Uterine Ruptures Associated with Prostaglandin Used with RU486

By Randall K. O'Bannon, Ph.D., NRL-ETF Director of Education & Research

When the manufacturer of the anti-ulcer drug Cytotec released a letter August 23, 2000, to warn doctors of injuries associated with unsanctioned ["off-label"] obstetrical uses of the drug, the pro-abortion American College of Obstetricians and Gynecologists (ACOG) publicly questioned the "content, timing, and tone" of G.D. Searle's letter.

What upset ACOG was its fear that Searle's letter could "limit the use of this new option for reproductive choice" (ACOG Letter, 10/26/00). ACOG was concerned that Searle's letter might have an impact on doctors or hospitals considering the use of Cytotec in conjunction with the abortion pill RU486, which received marketing approval from the Food and Drug Administration (FDA) last September.

Contrary to the implications of ACOG's letter, however, Searle's letter was prompted by reports of uterine ruptures that the company had received associated with some off-label uses of its drug. Searle specifically addressed Cytotec's off-label use as a cervical ripener, labor inducer, or a stand-alone abortifacient. Now, independent evidence has surfaced that Searle's concerns about Cytotec's use as a labor inducer were amply justified.

In its January/February issue, Mother Jones magazine reports that a Freedom of Information Act request made to the FDA has uncovered 30 cases of uterine ruptures reported to the FDA involving Cytotec in just the past three years and eight cases involved the death of a child in utero.
To illustrate, Mother Jones relates the case of 34-year-old expectant mother Suzanne Altomare. Eight days past her due date in November 1995, Altomare's doctor, Thomas Kahan, decided to administer two doses of Cytotec to induce labor.

The article then relates what transpired over the next few hours:

According to court records and sources familiar with the case, Altomare soon went into very active labor. But several hours later, a delivery nurse at the hospital in Salem, Oregon, was no longer able to detect a fetal heart tone or to find the baby's head on a vaginal exam. Altomare's uterus had ruptured, causing internal bleeding in the mother and leaving the baby without oxygen. The nurses called Dr. Kahan, who was at home. By the time he arrived and mobilized an emergency caesarean section, the infant was brain-dead. Kahan then performed an emergency hysterectomy. When Altomare awoke, she learned that she would never again be able to bear a child. Her newborn daughter died three days later.

Altomare was not the only woman Mother Jones gleaned information about. Lauren Car-roll, a Texas woman, had a hysterectomy and lost her newborn son after receiving Cytotec and suffering a uterine tear. Both women sued their doctors. Carroll received $1 million, and Altomare, $2 million.

A woman who was given Cytotec in Connecticut in 1998 died at the Yale-New Haven Hospital after receiving the drug. Mother Jones says the woman's severely impaired son, delivered from her lifeless body, died last year.

Mother Jones traces back the popularity of Cytotec's use for labor induction to two factors: its relative cheapness and an increased tendency among doctors to induce labor. A single dose of Cytotec costs less than 25 cents, compared to other labor- inducing agents that cost hundreds of dollars.

Mother Jones cites a survey conducted by a University of Florida (Jacksonville) professor of obstetrics and gynecology that found that women receiving Cytotec were more likely to have a vaginal delivery within 24 hours--and no more likely to have a caesarean section--than women receiving no medication or other labor- inducing drugs. Under such circumstances, the claim of Dr. Charles Lockwood, ACOG's chair of obstetrical practices, that Cytotec is "the predominant agent of choice" is not surprising.

Doctors are more likely to induce labor now than they were in the past. According to Mother Jones, the labor induction rate has doubled in the last decade, going from 1 in 10 to 1 in five. The induction of labor is important when a woman is significantly overdue or dealing with pregnancy-related high blood pressure or diabetes, but critics say that Cytotec is often being used for what Mother Jones calls "convenience inductions," i.e., inductions done for the doctor's convenience.

The magazine quotes Dr. Marsden Wagner, a neonatologist who served as a director of women's and children's health in industrialized nations for the World Health Organization, who says that "Cytotec enables doctors to practice daylight obstetrics....It means that as a doctor, I can come in at 9 a.m., give you the pill, and by 6 p.m., I've delivered a baby and am home having dinner."

It has been Cytotec's ability to induce uterine contractions that has attracted both abortion researchers and regular ob-gyns in the last several years to try to use the drug "off label," i.e., for purposes beyond those sought by the manufacturer or approved by the government. Abortion researchers, finding that abortifacients like RU486 didn't always "finish the job" when used alone,1 turned to Cytotec to complete chemical abortions after other prostaglandins proved too powerful.

Other ob-gyns sought to take advantage of Cytotec's uterine- contracting property by using the drug to induce labor among maternity patients for whom delivery was delayed.

Searle's letter of August 2000 was prompted by reports of uterine ruptures it received associated with some of these off-label uses of Cytotec. Though the FDA now seems to be backing off of any endorsement of Searle's letter or labeling changes, Searle says the FDA was aware of the problems and suggested some sort of action.

The debate has now made its way into the pages of the prestigious New England Journal of Medicine (NEJM). Writing on behalf of Searle, Michael Friedman, M.D., told the NEJM, "The FDA requested that we make a labeling change to clarify further the serious risks and to consider sending a letter to health care professionals. Our August 23 letter was a result of this dialogue and was conducted in consultation with the FDA." (Letter to NEJM, 1/4/01.)

After consulting with the FDA, Searle then sent the letter to some 200,000 health care providers in the United States, informing doctors that it had received reports of "serious adverse events" associated with these unsanctioned uses of Cytotec on pregnant women, including uterine rupture and maternal or fetal death. (For full details on the Searle letter, see the September 2000 edition of NRL News.)

Though its previous label had contained a clear warning that Cytotec was not to be used by pregnant women because of its abortifacient properties, Searle strengthened the warnings on its revised labeling. The company drew special attention to the new information on risks of uterine ruptures; 19 paragraphs of the new package insert offer special warnings to pregnant women.

Protests by doctors' groups and the FDA's subsequent approval of RU486 with a mandated Cytotec follow-up put the FDA in an awkward position. It was both advocating and discouraging off- label uses by pregnant women. Faced with the contradiction, the FDA has struggled to "clarify" its position.

While Searle made changes to its Cytotec label at the behest of the FDA and drafted its letter only after "lengthy discussions" with the FDA about the uterine ruptures, the FDA has since characterized some of the new warnings Searle has written for its label as "inappropriate and misleading" (Reuters, 10/18/00). There are reports that the FDA is now considering trying to induce Searle to change its label to include its use in tandem with RU486 for abortion as an approved use.

According to the drug industry trade weekly Pink Sheet, FDA Commissioner Jane Henney told Congress on October 3 that while the agency was "certainly very much engaged in the writing of the language of the letter that tells practitioners - - and women really - - that if they are pregnant, and they wish to remain pregnant, that there are side effects," the FDA felt the " termination of pregnancy" was "a different issue" and it was " engaged in discussions with Searle about changing the label to reflect that treatment plan" (10/9/00). Searle's Dr. Friedman's January 4, 2001, letter to the New England Journal of Medicine says that while discussions between Searle and the FDA continue about the labeling language regarding the risk of "adverse events," these discussions "have not included consideration of any alteration to Cytotec's approved indication."

National Right to Life warned that the FDA's approval of RU486 last September represented a corruption of both government and medicine, and now the controversy surrounding Cytotec represents simply one more step in the process.

ACOG representatives admit that there have been uterine ruptures associated with use of the drug for labor induction, but argue that reduced dosages and screening out patients with previous caesarean deliveries or major uterine surgeries would minimize such risk. ACOG's support of the RU486/Cytotec abortion regimen, and the prominence of this concern in its 10/26/00 letter to the FDA, however, causes one to wonder whether this recommendation is driven by abortion politics, rather than science.

Likewise, the FDA campaign on behalf of RU486 raises questions as to whether support for the abortion technique outpaces its commitment to protecting women's health and safety.

NOTE:

1. By itself, RU486 is "only" able to induce an abortion 64% to 85% of the time.