Diethylstilbestrol in Pregnancy

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).

Diethylstilbestrol Recipients by Hospital and Race

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).

DES Recipients by Total Dose in Boston Lying-In Hospital, Children’s Hospital, Buffalo, and the 10 Other Hosoitals.

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.

Relationship between Total Dose and Type of DES Administration in DES Recipients Taking the Drug for 3 Weeks or Longer

The table 3 (above) shows that, as expected, high total doses were closely related to increasing daily dosage schedules.

Percentile Distribution of the Total DES Dose, the Duration of Medication and Interval between Last Menstrual Period and the Start of Medication in 217 DES Recipients

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.

Time trends

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.

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Reducing the Adult Height of Tall Girls with DES: Effects on Fertility

image of tall-girls
Estrogens have been used to reduce the height of unusually tall girls since the 1950s based upon the concept that, during normal puberty, increased estrogen levels lead to epiphyseal fusion in the long bones. DES treatment in adolescence seems to reduce female fertility in later life by 40%.


Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.

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.

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.

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.

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.

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Pregnancy: DES Effects in DES Mothers and in DES Daughters

image of a pregnant-woman
Diethylstilbestrol causes a variety of birth-related adverse outcomes in DES daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death.

DES Pregnancy: DES Mothers

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.

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Effects of Exposure Period and Dose of Diethylstilbestrol on Pregnancy

These 2009 results showed that the strong estrogenicity of DES affected pregnancy in rats and that the exposure period and dose resulted in sterility, abortion, poor fetal growth and reduced number of pups born.


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:

  1. those fed a normal diet,
  2. a diet mixed with DES throughout pregnancy
  3. 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

  • sterility,
  • abortion,
  • poor fetal growth
  • and reduced number of pups born.

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DES tested on pregnant women without consent: ethical violations

“Choosing Wisely”: getting doctors to stop using interventions with no benefit.
“Back Bay golden goose ostrich” cartoon BOSTON MEDICAL LIBRARY.


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.


Ethical Violations
  • 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.
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Diethylstilbestrol DES use to prevent miscarriages and other adverse pregnancy outcomes

image of snake-oil-rep
The dictum ‘do no harm’ is relevant to the diethylstilboestrol saga of the 1950s. We need adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before they get introduced for consumption.


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.

Laboratory evidence in the 1940s demonstrated a positive role of placental hormones in the continuation of pregnancy. It was suggested that diethylstilbestrol was the oestrogen of choice for prevention of miscarriages. Observational studies were carried out with apparently positive results, on which clinical practice was based. This led to a worldwide usage of diethylstilbestrol despite controlled studies with contrary findings.

To determine the effects of antenatal administration of oestrogens, mainly diethylstilbestrol, on high risk and unselected pregnancy as regards miscarriages and other outcomes.

We searched the Pregnancy and Childbirth Group Specialised Register of controlled trials in November 2002.

Randomised and quasi-randomised trials were included.

Both reviewers extracted data from the studies identified that met the selection criteria, and the data were analysed using the RevMan software.


  • Miscarriage, preterm labour, low birthweight and stillbirth or neonatal death were not positively influenced by the intervention (diethylstilbestrol) as compared to the control group.
  • Diethylstilbestrol in utero exposure led to increased rate of miscarriage and preterm birth.
  • There was also an increase in the numbers of babies weighing less than 2500 grams.
  • The maternal outcome in terms of pre-eclampsia was not influenced.
  • Exposed female offsprings have a non-significant trend towards more cancer of the genital tract and cancer other than of the genital tract.
  • Primary infertility, adenosis of the vagina/cervix in female offsprings, and testicular abnormality in male offsprings were significantly higher in those exposed to diethylstilbestrol before birth.

There was no benefit with the use of diethylstilbestrol in preventing miscarriages. Both short and long-term adverse outcomes in exposed offsprings were demonstration of the harm that this intervention caused women and their offspring during its usage. The need for researchers to invest in properly designed trials cannot be overemphasised.

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The importance of controls in a clinical experiment

The importance of controls in a clinical experiment; stilbestrol therapy in pregnancy, Obstetrics & Gynecology, Volume 3 – Issue 4 – ppg 452-456 Citation/1954/04000, April 1954.

In 1954, HENRY FERGUSON, JAMES M.D. highlighted the need for adequate and rigorous research into the use of the DES drug in pregnancy – by using controls – to ensure that it actually had therapeutic value and was doing more good than harm.
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Effect of stilbestrol on pregnancy compared to the effect of a placebo

Compared to a placebo, there was no benefit with the use of stilbestrol in preventing miscarriages.


Effect of stilbestrol on pregnancy compared to the effect of a placebo, American journal of obstetrics and gynecology, Volume 65, Issue 3, Pages 592–601 0002-9378(83)90615-4, March 1953.

One hundred ninety pregnant women received increasing doses of stilbestrol. Treatment was begun by at least the twentieth week of pregnancy and continued through the thirty-fifth week of pregnancy, unless the patient delivered or aborted while on the treatment. The dose of stilbestrol began with 6.3 mg. to 50 mg. a day and ended with 137.5 mg. a day.

Two hundred three similar women received an indistinguishable placebo and provided a fair comparison.

The stilbestrol had no effect on :

  • pre-eclampsia,
  • prematurity,
  • fetal weight and survival,
  • or the size of the placenta.

The importance of adequate controls is discussed.


All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Antenatal oestrogen (stilbestrol) was not shown to be of benefit in preventing adverse fetal outcome. The miscarriage rate, preterm labour, birthweight, stillbirth or neonatal death were not positively influenced by the intervention as compared to the control group.

Another researcher presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts Smith’s 1948 theory. The DES tragedy buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

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Diethylstilbestrol in the prevention and treatment of complications of pregnancy

The widespread use of DES, specifically in the treatment of patients with threatening and habitual abortion, started in 1948 after O. Watkins Smith had published her article entitled Diethylstilbestrol in the Prevention and Treatment of Complications of Pregnancy


Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.

Laboratory evidence in the 1940s was proposed to support the concept that reduced placental hormone production was associated with a variety of adverse pregnancy outcomes such as miscarriage, preterm labour and hypertension in pregnancy. Animal models suggested that diethylstilbestrol, a synthetic oestrogen, was a suitable therapeutic agent. Diethylstilbestrol was thought to cause an increase in placental progesterone secretion because of its stimulatory effects on human chorionic gonadotrophin secretion without responding to negative inhibition by progesterone. On the basis of this, a rationale for providing hormone therapy to women in pregnancy, particularly those at risk of miscarriages, was advanced. Synthetic oestrogens were administered to women, often at an incremental dosage, throughout pregnancy.

The rationale for the use of DES was based on observations in animals and humans that stilbestrol might enhance the production of progesterone, thereby preventing early abortion and later pregnancy complications. As emphasized by Drs Olive and George Smith, prophylactic therapy was necessary.

1948 Study Abstract (Smith OW)

Diethylstilbestrol in the prevention and treatment of complications of pregnancy, American journal of obstetrics and gynecology, Volume 56, Issue 5, Pages 821–834, AJOG 0002-9378(48)90440-2, November 1948.

Free full text available via sci-hub.

The basis for the use of stilbestrol in pregnancy is briefly reviewed, together with the indications and the dosage schedule recommended. Complete case reports on 632 pregnant women, to whom diethylstilbestrol was given largely for the indications and in the amounts recommended by us, have been analyzed. They have been divided according to the indications for therapy, i.e., threatened abortion (219 cases), abortion prophylaxis (272 cases) and prophylaxis against late pregnancy toxemia, intrauterine death, and premature delivery (98 cases). Although we have not recommended stilbestrol as a definitive measure in later pregnancy, 24 patients were so treated and are considered separetely. Nineteen cases that fell into none of these categories are omitted.

Seventy-eight per cent of the patients who were treated for bleeding between the sixth and twenty-first weeks carried to twenty-eight weeks, and 72 per cent had living and well babies. The highest spontaneous cure rate reported in the literature is 50 per cent. Eighty-three per cent of the patients who were given stilbestrol prophylactically against abortion carried to twenty-eight weeks, and 78 per cent had living and well babies. In the 127 cases who had two to five consecutive abortions prior to the one in which stilbestrol was given, the fetal salvage 77 per cent. In each group it was very significantly higher than the spontaneous cure rate as established by Malpas and Eastman. In the total 491 cases treated for abortion the incidence of abortion and of later pregnancy complications was higher when the dosage schedule was not followed than it was in the group as a whole.

In many of the patients treated prophylactically for late pregnancy complications it was impossible to evaluate the effect of stilbestrol therapy, and this part of our report must be considered preliminary. Twenty-two of them, however, had had three or more previous obstetric abnormalities, 27 had had two or more premature deliveries, 17 had known essential hypertension with bad obstetric histories, and nine had diabetes, six of these with bad obstetric histories. Considering the past obstetric histories of these patients, the course and outcome on stilbestrol gave good indication that the administration of this drug as a preventive measure may be expected to reduce the incidence of those complications of later pregnancy associated with a premature deficiency of the placental steroid hormones, estrogen and progesterone. There was even stronger evidence that the onset of thse complications would be postponed and the fetal mortality reduced. The results of the use of stilbestrol as a definitive measure in later pregnancy were not promising. “


Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.

The dictum ‘do no harm’ is relevant to the diethylstilboestrol saga of the 1950s. It was demonstrated physiologically that oestrogens and progesterone were necessary for pregnancy continuation. Thus, it was scientifically logical to postulate that diethylstilboestrol might prevent adverse pregnancy outcome. The sound physiological reasoning and impressive results from non-randomised studies resulted in enthusiastic uptake of the treatment before it was adequately tested in controlled clinical trials.

Dieckmann presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts the findings of Smith. During discussion time, Smith made a remark:

Our experience with the use of stilbestrol continues to be satisfactory … we are convinced that it has reduced the complications of late pregnancy and saved many babies“.

He was at this time an authority in the field and the objective evidence provided by Dieckman was largely ignored. Doctors continued prescribing DES to several million women over the next 20 years. There were no known side effects, and despite lack of objective evidence of effectiveness, both doctors and women were happy with the therapy.

In view of the brilliant concept of the alleged value of DES in complications of pregnancy, i.e., threatening and habitual abortion, the seemingly good results, the low price of the drug, and the reputation of O. Watkins Smith of the famous husband-and-wife team, Smith and Smith, DES was used during the next twenty years by thousands of obstetricians in this country and abroad.

Biological inferences in clinical practice without properly designed clinical trials may lead to more harm than good. All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Had the principle of ‘best evidence’ been followed, the embarrassment of diethylstilboestrol as a medical intervention, and the effects on offspring who were exposed to it before birth, would have been avoided.

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Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters

Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. trying to rest.


Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters, American journal of obstetrics and gynecology, NCBI PubMed PMID: 7315913, 1981 Dec.

Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago.

  • A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less.
  • A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known.
  • Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001).
  • The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005).
  • An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges.
  • However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child.
  • More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group.
  • The spectrum of diseases at operation in both groups was similar.
  • Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar.
  • For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
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