Still Concerned

Alice Dreger, Ellen K. Feder, and Hilde Lindemann

(published in the American Journal of Bioethics, vol. 10, no. 9, Sept. 2010)

We would have been very happy had McCullough et al. shown that we never had anything to worry about. Instead, their paper has given us additional reasons for concern.

Before we get to that, we would like readers to note that, although the target article names us as unethical, AJOB sent us no invitation to respond. We learned of this paper through the standard mass e-mail. Like everyone else, we had to apply to be allowed to submit a commentary. To our knowledge, the commentaries of at least two clinician-researchers critical of the Target Article were not accepted, which leaves us wondering why those with relevant medical and scientific expertise weren’t allowed to weigh in to correct key errors and omissions.

In addition, one business day after receiving the mass mailing, Alice Dreger notified the authors and AJOB’s editor, Glenn McGee, that the title, abstract, and paper misrepresented the domain name fetaldex.org as being some kind of organization, perhaps equating to the LoC’s signatories. Dreger offered help to fix the abstract and paper simply to correctly attribute actions the paper deems unethical. That way no researcher would be wrongly accused, implicitly or explicitly. McGee and the authors did change the paper’s subtitle and, after much pressing from Dreger, altered some of the paper, but they did not fix the muddled accounting of actions.

[NB from AD: McCullough also did not disclose in the article that he works for Weill-Cornell and for Mount Sinai School of Medicine, the two institutions at the center of the investigation he insisted we call off! He only disclosed his Baylor affiliation. Nor did AJOB think it important to explain to readers that one of the other authors, Frank Chervenak, works in and for the administration of Cornell. How very ironic that Weill Cornell calls McCullough and Chervenak “world leaders in prenatal medical ethics.”]

This is not the only reason the target article represents an exercise in irony. But it is surely ironic that the authors have refused to clarify basic facts in a paper in which they argue that misrepresentations are unethical. The authors might claim that they can’t understand the plain language on the “about” page of fetaldex.org (“[This site...]is personally funded by Alice Dreger. Unless otherwise indicated by signatures, all material is written by Alice Dreger.”) But we are baffled as to why they will not get the facts right now. Perhaps they are doing a participation-observation experiment in what they’ve called “unethical transgressive bioethics.”

The authors accuse us of selectively using the literature in raising our concerns. Indeed, they seem to require that systematic reviews be completed before anyone raises the possibility of an IRB violation. Leaving that weird logic aside, we again see irony here, because the authors have selectively used the literature in making their arguments. We will just point to particularly egregious instances.

First, the authors cite Maria New’s work to prove that New has long been studying and publishing on the long-term effects of prenatal dex, drawing systematic and generalizable conclusions with IRB approval for New’s many follow-up studies. But they fail to ask (as we have) why she apparently did not seek IRB permission to treat the drug administration itself as experimental.

McCullough et al. reveal to us New’s apparent excuse for not having IRB approval: she actually wrote only one script for prenatal dex. So why does The Maria New Children’s Hormone Foundation boast to prospective patients that “She has treated over 600 pregnant women at risk for the birth of a CAH-affected child”? (http://www.newchf.org/testing.php) And why do McCullough et al. laud New’s IRB approval for the follow-up studies and not ask, as we have, why these women didn’t have the benefit of IRB oversight when they were actually given the drug after being recruited by Cornell via New’s own foundation and via the CARES Foundation with assurances that this off-label use is “safe for mother and child”?1 (See also http://www.newchf.org/testing.php.) That the authors report that New in fact only wrote one prescription makes us worry that she pushed all of the risk onto obstetricians who may have had no idea what they were a part of and none of the expertise required to inform patients of the risks and unknowns.

The authors also fail to note that Dr. New’s own papers on prenatal dex began to speak of risks and worrisome unknowns as far back as 1995.2 And yet apparently this acknowledgment did not move her to consistently protect these women and children by making sure there was IRB oversight for the drug administration. McCullough et al. also don’t mention that in 2001 a committee of the American Academy of Pediatrics (AAP) felt the need to remind Dr. New in Pediatrics that her own research indicated that the drug should be treated as experimental in the prenatal period:

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.3 [emphasis added]

McCullough et al. do not mention why the AAP might invoke the memory of DES: evidence that dexamethasone may involve epigenetic risks, meaning that these women’s grandchildren may also be affected by the drug. McCullough et al. also do not mention that the AAP’s take—that prenatal dexamethasone for CAH should be treated as experimental—was shared by many others, including Seckl and Miller (in 1997),4 Ritzen (2001),5 Hughes (2003),6 and Speiser (2008).7 McCullough et al. do not mention that the French physician who pioneered the treatment stated in 2004 that “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.”8

Astoundingly, McCullough et al. quote the Joint LWPES/ESPE statement to show that “there is substantial difference of opinion concerning whether prenatal treatment of CAH is a research endeavor,” but do not mention that the joint statement concludes:

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 treated children whether they have CAH or not.9

We have recently learned that this fall, consensus guidelines will be published which, after articulating the considerable risks and unknowns of this treatment, conclude that this prenatal therapy should only be pursued through IRB-approved clinical trials “at centers capable of collecting outcomes data on a sufficiently large number of patients so that risks and benefits of this treatment can be defined more precisely.”10 This consensus is endorsed by the AAP, LWPES, ESPE, the European Society for Paediatric Endocrinology, the Society for Pediatric Urology, the Androgen Excess and PCOS Society, and the CARES Foundation, and its writing predated our actions by at least six months (see http://www.endo-society.org/advocacy/insider/ClinicalPracticeGuidelineonCAHApprovedbySociety.cfm). [See also http://www.endocrinetoday.com/view.aspx?rid=76649 and see http://www.nxtbook.com/tristar/endo/day4_2010/index.php?startid=8.]

Finally, the irony of the authors’ use of Socrates makes us wince, as much of their criticism engages in just the sort of sophistry Socrates opposed. While more than delighted to engage in valid argumentation (and we believe we have done so), we hope we are putting such arguments to better use than McCullough et al. do, by asking what really happened to these women and their children.

The target article gives us so many reasons for concern. Nowhere do the authors consider any of the effects on the women being given this drug. Nowhere do they join us in wondering exactly what consent looked like when women were given this drug. As proof that we should not be worried, McCullough et al. cite a textbook that speaks of prenatal dex as standard of care, yet this makes us far more worried! Do the textbook authors know how many physicians have raised questions about the experimental nature of this drug and the fact that, although Dr. New regularly boasts to parents that she “maintains contact with all the children [she] treated prenatally” (http://www.newchf.org/testing.php), most are missing from her outcome studies?

McCullough et al. refer to “the virilization of the brain [as] an ‘irreversible’ complication” as if it is a reason to justify prenatal dex. Are they—and New, and other clinicians—really thinking that it’s a good idea to use prenatal dex because otherwise girls are more likely to end up tomboyish, aggressive, and lesbian? And why didn’t McCullough et al. tell their readers that these are presumably the “brain complications” they’re worried about? (Insert a “hmm” in the style of Rachel Maddow here.)

Since the authors are in communication with Dr. New, and the second author is Chairman of OB/Gyn and Director of Maternal Fetal Medicine at Weill-Cornell—the institution most implicated in the investigation he wants us to call off—we wonder if they can get some questions answered for us. What did consent consist of in these cases? Does Dr. New pay herself from her private foundation, so that she stands to directly profit by recruiting more potential research subjects? Did Dr. New leave Cornell for some reason other than her involvement in the fraud case with the NIH that cost Weill-Cornell a $4.4 million settlement, as reported in the Wall Street Journal?11

We have not been given the space to point out and answer the many problems in logic, history, and medicine in the target article. We encourage the reader to understand that just because we did not answer a charge does not mean we could not. We would like to conclude, though, by pointing out that volleying accusations of immorality or (for some of us, worse still) bad philosophy back and forth is ultimately unproductive, as it diverts attention away from the worry that resulted in the Letter of Concern in the first place: as far as we can tell, the pregnant women who continue to subject themselves and their fetuses to medically questionable and possibly dangerous steroids may not have been adequately informed before giving consent to prenatal dexamethasone treatments.

1.Prenatal diagnosis & treatment for classical CAH. 2003. (Accessed at http://www.caresfoundation.org/productcart/pc/news_letter/winter02-03_page_9.htm.)

2.Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 1995;20:439-49.

3.Frias J LL, Oberfield SE, Pang S, and Silverstein J. For the AAP Ad Hoc Writing Commitee, in reply to Maria New. Pediatrics 2001;107:805.

4.Seckl JR, Miller WL. How safe is long-term prenatal glucocorticoid treatment? JAMA 1997;277:1077-9.

5.Ritzen EM. Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol 2001;6:357-62.

6.Hughes IA. Management of fetal endocrine disorders. Growth Horm IGF Res 2003;13 Suppl A:S55-61.

7.Speiser PW. Prenatal treatment of classic CAH with dexamethasone (pro). Endocrine News (Tri-Point Series) 2008:15-6.

8.Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update 2004;10:469-85.

9.Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW. Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res 2002;58:188-95.

10.Speiser PW, Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T., Merke, D., Meyer-Bahlburg, H., Miller, W., Montori, V.M., Oberfield, S.E., Ritzen, M., and White, P.C. A summary of the Endocrine Society Clinical Practice Guidelines on Congenital Adrenal Hyperplasia due to steroid 21-hydroxylase deficiency. International Journal of Pediatric Endocrinology 2010.

11.Wysocki B. As Universities Get Billions in Grants, Some See Abuses: Cornell Doctor Blows Whistle over Use of Federal Funds, Alleging Phantom Studies. Wall Street Journal 2005:A1.