VANCOUVER, British Columbia — On Aug. 28, a woman entered an unidentified Canadian hospital and complained of severe abdominal cramping, bleeding, dizziness and weakness. She was participating in a trial of the chemical abortion cocktail RU-486 and had begun an abortion five days earlier.
Three days later, she was dead.
Doctors who examined her Aug. 28 thought her symptoms were normal for the chemical abortion procedure and sent her home. The following day she was admitted to hospital. On Sept. 1, she died of a gangrene infection that had spread rapidly from her uterus releasing toxins that poisoned her vital organs and eventually stopped her heart.
The woman — and more than 800 other women who have participated in the Canadian RU-486 trial — were not told about a stern letter issued last year by the manufacturer of misopristol, one of the two drugs used in RU-486, warning that misopristol's use in an abortion could cause “serious adverse events” including death. Dr. Ellen Wiebe of Vancouver, the abortionist supervising the Canadian study, told the Register that a specific decision was made to not inform the women about the drug manufacturer's warning.
The New York-based Population Council, owner of North American rights to RU-486 and sponsor of the Canadian trial, refused to reveal any personal details about the deceased woman. “We're not disclosing any of that information to protect the privacy of the individual and her family,” said public information officer Christina Horzepa.
Horzepa said the study has been temporarily suspended while Canadian health authorities and the U.S. Food and Drug Administration investigate the death.
RU-486 is a combination of two drugs that induce abortion within the first seven weeks of pregnancy. The first drug, mifepristone, withers the developing fetus by cutting off vital hormones to the unborn child's nutrition supply, the placenta. The second drug — misopristol — induces uterine contractions to expel the dead fetus.
The Canadian government has not yet approved RU-486 for sale, but the FDA okayed it in September 2000 for use in the United States under protest from pro-life groups, who argued that standard safety protocols were ignored in the rush to approve the abortion drug cocktail.
Adding to the bitter controversy, just weeks before the FDA approved RU-486, G.D. Searle, the manufacturer of misopristol, issued a “physician alert” to the FDA and to every obstetrician and gynecologist in the country, warning that misopristol “is not approved for the induction of labor or abortion.”
The Peapack, N.J.-based subsidiary of Pharmacia Inc. said that misopristol, sold under the shelf name Cytotec, was developed and clinically tested only to treat gastric ulcers. Searle warned, “Serious adverse events reported following off-label use of Cytotec in pregnant women include maternal or fetal death, uterine hyperstimulation, rupture or perforation requiring uterine surgical repair, hysterectomy … amniotic fluid embolism, vaginal bleeding, retained placenta, shock, fetal bradycardia and pelvic pain.”
The FDA, which had recommended that misopristol be used in combination with mifepristone as part of RU-486 treatment, posted Searle's warning letter on its Web site, but did not withdraw its recommendation.
The Population Council would not release a copy of the informed-consent papers women in the trial signed before taking part in the Canadian study, and Horzepa refused to say if the women in the trial were aware of the Searle letter.
Roslyn Tremblay, a spokes-woman for Canada's federal health department, also declined to confirm if the women in the study were aware of the warning. “Within the Canadian context, any research information is proprietary information and would have to be released by the company,” said Tremblay.
But abortionist Wiebe disclosed that none of the women were informed about Searle's physician alert. “They [Searle] were trying to get out of any liability,” Wiebe said. “It [the letter] was a terrible thing because we need [misopristol]. We use it for miscarriages as well as induction of labor.”
The informed-consent papers were approved by five separate “ethics boards” in each of the five Canadian cities where RU-486 is being tested — Quebec, Sherbrooke, Toronto, Vancouver and Winnipeg. Searle's warnings were not included in the information because, Wiebe said, “They felt [the warnings] were not based on good evidence.”
Doctors Ralph Hale and Stanley Zinberg complained in a New England Journal of Medicine editorial in January that the firm's letter had prompted some hospitals to refuse to allow misopristol to be used for abortions. Hale and Zinberg demanded that Searle issue a retraction, and Wiebe claimed last week that, “Searle rescinded that letter.”
But Mark Wolfe, manager of external communications at Pharmacia, denied Oct. 1 that the letter had ever been retracted. In fact, Michael Friedman, the company's senior vice president of research and development, issued a response, also published in the New England Journal of Medicine, to Hale's and Zinberg's criticisms.
Friedman reiterated Searle's warning against use of misopristol in abortion cocktails and insisted the drug should be prescribed only for ulcers. “This is the only approved indication for Cytotec, and we are prohibited by FDA regulations from promoting or even suggesting its use for any other purpose,” he said.
Infection, the specific cause of death for the Canadian woman, was not listed as a risk on the informed-consent papers either, according to Wiebe. “It wasn't considered necessary by our ethics board,” he said. “The reason is that less than half of 1% of women in other clinical trials developed infections.”
Wiebe said the woman succumbed to a rare infection caused by a bacterium called clostridium sordelli. It is part of the body's naturally occurring flora and doctors don't know why it turns gangrenous in rare instances. Wiebe said her review of medical literature for the past 40 years yielded few cases, all but one among pregnant women who had miscarried, had surgical abortions, or had complicated deliveries.
Richard Carpentier, executive director of Ottawa's National Council on Ethics in Human Research, said that in Canadian clinical trials, “the standard is to disclose anything the patient should know to make an informed decision.”
Carpentier cited a 1989 court case, Weiss v. Solomon, in which a man died of a rare allergic reaction while testing a product. The court ruled that although the risk was small, the possibility was grave enough that he should have been informed of it.
Asked if patients in a study should be informed of a letter from the manufacturer of a product warning about its adverse effects, Carpentier said, “Of course.” But he added that in the case of RU-486, the paperwork would have to be reviewed to decide if the women in the trial were sufficiently informed.
Dr. Beverly Winikoff, program director for the reproductive health program of the Population Council, told Reuters news service, “We do not want to resume the study until we are sure everything is okay, but as of now we have no reason to believe that the death [of the Canadian woman] is drug-related or study-related.”
Randall O‘Bannon, director of education and research at the National Right to Life Committee, points out that ordinary RU-486 symptoms may mask underlying complications of the abortion drug cocktail. “If you're already having nausea and cramping and diarrhea, how do you know you're not dealing with underlying serious side effects?” he said.
One in 100 women was hospitalized in U.S. trials, under carefully controlled clinical circumstances, O‘Bannon said. He wondered what the rates are under ordinary circumstances, where follow-up is likely to be much less rigorous after the abortion cocktail is prescribed.
Vancouver family physician Will Johnston, president of Physicians for Life in Canada, thinks is difficult to absolve the drugs of any involvement in the death.
Interrupting a healthy pregnancy by abortion always exposes a woman to risks, Johnston said. During a natural miscarriage, hormonal signals have been telling the mother's body for some time that the situation isn't right, preparing for the necessary expulsion of the dead fetus.
In a chemical abortion, by contrast, RU-486 interrupts healthy signals to dislodge the fetus. Misopristol, charged with expelling the baby, has to work against a healthy body clinging to its placenta and fetus. Johnston warned this increases the chance of dead tissue being left behind and the chances of infection.
Johnston compared the maternal death rate — 5 maternal deaths per 100,000 women — to the much higher death rate for RU-486 in the abortion drug trial. Extrapolating from that trial, the number would be 125 maternal deaths per 100,000 women.
Concluded Johnston, “The one death in 800 [in the RU-486 trial] has to be compared with the overwhelming safety of natural pregnancy and childbirth.”
Celeste McGovern writes from Portland, Oregon.