Tag: 1998

HIV, Women and Access to Clinical Trials: Tort Liability and Lessons from DES

Are we destined to repeat the DES experience with AZT use by pregnant women?

image of pregnant-woman-1950s
In the early 1950s, large controlled clinical trials of DES were conducted on pregnant women.

SELECTED Abstracts

The purpose of this Article is to examine the tort liability experience with DES, compare it to the recent and ongoing trials of AZT in pregnant women, and extract lessons that can be used to mitigate against the likelihood of tort liability and to encourage the inclusion of women of childbearing age in clinical trials.

… “Although many factors may have contributed to the underrepresentation of women in clinical studies, the potential exposure of drug trial sponsors to tort liability frequently is cited as one of the primary reasons for excluding women from trials. The true source of legal anxiety in the recruitment of female research subjects arises, however, not from a concern for women’s safety, but from the fear of potential injuries to their offspring. Observations and reports of birth defects in children of women who had been treated with thalidomide or bendectin brought liability concerns to the forefront.  When the courts held manufacturers liable for injuries caused to the offspring of women exposed to Diethylstilbestrol (DES), it became yet another reason for excluding pregnant women and women of childbearing age from clinical trials. “…

…”In the early 1950s, large controlled clinical trials of DES were conducted on pregnant women at the University of Chicago, which led to the cases of alleged research-related injury. Both cases were brought after the discovery of the carcinogenic potential of DES in offspring of women who had been given DES. In Mink v. University of Chicago,  three women, on behalf of themselves and approximately one thousand women who had participated in the trials, alleged injury, as well as increased risk of injury, to their daughters. In Wetherill v. University of Chicago, the plaintiffs were two daughters who had contracted cancer that they attributed to the DES that was administered to their mothers while they were pregnant. In both Mink and Wetherill the plaintiffs claimed that the women taking DES never knew that they were participating in an experiment or that they were even taking DES.

Read the Full Paper,
DUKE JOURNAL OF GENDER LAW & POLICY,
Volume 5:167, 1998.

In the hearing in Mink on whether the case brought by the mothers against the manufacturer and the institution conducting the research should be dismissed, the court held that the manufacturers had a duty to notify the women about the risks posed by DES at the time when the company became aware of them or should have become aware of them.63 The court permitted the battery allegations against the University of Chicago to stand, stating that nonemergency treatment performed without consent or knowledge raises a claim of battery. The case was settled with financial compensation to the plaintiffs and an agreement by the University of Chicago to provide medical services to women in the trials and to their offspring. In Wetherill, the court permitted the daughters to bring an action against the manufacturer and the University of Chicago. This case also settled, although the terms of the settlement were undisclosed.”…

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DES may suppress gene important to normal female reproductive tract development

Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis

de-regulation-of-Wnt7a
Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Image dev.biologists. Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis.

1998 NIH News Release

Exposure to a synthetic estrogen-like hormone, Diethylstilbestrol (DES), during a critical gestational period appears to suppress a gene that controls reproductive tract development in mice causing changes in the uterus and vagina that are similar to those found in women exposed to DES before birth.

Scientists at the Mt. Sinai School of Medicine, New York City, found that defects in the reproductive tracts of mice exposed in utero to DES are similar to those in mice missing the Wnt7a gene, one of a family of genes that regulate cell interactions in the development of the body and specific organs in living organisms from fruit flies to humans.

Between 1947 and 1971 over 1,000,000 American women were exposed to DES when their mothers took the drug during pregnancy to prevent miscarriage. Women exposed to DES during the first three months of in utero development often exhibit changes in the tissue and/or structure of their uterus, cervix, or vagina. These changes resulted in later infertility problems and also place them at risk of developing a rare form of cancer, clear cell adenocarcinoma of the vagina or cervix, at a young age.

“These animal studies should greatly enhance our understanding of the molecular effects of DES exposure, and possibly that of other estrogenic compounds, whether found in the environment or used for medical treatment,” explained Dr. Francis Bellino, Acting Associate Director of the Biology of Aging Program at the National Institute on Aging (NIA). Because the risk of uterine cancer increases with age, the NIA is interested in understanding the molecular response to estrogen and estrogen-like substances used to treat menopause or to prevent breast cancer and how they may contribute to this risk.

These results were reported in the November 1998 issue of the journal, Nature Genetics. The study, conducted by David A. Sassoon, Ph.D., Cary Miller, and Karl Degenhardt, at Mt. Sinai’s Brookdale Center for Developmental and Molecular Biology, was supported by the National Institute on Aging, the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of General Medical Sciences (NIGMS).

Initially, the scientists exposed pregnant mice to 200 micrograms/day of DES suspended in sesame oil or to the oil alone on days 15 to 18 of their pregnancy. Samples of reproductive tract tissue from the resulting DES-exposed female offspring were compared to similar samples from Wnt7a mutant mice and the control group. As compared with the control mice, both the DES mice and the Wnt7a group showed similar changes in the epithelium (outer layer of tissue), stroma (the underlying tissue), and the smooth muscle in their uteri. These similarities suggested that Wnt7a was involved in the DES response. In fact, they saw that DES exposure blocks the expression of Wnt7a in the uterus during a time period critical to uterine development in mice. Although expression of Wnt7a does return to normal 5 days after birth, irreversible changes in the organization of the reproductive tract have already occurred.

The scientists also observed structural changes in the reproductive tracts of DES-treated and Wnt7a mutant mice including poorly formed oviducts and vaginal fornices (the area in the vagina near the cervix), as well as hardened areas and abnormal glandular material in the vagina.

Sources and more information
  • DES (Diethylstilbestrol) May Suppress Gene Important To Normal Female Reproductive Tract Development, NATIONAL INSTITUTES OF HEALTH, October 26, 1998.
  • Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis, Nature Genetics 20, 228 – 230 (1998), doi:10.1038/3027, 01 November 1998.
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Increased Tumors in the Female Descendants of Mice exposed developmentally to DiEthylStilbestrol

An increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was seen in DES lineage mice, apparently transmitted to subsequent generations

Abstract

image of PubMed NCBI The Endocrine Society logo
Increased susceptibility to tumor formation is apparently transmitted to subsequent generation.

Prenatal exposure to Diethylstilbestrol (DES) has been associated with the subsequent development of reproductive tract abnormalities, including poor reproductive outcome and neoplasia, in experimental animals and humans. Experimental animal studies with chemical carcinogens have raised the possibility that adverse effects of DES may be transmitted to succeeding generations. To evaluate this possibility and to determine if there is a sensitive window of developmental exposure, outbred CD-1 mice were treated with DES during three stages of development: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 microg/kg maternal body wt), the time of major organogenesis; group II was treated once on day 18 of gestation (1000 microg/kg maternal body wt) just prior to birth; group III was treated on days 1-5 of neonatal life (0.002 microg/pup/day). Female mice (F1) in each group were raised to sexual maturity and bred to control males. As previously reported, fertility of the F1 DES-exposed females was decreased in all groups. Female offspring (DES lineage or F2) from these matings were raised to maturity and housed with control males for 20 weeks. The fertility of these DES lineage female mice was not affected by DES exposure of their ‘grandmothers’. DES lineage mice were killed at 17-19 and 22-24 months of age. An increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was seen in DES lineage mice but not in corresponding controls; the range and prevalence of tumors increased with age. Because uterine adenocarcinomas were seen in all three DES groups, all developmental exposure periods were considered susceptible to the adverse effects of DES. These data suggest that the reduced fertility observed in the DES F1 female mice was not transmitted to their descendants; however, increased susceptibility to tumor formation is apparently transmitted to subsequent generations.

Sources:
  • Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol, NCBI, PMID: 9771938, 1998 Sep;19(9):1655-63.
  • Full text – Carcinogenesis vol.19 no.9 pp.1655–1663, OxfordJournals, 19/9/1655.long 1998.
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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

TheEndocrineSociety logo
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 diethylstilbestrol, NCBI, 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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