The Diethylstilbestrol Legacy

A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016 Report Abstract

Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.

In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy,
Pediatrics, November 2016, VOLUME 138 / ISSUE Supplement 1, Supplement_1/S42.abstract, November 2016.

Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for “routine prophylaxis in ALL pregnancies” and administered to women with otherwise healthy pregnancies.

By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. Several months later, the Food and Drug Administration issued a bulletin indicating that the use of DES was contraindicated in pregnancy. By then, however, millions of women, along with their sons and daughters, had been needlessly exposed.

In addition to the increased risk of CCA of the vagina and cervix, daughters exposed in utero to DES also suffered from an increased occurrence of reproductive tract abnormalities, infertility, and pregnancy complications; earlier menopause; twice the incidence of cervical dysplasia; and a possible elevated risk of breast cancer and continued increased risk of CCA in middle age. Recent preliminary data indicate the possibility of an increased risk of cardiovascular disease and diabetes in the prenatally exposed women. Mothers administered DES during pregnancy have an increased risk of breast cancer incidence and mortality. Sons who were exposed in utero have an increased risk of genitourinary defects and a possible increase in testicular cancer. The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation. Preliminary findings showed increased menstrual irregularity and a possible excess of ovarian cancer in very young women.

The link between prenatal DES exposure and subsequent adverse health outcomes, most of which are fairly common, may easily have escaped detection. The investigation of DES outcomes was initiated solely because a rare tumor occurred in a cluster of cases at an unusually young age, decades before the usual age of presentation. This historical example underscores the necessity of carefully weighing the risks and benefits of interventions in pregnancy and long-term monitoring of the health outcomes in mothers and offspring.

Whether and/or when to use pharmaceutical intervention in pregnancy continues to pose special challenges. At the present time, progesterone used to prevent pregnancy loss appears to be effective, although more data are needed. Thus far, there is little evidence of short-term adverse consequences for the offspring, but continued monitoring of mothers and offspring is warranted to identify any short- or long-term adverse effects. The use of progestins for luteal phase and early pregnancy support after in vitro fertilization is routine, and there are even fewer data on potential short- and long-term risks of this therapy. The tragic legacy of DES supports a cautious approach to the use of pregnancy interventions and assiduous appraisal of their effects.

Rebecca Troisi, Elizabeth E. Hatch, Linda Titus,
Reviewed by Dr Robert Hoover,

Click to download the full paper.

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Over 50 years later, DES’ adverse effects continue

Women Exposed to DiEthylStilbestrol In Utero Face Ongoing Risks for Adverse Health Outcomes

October 8th, 2011, NEJM Journal Watch talked with two authors of the reportAdverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol“.

Press Play > to listen to the recording.

Sources and more information

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Prenatal diethylstilbestrol exposure and risk of obesity in adult women

DES exposure may be associated with an increase in adult obesity

image of obese-women
This 2015 study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.
Women in Black image by Sandra Cohen-Rose and Colin Rose.

2015 Study Abstract

Diethylstilbestrol DES is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances.

Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height.

The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22],

  • and RRs were 1.23 (CI: 1.07, 1.42)
  • and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure.
  • DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)].

This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

Sources
  • Prenatal diethylstilbestrol exposure and risk of obesity in adult women, NCBI PMID: 25697972, J Dev Orig Health Dis. 2015 Jun;6(3):201-7. doi: 10.1017/S2040174415000033. Epub 2015 Feb 20.
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DES Researchers Doctor Robert N. Hoover and Scientist Rebecca Troisi

The DCEG’s coprincipal investigators of the 1992 DES Follow-Up cohort study

Dr-Robert-Hoover
Dr. Robert Hoover and Rebecca Troisi, Sc.D., a staff scientist in EBP, have been DCEG’s coprincipal investigators of the 1992 DES Follow-Up cohort study.

Recognizing the need to continue observing DES-exposed mothers and their offspring, Dr. Robert N. Hoover reached out to several principal investigators at the various study centers and suggested reviving the cohorts and pooling the data to better answer the many questions that remained.

Dr. Hoover and Rebecca Troisi, Sc.D., a staff scientist in EBP, have been DCEG’s coprincipal investigators of the 1992 DES Follow-Up Study cohort study.

  • see the DES Follow-up Study Published Papers list.
  • watch Dr. Robert Hoover’s video interview.
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Incidence of squamous neoplasia of the cervix and vagina in DES-exposed daughters

Association between in utero DES exposure and high-grade squamous neoplasia

2000 Study Abstract

image of PubMed NCBI The Endocrine Society logo
The 2000 study findings support an association between in utero DES exposure and high-grade squamous neoplasia

PURPOSE:
Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.

METHODS:
A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.

RESULTS:
The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).

CONCLUSIONS:
The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out..

Sources

  • Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters, NCBI, PMID: 11018391, Ann Epidemiol. 2000 Oct 1;10(7):467. Full text link.
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Long-Term Cancer Risk in Women given DiEthylStilbestrol (DES) during Pregnancy

27% increased breast cancer risk in DES-exposed women

2001 Study Abstract

PubMed logo
This 2001 study found a 27% increased breast cancer risk in DES-exposed women.

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in DES-exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.

Sources

  • Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy,NCBI, PMID: 11139327, 2001 Jan 5;84(1):126-33. and PMC2363605 2001. doi: 10.1054/bjoc.2000.1521. Full text PDF link.
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Gender-related Behavior in Women exposed prenatally to DiEthylStilbestrol

The physical and psychological impact of the problems associated with DES exposure are well documented

1993 Study Abstract

Gender-related behavior in women exposed prenatally to diethylstilbestrol
The physical and psychological impact of the problems associated with exposure to DES are well documented

Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones. Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES). This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented. If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women. In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior.

Sources: Gender-related Behavior in Women exposed prenatally to DiEthylStilbestrol
Dr R Hoover, NCBI, Aug 1993 – full study PDF

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Mortality in Women given DiEthylStilbestrol during Pregnancy

Association with breast cancer mortality more evident in trial participants who received high DES doses

DES Follow-up Study Summary

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In this 2006 study, the association with breast cancer mortality was more evident in trial participants, who received high DES doses.

This analysis examined cause of death in women who were given Diethylstilbestrol (DES) during pregnancy. The mothers cohort has not been actively followed since 1994, so survival was assessed through a search of the National Death Index. The results suggested a modest increase in death from breast cancer in the DES exposed mothers, compared to the unexposed. We did not, however, see an excess of overall mortality in the DES-exposed mothers, or an excess of death from any specific cause other than breast cancer. In particular, DES was not associated with an increased mortality from gynecologic cancers.

2006 Study Abstract

Abstract:
We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort,

  • the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths.
  • The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths.
  • The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment.
  • The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15).
  • Diethylstilbestrol did not increase mortality from gynaecologic cancers.
  • In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Sources

  • Mortality in women given diethylstilbestrol during pregnancy,NCBI, PMID: 16786044, 2006 Jul 3;95(1):107-11. Epub 2006 Jun 20. Full text Br J Cancer. Jul 3, 2006; 95(1): 107–111. PMCID: PMC2360488 link.
  • NCI, DES Follow-up Study Published Papers.
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Cancer Risk in Women exposed to DiEthylStilbestrol in Utero

DES-exposed daughters need continued surveillance to determine whether any increases in cancer risk occur during the menopausal years

1998 Study Abstract

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DES-exposed daughters showed no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in the 1998 study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.

CONTEXT:
The association between in utero exposure to diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the vagina and cervix is well known, yet there has been no systematic study of DES-exposed daughters to determine whether they have an increased risk of other cancers. As many as 3 million women in the United States may have been exposed to DES in utero.

OBJECTIVE:
To determine whether women exposed to DES in utero have a higher risk of cancer after an average of 16 years of follow-up.

DESIGN:
A cohort study with mailed questionnaires and medical record review of reported cancer outcomes.

PARTICIPANTS:
A cohort of 4536 DES-exposed daughters (of whom 81% responded) and 1544 unexposed daughters (of whom 79% responded) who were first identified in the mid-1970s.

MAIN OUTCOME MEASURES:
Cancer incidence in DES-exposed daughters compared with population-based rates and compared with cancer incidence in unexposed daughters.

RESULTS:
To date, DES-exposed daughters have not experienced an increased risk for all cancers (rate ratio, 0.96; 95% confidence interval [CI], 0.58-1.56) or for individual cancer sites, except for CCA. Three cases of vaginal CCA occurred among the exposed daughters, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1-126.2) in comparison with population-based incidence rates. The rate ratio for breast cancer was 1.18 (95% CI, 0.56-2.49); adjustment for known risk factors did not alter this result.

CONCLUSIONS:
Thus far, DES-exposed daughters show no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in our study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.

Sources

  • Cancer risk in women prenatally exposed to diethylstilbestrolNCBI, PMID: 9718055, 1998 Aug 19;280(7):630-4.
  • Full text JAMA. 1998;280(7):630-634. doi:10.1001/jama.280.7.630. link.
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Offspring of Women exposed in Utero to DiEthylStilbestrol: malignant pathology in Third Generation

Increased risk of ovarian cancer in DES Grand Daughters

DES Follow-up Study Summary

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Increased risk of ovarian cancer in DES Grand Daughters.

Studies have shown a slightly increased risk of breast cancer in women who were given Diethylstilbestrol (DES) while they were pregnant. Their daughters, who were exposed to DES prenatally (before they were born), have an elevated risk of reproductive tract conditions, including a rare vaginal cancer. A question now being studied is whether DES health effects can be passed from the prenatally exposed women to their offspring (intergenerational transmission).

Studies in mice suggest that intergenerational transmission of DES health effects may be possible. Recent evidence indicates that prenatal exposure to DES may cause changes in the behavior of genes that influence hormones and the development of the female reproductive tract. These changes in gene behavior may be passed on to the next generation. Evidence for intergenerational transmission comes from mouse studies showing a higher number of reproductive tract tumors in the daughters of prenatally exposed female mice. We used the DES Follow-up Study data to assess whether cancer was more common in the offspring of women who were prenatally exposed to DES. Cancers affecting these offspring (the third generation) were identified using two approaches. First, we asked women participating in the DES Follow-up Study to report cancers diagnosed in their 8,216 third generation sons and daughters. Second, we asked 793 third generation daughters participating in the Third Generation Study to tell us about their cancers. We also asked the third generation daughters to tell us about their reproductive tract and breast biopsies. Next we confirmed the reported biopsies and cancers by checking the medical records of these third generation daughters.

Our results did not show an overall increase of cancer in the sons or in the daughters of prenatally DES-exposed women. However, based on only three cases, the number of ovarian cancers was higher than expected in the daughters of women exposed prenatally to DES. Because of the small number of cases, this result must be considered preliminary. The association may be a chance finding or may be due to the way in which the data were reported or collected. We did not find an association between DES and benign breast disease or reproductive tract conditions, but most of the women are too young for a meaningful assessment of these outcomes. Further follow-up is needed to assess whether prenatal DES exposure can affect the third generation in humans.

2008 Study Abstract

BACKGROUND:
Animal studies suggest that prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes epigenetic changes that may be transmitted to the next generation. Specifically, these studies show an elevated incidence of reproductive tumors in the female offspring of prenatally-exposed mice.

METHODS:
We assessed cancer and benign pathology diagnoses occurring in the offspring of women whose prenatal exposure to DES (or lack of exposure) was verified by medical record. Our data arose from 2 sources: the mothers’ reports of cancers occurring in 8216 sons and daughters, and pathology-confirmed cancers and benign diagnoses self-reported by a subset of 793 daughters.

RESULTS:
Although statistical power is limited, our data are consistent with no overall increase of cancer in the sons or daughters of women exposed in utero to DES. Based on pathology-confirmed diagnoses reported by the daughters, we saw no association between DES and risk of benign breast disease or reproductive tract conditions. Based on 3 cases, the incidence of ovarian cancer was higher than expected in the daughters of women exposed prenatally to DES.

CONCLUSIONS:
Our data do not support an overall increase of cancer risk in the sons or daughters of women exposed prenatally to DES, but the number of ovarian cancer cases was greater than expected. While preliminary, this finding supports continued monitoring of these daughters.

Sources

  • Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation,NCBI, PMID: 18223485, 2008 Mar;19(2):251-7. doi: 10.1097/EDE.0b013e318163152a.
  • NCI, DES Follow-up Study Published Papers.
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