Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed children
In utero exposure to diethylstilbestrol (DES) was initially linked to vaginal-cervical cancer and subsequently to reproductive difficulties. These unanticipated and ongoing health risks to female offspring may constitute a chronic source of stress for DES mothers.
Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed daughters, US National Library of Medicine, Journal of human stress, NCBI PubMed PMID: 3855173, 1985.
We interviewed 60 mothers of exposed daughters and 30 acquaintance controls. Two hypotheses were tested in regard to DES mothers: DES discovery and its aftermath have a direct, long-term, negative effect on psychological health and the DES experience intensifies the negative psychological effects of other adverse life circumstances.
To operationalize psychological health, we measured symptoms of “demoralization” and positive health practices–the latter as a behavioral indicator of mastery and personal control. We also measured adversities that may mediate the threat posed by DES, including stressful events, medical problems, and chronic burdens. We found DES history to be associated with poorer psychological health only when mothers encountered other losses and threats to themselves and their families.
We concluded that DES mothers may manifest increased vulnerability to subsequent stresses in their lives.
Physicians can help the DES-exposed deal with their emotional issues
The emotional impact of diethylstilbestrol (DES) exposure is described in a series of 50 mothers and daughters interviewed by psychiatrists. Patterns of response to this trauma and methods of resolution are discussed, and opportunities for preventive intervention by gynecologists are suggested. Specific, open dialogue about DES with the patient as a colleage can minimize the emotional sequelae of the experience.
Observations on the psychological impact of diethylstilbestrol exposure and suggestions on management, US National Library of Medicine National Institutes of Health, The Journal of reproductive medicine, NCBI PubMed PMID: 7373597, 1980 Mar.
This study analyzes the emotional impact of diethylstilbestrol (DES) exposure in an index population consisting of 50 women at risk plus 30 mothers who were all interviewed about their DES experience in an open-ended, in-depth, clinical style. The findings show that significant emotional upset is the normal response to the knowledge that the ingestion of a drug during pregnancy can cause or has caused some abnormality in the offspring.
Nevertheless, the capacity of a woman to come to terms with the anxiety DES has generated, once she had been given the chance to express her feelings and fears, was impressive.
DES daughters reacted to the DES experience in one of 3 ways, in descending order of frequency:
trust (80%). Most DES daughters rationalized that their mothers and doctors did the best they could, and were generally cooperative in their follow-up care;
and fear (10%).
90% of DES mothers came to terms with the knowledge and implications of DES exposure in ways characteristic of their life-long personality styles; in contrast, the remaining 10% who did not come to terms with the reality of DES exposure felt overwhelmed by quilt, paranoid rage, fear, and despair.
Physicians can help patients deal with such problems by:
acknowledging problematical feelings and expecting them to be difficult to deal with;
noting the patient’s pattern of response, and supporting her strengths;
giving factural information matter-of-factly;
listening to reactions to this information;
giving a structured plan in which the woman participates and be available for follow-through on it (eg, periodic colposcopic examinations);
and referring the women to support groups for an extended network of information and continued support.
Initial anxiety was usually followed by acceptance of the condition after examination and counseling. Patients responded best when informed of their problem by their mothers and when the relationship between mother and daughter was good.
The majority of patients found colposcopy to be unpleasant; they tended to be disturbed in proportion to the degree of being upset about DES exposure. The most common problem among mothers was guilt.
A questionnaire survey of physicians showed that they had less concern for psychological problems than patients or mothers did. Sensitivity and good communication on the part of medical personnel are recommended.
In view of the reported association between exposure in utero to diethylstilbestrol (DES) and clear-cell adenocarcinoma of the vagina, data on the prenatal use of DES in some 51,000 pregnancies in 12 hospitals between the years, 1959 and 1965, were examined. Among these women, in whom prenatal drug exposure was carefully documented, there was considerable variation in DES usage, the frequency being highest in the Boston LyingIn Hospital (exposure in 1.5% of pregnancies) and the Children’s Hospital, Buffalo (exposure in 0.8% of pregnancies). Data from two marketing research sources were used to estimate DES usage in the United States. It is calculated that a maximum of 50,000 liveborn females per year, born between 1960 and 1970, were exposed to DES in utero, while the most likely estimate is in the range 10,000 to 16,000.
DIETHYLSTILBESTROL IN PREGNANCY, Frequency of Exposure and Usage Patterns, From The Boston Collaborative Drug surveillance Program, Boston University Medical Center, Manuscript Prepared by OLLI P. HEINONEN, MD, ER March 1972.
There is now substancial evidence that the administration of diethylstilbestrol (DES) during pregnancy may produce clearcell adenocarcinoma of the vagina in female offspring. More than 60 cases of this malignancy, which has hitherto been extremely rare in young females, have now been reported to the Registry of Clear-Cell Carcinoma of the Genital Tract in the United States. The size of the population exposed to DES during the past two to three decades is unknown. The present report is concerned with a description of the use of DES in some 51,000 pregnancies seen in 12 hospitals. Prescription data obtained from two marketing research groups concerning DES usage in the population of the United States at large are also reported.
The information from the hospitals was collected as part of the Collaborative Study on Cerebral Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of Infancy and Childhood of the National lnstitute of Neurological Diseases and Stroke (Collaborative Perinatal Study-CPS). It should be noted that this study had no influence in determining the medical care provided. The study design and methods of data collection employed by the CPS have been described in detail previous1y.l For the purposes of the present report, the following details are emphasized. On entry into the study, each woman was interviewed to obtain a medical, social, and medication history. Irrespective of the time of entry into the study, a detailed history of drug use was obtained for each woman including the one month prior to her last menstrual period. The systematic interview on medication intake was repeated at four weekly intervals. With few exceptions, each medication history was confirmed by the attending physician. To secure complete information on medications, hospital records and charts from private doctors were aIso reviewed. The data were abstracted, coded, placed on computer tape, and processed. In the present study, the original record of each woman identified from the computer tape as having received DES was reviewed by hand.
The original material consisted of 58,807 pregnancies from 12 participating hospitals. Cases were excluded for the following reasons: entry into the study during labor; abortion: stillbirth; multiple birth; race other than Caucasian, Negro, or Puerto Rican; and use of an unidentified drug during the first 4 lunar months of pregnancy. In the final analysis, 51,071 pregnancies were considered.
In nine hospitals, the sampling scheme was systematic; in one, it was random, and, in two, all patients presenting were entered into the study. About 20% of the participating women had more than one pregnancy while in the study.
Age, parity, socioeconomic status, and other characteristics of the study cohort have been described in detail elsewhere.
The 51,071 pregnancies included 23,096 Caucasians, 24,443 Negroes, and 3,532 Puerto Ricans. Their mean age was 24.1 years (whites including Puerto Ricans, 24.7 years; non-whites, 23.7 years). The proportion of nulliparous women was 28.1%, and the mean parity was 2.8 (whites, 2.8; non-whites, 2.9). The mean socioeconomic index was 6.8 (whites, 8.3; non-whites, 5.5). Most of the women (63.0%) entered the study during the first and second trimester, the mean time of entry being 21.6 weeks from the last menstrual period. Vaginal bleeding during the first trimester was recorded in 13.5% of the pregnancies.
DES was received by 217 pregnant women in this series (0.42%). The distributions of patients by hospital and ethnic group are given in Table 1 (below).
The mean age of the DES recipients was 27.6 years, and 10.6% were nulliparous. As expected, the frequency of vaginal bleeding during the first trimester was higher in women who received DES (36.3%). DES usage had no effect on the sex ratio observed in the liveborn.
Variation of DES usage frequency, by hospital
The frequency of DES usage was relatively high in 2 of the 12 hospitals. The drug was administered in 174 pregnancies at the Boston Lying-In Hospital (1.5%), and in 19 pregnancies at the Children’s Hospital in Buffalo (0.8%).
In the remaining 10 hospitals, the drug was given in only 24 out of 37,821 pregnancies (0.0670), and in two of these hospitals-the Johns Hopkins Hospital, Baltimore, and the Columbia-Presbyterian Hospital, New Yorknone of the women received the drug.
Dosage and duration
The total doses of DES received by women in the 12 hospitals are summarized in Table 2 (below).
At the Boston Lying-In Hospital, 146 out of 174 pregnancies were treated with the following schedule: the drug was started at a relatively low dose (0.0025 – 0.05 g/day) as early as feasible in the pregnancy. The dose was then increased every 2 weeks until a daily dose of 0.15 g/day was reached. The total dose received with this regimen varied from a low of 0.175 g to a high of 46.6 g, and the duration of treatment varied from 10 days to 9 lunar months. In the remaining 28 pregnancies, constant doses were generally used for short periods of time; in only two did the total DES dose reach high levels (16.5 g and 19.0 9). The total dose was less than 1 g in 19 pregnancies, and, in 10, DES was administered for less than 1 week.
At the Children’s Hospital, Buffalo, dosage was generally constant (0.1 to 5.0 mg per day). In 5 of 19 pregnancies in which DES was used, the total dose was 0.1 to 1.3 g, while, in 14, the total doses were all less than 0.1 g. In the remaining 10 hospitals, 22 out of 24 DES recipients received total doses of less than 1 g. One woman received 1.6 g, and one received 16.5 g.
Table 3 (below) shows the total dose of DES, across hospitals, divided according to whether constant or increasing daily dosage schedules were recieved.
The table 3 (above) shows that, as expected, high total doses were closely related to increasing daily dosage schedules.
Table 4 (above) summarizes the total dose, duration of administration, and time during pregnancy when exposure to DES commenced. The data on the 217 pregnancies exposed to DES are shown as percentile distributions. The table shows that more than 10 g were administered during half of the pregnancies.
In all hospitals in the study, the frequency of exposure to DES remained reasonably stable between the years, 1959 and 1965.
The reported association between maternal diethylstilbestrol usage and the subsequent development of adenocarcinoma of the vagina in female offspring has been given considerable publicity. Furthermore, it has been suggested that females known to have been exposed in utero to DES should undergo regular and frequent gynecological examinations. Any public health action, however, would depend upon the size of the population exposed, and the risk of developing vaginal adenocarcinoma in an exposed individual. While the present CPS data do not provide any direct information concerning the magnitude of the risk which is to date unknown, they do provide information on the population at risk after exposure to DES in 12 hospitals in the United States between the years, 1959 and 1965.
The data reveal that use of the drug varied considerably between hospitals located in different areas of the United States. Its use was uncommon in 10 of the 12 hospitals and, when used in these hospitals, the total dose was generally low. In only two hospitals was the usage relatively high in terms of either frequency or dosage.
For certain types of cancer, there is considerable evidence that the dose, duration, and time of exposure to carcinogens are all important determinants of risk. In the investigation of the relationship between intrauterine exposure to DES and the development of vaginal clear-cell adenocarcinoma, the relative importance of these factors remains to be established.
The present data suggest that increasing dose regimens generally result in high total doses while constant dosage regimens do so infrequently. Knowledge of the regimen employed might provide a reasonable index for investigators obtaining DES medication histories in pregnancies which occurred some 15 or more years previously. On the other hand, the CPS data suggest that knowledge of the duration of exposure alone will not provide a completely satisfactory index of the total dose administered.
Since the material from 12 hospitals studied in the CPS cannot be considered as representative of the country at large, and in view of the large differences in DES use between the participating institutions, it is clear that no approximation of the number of DES users for the United States can be made from these data alone. However, in view of the importance of providing some estimate of DES exposure, albeit provisional and approximate, we requested and obtained information from two further sources.
The first of these, Lea, Inc. (Ambler, Pa.), obtains information from 1,500 private physicians who report on all pharmaceutical products which they prescribe, together with the indication for each drug and some selected patient characteristics. This information is obtained four times a year and covers a 48-hour period of practice. The sample of physicians is continuously changed. It consists of slightly less than 1% of the prescribing physicians in the United States who are mainly in private practice. The sample is selected at random from 72 region and specialty strata, each subsample being of equal size. Data were collected uninterruptedly from 1960 to 1970, and the reporting periods were equally distributed over time. The response rate was approximately 70y0. In order to derive estimates for the entire United States, the projection factor for each stratum was calculated monthly.
The second source, R. A. Gosselin and Company, Inc. (Dedham, Mass.), is based on new and refill prescription data collected on a 2-week basis, from 1964 to 1970, from 400 randomly selected pharmacies throughout the United States. The methods of sampling and projection were similar to those described for the first source. An average of 100,000 prescriptions per month were collected.
For the years, 1964 to 1970, the data from these two sources are in substantial agreement concerning the average total number of prescriptions which have been written for DES in the United States. The first source estimates 2.51 million prescriptions per year, and the second, 2.49 million per year.
In addition to obtaining the total number of prescriptions for each drug, the first source determines the indication for drug therapy. The data show that during the period between 1960 and 1970, an average of 100,000 prescriptions for DES, per year, were written in the United States for women who were pregnant. It is interesting to note that there was regional variation. If nine United States’ census areas are combined into four geographical regions, the drug was more commonly used for prenatal care in the East and Midwest than in the South and West (3.67 and 2.93 vs. 1.94 and 1.68 DES prescriptions per 100 livebirths).
Of the 100,000 DES prescriptions written each year for pregnant women, approximately 50,000 might have affected female offspring. It can be assumed, however, that not all of these pregnancies would have resulted in liveborn infants particularly since threatened abortion is a common indication for this drug. Since there are no data concerning rates of DES use in pregnancies resulting in abortion or stillbirth on the one hand, compared with pregnancies resulting in a liveborn child on the other, we examined the CPS material. Somewhat less than 5% of DES use occurred in the stillbirth/abortion group, and this proportion was similar at the Boston Lying-In Hospital, the Children’s Hospital in Buffalo, and at the other participating hospitals. However, it should be borne in mind that abortions are likely to be underrepresented in the CPS data because of the study design.
Unfortunately, information concerning the number of DES prescriptions per pregnancy is not available from the marketing research data. However, if it is assumed that DES is usually prescribed every 4 weeks, then the number of prescriptions, for any individual pregnancy, could not exceed 10. If the average number is between three and five, then the number of liveborn female offspring exposed to DES in utero would be between 10,000 and 16,000 per annum in the United States during the period 1960 to 1970. In the CPS material, it is of interest that the average number of prescriptions for DES was 4.4 per pregnancy, assuming the prescription was given every 4 weeks.
Herbst et al reported that DES was used in 4.60%, of pregnancies at the Boston Lying-In Hospital between the years, 1946 and 1951. The authors point out that this estimate is derived from all pregnancies including those resulting in abortions and stillbirths. No data are available on exposure to DES during pregnancy in the 1950’s. The current CPS data do not show any major change in usage of DES between 1959 and 1965. Since 1967, however, data from Lea, Inc., suggest a declining use of DES in pregnancy.
Other nonsteroidal synthetic estrogens are also under suspicion. At least one case of vaginal adenocarcinoma following in utero exposure to dienestrol has been reported. Oral use of this drug appears to be rare in pregnancy: no case was observed in the CPS data, and in the prescription data provided by the R. A. Gosselin and Company, Inc., it was used about 100 times less frequently than DES.
OLLI P. HEINONEN, MD, received for publication August 26, 1972.
Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.
BACKGROUND Treatment with oestrogen to reduce the adult height of tall girls has been available since the 1950s. We undertook a retrospective cohort study to assess the long-term effects of this treatment on fertility.
METHODS Eligible participants were identified from the records of Australian paediatric endocrinologists who assessed tall girls from 1959 to 1993, and from self-referrals. Individuals included girls who had received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) (treated group) and those who were assessed but not treated (untreated group). Information about reproductive history was sought by telephone interview.
FINDINGS 1432 eligible individuals were identified, of whom 1243 (87%) could be traced. Of these, 780 (63%) completed interviews: 651 were identified from endocrinologists’ records, 129 were self-referred. Treated (n=371) and untreated (n=409) women were similar in socioeconomic and other characteristics. After adjustment for age, treated women
were more likely to have ever tried for 12 months or more to become pregnant without success (relative risk [RR] 1.80, 95% CI 1.40-2.30);
more likely to have seen a doctor because they were having difficulty becoming pregnant (RR 1.80, 1.39-2.32);
and more likely to have ever taken fertility drugs (RR 2.05, 1.39-3.04).
Time to first pregnancy analysis showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse (age-adjusted fecundability ratio 0.59, 95% CI 0.46-0.76). These associations persisted when self-referred women were excluded.
INTERPRETATION High-dose oestrogen treatment in adolescence seems to reduce female fertility in later life. This finding has implications for current treatment practices and for our understanding of reproductive biology.
Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, National Institutes of Health, NCBI PubMed PMCID: PMC3817964, 2013 June.
Although women were prescribed DES to improve the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous abortion, prematurity or postmaturity, and the study suggested that DES enhanced premature labor. However, it continued to be used for another nearly 20 years.
DES Pregnancy: DES Daughters
Hoover determined that DES daughters have an increased risk for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm delivery (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life. Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery have been reported in more than one study, and appear to be exacerbated effects for which DES was prescribed to prevent.
The effects of prenatal DES exposure on the ability to reproduce are substantial. The risk for infertility (defined as ? 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001), and full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80). The Dutch DES cohort reports that 33% of DES daughters are nulliparous at the age of ? 40 yr, compared with only 17% in the Dutch population. Kaufman and co-workers also reported that that once pregnant, 20% of DES daughters experience preterm delivery (versus 8% of unexposed population (RR=2.93; 95% CI, 2.23–3.86)), their risk of ectopic pregnancy was 3 to 5 times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, 1.54–2.60). These adverse pregnancy-related outcomes in DES daughters are also experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant. Also, there are strong data suggesting that the presence of vaginal epithelial changes at cohort entry examination adds to the cumulative risk for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.
Effects of exposure period and dose of diethylstilbestrol on pregnancy in rats, The Journal of veterinary medical science / the Japanese Society of Veterinary Science, NCBI PubMed PMID: 19887736, 2009 Oct. Full text: J-Stage, Laboratory Animal Science, 71/10/71_001309, August 2009.
The aim of this study was to investigate the effect of exposure period and dose of diethylstilbestrol (DES), which has strong estrogenic activity, on pregnancy in rats.
All rats with observed vaginal plugs or sperm in vaginal smear tests after mating were divided into 3 groups:
those fed a normal diet,
a diet mixed with DES throughout pregnancy
and a diet mixed with DES from day 13 of pregnancy.
DES was mixed into the diet at 0.1, 1, 10 and 100 ppm.
All bred rats fed the normal diet and 0.1 ppm DES from day 13 of pregnancy delivered pups, while none of the rats treated with 1-100 ppm DES during pregnancy and 100 ppm DES from day 13 of pregnancy delivered any pups. The number of male and female pups born decreased in rats treated with 10 ppm DES from day 13 of pregnancy.
These results suggest that DES could affect pregnancy and that the exposure period and dose may result in
Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume I, Institute of Medicine (US) Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies, NCBI PubMed NBK236538, 1994.
Diethylstilbestrol (DES), synthetic estrogen, was first produced in London in 1938. The earliest studies of DES in pregnant women in the United States were conducted at Harvard University in the late 1940s. Although the studies were criticized because they were conducted without the use of controls, the physicians directing the studies concluded that “DES was effective against a variety of pregnancy complications and resulted in a healthier maternal environment“. In 1947 the FDA approved new drug applications (NDAs) to market DES for the purpose of preventing miscarriages.
In the 1950s, however, controlled studies of DES in pregnant women yielded different results. At Tulane University, researchers found that more of the DES-treated women had miscarriages and premature births, while the controls had bigger, healthier babies. At the University of Chicago, every pregnant woman at the University’s Lying-In Hospital (1,646) was a test subject for a DES experiment without their knowledge or consent, and became part of a clinical trial: one-half were randomized to receive DES and the other half received placebos. None of the women were told they were part of a study, nor were they told what drug they were taking. The study found that twice as many of the DES-treated mothers had miscarriages, premature births, small babies, thereby confirming the finding of a Tulane study that contradicted the original uncontrolled Harvard study which extoled high doses of DES effectiveness against pregnancy complications.
In 1951 the FDA concluded that DES was safe for use during pregnancy and stopped requiring manufacturers to complete NDAs prior to marketing the drug as a preventive against miscarriage.
Despite growing evidence that DES was ineffective and the confirmatory findings of harm, physicians continued prescribing DES for 20 years resulting in numerous birth complications and exposing the unborn daughters and sons of their patients to serious risk of cancers.
Informed Consent: the women in this study did not know that the study was taking place and did not know about the study.
Voluntary Participation: these women did not choose to participate in the study.
Failure to prevent unnecessary harm: the Tulane University study should have been considered before proceeding with this case and ultimately leading to harm.
Self-determination: the women did not have the choice to participate or decline participation in the study.
Declaration of Helsinki Violations
The risk and benefits were not weighed in this study.
The loyalty of the doctor did not lie with the women, but to research and the general population.
The women did not have self-determination prior to or during the study.
The University’s Lying-In Hospital experiment should not have been conducted.
That study violated the Hippocratic Oath, the Nuremberg Code, and the Declaration of Helsinki.
The data results from this study should have been published and used.
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, The Cochrane database of systematic reviews, NCBI PubMed PMID: 12918007, 2003. Full text: The Cochrane Collaboration, doi/10.1002/14651858.CD004353, 26 APR 2003.