. It is expected that information regarding fertility will be delayed for several years as these young men belatedly enter marriage and attempt fatherhood. As with females exposed to DES, it is recommended that DES-exposed males, if they are past puberty, be examined, preferably by a urologist.
An HEW-DES Task Force in which NICHD had active participation was formed early in 1978 to examine the effects on health of DES in pregnancy. Concurrent with its report, Julius B. Richmond, Assistant Secretary for Health and Surgeon General, issued a Physician Advisory with recommendations to assist clinicians in managing patients who may have been exposed. The NICHD shares responsibility with the National Cancer Institute (NCI) for the support of research related to exposure to DES in utero, and of alerting pediatricians and the public at large to conclusions of the task force. Animal studies have also been conducted by the National Institute of Environmental Health Sciences.
There are a number of unresolved issues that must be addressed by future research. Vaginal adenosis and other changes may be precursors of cancer. The reproductive performance of women exposed in utero must be carefully watched. Some case reports suggest that they may have an increased rate of abortion, some trouble conceiving, and some increase in prematurity. As to the young men - in addition to continued studies of possible infertility, there has been speculation regarding cancer of the testes.
A major problem of DES exposure is that the majority of young men and women, many of whom are still in the care of pediatricians, do not know that they were exposed. The estimate is as high as 90 per cent.
For further information or a copy of the Task Force report, write to the Office of Cancer Communications, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, Maryland 20014.