This article is part of a series of stories related to cancer advocacy. You can read more articles in the series here.
After DES: Tracking the Harms of a Prenatal Drug Exposure
This ad was placed by a drug maker in a major medical journal in 1957. It urges doctors to prescribe DES to all pregnant women. (Image courtesy of DES Action)
Kari Christianson was 23 years old when she first heard of a drug called diethylstilbestrol, or DES. It was the spring of 1972, and Dr. Arthur Herbst was on television discussing concerns about the drug. For decades, doctors had prescribed DES to millions of healthy pregnant women, including Christianson’s mother, based on unsubstantiated claims that it reduced the complications of pregnancy.
Dr. Herbst had recently published a study suggesting that the drug, when used by pregnant women, might cause cancer in their offspring years later. He had identified a group of young women who had a rare vaginal cancer typically seen only in older women. With the help of some astute mothers, he had confirmed that these women had been exposed to DES in the womb (in utero).
Christianson knew that her mother, after three miscarriages, had taken a drug while pregnant. And as she watched Dr. Herbst’s television interview, she realized that the drug must have been DES, the first synthetic form of estrogen. She wondered if this could explain her history of severe menstrual problems or a polyp that doctors had removed from her cervix.
When doctors at the Mayo Clinic in Rochester, MN, evaluated her a week later, they did not find cancer. But Christianson was never able to become pregnant. “It was a sobering experience,” she said recently. “I was fortunate, though, to have support from people in the health care system who were experts and knew what I was going through.”
Estimating the Health Risks of Exposed Daughters
On a return trip to the Mayo Clinic, Christianson joined a clinical study to track the health of women who had been exposed to DES in the womb. The results of this and two other studies have now been summarized in a single report documenting the range of long-term health problems associated with in utero exposure to DES.
“The toll of health problems caused by giving this drug to healthy women is unprecedented,” said the study’s lead author, Dr. Robert Hoover of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “And the longer we follow these women, the more we seem to find.”
In the October 6 New England Journal of Medicine (NEJM), Dr. Hoover and his colleagues estimated the absolute risks of 12 health outcomes associated with prenatal exposure to DES, including certain cancers and reproductive problems such as infertility, ectopic pregnancies, and preterm births.
Exposed daughters, for instance, have twice the risk of infertility and five times the risk of having a preterm delivery than unexposed women. Exposed women also have a slightly increased risk of breast cancer after age 40. (See a complete list of risks here.)
In contrast to what is now known about the health risks of DES, pharmaceutical companies marketed the drug as a way to prevent complications of pregnancy, such as miscarriage, though there was little evidence to support such claims. In fact, by 1953, a clinical trial had demonstrated that DES was not effective for these purposes, though doctors continued to prescribe the drug for almost two more decades.
Then, in April of 1971, Dr. Herbst published his landmark study linking DES to clear cell adenocarcinoma of the vagina in exposed daughters. Later that year, the U.S. Food and Drug Administration advised physicians that DES should not be prescribed to pregnant women.
“DES is a cautionary tale about not using drugs during pregnancy unless they are absolutely necessary,” said Dr. Elizabeth Hatch of the Boston University School of Public Health, a co-author of the current study.
Enormous Health Care Costs
As the authors of a recent editorial on DES in NEJM wrote, “The enormous health care costs for this cohort and the disruptions of their lives cannot be fully measured; in some cases, these effects have been devastating.”
Susan Helmrich is one such case. Exposed to DES in the womb, Helmrich was 21 years old when doctors found two malignant tumors in her vagina. During a 10.5-hour operation, surgeons removed most of her reproductive organs and reconstructed her vagina using tissue from her colon.
She has since survived two other rare cancers. Whether these were related to DES, she will probably never know. “There’s not a doctor or epidemiologist who would say that these cancers were related to my exposure to DES because no studies have been able to really look at these questions adequately,” said Helmrich, who herself is an epidemiologist and works as a wellness coach in Berkeley, CA.
DES is a cautionary tale about not using drugs during pregnancy unless they are absolutely necessary.
—Dr. Elizabeth Hatch
With data on more than 6,500 women (4,600 exposed and 1,900 unexposed), the current study “represents the culmination of years of work,” noted Helmrich, a longtime advocate for DES research.
In the late 1980s, Dr. Hoover and his colleagues combined three existing studies, or cohorts. This provided sufficient statistical power “to draw some legitimate conclusions about DES exposures,” said Dr. Herbst, who spent most of his career at the University of Chicago and is a co-author.
The new findings will help distinguish actual risks associated with DES exposure from unrelated risks, Dr. Herbst noted. Many anecdotal reports of risks caused by DES exposures have appeared over the years.
One challenge in documenting the full public health impact has been the lack of information on the total number of women who were exposed to DES. This information could affect estimates of the global burden of DES, but it will never be known, according to Dr. Annekathryn Goodman of Harvard Medical School.
The current study “is important and as good as it gets in terms of describing the burden of disease for this population many years after the initial exposures,” said Dr. Goodman, who was not involved in the study but co-wrote the recent NEJM editorial on DES.
Margaret Braun, author of DES Stories and an advocate for DES research, added: “This study came about because of the courage of profoundly traumatized people who were willing to talk about their experiences. We also needed the extraordinary persistence and expertise of these investigators to make the information concrete.”
Kari Christianson (center), pictured in 1973 with her husband and grandmother, suffered from infertility and other health problems.
DES as a Research Catalyst
Among other findings, the research shows that exposed daughters have twice the risk of early menopause compared with unexposed women. When early menopause occurs in exposed women, Dr. Hatch explained, it is another indication that a woman’s reproductive tract was damaged as the result of a prenatal exposure to DES some 40 to 50 years earlier.
“This is really remarkable,” she continued. “It makes one wonder whether other chemicals [in drugs] or in the environment might also be crossing the placenta and causing health effects years later.”
DES is an endocrine disrupter, a chemical that alters hormonal balance. The drug has become a research catalyst for investigating potentially similar effects of other chemical and environmental exposures that affect the endocrine system. Identifying these exposures is a challenge, however, particularly if the harmful health effects of an exposure in utero are not seen for decades.
“The potentially harmful effects of chemicals, including endocrine-disrupting chemicals, won’t always be as detectable as DES was,” said co-author Dr. Linda Titus-Ernstoff of Dartmouth Medical School. The rare vaginal cancers, she noted, were “a red flag” that sparked further investigations of exposed women.
We have more to learn from this experience. We're not done living yet, and as long as there are opportunities to study us, we want the research to continue.
—Kari Christianson, DES research advocate
Dr. Hoover pointed out that, if the vaginal cancers had not occurred, the more common side effects such as infertility and miscarriage would never have been linked to DES because these conditions are common in the general population.
The lessons learned from DES underscore the need for systematic long-term surveillance of drugs after they reach the market, he added.
Dr. Hoover and his colleagues are also studying sons exposed to DES in utero. These men have a higher risk of malformations in the genital tract than unexposed men.
The researchers have also begun to collect information on the granddaughters of exposed mothers. This work was sparked by animal models and subsequent studies in humans suggesting that DES exposure may alter genes in a way that persists into a third generation.
As for the exposed daughters, whether they will experience more health problems as they age remains to be seen. But the researchers intend to continue following them.
“We have more to learn from this experience,” said Christianson, who has been an advocate for DES research. “We’re not done living yet, and as long as there are opportunities to study us, we want the research to continue.”
As an invited lecturer in epidemiology, Dr. Robert Hoover has been asking students at medical schools the same question for 40 years: Have you heard of DES? Throughout the 1970s and into the 1980s, every hand in the room went up. But in the last 15 years, not a single student has heard of DES. Awareness of this public health disaster has declined.
By the late 1980s, grant support for long-running cohort studies of women exposed to DES had run out. To keep the studies active into the future, Dr. Hoover and the leaders of these cohorts came together in 1992 to form the NCI-sponsored DES Follow-up Study. Advocates for DES research played a critical role in helping to secure funding for this work and serving as advisors on the study steering committee.
By combining the cohorts, the researchers immediately had enough statistical power to rapidly uncover new health risks associated with prenatal exposure to DES. With the long-term follow-up offered by the combined study, they were also able to identify previously unrecognized effects and solidify the risks for some already established outcomes. This body of work, which is summarized in a new study, sparked interest in new research on chemical exposures that go beyond DES.
“The new study is quite an accomplishment,” wrote DES research advocate Margaret Braun in an e-mail. “It shows the need for decades-long research because exposed populations may show injuries over time. It is also a tribute to persistence. The NCI investigators have worked meticulously to gather information on DES health outcomes.”