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DES concerns: the next generation

A drug given to pregnant women years ago has had consequences for them, their children — and possibly their grandchildren

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By Deborah Kotz
Globe Staff / April 18, 2011

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For nearly 30 years, pregnant women who’d had repeated miscarriages jumped at the chance to take a pill that promised a “96 percent chance’’ of delivering a baby with “no gastric or other side effects,’’ as one advertisement from the 1950s read. Then came a landmark paper from the New England Journal of Medicine — published 40 years ago this month — which linked the drug, called diethylstilbestrol or DES, to a very rare form of vaginal cancer in eight young Boston women ages 15 to 22 years old. They all had mothers who took the drug when they were pregnant with them.

Arthur Herbst, lead author of the article, remembers preparing himself for the media onslaught just before the paper was published. He was worried about panicking the several million women who had given birth to daughters while on DES. “We felt the possibility of any young lady getting this cancer was a very remote risk,’’ says Herbst, “and we wanted to convey that to the media.’’

But the floodgates opened, and DES came crashing down. Congressional hearings conducted by Senator Ted Kennedy, among others, led to a US Food and Drug Administration warning against the use of DES in pregnant women and its eventual withdrawal from the US market. Further research found infertility problems in nearly one-third of the estimated 2.4 million DES daughters as well as a possible increased risk of breast cancer in the 4.8 million DES mothers. (The 2.4 million DES sons don’t face these risks but do have a greater likelihood of developing non-cancerous cysts on their testicles.)

While attention to DES has waned — along with the initial spike in vaginal cancers that were primarily seen in those under 30 — many DES daughters have found their fears persist: Do they face an increased risk of breast cancer, as some studies now suggest? Will they face another increased risk of vaginal cancer in their 60s when this rare cancer normally strikes? What risks will their children face?

“It’s like living under a medical guillotine,’’ says DES daughter Caitlin McCarthy. “When is that blade going to hit me?’’ The Worcester high school English teacher found out only six years ago that she was a DES daughter after developing precancerous cells in her cervix. Before McCarthy was born in 1970, her mother was unknowingly prescribed prenatal vitamins that contained DES. The gynecologist Caitlin saw was able to quickly identify DES exposure based on the shape of her cervix, but she worries that there are thousands of other women like her who have no idea that they were exposed.

And now there are hints that DES could be affecting a third generation, with a study published in 2009 showing a possible increased risk of birth defects in the babies of DES daughters, and a 2008 finding suggesting a slight uptick in ovarian cancers in DES granddaughters.

“We can’t draw firm conclusions from either study,’’ says Dr. Linda Titus, a professor of pediatrics at Dartmouth Medical School who led both studies. “But the cancer study is worrisome since it replicates the increase in reproductive cancers that we’ve seen in third-generation mice.’’

Since the initial New England Journal of Medicine finding, Herbst and other researchers have ascertained that DES daughters have about a 1 in 1,000 risk of developing the rare cancer called vaginal adenocarcinoma. That’s very small, but it’s still 40 times greater than the average woman’s risk, points out Titus.

Far more common are the infertility problems, due to structural abnormalities in the reproductive tract caused by DES delaying the maturation of these organs during fetal development. “I have a deformed uterus, which has led to ectopic pregnancies and a miscarriage of twins,’’ says Andrea Goldstein, a Boston nurse whose mother took DES when she was pregnant with her in 1953. In 1985, she won a settlement from Eli Lilly & Company, which had been a maker of DES.

About 28 percent of DES daughters experience infertility, compared with 16 percent of women not exposed to DES, according to Boston University epidemiologist Julie Palmer, who has been studying 4,800 DES daughters for more than 15 years in a collaborative research project sponsored by the National Cancer Institute. DES daughters who do get pregnant are more likely to miscarry or deliver prematurely. Palmer’s research also found that DES exposure modestly increased a woman’s breast cancer risk — on par with having a mother or sister with breast cancer — though she emphasizes that further research is needed to determine whether there’s a true association.

In this day and age, when pregnant women are told to fear everything from fish to plastic containers, it may be tough to fathom how a drug could be so cavalierly given during pregnancy. “Back in the 1950s, the belief in preventing miscarriages with high-dose estrogen was very popular,’’ says Dr. Anne Kathryn Goodman, assistant director of gynecologic oncology at Massachusetts General Hospital.

The scientists who developed DES, a form of estrogen, back in 1938 never dreamed it would cause the kinds of trouble it did. “I remember being very excited by DES,’’ recalls P. Harry Jellinck, a retired biochemist who conducted DES studies nearly 60 years ago in the lab of the compound’s inventor, Charles Dodds. It was “cheap and easy to produce, and could be taken by mouth, rather than injected.’’ It had been used with some success to treat prostate cancer in men as well as advanced breast cancer in women.

Dodds came to regret his creation, Jellinck says, after the drug’s risks became known, soon before he passed away in 1973. “He’d worried that it was going to turn out to be another thalidomide,’’ the morning-sickness drug used by pregnant women in Britain and other countries — though never in the United States — until it was linked to severe birth defects in 1961.

While the Food and Drug Administration’s refusal to approve thalidomide has been deemed one of its greatest success stories, its 1947 approval of DES for use in pregnancy could be deemed one of its greatest failures. Some experts wonder why the FDA didn’t reverse course in 1953, when a University of Chicago study found that DES was no more effective than a placebo at preventing miscarriages or improving pregnancy outcomes. Or why doctors didn’t stop prescribing it. “Perhaps they thought it gave women great hope,’’ Palmer says.

For the past year, McCarthy has worked with senators John Kerry and Scott Brown to get the FDA to issue an apology. In a February letter addressed to the senators, the FDA declined to apologize but did acknowledge that the DES debacle was a “tragedy,’’ citing the litany of health problems caused by the drug.

But, McCarthy emphasizes, the two hours a day she spends advocating for DES awareness — she also wrote a screenplay about its history — is for the human health issue, not a political one. Since her Tufts Medical Center gynecologist recently left Boston, she’s had a tough time finding a new one who is well versed in DES daughters’ special health needs: what to look for in a pelvic exam; the need for annual Pap smears instead of one every three or four years if previous screens are negative; the small increase in breast cancer risk and whether it warrants additional screening.

Goldstein, who had used the same gynecologist as McCarthy, says she’s also in search of a new doctor. “I’ve been looking for two years and still can’t find anyone who’s DES-knowledgeable,’’ she says. “My biggest concern is that there will be no doctors left to adequately take care of us or the next generation. No one’s paying attention anymore.’’

Deborah Kotz can be reached at dkotz@globe.com.

Correction: Because of reporting errors, the article titled "Charting Effects of DES on Generations" misidentified the specialty and affiliation of the doctor who treated Caitlin McCarthy. He was a gynecologist at Tufts Medical Center. It also misidentified the school system in which McCarthy teaches. She is a high school English teacher in Worcester.

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