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“The Dex Diaries” constitutes a blog series designed to unpack the story of the off-label use of prenatal dexamethasone for congenital adrenal hyperplasia. (If you’re not sure what I’m talking about, you can read more in Slate or Buzzfeed, or download for free our very readable new peer-reviewed journal article on the history of this drug use.) In the first Dex Diary, Kiira Triea spoke from her own experiences of having had her life course radically changed by a sex-development-altering prenatal drug. Here I explain why, in 2010, we asked the federal government to look into what was going on with prenatal dexamethasone for CAH.
Calling on the feds was a radical act. I had never done it before, and to my knowledge, neither had any of the 31 colleagues who did it with me. But what we were seeing seemed so absolutely outrageous, we weren’t sure what else to do. Importantly, we were not the first to have seen it, and those who had seen it—clinicians and patient advocates active in the care of children born with congenital adrenal hyperplasia (CAH)—had obviously tried to stop the ethical train wreck and failed. Something had to be done to protect the pregnant women, their children, and their doctors, many of whom seemed to be unsuspecting participants.
When I started looking at the off-label use of prenatal dex for CAH, I necessarily did it through two historical lenses. The one historical lens came from my own work on the history of the medical treatment of people born with atypical sex development, including “ambiguous” genitalia. From that lens, I knew the long history of generally-well-intentioned mistreatment involving lies, unnecessary medical procedures, sexism and heterosexism, and appalling “medical science.”
The second historical lens—the one that allowed me binocular vision—came from my work teaching the history of DES and thalidomide to aspiring doctors.
Starting in the 1950s, thalidomide was promoted in Europe as a sedative and as a treatment for nausea, including morning sickness. When approval was sought from the FDA by the Cincinnati-based William S. Merrell Company, the application landed on the desk of one Dr. Frances Oldham Kelsey, who just happened to have the sort of scientific background that made her wonder if it was really safe.
Dr. Kelsey doggedly investigated thalidomide and discovered that it was linkable in Europe to startling birth defects—including missing, malformed, and misplaced limbs—among children exposed in utero. It is probably safe to say that, had it not been for Dr. Kelsey, the United States would have added thousands of harmed children to Europe’s ten thousand long before anybody figured out it was all due to thalidomide.
Tragically, the case of DES had no Frances Kelsey. DES is a synthetic hormone that, between 1938 and the 1970s, was dispensed by prescription to somewhere between five and ten million pregnant women. Sometimes doctors gave women DES because they thought it could prolong pregnancies in women with histories of miscarriage, but, as Nancy Langston talks about in her terrific book, Toxic Bodies, drug companies selling DES also marketed it to doctors with the claim that it could “make a normal pregnancy more normal.”
In 1971, a group of physicians in Boston became alarmed that a very rare vaginal cancer was showing up among young women in the region. After one victim’s mother suggested maybe her daughter’s cancer had been caused by the DES the mother had taken during pregnancy, the physicians compared the girls who had the cancer to an age-matched set who did not. The victim’s mother was right. Millions of women and men exposed to DES in utero may have been harmed. Many thousands have died from cancers that are traceable to the use of DES in pregnancy, and tens of thousands more have had other medical problems, including with fertility. (To read more, go to DES Action.)
Today, largely because of DES and thalidomide, all sorts of protections around medical research are supposed to come into play especially in the case of pregnant women. We don’t just believe philosophically that experimentation on pregnant women greatly complicates the moral and scientific equations of medical research—although it does. Doctors have learned the hard way that using drugs on women during pregnancy can harm their children in unpredictable ways.
This is why I was stunned, when I started looking into prenatal dexamethasone for CAH in late 2009, to discover that this off-label drug use—explicitly intended to significantly alter fetal development—seemed to have been employed in the U.S. entirely outside of prospective, controlled, long-term clinical trials. This was particularly shocking given that nearly 90% of the fetuses exposed didn’t even have the condition of concern (CAH with 46,XX).
I could quickly see that I wasn’t the only one with my jaw hanging open. As we show in our Journal of Bioethical Inquiry paper, one expert clinician after another had said the equivalent of “for God’s sake, don’t do this outside of the most scientifically and ethically strict type of study imaginable!” In 2001, the American Academy of Pediatrics even specifically admonished the chief proponent of prenatal dexamethasone for CAH, Dr. Maria New, to remember history. Writing in the leading journal Pediatrics to Dr. New, they insisted:
“The maxim of ‘first do no harm’ requires a cautious, long-term approach, which is why the Academy Committee unanimously agrees that prenatal glucocorticoid therapy for CAH should be confined to centers doing controlled prospective, long-term studies. The memory of the tragedies associated with the prenatal use of diethylstilbestrol (DES) and thalidomide demands no less.”
The Academy was joined by one medical society after another in these calls for these scientific and ethical safeguards. (Details here.) But it appears that Dr. New never enrolled any of the families she talked into prenatal dexamethasone into prospective, controlled, long-term trials in spite of the fact that by 2003 she claimed to have “treated over 600 pregnant women at risk.” Her 2001 application for a continuation grant to the NIH—which we obtained via the Freedom of Information Act (FOIA)— showed a table indicating that she had been involved in 2,144 cases of “prenatal dx [diagnosis] and treatment in families at risk.”
New did occasionally seek to do short-term pregnancy trials and retrospective (“look back”) sampling studies on those treated in utero, partly to see how they turned out in terms of gender and sexual orientation. But nowhere could I find the kinds of strict scientific and ethical protections that were supposed to be in place for the kind of experiment where you see if you can alter fetal development with a prenatal drug!
What disturbed me and my colleagues most, and what moved us to call the feds, was the juxtaposition of two things: (1) Dr. New advertising the drug to prospective patients as having been found “safe for mother and child,” and (2) her simultaneous seeking and obtaining federal grants to do a retrospective study to see if it really was safe.
How could she tell pregnant women it was safe while taking government funding to see if it was safe?
Before I took any action, I wrote to Dr. New—who knew me for at least a decade via mutual professional interest in this field—and asked her if to show me the consent form she was using. She didn’t answer. A few weeks later, Dr. Eric Vilain of UCLA directly confronted Dr. New at a medical meeting in Miami, asking her in front of a large audience what the informed consent looked like— what was she telling the mothers? She brushed him off. (A doctor there later told me that at that moment, the room went silent.) I tried but could also not find out whether there were any IRB (ethics boards) protections in place for pregnant women being given the drug at Dr. New’s institution.
At that point—early 2010—I felt we had to do something radical. All of these doctors challenging New for all these years were having no effect. At the time, I was trying to wrap up a book manuscript, the thesis of which is that the quest for evidence constitutes an ethical imperative—that the pursuit and use of evidence is absolutely necessary to doing good in science, in medicine, and in democracy. I somehow thought everyone reasonable felt the same way.
So I thought if we just threw down the evidence gauntlet to the big grown-ups—the federal agencies charged with protecting pregnant women from bad and/or essentially unconsented drug experimentation—everything would be fixed. The ethical and scientific travesty would cease. And I’d have a nice story for the end of the book about how reason can and will win out in a scientific democracy.
In February 2010, with my most excellent colleague Ellen Feder of American University leading as our corresponding author, 32 of us from 28 institutions together wrote to the FDA and the Office of Human Research Protections (OHRP) sounding the alarm. In our letters of concern, we specifically asked the feds to investigate what Dr. New had really been doing at the medical schools of Cornell and Mount Sinai with prenatal dexamethasone for CAH.
In September of 2010, the feds responded with a pair of memos that basically came down to “nothing to see here.” In our Journal of Bioethical Inquiry report, Ellen and I (along with attorney Anne Tamar-Mattis) show that, in fact, the government’s own investigatory findings along with the published record and Maria New’s NIH grant materials strongly suggest we were right all along: that this has been a phenomenally unethical and unscientific run on perhaps thousands of pregnant women, with a drug the prescribers had always known would change—had always intended to change—fetal development.
In the next Dex Diary, I’ll explain how many obstetricians probably had no idea what they were becoming parties to. If you want to learn more right now, you can read our article, the Buzzfeed article, Slate article, my response to Mount Sinai’s latest brush-off, or go to the website I set up to triage information.
