Consequences of DiEthylStilbestrol during Pregnancy ; 50 Years later still a Significant Problem

From animal experiments it becomes clear that DES administration to pregnant mice results in an increased incidence of genital tumours not only in the second generation but also in the third

Abstract

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It becomes clear that DES administration during pregnancy resulted in an increased incidence of genital tumours not only in the second generation but also in the third…

Since the 1940s, diethylstilboestrol (DES) has been administered to about three million pregnant women in the United States and in the Netherlands, between 1947 and 1975, to about 220,000.
The most important consequences described are: for DES mothers an increased risk of mammary carcinomas and for DES daughters a 1 in 1000 chance of clear cell adenocarcinoma (CCAC) as well as an increased risk of (pre)malignant abnormalities of the stratified epithelium in the vagina and cervix.
In addition to this, DES daughters frequently have developmental disorders of the cervix and corpus uteri. In connection with this fertilisation disorders have been described as well as unfavourable outcomes of pregnancy: more ectopic pregnancies, abortion and premature birth. DES sons exhibit an increased frequency of several benign abnormalities of the genitalia. The DES problem continues to be an important issue. The entire cohort of DES mothers is in the age group with a high risk of mammary carcinoma. The youngest DES daughters will be of childbearing age for at least another 15 years; the risk of ectopic pregnancies and pre-term labour is increased. The oldest DES daughters are now reaching postmenopausal age. The incidence of CCAC of the vagina and cervix in the population is bimodal, with a second peak at older age. It is still unknown if at this age DES daughters will have an increased incidence of these malignancies.

From animal experiments it becomes clear that DES administration to pregnant mice results in an increased incidence of genital tumours not only in the second generation but also in the third. This has yet to be investigated in humans and deserves special attention.

The legally imposed destruction of patient files after a period of ten years is a serious threat to patient care and scientific investigation, notably in obstetrics and child medicine.

Sources:
  • Consequences of diethylstilbestrol during pregnancy; 50 years later still a significant problemNCBI, PMID: 11530703, Ned Tijdschr Geneeskd. 2001 Apr 7;145(14):675-80.
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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

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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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Cancer Risk in Men exposed in Utero to DiEthylStilbestrol

Testicular cancer may be elevated among DES-exposed men

2001 Study Abstract

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Testicular cancer may be elevated among DES-exposed men

BACKGROUND:
An association between prenatal Diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up.

METHODS:
A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided.

RESULTS:
Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation.

CONCLUSIONS:
To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

Sources

  • Cancer risk in men exposed in utero to diethylstilbestrol,NCBI, PMID: 11287449, 2001 Apr 4;93(7):545-51. Full text: Oxford Journals Medicine & Health International Journal of Epidemiology link.
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Infertility among Women exposed prenatally to DiEthylStilbestrol

DES-exposed women have a higher risk of infertility

2001 Study Abstract

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DES-exposed women have a higher risk of infertility

Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy. In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility. A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5), and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1). Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively. The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.

Sadly for many DES daughters having their own children is not possible! Many of us who have experienced miscarriages, want to have kids but are struggling or unable to…

Sources

  • Infertility among women exposed prenatally to diethylstilbestrol,NCBI, PMID: 11495854, 2001 Aug 15;154(4):316-21. Full text: Oxford Journals Medicine & Health International Journal of Epidemiology link.
  • NCI, DES Follow-up Study Published Papers.
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Incidence of Squamous Neoplasia of the Cervix and Vagina in Women exposed prenatally to DES

The 2001 stuy findings support an association between in-utero DES exposure and high-grade squamous neoplasia.

DES Follow-up Study Summary

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The 2001 stuy findings support an association between in-utero DES exposure and high-grade squamous neoplasia.

Women exposed to Diethylstilbestrol (DES) before birth (in the womb), known as DES Daughters, are at increased risk for clear cell adenocarcinoma of the vagina and cervix, but the effect of in utero DES exposure on later development of squamous neoplasia in the cervix and vagina is uncertain. This combined follow-up study of 3,899 DES Daughters (median age 38) and 1,374 unexposed daughters (median age 39) was followed 1982-1995. Subjects were drawn from three previously studied cohorts (DESAD, Dieckmann, and Horne). The purpose was to examine the long-term risk of developing high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract in DES Daughters compared with unexposed daughters.

The study found a small but significant increase in HSIL among DES Daughters in all age groups, including those over age 40. A total of 111 pathology-confirmed HSIL cases occurred, including five of the vagina, one of the vulva and two cases of invasive cervical cancer. The overall relative risk was 2.1 among DES-exposed versus unexposed. The relative risk among those whose mothers were prescribed DES within 7 weeks of the last menstrual period was 2.8 compared with 1.35 among women exposed for the first time at 15 weeks or later. Women with documented high-grade neoplasia before 1982 were excluded because prior treatment of the cervix may lower the subsequent finding of intraepithelial neoplasia. Researchers could not rule out that more frequent and intensive screening among DES-exposed women played a role in these findings.

Neoplasia is abnormal and uncontrolled cell growth; a neoplasm is new growth of benign or malignant tissue. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. These flat cells look like fish scales under a microscope. Squamous intraepithelial lesion (SIL) is a general term for the abnormal growth of squamous cells on the surface of the cervix. The changes in the cells are described as low grade or high grade, depending on how much of the cervix is affected and how abnormal the cells appear. Cervical intraepithelial neoplasia (CIN) is a general term for the growth of abnormal cells on the surface of the cervix. Numbers from 1 to 3 may be used to describe how much of the cervix contains abnormal cells. High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition in which the cells of the uterine cervix are moderately or severely abnormal. In this study, grades 2 and 3 were considered high.

2001 Study Abstract

OBJECTIVES:
Women exposed prenatally to Diethylstilbestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix, but the effect on the incidence of squamous neoplasia is uncertain. The purpose of the current study was to evaluate the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to DES.

METHODS:
A cohort comprising 3,899 DES-exposed and 1,374 unexposed daughters was followed for 13 years (1982 1995) for pathology-confirmed diagnoses of high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (95% CI), adjusting for age, calendar year, and other covariates.

RESULTS:
The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.1 (1.2-3.8). Adjustment for screening history estimated by the number of years since the last Pap smear had little effect. Risk estimates were higher with earlier intrauterine exposure; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.8 (1.4-5.5). Only two cases of invasive squamous cervical cancer occurred in total, precluding separate analysis.

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 women exposed prenatally to diethylstilbestrol (United States),NCBI, PMID: 11714112, 2001 Nov;12(9):837-45.
  • NCI, DES Follow-up Study Published Papers.
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