Born in the USA (17 page)

Of the studies on using Cytotec to induce labor at the end of pregnancy, many are not randomized experimental trials (the most reliable scientific method for evaluating drugs) and all, including those that are trials, are far too small. With one or two exceptions, the studies all involve fewer than 1,000 women, and most of them involve fewer than 400 women, but it would take a sample of at least 3,000 women to reliably investigate the risk of an adverse outcome such as uterine rupture. After lumping together all Cytotec data, the review goes on to say that prescribing a medication for an off-label indication is common in the treatment of pregnant women, as if this were a justification, when it is actually an indictment of obstetric practice. Doing something often does not prove that it's a good idea—a lot of banks are robbed, but that doesn't make it a good idea. The authors try to justify ignoring the FDA by saying that off-label use (i.e., not FDA-approved use) is not considered experimental if based on sound scientific evidence. Essentially, what they are saying is that it's okay for obstetricians to experiment on women without their knowledge or consent if they have good scientific data that it's safe. But if doctors already have good data, they don't need to experiment on patients. Furthermore, if there were good
scientific data, the drug would have been approved by the FDA. So this is catch-22 nonsense. The whole purpose of the FDA is to guarantee the consumer that on-label use of approved drugs is backed by sound scientific evidence. And the best scientific opinion has been saying for ten years that we still don't have “sound scientific evidence” on the risks of Cytotec induction.

The paper by Goldberg and colleagues goes on at length documenting the efficacy of induction with Cytotec, but, again, no one is debating whether the drug works. The debate is over the risks, and here the authors admit that the relative risk of rare adverse outcomes with the use of misoprostol (Cytotec) for labor induction
remains unknown
. So the authors themselves never say that this drug is safe for induction and they admit that we do not know enough about the risks. Then, in the very next paragraph, they go on to recommend its use for induction, having just admitted that the risk of “rare adverse outcomes” (meaning uterine rupture, AFE, and fetal and maternal death) is unknown. Incredible. The paper also uses the word
safe
, but if we don't know the risk of these tragic outcomes, what can we say about safety?

As discussed earlier, there are prominent groups, such as the Cochrane Library, that disagree with the authors' conclusion that it's okay to use Cytotec for induction of labor at the end of pregnancy. When experts disagree on the evidence, the prudent course for doctors is to follow the fundamental principle of all medical practice: first, do no harm.

A fundamental obstetric attitude is revealed in this paper by Goldberg and colleagues. Is a new drug or intervention considered unsafe until proven safe (precautionary approach) or, as clearly illustrated in this paper, considered safe until proven unsafe (anti-precautionary or vigilante approach)? These are two diametrically opposed approaches to the introduction of new interventions in medical practice. The Goldberg and colleagues review—and most of obstetric practice in the United States—clearly uses the anti-precautionary or vigilante approach of assuming that something is safe, calling it safe in published articles, and using it until something happens that proves it to be unsafe.

The precautionary principle used in science states: “When an activity raises threats of harm in human health, precautionary measures should be taken even if some cause-and-effect relationships are not fully established scientifically.”
²⁰
This means that the burden is on those introducing a new technology to prove it safe, not on the rest of us to prove it harmful. This principle is based on the same assumptions as in courts of law. Society balances a trial in favor of the defendant because convicting an innocent person
is far worse than failing to convict someone who is guilty. In the same way, we should balance decisions on risks in favor of safety, especially where the damage, should it occur, is serious and irreparable.

And the anti-precautionary principle? According to Peter Saunders, a professor of mathematics at Kings College, London, and a pioneer in the precautionary principle, using the anti-precautionary principle means that when a new technology is being proposed, it must be permitted unless it can be shown beyond a reasonable doubt that it is dangerous. The burden of proof is not on the innovator, it is on the rest of us. Those who accept this anti-precautionary principle and pursue vigilante practices push forward with untested, inadequately researched technologies and insist that it is up to the rest of us to prove them dangerous before they can be stopped, and, furthermore, the perpetrators refuse to accept liability if the technology turns out to be hazardous.
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Advocates of the anti-precautionary principle—such as Goldberg and colleagues—do not wait for a new drug or intervention to be proven safe through experimental trials; rather, they assume it is safe and continue to do so until someone proves it to be unsafe.

This is what happened with Cytotec induction of VBAC in the 1990s and with all the earlier obstetric tragedies mentioned in
chapter 3
. A concrete example illustrates that obstetricians—including an academic obstetrician in a prestigious university hospital—see no problem with the anti-precautionary approach, even when it results in tragedy. Yale–New Haven University Hospital was among the earliest to use Cytotec induction even when not part of formally approved research trials. In the mid-1990s, an assistant professor there was asked to develop a protocol for misoprostol (Cytotec) induction and he wrote such a protocol after talking with others around the country. He believed that it was okay to use a drug off-label based only on the experience of others and without experimental data—anti-precautionary.

Then in 1998, a woman at the Yale–New Haven hospital with a previous C-section died following Cytotec induction of labor. During a subsequent legal deposition, this same physician testified that if the data on the risks with VBAC had been available in 1998, obstetricians at the hospital would not have used misoprostol for induction, showing no apparent concern about using a drug when no data are yet available. He testified that there were no data out there in 1998 demonstrating that induction with misoprostol was more dangerous in VBAC than in other births. He then admitted that since that time, data have been published that show that it is more dangerous. He argued that since in 1998 there was nothing “out there” to suggest that misoprostol induction of VBAC was dangerous, it was
okay to induce VBAC using it. He insisted that you must have a suspicion of a risk in order to study it—a classic anti-precautionary position.

This case, as well as many other examples discussed in this book, leaves no doubt that the anti-precautionary or vigilante principle is widely used and accepted in U.S. obstetrics today. But the fundamental principles of medical practice and of drug assessment operate on the precautionary approach—first, do no harm; assume a new drug may not be safe; and do not approve its use until it is proven safe. How did the obstetric profession come to follow the opposite principles?

The second paper some obstetricians rely on to justify Cytotec induction of labor is a meta-analysis by Sanchos-Ramos and colleagues.
²²
First, even when adding up eight small trials, the combined sample size of experimental subjects is 966 (488 recipients of the drug and 478 controls). As indicated earlier, in order to have sufficient statistical power to determine the risk of rare but very serious adverse outcomes such as uterine rupture, AFE, perinatal mortality, and maternal mortality, the minimum sample size would have to be at least three times as large as this. Furthermore, some of the individual trials included in the analysis had extremely small sample sizes (four had a total sample size of less than one hundred), and these tiny trials cannot be expected to have a high level of individual validity.

An equally serious flaw in this meta-analysis is the wide variation in methodology among the eight trials on elements such as dose of the drug, dose interval, definition of controls, and indications for induction, which make it impossible to add the results together. What the authors of this meta-analysis have done is the equivalent of adding up apples, oranges, and bananas.

It appears that the authors do not understand the basic scientific flaws in this meta-analysis, as the paper concludes: “Published data confirm the safety and efficacy of intravaginal misoprostol as an agent for cervical ripening and labor induction.”
²³
The fact that some obstetricians accept this faulty study and that those who peer-reviewed the paper did not mention the problems with it is perhaps even more disappointing.

When I was a medical student and then a young practicing doctor, I believed that the highest quality of medical care was found in medical schools and university hospitals. Because research is conducted there, it seemed logical to assume that these institutions would have a serious investment in evidence-based practice. But the Yale–New Haven and UCLA hospitals were among the first to use Cytotec induction, and not as part of formally approved research trials. This is bad, because it demonstrates to
medical students and doctors in training that it's okay to use drugs for conditions that are contraindicated on the label. It promotes vigilante medical practice among those who are most vulnerable to influence. In South Carolina in 2000, a woman died after Cytotec induction, and when the young obstetrician who had given it to her was asked why he did it, he replied that he had been taught to use Cytotec for induction just a year or two before while in training in obstetrics at the University of Maryland Hospital.

In August 2000, a Cytotec drama was played out that raised the situation to a new level of hypocrisy. By this time, the FDA and Searle Pharmaceutical had received so many reports of women and babies dying after induction with Cytotec that Searle, working closely with the FDA and with the FDA's encouragement, sent a letter of warning to all health care providers in the United States. After reminding doctors that giving the drug by any method to women who are pregnant is contraindicated, the letter went on to say, “Serious adverse events that have been reported following off-label use of Cytotec in pregnant women include maternal or fetal death, uterine hyperstimulation or rupture or perforation requiring uterine surgical repair, hysterectomy or salpingo-oophorectomy [surgical removal of the uterus or ovaries], amniotic fluid embolism, severe vaginal bleeding, retained placenta, shock, fetal bradycardia and severe pelvic pain.” This is a horrendous list of risks, and ACOG, as well as the many obstetricians using Cytotec for induction of labor, were very upset with the letter. Instead of taking the message to heart, however, they launched a spin campaign. The letter put them in danger of severe criticism and great vulnerability to litigation. They had to neutralize it.

First, in October 2000, they wrote a letter to the FDA (and sent a press release to the media) saying that the vast majority of adverse effects reported to Searle and the FDA were the result of the drug not being used correctly. The doses were too high or too frequent, or Pitocin was given too soon afterward, or the drug was given to women who had had too many babies or had had previous C-sections. Needless to say, ACOG did not present any data to back up this claim, as there is very little systematic data on the practice of induction of labor with Cytotec. ACOG did not indicate that the organization's leadership had seen the adverse reports sent to the FDA and Searle, nor did it acknowledge the many cases where there were bad outcomes that did not fit into a high-risk category (such as the case of Ms. S, recounted at the beginning of this chapter). Finally, their implication that Cytotec induction is safe if used correctly was not backed
up with scientific evidence, as there has been no trial large enough to prove such a statement.

Then, in November 2000, ACOG sent a “citizen petition” to the FDA demanding that the FDA require Searle to withdraw its letter. In this petition, ACOG went so far as to imply that Searle's letter to doctors was motivated by something other than regard for the safety of women and babies, saying, “ACOG is concerned about the content, timing and tone of this [Searle's] letter.” The petition went on to accuse Searle of being less concerned about the use of Cytotec for labor induction than its use together with RU-486 in medical abortion early in pregnancy. There was no evidence to support this accusation that Searle was playing abortion politics, and, in reality, it was ACOG that was introducing abortion into the discussion.

The FDA did not demand that Searle retract the letter, so the campaign continued. Two months later, in January 2001, ACOG wrote an editorial that was published in the same issue of the
New England Journal of Medicine
as the biased and flawed review of Cytotec induction by Goldberg and colleagues critiqued earlier. In its editorial, ACOG calls the article “an excellent review,” further demonstrating the organization's inability to recognize faulty science, and then complains bitterly that Searle made its letter public without first consulting ACOG. The source of the organization's bitterness was that the Searle letter had the intended effect. As explained in the editorial, “The [Searle] letter did provoke a response from many hospital attorneys, administrators, and pharmacies—an automatic refusal to allow misoprostol (Cytotec) to be dispensed or used.” Some hospitals (but certainly not all) stopped using Cytotec for induction out of fear of litigation. The editorial ends by begging Searle and the FDA to retract the Searle letter.
²⁴

Searle has never retracted its letter, but the use of Cytotec continued. In April 2002, the FDA made another effort to stem the tide and published a statement saying that of course it was aware that Cytotec was being used off-label for labor induction and, if you are to use it, for God's sake don't ever use it on certain extremely high-risk women.
²⁵
This statement is not a form of FDA approval of Cytotec induction under any circumstances (high-risk or not), but, predictably, many obstetricians now claim that, with this statement, the FDA approved Cytotec induction.