Even by academic standards, the language was restrained. “It is likely,” the authors note, near the end of the discussion section, “that more patients with this tumor will appear as girls who were exposed in utero come to maturity.”
That quaint, passive construction, in the April 22, 1971, issue of the New England Journal of Medicine, triggered an active response. The three-page paper, “Adenocarinoma of the Vagina,” focused on eight young women, ages 15 to 22, with an extraordinarily rare tumor.
“While the disease had been described in older women, none of us had heard of it in young people,” recalled study author Arthur Herbst, MD, the Joseph Bolivar DeLee distinguished service professor emeritus and former chairman of obstetrics and gynecology at the University of Chicago.
Thanks to luck, diligence and some clever detective work, Herbst and colleagues figured out why. Early in their pregnancies, the mothers of seven of the eight women had taken a drug – a synthetic hormone called diethylstilbestrol, DES for short – to prevent miscarriage. The problem was that in the previous 25 years, an estimated 4.8 million women in the United States – and as many as 10 million worldwide – had taken DES during pregnancy. These eight cases were the first warning of a rare, delayed, but devastating side effect.
“While the medical community was being cautious,” recalled Susan Helmrich, a DES daughter who is now 55, “mothers who took DES were hysterical. They were basket cases. The daughters,” she added, “also went a little crazy.”
DES, created in 1938, was the first synthetic estrogen. It was a cheap, potent, unpatented pill – for humans or livestock. The FDA approved it in 1941 for a wide range of “estrogen-deficient states.” In 1947 they added miscarriage prevention. One advertisement claimed that DES could prevent abortion, miscarriage and premature labor and was “recommended for routine prophylaxis in ALL pregnancies.” In 1953, William Dieckmann, MD, chairman of obstetrics at the University of Chicago at the time, showed that DES had “no beneficial effect whatsoever on the prevention of miscarriage.” Nevertheless, the drug remained in use for that purpose. But then, beginning in 1966, the first few odd cases began turning up – young women with an old-lady tumor.
“Dr. Robert Scully, gynecologic pathologist at the Mass General and I got together seven cases of clear-cell adenocarcinoma and described their clinical and pathological characteristics,” said Herbst. They began interviewing the mothers. One mentioned that she took a drug during pregnancy, something called DES, and wondered if that had anything to do with it.”
“I was also following a mother whose daughter unfortunately died of this disease because it had never been diagnosed properly,” Herbst said, “and she mentioned the same thing.”
So he, his section chief Howard Ulfelder, MD, and epidemiologist David Poskanzer, MD, decided to design a study. By that time they had an eighth case; they then selected 32 controls: four for each case, daughters born at about the same time to women at the same hospitals. They found that seven of the eight mothers of daughters with cancer took DES during the first trimester for either bleeding or prior miscarriage, and only one of the 32 controls did. The odds of that happening by chance were less than one in 100,000.
As soon as the paper was published “it was all over the news,” Herbst said.
An accompanying editorial described it as a work of “great scientific importance and serious social implications.” The press called it a “time bomb” for exposed children, and DES was removed from the market later that year.
From eight cases in 1971, the numbers quickly grew. A follow-up study, published in 1972, included 91 cancer cases, patients diagnosed at ages 8 to 25. By 1981, 10 years after the initial study, the registry included nearly 500 adenocarcinomas of the vagina or cervix, aged 7 to 30 at diagnosis, with a five-year survival rate of about 80 percent – thanks to early diagnosis and aggressive surgery. There are now approximately 775 known cases.
Although four out of five of the cancer patients were still alive after five years, most had extensive surgery. “I had a ten-and-one-half hour operation,” recalled Helmrich. “They removed basically everything: my vagina, my uterus, lymph nodes. They reconstructed my vagina with my colon, which required two more operations and 10 hospital stays over the next three years. I was 21 years old.”
Mothers who ingested DES also appear to have an increased risk of breast cancer, estimated at 30 to 40 percent higher than average. The daughters exposed in utero also have an increased risk of breast cancer after age 40. Many have structural changes that can make it more difficult to conceive a child or to carry a pregnancy to term. DES sons have some genital-tract abnormalities. The grandchildren, although still being assessed, do not appear to have any third-generation effects.
Two things are clear. The DES story, coming only ten years after the thalidomide tragedy, convinced scientists to jettison the commonly held view of the fetal environment as a safe place, protected by the placental barrier. They replaced it with a better understanding of the extreme vulnerability of the developing fetus. A recent perspective in the New England Journal, 40 years after the original, emphasized how the discovery, “changed medical thinking” about embryologic development and the mechanism of carcinogenesis.
“Ultimately, the DES story humbles us,” the authors wrote. “It serves as a reminder that though the narrow lens of today might reassure us that an intervention is safe, it is only with the wisdom of time that the full consequences of our actions are revealed,”
“As a representative of the cancer daughters and watching this story unfold over the last 40 years, I can’t thank you enough for what you did,” Helmrich told Herbst when they met in April. “I truly believe you saved my life and the lives of many other cancer daughters who are around today. I go about my life as if nothing ever happened to me, but I have a good life because of Dr. Herbst.”
[A full-length video with more detail of Herbst’s discovery and Helmrich’s life as a “DES daughter” is also available. Thanks to Fran Howell and Kari Christianson of DES Action, who assisted in the interview with Dr. Herbst.]
Herbst AL, Ulfelder H, & Poskanzer DC (1971). Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. The New England journal of medicine, 284 (15), 878-81 PMID: 5549830
Goodman A, Schorge J, & Greene MF (2011). The Long-Term Effects of In Utero Exposures – The DES Story. The New England journal of medicine PMID: 21506735