Galileo's Middle Finger (26 page)

Hint: Never.

 • • • 

A
S I BEGAN
THINKING
ABOUT
the dex issue, one of the clinicians I was talking to was
David Sandberg
, a pediatric psychologist from the University of Michigan and Mott Children’s Hospital in Ann Arbor, with whom I’d long been collaborating on efforts to push back against risky attempts at medically “normalizing” healthy kids. Neither David nor I saw in theory any deep moral problem with preventing the development of ambiguous genitalia in utero. Neither of us saw intersex genitals as any more special or sacred than any other genitals, and all other things being equal, especially in our still-crazy medical system and in our culture at large, a child would almost certainly be better off born with typical genitals. Doing something to prevent “the need” for a surgeon to come at these children’s genitals with a knife? In theory, sounds good.

But as David talked me through what was going on, he made clear that the major concerns he and others had were not with theory but with practice. First off, there was the concern that the drug had to be given so early that it meant women were started on it as early as the fourth or fifth week of pregnancy. At that point, the embryo being targeted would be as small as a sesame seed, and the total dose of glucocorticoids reaching it would probably be
sixty to a hundred times
the naturally occurring level of glucocorticoids. Much more disturbing, it wasn’t at all clear whether the pregnant women understood that doctors had very little idea what this drug might do to them or their children in the long run or that many experts were plenty worried.
Twenty-five years into use, we didn’t even have a placebo-controlled study to show it even did what was intended.
All we had were reports
from the doctors like Dr. New who had themselves recommended the drug saying they judged the intervention to be fairly effective in reducing genital masculinization in the females. Not terribly objective science, to say the least.

Now
data coming out of Sweden
were showing statistically significant unintended effects on brain development. There could be lots of other problems we didn’t know about yet—and wouldn’t know about anytime soon if this experimental intervention was conducted unscientifically and without mothers even realizing that it was experimental. Not knowing they were in what amounted to a big, sloppy experiment, the mothers wouldn’t necessarily consider the possibility that their children’s physical and cognitive problems might be side effects of prenatal dex. Even if, like Penny Stone, they
did
suspect prenatal drug exposure to be the cause of problems, few would know how formally to report their concerns. In the United States, there was no standardized registry of those exposed in utero, only Dr. New’s closed clinical records. Dr. New was supposed to be using her NIH grant to follow up with those treated years earlier, but many families were either
missing or choosing not to participate
when Dr. New’s research team called on them to be in the survey.

Because I teach the history of medicine, my friend David Sandberg didn’t have to tell me to think about all the parallels to DES and thalidomide. It seemed to us as if the American clinicians using prenatal dexamethasone for CAH had learned nothing from history. But it was also like they were learning nothing from the contemporary scientific literature. By the time I turned my attention to this, bench researchers studying the physiology of development in nonhuman animals had steadily been reporting that glucocorticoids like dexamethasone, when deployed during fetal development, appeared to lead to “
fetal programming
” of adult pathologies in various organ systems; in other words, prenatal glucocorticoids could permanently skew the developing body, reprogramming the tissues to develop major diseases like cancer in adulthood. Just like DES.

Listening to David rattle off his concerns, I was reminded that Dr. New had left Cornell’s medical school a few years back under the cloud of a major NIH fraud case and had then taken a job in another part of New York City, at Mount Sinai’s medical school. In 2005, the
Wall Street Journal
had reported that the NIH grant on which Maria New was the principal investigator—the grant that had included Dr. New’s research on prenatal dexamethasone—had been at the center of a fraud investigation that resulted in Cornell paying the NIH a $4.4 million settlement. According to the whistleblower, a Greek pediatric endocrinologist named Kyriakie Sarafoglou, who had been working in Dr. New’s unit, there appeared to be “phantom research projects” i.e., research projects that were being funded but were not actually happening. (Perhaps this helped explain why, although New kept promising the NIH and her colleagues extensive follow-up data on long-term outcomes of prenatal dexamethasone exposure, the data were strangely absent in the published literature.) According to Sarafoglou, at first Cornell had tried coming after her for raising an alarm about what she was seeing, even requiring her to submit to a psychiatric exam. Instead
Sarafoglou went to the Feds
.

As he talked me through what he knew, David also wanted to make sure I understood that it wasn’t just the females with CAH who were being exposed. Because the intervention for CAH had to start so early in embryonic life if it was going to work as planned, it had to begin before doctors could know if the woman was even carrying the kind of embryo they were worried about: a female with CAH. Remember that, on average, only one out of four offspring of at-risk couples will turn out to have CAH, and of those the issue of ambiguous genitalia affects only the females. Bottom line: Seven out of eight of the embryos exposed to dexamethasone in the first trimester could never gain any of the intended benefits from the intervention, because only one of eight “at-risk” pregnancies would produce a female with CAH—but all would bear the unknown risks of early dex exposure.

Actually, when I redid the math after some research, it turned out to be more like nine out of ten fetuses exposed to the risks with no chance of benefit—because not all girls with CAH develop ambiguous genitalia, and because even the proponents of dex estimated that it achieved its goal
only about 80 percent of the time
. Yet 100 percent of these couples’ developing offspring would be blasted, starting in the embryonic stage, in hopes of “saving” 10 percent of them from developing to be sexually atypical. The fetuses identified in utero as females with CAH potentially faced even higher adverse-event risk than the rest, because for them, the dexamethasone dosing continued all the way through the pregnancy, whereas for the rest, the intervention ended after a few weeks, once the obstetrician determined that the fetus being carried was most likely not a female with CAH.

Given all this, even some fairly old-guard doctors were speaking out against this whole intervention, essentially saying “this is just plain nuts.” One senior pediatric endocrinologist, Walter Miller of the University of California’s medical school in San Francisco,
had been warning
about the dangers for years.
Miller had finally declared
in 2008 in
Endocrine News
that “the accumulating evidence that prenatal exposure to dexamethasone has mild but deleterious effects on the developing brain of the 7 of 8 fetuses treated needlessly should clearly indicate that prenatal treatment of CAH is fraught with ethical (and possibly legal) problems. It is this author’s opinion that this experimental treatment is not warranted and should not be pursued, even in prospective clinical trials.”

But the intervention wasn’t even being pursued in prospective clinical trials, except in Sweden, where in 1999 researchers intentionally halted access to it through any other route because of their findings that children had been harmed. As far as I could ascertain, in the United States there had been no meaningful long-term oversight from medical-school institutional review boards (IRBs, or medical ethics committees), so there were no meaningful protections in place to assure that these pregnant women were fully informed before taking on these significant risks. Without IRB protocols in place for a prospective trial that would track the children continuously, without independent safety monitoring, there would be no meaningful assurance that adverse outcomes would be detected and reported promptly.

As I soon discovered, the truly amazing thing was that
numerous medical societies
had long been calling for the highest scientific and ethical precautions when using prenatal dexamethasone for CAH. Even a committee from the top American pediatrics group, the
American Academy of Pediatrics
, (AAP), had called for the greatest caution in an open (and ugly) debate with Maria New in 2001, the very year she was recommending the treatment at that support group meeting. The AAP representatives admonished New: “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 prenatal use of DES (diethylstilbestrol) and thalidomide demands no less.”

Yet almost a decade after that admonishment, nothing had changed.

 • • • 

R
ESOLVED TO WORK
on this issue, my only question was
how
. This was different—really different from our old intersex fights over genital surgeries. For one thing, I was actually ideologically
allied
with most of the medical establishment types this time around. For another, intentional exposure of human fetuses to a development-altering steroid was something about which all kinds of protections were
already
supposed to be guaranteed. It seemed we just needed to pull some particular lever. But which one?

Before I did anything, based on what I had learned from talking to criticized researchers, I thought I had best first write to Maria New and ask her whether she had been obtaining informed consent of the parents. Maybe I was wrong. Maybe there was an explanation for what I thought I was seeing. When we had met years earlier at a meeting of intersex specialists, I had walked in to find Maria New recommending my first book to her colleagues, even though it contained sharp ethical criticisms of them all. She surprised me then. Maybe she would surprise me now. So on December 8, 2009,
I wrote to her
: “Dear Maria, I hope this finds you well. I have two questions for you with regard to prenatal dex treatments for CAH: Do you have any forthcoming publications on the long-term outcomes of these treatments? May I see the consent form you’re using for this experimental treatment?”

There came no reply. But it was safe to guess that New saw my message; in early January, at a conference of pediatric endocrinologists in
Miami
, the clinicians who had called me found her even more defensive than usual. In a session on long-term follow-up of prenatal dex for CAH, New raced through the slides, failing to let anyone really see the data. From what those calling to report to me could see, more than half of those exposed appeared to be completely unaccounted for, and the scientific quality of what data New did purport to have
was very poor
. One of my colleagues present at the meeting, pediatric geneticist Eric Vilain of UCLA, had boldly pressed New during the Q&A: What did the consent for this look like? What was she telling the mothers? She responded that his question was out of line. She wasn’t going to answer him. Others told me that her response to Eric had caused the room to go still. Then she’d gone on to assure the audience that she wasn’t accidentally making the prenatally exposed boys gay. Perhaps she said this because she knew that in the Swedish cohort
at least one boy exposed
in utero had been born with genitals that suggested incomplete masculinization, a sign that perhaps the boys were also becoming collateral damage in the sex-normalization quest.

I couldn’t let this continue without trying to help bring it to light. After pulling all the published information I could find and looking for evidence of proper ethics and scientific oversight, what I was seeing just seemed to confirm our worst fears. Besides promoting the intervention via the support group for CAH and her own foundation Web site, when writing about CAH for various textbooks, Dr. New had made a point of
plugging prenatal dex
to other doctors, writing as if it simply was the standard of care among clinicians in regular practice. As a result, all over the country, obstetricians and genetic counselors were using prenatal dex believing it to be safe and effective.

Still unsure exactly what to do, I talked to Aron’s boss,
Marsha Rappley
, who just happened to be recently retired from chairing an FDA panel on pediatric therapeutics. Marsha seemed skeptical that people would really be giving a fetus-altering drug outside of prospective long-term studies, but she helpfully suggested that, in addition to writing the specific medical schools involved, we might also formally register our concerns with the FDA Office of Pediatric Therapeutics and the federal Office for Human Research Protections (OHRP).
This
was the big idea I needed—to call specifically on the federal agencies charged with protecting people in just these kinds of situations. The same day I talked to Marsha, I also purchased the domain name FetalDex.org as a way to provide information for everyone, and I let the editors at the Hastings Center, the largest independent bioethics center, know I was planning to write a blog post for them about prenatal dex. The article would be used to gather up names of people in bioethics and allied fields willing to sign letters of concern to the FDA and the OHRP.

Still feeling more than a bit queasy, I decided I’d also better write
another e-mail message
to Maria New, letting her know I was about to start criticizing her publicly and giving her another chance to show me evidence that she was protecting the rights of the families. The subject line I used this time was “IRB oversight,” to indicate clearly that I was worried about violations of regulations governing research on humans: