In the previous Dex Diary, I explained why we called on the feds to look into the off-label use of prenatal dexamethasone for congenital adrenal hyperplasia. In this installment, I explain why, besides worrying about the mothers and children, I’m also worrying about the doctors who have been dispensing the drug. (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.)
The story of prenatal dexamethasone for CAH has taught me that, just as it is possible in marketing to sell consumers what they don’t really need, it is also possible for one irrationally exuberant medical expert to “sell” a whole group of physicians an intervention as "standard of care" when, in reality, the intervention is essentially experimental.
That's scary not only for the patients who have no idea they're in a messy experiment, but also for the physicians involved. Because the physicians who "buy" and in turn "sell" the intervention as "standard of care" may find themselves at risk, liability wise, if their patients are hurt.
In the case of prenatal dexamethasone for CAH, one of the primary defenses coming out of Mount Sinai School of Medicine – where the major proponent of this intervention, Dr. Maria New, now works – has been that Dr. New didn’t write the prescriptions. Dr. New is a pediatric endocrinologist, and the people writing the prescriptions appear to have mostly been obstetricians. So, Mount Sinai is implying, any fault that exists falls on the obstetricians.
Let’s leave aside for now the question of why Dr. New’s Cornell clinic boasted of her having “treated” 600 pregnant women with this intervention if she wasn’t professionally responsible in these interventions. Let’s leave aside for now the question of why, if she wasn’t critically involved in this “treatment” system, in 2006 Dr. New reported to the NIH that her clinic at Mount Sinai was “galloping ahead” with the off-label use of prenatal dexamethasone for CAH.
What about the idea that the obstetricians were the ones responsible for any harm or misrepresentation of the intervention's status to prospective patients?
So far as I can ascertain in looking at the history of this intervention, if a U.S. obstetrician considering prenatal dex for CAH in the last 10-15 years had looked to the biggest expert in prenatal dexamethasone for CAH – Maria New – chances are that that obstetrician believed the intervention had been found safe and effective. Because that’s what Dr. New kept saying about it.
For example, in the 2000 edition of Cecil Textbook of Medicine, this is what Dr. New and a co-author told doctors: “Prenatal treatment with dexamethasone has been shown to be safe and effective for both mother and child in the largest human studies.” Never mind that there had never been large human studies capable of establishing safety and efficacy in terms of modern evidence-based medicine. In the 2007 edition of the textbook Pediatric Endocrinology, Dr. New and her co-authors said something very similar: “we believe that proper prenatal treatment of fetuses at risk for CAH can be considered effective and safe.”
Same deal in the obstetrical textbooks, although in those cases, other authors were writing while relying on Dr. New’s representations. So, for example, the current issue of the dominant textbook Williams Obstetrics tells obstetricians, “Treatment to prevent virilization must begin early, ideally prior to 9 weeks, before it is known whether the fetus will be affected or even its gender.” It then goes on to explain how you do the intervention, citing Dr. New. No mention of it being experimental.
The current edition of Creasy and Resnik’s Maternal-Fetal Medicine, widely considered the leading textbook in the field, instructs obstetricians that “Prenatal treatment of the mother with high-dose glucocorticoids has been effective in preventing virilization of the affected female fetus […] The current approach is to treat all such mothers with glucocorticoids.” Again, the citation leads to Dr. New.
The end of that particular textbook’s entry actually gives the careful reader a clue that maybe all isn’t quite so simple. It reveals that in fact, “there are few data on long-term risks,” and notes that “a consensus conference recommended that only an experienced team direct this therapy, preferably under a research protocol, with consent and prospective and long-term follow-up of the children.”
But it is entirely possible that many obstetricians would not notice the deeply mixed message here, believing what they read first: “The current approach is to treat all such mothers with glucocorticoids.” Looks like standard of care.
In our new report in the Journal of Bioethical Inquiry (download for free here), we show that on at least one occasion, Dr. New actively resisted changing a very influential online NIH-sponsored textbook when the editors moved to revise the description of prenatal dex for CAH to stop portraying it as standard of care and start describing it as experimental.
It's entirely possible that many obstetricians who, in the last 10-15 years, considered this intervention simply did not wander far enough away from Dr. New’s influence field to see that, within Dr. New’s own field – pediatric endocrinology – physicians had been sharply warning against the use of prenatal dexamethasone for CAH outside of the strictest type of clinical trial, because of the risks and unknowns. The average obstetrician – even the average maternal-fetal medicine specialist OB – would probably not look so deep into the literature on CAH to see that one medical consensus after another described this intervention as experimental, not standard of care. They probably never saw the American Academy of Pediatrics' 2001 warning to Dr. New to remember thalidomide and DES.
Today, an OB doing a literature search might find the 2010 systematic review and meta-analysis that revealed a total absence of data on long-term metabolic safety and a near-total absence of scientific data even on efficacy. An OB searching today might find the 2012 report from a group of Swedish researchers revealing that they’ve stopped clinical trials in that country because those children exposed are found to have had a “severe adverse event” history of nearly twenty percent. A search today might turn up the 2012 article from two physicians explicitly warning genetic counselors that this intervention is not standard of care.
But odds are that, through the last decade at least, most OBs would not have known the real status of the intervention they were deploying when they gave pregnant women at risk for having children with CAH dexamethasone off-label. When in early 2010 I started this work, and in great agitation I told my History of Medicine class about it all, the students in my class who were earning their degrees in medicine and genetic counseling at my own university confessed to me that they had been taught that prenatal dexamethasone for CAH is standard of care. I'm sure the education occurring at my school is not special that way.
Whether an OB who got caught in this system can be successfully sued by a family whose child was hurt – that is a question that I fear the courts will soon answer. Morally, I don’t see how they could be seen as responsible. But if there’s one thing I’ve learned in this work, it’s that “legal” and “moral” are two different things.
I can’t conclude this without explaining the sick feeling I get whenever I read what the FDA official investigating our complaints determined in 2010. In his memo to the Office of Human Research Protections, Dr. Robert "Skip" Nelson wrote:
“The current administration of dexamethasone to pregnant women in order to prevent genital virilization in ‘at risk’ females does not constitute a ‘clinical investigation’ as the drug is being prescribed based on the clinical judgment of the women’s personal physicians who are then referring the women for follow-up in Dr. New’s IRB-approved research protocol.” (emphasis added)
You read that right. The logic there is that obstetricians went and made their OWN decisions about prenatal dex, and LATER just happened to send those patients who had been "treated" on to Dr. New, because I guess they just happened to know that Dr. New had applied and obtained federal funding for retrospective studies meant to determine whether the intervention actually is safe and effective.
So it was just the obstetricians out there making these risky decisions like there was nothing to it, and Dr. New helpfully cleaning up after them, using federal money to see if all these obstetricians had made bad decisions about prenatal dex, and hurt their patients.
If I were an obstetrician in this position, I'd feel pretty screwed by all of this. And this is what I've been trying to explain to reporters who seem confused when they say to me, "You're worried about the mothers and the children, right?" and I answer, "and the doctors. I'm really worried about the obstetricians." I wish Dr. Nelson at the FDA was worried about them, too.
In the next installment of the Dex Diaries, a physician explains how medical treatment, when combined with medical research, can be used to build a perpetual motion machine.