issue: accurately disseminating standards of care


Imagine a scenario where a very charismatic, extremely prominent clinician assures pregnant women a drug treatment that is begun in the first few weeks of pregnancy is safe and effective, and where simultaneously lots of quieter, more clinically conservative clinicians are wringing their hands and trying to speak up with warnings, knowing the drug has not been shown to be safe, and could turn out to be really dangerous.

Who are the parents going to hear--the less well-known, less charismatic clinicians writing up their fears in hard-to-access medical journals, or the charismatic, reassuring clinician who shows up at their support groups with offers of a supposedly safe and effective treatment? Especially when that support group is giving that charismatic doctor awards and letting her use their newsletter to essentially advertise for her clinic?

Once I started pulling the papers that have been published about prenatal dex for CAH, I was pretty stunned to see there seemed to be two fairly distinct camps:

  1. Maria New and her immediate associations (e.g., Saroj Nimkarn) who described this treatment as if a standard of care (though when seeking money through a grant, New suggested the drug’s effects were still unclear);

  2. everyone else in medicine, who was warning that this treatment is so risky that, if it is done at all, it should only be done within IRB-approved clinical trials with written informed consent.

Maybe that’s an oversimplification, but here’s what I found when I went beyond New’s web-based direct-to-consumer promotion of prenatal dex, and looked to see what other clinicians thought about it:

1997, Secle and Miller: “we recommend that it be subject to prior approval and regulation by appropriate institutional review boards (IRBs).”

1999, Miller: “the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees.”

2001 Ad Hoc Writing Committee, Section on Endocrinology and Committee on Genetics of the American Academy of Pediatrics: “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.

2002, Ritzen: “future treatments should be undertaken as part of prospective clinical trials, approved by ethics committees. This will ensure correct information to parents about pros and cons of this treatment. Also, such studies will shorten the time until conclusive evidence for its safety has been collected, be it short-term treatment [...] or long-term.”

2002, Joint Statement of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society: “We believe that this specialized and demanding therapy should be undertaken by designated teams using nationally or multinationally approved protocols, subject to institutional review boards or ethics committees in recognized centers. Written informed consent must be obtained after the balanced review of the risks and benefits of treatment. Families and clinicians should be obliged to undertake prospective follow-up of prenatally treatment children whether they have CAH or not.”

2003, Hughes: “it must be recognised that prenatal treatment of CAH by maternal administration of dexamethasone remains experimental, and long-term effects are unknown. Thus, it is mandatory that all treated pregnancies be conducted as part of nationally organized clinical trials that include standardised monitoring both throughout the pregnancy and postnatally.”19

2004, Forest: “the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees at centres that see enough of these patients to collect meaningful data.”

2004, Lajic et al.: “we strongly feel that the efforts must continue to collect as much data as possible, and despite the long-term commitment and lack of immediate feedback, we maintain our standpoint and do not offer treatment outside the frames of the follow-up study.”

2008, Speiser: “The long-term safety of gestational dexamethasone should be monitored prospectively.”

2008, Miller: “It is this author's opinion that this experimental treatment is not warranted and should not be pursued, even in prospective clinical trials.”

(Citations available through this page.)

What’s the truth about the status of prenatal dex? The truth is that the major medical societies that have weighed in on it have consistently warned that it should be seen as an experimental treatment because the risks and unknowns remain high. Those warnings have only gotten louder. In the fall of 2010, the major pediatric and endocrine groups came together and again reiterated the experimental and risky nature of prenatal dex for CAH. You can read the news about that here and here.

So it looks like many clinicians have been trying to protect pregnant women and their children. Good! Well done! We’re proud of them. The problem is that they’re up against an 800-pound gorilla who apparently has been telling parents something else entirely about dex. So the clinicians are going to have to do even more to make sure parents and clinicians who might offer the treatment know that it is experimental, risky, and should not be conducted outside of IRB-approved clinical trials.

Meanwhile, I’ve been working with others to try to make enough noise that parents and clinicians know about the real status of prenatal dex. This past fall and summer, I worked with Taylor Sale, a genetic counselor and a student in our MA program, to try to get the word out to clinicians about the renewed consensus. Taylor figured out that a major target of our efforts needed to be the article on CAH at GeneReviews, an NIH-sponsored online kind of living textbook for genetic counselors and others. There, New and Nimkarn were describing prenatal dex as if it were essentially standard of care, even describing how to administer it.

Taylor and I contacted the editors of GeneReviews with the evidence for the medical consensus that prenatal dex is experimental. We also asked them to update the article by New and Nimkarn to reflect the 2006 consensus regarding the treatment of children with disorders of sex development, so that remarks about surgery, for example, were up-to-date in terms of the medical consensuses.

The editors were highly responsive, and I am happy to report that today the article by New and Nimkarn in GeneReviews statesPrenatal treatment should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial.”

So, New herself now admits this. Of course, this raises the question of how it can be that New is now telling her colleagues that this is the status of prenatal dex, while telling patients it has “been found safe for mother and child”. We have asked the FDA “Bad Ad” division why this apparent double-speak by New is allowed. We haven’t heard back from them yet.

Update: May 26, 2012: Journal of Genetic Counseling releases very helpful new article, “Prenatal Treatment of Congenital Adrenal Hyperplasia--Not Standard of Care.”

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(Written by Alice Dreger; copyright Alice Dreger, 2010)