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A drug that millions of pregnant women took decades ago to prevent miscarriage and complications has put their daughters at higher risk for breast cancer and other health problems that are showing up now, a new federal study finds.

Many of these daughters, now over 40, may not even know of their risk if their mothers never realized or told them they had used the drug, a synthetic estrogen called DES.

The new study suggests that infertility is twice as common and that breast cancer risk is nearly doubled in these daughters.

Debbie Wingard is one of them. The 59-year-old San Diego woman adopted two boys after being unable to conceive and has had breast cancer twice — when she was 39 and 49.

"There's no knowing what's going to happen as we age. There's always the fear there's going to be another cancer or another outcome," she said. "I don't think I'll ever get to the point where I feel it's behind me."

The sons of DES users also face health risks — testicular problems and cysts — but these are less well studied and don't seem to be as common. Even less is known about the third generation — "DES grandchildren." Some research suggests these girls start menstruating late and have irregular periods, possible signs of fertility issues down the road.

In the United States alone, more than 2 million women and 2 million men are thought to have been exposed to DES while in the womb and may now want to talk with their doctors about when they should be screened for health problems.

"We don't want to cause a panic of everyone rushing out thinking they're going to get cervical or breast cancer. They just need to have that conversation with their physician," said Sharmila Makhija, women's health chief at the University of Louisville.

The average woman has about a 1 in 50 chance of developing breast cancer by age 55; for DES daughters it's 1 in 25, the study found. Risks for other health problems vary.

DES, or diethylstilbestrol, was widely used in the United States, Europe and elsewhere from the 1940s through the 1960s to prevent miscarriage, premature birth, bleeding and other problems. Many companies made and sold it as pills, creams and other forms.

Studies later showed it didn't work. The government told doctors to stop using it in pregnancy in 1971, after DES daughters in their late teens and 20s were found to be at higher risk of a rare form of vaginal cancer. Further research has tied DES to infertility and various pregnancy problems.

"They've been identified one at a time. Nobody's been able to get the whole picture," said Robert Hoover, a researcher at the National Cancer Institute. The new study, which he led, "takes the woman and looks at everything that can happen as a result of this drug," and adds evidence for some previously suspected risks like breast cancer, he said.

Results are in Thursday's New England Journal of Medicine.

The study started in 1992 and involved about 4,600 DES daughters and a comparison group of 1,900 similar women whose mothers had not used DES. Their health was tracked over time through surveys and medical records. Their average age at the last followup was 48.

In the study, researchers found these rates of health problems in DES daughters compared to non-exposed women:

—Breast cancer, 3.9 percent versus 2.2 percent.

—Cervical pre-cancer, 6.9 percent versus 3.4 percent.

—Infertility, 33.3 percent versus 15.5 percent.

—Early menopause, 5.1 percent versus 1.7 percent

These complications were seen among women who were able to become pregnant:

—Preterm delivery, 53.3 percent versus 17.8 percent.

—Miscarriage, 50.3 percent versus 38.6 percent.

—Tubal pregnancy, 14.6 percent versus 2.9 percent.

—Stillbirth, 8.9 percent versus 2.6 percent.

—Preeclampsia (high blood pressure during pregnancy), 26.4 percent versus 13.7 percent.

The claim of added breast cancer risk is being tested by 53 women in a lawsuit against DES makers under way now in Boston. One of them is Jackie White, 48, who lives in Centerburg, Ohio, north of Columbus. She said she had a misshaped uterus and reproductive problems, and found a lump last year that turned out to be breast cancer. Tests showed 20 tumors in one breast, two pre-cancers in the other and spread to her lymph nodes.

"I ate a low-fat diet. I exercise faithfully so I was not overweight. I had none of the normal risk factors," she said.

When and how often to screen women for breast cancer is the subject of much debate. A government task force recommends that women at average risk of breast cancer get mammograms every other year starting at age 50, and talk to their doctors about screening before then. Many medical groups urge starting at age 40.

DES exposure needs to be considered with the whole picture of a woman's risk, said G. Wright Bates, director of reproductive medicine at the University of Alabama at Birmingham.

"In some cases, frequent Pap smears and early mammography or breast MRI may be warranted for women with DES exposure," he said.

Others are focused on possible risks to the next generation.

Sally Keely, who was part of the federal study, and her husband are both offspring of women who took DES during pregnancy. Keely, 49, of Kalama, Wash., had miscarriages and a tubal pregnancy and required fertility treatments to have a daughter, now 9.

"I would like to push for more funding on the third generation exposed so I would know best how to advise my daughter," she said.

Fran Howell, executive director of DES Action USA, an advocacy group based in Jupiter, Fla., adopted a daughter, now 20, after being unable to conceive.

"So many of the DES daughters worry about problems with their children," she said. "The DES ends with me."



Advocacy group:

What the study found

Rates of health problems in DES daughters compared to nonexposed women:

Breast cancer • 3.9 percent versus 2.2 percent

Cervical pre-cancer • 6.9 percent versus 3.4 percent

Infertility • 33.3 percent versus 15.5 percent

Early menopause • 5.1 percent versus 1.7 percent

Complications among women able to become pregnant:

Preterm delivery, • 53.3 percent versus 17.8 percent

Miscarriage • 50.3 percent versus 38.6 percent

Tubal pregnancy • 14.6 percent versus 2.9 percent

Stillbirth • 8.9 percent versus 2.6 percent

High blood pressure during pregnancy • 26.4 percent versus 13.7 percent —

Online health resources

Advocacy group •