fetaldex.org Letter of Concern From Bioethicists

By . First posted . Last updated

The following letter has been sent to:

  1. the FDA Office of Pediatric Therapeutics;
  2. the HHS Office for Human Research Protections;
  3. Mount Sinai Medical Center (Dr. New’s current institution);
  4. Weill Medical School of Cornell University (from which much of this treatment appears to have been administered, under Dr. New’s guidance);
  5. Florida International University (where Dr. New is Associate Dean for Clinical Research).

Dear Sir or Madam:

We write to express our grave concern over possible non-IRB-approved clinical research on pregnant women that has been conducted under the auspices of Mount Sinai Medical Center and Weill Cornell Medical College, Cornell University, under the direction of Dr. Maria New.

This work involves off-label administration of dexamethasone to pregnant women who may give birth to girls with Congenital Adrenal Hyperplasia (CAH). It is our understanding that Dr. New has long prescribed dexamethasone for purposes of preventing genital virilization associated with CAH in 46,XX females. This indication is not approved by the FDA. Genital virilization is a cosmetic issue, one that has been recognized within Dr. New’s field as independent of the genuine medical concerns – often serious and life-threatening in some forms of CAH–unaddressed by prenatal dexamethasone treatment. That is to say, prenatal treatment with dexamethasone is intended to avoid a cosmetic issue associated with CAH, rather than to treat the medical issues that should be the primary concern of physicians.[1] Furthermore, use of prenatal dexamethasone has been demonstrated to bear significant iatrogenic risk.[2]

Off-label use of prescription medication is a long-time practice of medicine that has not been understood to constitute research requiring IRB oversight. We do not take issue here with the practice of off-label prescribing in general. We are concerned instead with a particular instance of what appears to constitute a de facto clinical trial involving many hundreds of patients now among the targeted “subjects” of long-term research. In clear violation of established bioethical protocols, these pregnant women appear to have been recruited (and perhaps are still being recruited) without the benefit of IRB oversight.[3]

In professional contexts among her peers, Dr. New has publicly resisted discussion of the details of the information pregnant women and their partners are provided. One online promotion of the treatment with dexamethasone administered by Dr. New’s clinic nevertheless promised that follow-up with hundreds of children treated prenatally over 20 years “has found no adverse developmental consequences….the treatment appears to be safe for mother and child.”[4]

Human studies have demonstrated, on the contrary, that prenatal dexamethasone treatment results in detrimental changes to the brains of children,[5] over 90% of whom will receive no benefit from this treatment. (Only 1 in 8 fetuses started on this treatment are actually 46,XX CAH, and of the 1/8 who are, 20% will not benefit from the treatment.) Children exposed prenatally to dexamethasone for CAH show problems with working memory, verbal processing, and anxiety.[6] Animal studies have also indicated reason to be very concerned about prenatal dexamethasone’s effect on fetal brains.[7] Therefore, contrary to the apparent claims aimed at prospective patients, dexamethasone treatment cannot responsibly be characterized as benign.[8]

Despite knowledge of risks to fetal development, it does not appear that physicians prescribing this drug to hundreds of women have sought IRB approval for clinical trials of dexamethasone for the purposes of minimizing genital virilization in 46,XX females at risk for CAH in utero. Pregnant women who have been prescribed dexamethasone external to IRB-approved trials may not have provided fully informed consent as would happen formally under an IRB-approved trial. Public descriptions of this drug as safe and effective may have misled some women to believe the use is FDA-approved, when it is not.

Given the well-established risks to fetal development, physicians should initiate treatment of this type only through structured clinical trials with human subjects research protections in place. Registered clinical trials ensure that women and their families make fully informed decisions with respect to the risks they assume for themselves and on behalf of their future children. Studies such as these also ensure that adverse effects will be noticed as soon as possible, and that any harm that comes to women and their children provide the benefit of increased scientific knowledge that can subsequently protect other women and babies from the same harms.

We call for rigorous investigation into possible regulatory violations in this matter. We also believe that women who have been treated without the protection of IRBs should now be advised of the information that may not have been made available to them at the time of treatment, and that they should be given the most recent information from studies indicating long-term risks to women and children. Finally, we agree with Dr. Walter Miller, Distinguished Professor of Pediatrics and Chief of Endocrinology at the University of California San Francisco, who has written that “this experimental treatment is not warranted and should not be pursued even in prospective clinical trials.”[9]

Citations:

[1] Miller WL. “Dexamethasone treatment of Congenital Adrenal Hyperplasia in utero: an experimental therapy of unproven safety.” J Urol 1999;162:537-40.
[2] National Institutes of Health Consensus Development Panel, “Antenatal Corticosteroids Revisited: Repeat Courses. National Institutes of Health Consensus Development Conference Statement, August 17-18, 2000.” Obstet Gynecol 2001;98:144-50.
[3] Kitzinger E (Weill Medical School of Cornell University). “Prenatal Diagnosis & Treatment for Classical CAH.” CARES Foundation, Winter 2003.
[4] Ibid.
[5] French NP, Hagen R, Evans SF, Mullan A, Newnham JP. “Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior.” Am J Obstet Gynecol 2004: 190:588-95.
[6] See, for example: [a] Hirvikoski T, Nordenstrom A, Lindholm T, et al. “Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone.” J Clin Endocrinol Metab. 2007;92:542-8; and [b]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;20:439-449.
[7] Uno H, Eisele S, Sakai A, et al. “Neurotoxicity of glucocorticoids in the primate brain.” Horm Behav 1994;28:336-48.
[8] Lajic S, Nordenstrom A, Hirvikoski, “Long-term outcome of prenatal treatment of congenital adrenal hyperplasia.” In Fluck CE and Miller WL (eds): Disorders of the Human Adrenal Cortex. Endocr Dev. Basel: Karger, 2008, vol. 13:82-98.
[9] Miller W. “Prenatal treatment of classic CAH with dexamethasone: pro vs. con.” Endocrine News Tri-Point Series 2008: 16-18. [Part 1 and Part 2.]

Signed:

  • Ellen Feder, Ph.D., American University (corresponding author)
  • Alice Dreger, Ph.D., Northwestern University’s Feinberg School of Medicine
  • Hilde Lindemann, Ph.D., Michigan State University
  • Shannon B. Lundeen, Ph.D., University of Pennsylvania
  • James Lindemann Nelson, Ph.D., Michigan State University
  • Gaile Pohlhaus, Ph.D., Miami University
  • Lawrence J. Nelson, Ph.D., J.D., Santa Clara University
  • Mark Sheldon, Ph.D., Northwestern University
  • Sharon E. Shannon, Ph.D., R.N., University of Washington
  • Susan Sherwin, Ph.D., Dalhousie University
  • Shari Stone-Mediatore, Ph.D., Ohio Wesleyan University
  • Elizabeth Reis, Ph.D., University of Oregon
  • Kathryn Montgomery, Ph.D., Northwestern University’s Feinberg School of Medicine
  • Kenneth Kipnis, Ph.D., University of Hawaii at Manoa
  • Sophia Wong, Ph.D., Long Island University, Brooklyn Campus
  • Katrina Karkazis, Ph.D., M.P.H., Stanford University
  • Kathryn Hinsch, M.S., Founder and President of the Women’s Bioethics Project
  • Anna Gotlib, J.D., Ph.D., Binghamton University (SUNY)
  • Gillian K. D. Crozier, Ph.D., Loyola University Chicago
  • Kimberly Leighton, Ph.D., American University
  • Sally Haslanger, Ph.D., Massachusetts Institute of Technology
  • Ellen M. McGee, Ph.D., Long Island University (ret.) and Long Island Center for Ethics (emeritus)
  • Joan McGregor, Ph.D., Arizona State University
  • Cheryl D. Lew, M.D., M.S.Ed., F.A.A.P. Childrens Memorial Hospital, Los Angeles
  • Suzanne Kessler, Ph.D., Purchase College (SUNY)
  • Miriam Solomon, Ph.D., Temple University
  • Richard Ashcroft, Ph.D. University of London
  • Anne Fausto-Sterling, Ph.D., Brown University
  • Udo Schuklenk, Ph.D., Queen’s University (Ontario)
  • Rory E. Kraft, Jr., Ph.D., York College of Pennsylvania
  • Rebecca Kukla, Ph.D., University of South Florida
  • Mark Lance, Ph.D., Georgetown University

Additional supporters of inquiry (offered to sign after letters had already gone in):

  • M.Carmela Epright, PhD., Furman University
  • Zahra Meghani, Ph.D., University of Rhode Island
  • Sonya Charles, Ph.D., Cleveland State

This letter is online at http://fetaldex.org/letter_bioethics.html