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Entering the shadow of DES: Health risks still loom

Diethylstilbestrol was prescribed to millions of pregnant women. Doctors and patients now confront its legacy -- increased cancer risk, fertility issues and other potential health problems.

By Victoria Stagg Elliott, AMNews staff. Aug. 4, 2003.

Anne Leavitt, MD, remembers when her mother told her she had been exposed in utero to diethylstilbestrol. It was in the early 1970s, soon after the news of the drug's ill effects on offspring hit the headlines. Dr. Leavitt, a Seattle developmental pediatrician, was upset by the news and her emerging understanding of risks she faced.

But knowing led her to take action. She became more aggressive about cancer screening. She also asked her gynecologist to automatically consider her pregnancies high risk.

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"I understood that it needed to be dealt with, and I went to see a doctor and got screening from then on," she said. "I knew that DES-exposed daughters had more pregnancy problems so when I got pregnant I was followed by a high-risk obstetrician group, ended up on some bed rest for all three pregnancies, but all three children were born at full term." At age 40, though, she was diagnosed with clear cell adenocarcinoma, the cancer most associated with DES exposure.

"I'm living proof of several things," said Dr. Leavitt, who works at the Child Development Clinic at the University of Washington. "Women over 40 are still at risk for the DES-related cancer, but it is also treatable. It's been eight years since my cancer, and I'm healthy."

Dr. Leavitt's experience proves that the problems of DES exposure didn't end when the Food and Drug Administration took the drug off the market in 1971. As a result, the Centers for Disease Control and Prevention launched DES Update, an informational campaign aimed at physicians and their patients. Its goal is to help people determine if they were exposed and manage the associated risks.

"The message for physicians is quite simple," said Dr. Leavitt. "Be aware of DES exposure in your patients and know that as this cohort ages, risks remain. It's still something you have to pay attention to."

"People thought it worked"

DES was widely prescribed in the United States between 1938 and 1971, and was used abroad for many years after. Marketed under more than 200 different names, it was primarily used to prevent miscarriage and other pregnancy-related problems. Experts now say it was likely prescribed even for women without a history of pregnancy-related problems because of the belief that it would make for healthier babies.

"People thought it worked," said Burton Krumholz, MD, director of a DES screening center in New York from 1979 to 1999. He is now a professor of obstetrics & gynecology and women's health at the Albert Einstein College of Medicine in New York City. "In fact, it may have prevented some miscarriages, but at what price?"

Studies published soon after the drug's discovery in the late 1930s suggested that it might cause cancer in mice. A pivotal 1953 study published in the American Journal of Obstetrics and Gynecology showed that it didn't even do what it was supposed to do. But it was a 1971 report in the New England Journal of Medicine linking DES exposure in utero to clear cell adenocarcinoma in adolescent girls that ended the drug's long run. The FDA advised doctors to stop prescribing it. Doctors reviewed their records and looked for cases of this rare vaginal cancer in young female patients. This incident, on the heels of the thalidomide experience, ended the notion that it was possible to prescribe anything and everything to pregnant women without risking harm to the fetus.

"DES is a very important historical lesson because it was prescribed even after it was shown not to be effective because people said, 'We can prescribe it, so let's do it,' " said Janet Pregler, MD, who helped develop the clinician materials for DES Update and is director of the Iris Cantor-UCLA Women's Health Center in Los Angeles.

But only one in 1,000 of DES-exposed daughters actually developed the disease. And for a while, it appeared that if a women did not get this cancer by age 30, she was in the clear. Sons did not appear to suffer any ill effects.

"DES is so far in the past that many physicians aren't thinking about it," said Nancy Church, MD, an ob-gyn at the Wellness Connection in Chicago. "It's really fallen by the wayside, but it really needs to be a part of our consciousness because that generation -- they're still our patients."

The need for this consciousness is supported by a growing body of evidence indicating the impact of DES may be more long lasting than previously thought. Dr. Leavitt had her cancer after the cut-off age and DES-daughter registries are proving the vaginal cancer can pop up at any time.

"When a woman is 30 years old, you can't say she's past the zone of being at risk," said Dana Beyer, MD, a retired ophthalmic surgeon based in Chevy Chase, Md., who was DES-exposed in utero. "Women haven't lived to 50 or 60 yet having been exposed to this drug. This is all new territory."

There also is evidence of a higher rate of breast cancer among women who took the drug, although it is not conclusively linked to DES exposure. Both Dr. Beyer's and Dr. Leavitt's mothers had breast cancer.

Meanwhile, the daughters of DES moms, even if cancer-free, may have problems conceiving and carrying a fetus to term. They might also be completely infertile. Sons have a higher rate of genital abnormalities and non-cancerous growths on the testes and may be at higher risk for prostate and testicular cancer. Questions also persist about possible links between DES exposure and gender issues. Dr. Beyer, for example, was born intersex.

Challenge of identification

Awareness is critical to managing these potential aspects of the DES legacy. The CDC's campaign targets a wide audience. It is not just for those who know they were exposed. It's also for the many who don't, and can't take advantage of the decades of research on the subject. According to the CDC, as many as 50% of those exposed may not be aware of it -- meaning their doctors might not know to take extra precautions with their pregnancies or to be a little more aggressive about recommending various screening services. Dr. Leavitt, for example, credits her three successful deliveries to the fact that all were automatically considered high risk.

"Part of the reason I had good pregnancies was I knew of my exposure and got the appropriate medical care," said Dr. Leavitt.

Dr. Leavitt's mother told her, but many mothers might not have known what they were taking, may not realize that the information is important to share with their children or may be hesitant to share the information, particularly if their children are not currently suffering any ill effects.

"My mother has borne the guilt and shame of having done what her doctor told her to do," said Dr. Beyer. "It's been a hard road for her."

Mothers also may not be available because they have died or their children were put up for adoption. Medical records are probably long gone. And since DES does not stay in the body, there is no test to determine exposure.

The CDC hopes to provide physicians with the tools to identify the distinct malformations that mark DES daughters or to ask the questions that might indicate exposure. There are no specific markers for sons.

"In many cases, you're just never going to find out for sure," said Raymond H. Kaufman, MD, professor of ob-gyn and pathology at Baylor College of Medicine in Houston, who researches DES issues. "The key is to get a good history. If you get a history that the mother had recurrent miscarriages, had problem births ... then there should be some suspicion."

Figuring out who was DES exposed is important to public health officials. There is concern that a DES generation is approaching an era of highest cancer risk. Moms who took the drug are between 50 and 90 years old. Their children are between ages 30 and 60. The CDC suspects that a statistical bubble of DES-related cancers is heading our way.

"The clear cell carcinomas that led to the whole discovery of the DES problem in the first place was originally a post-menopausal condition," said Dr. Krumholz. "Is there going to be a second peak? Nobody knows."

Experts concede that in many cases the knowledge of DES exposure may not necessarily change how a physician treats a patient. A DES mom should be advised to get annual mammograms and regular breast self-exams in order to deal with the increased breast cancer risk, but that's what should happen as the woman ages anyway.

"It's another risk factor to follow just like having an early period or late childbearing. With women having a one out of eight chance of breast cancer, we're worrying about everybody," said JoAnn V. Pinkerton, MD, director of the Women's Place Midlife Health Center at the University of Virginia in Charlottesville.

Still, the knowledge is important and may make patients more compliant with screening recommendations.

There also are many unanswered questions that may only be answered as this population ages and will only be settled if large groups of people are available for study. The question of DES exposure and prostate or endometrial cancer risk won't be answered for years because the DES children are just entering the age range when they are most at risk for these cancers.

There is also the nagging question of whether the impact of DES may trickle down to the third generation. Early studies in the grandchildren of DES moms have not shown any significant abnormalities or increased cancer risk, although mouse studies have, and this group is not really old enough for all of the impact to be apparent.

"For myself, I never really worried a whole lot. I knew of my exposure and stayed on top of what the recommendations were for screening and got screening," said Dr. Leavitt. "I will do the same thing for my daughter."

And ultimately, while the possibility of exposure to the drug should be on physicians' radar screens and patients' medical history forms, the situation begs for increased vigilance rather than living in fear.

"I tell my patients not to get all tied up in knots," said Dr. Kaufman. "Get checked on a regular basis and don't drive yourself nuts. Be vigilant. Be aware. And go about your life."

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