fetaldex.org

letter to the CARES Foundation

 

Monday, February 22, 2010


Dina Matos, Executive Director

CARES Foundation

2414 Morris Ave., Suite 110

Union, NJ 07083


Dear Ms. Matos:


As you know, I wrote to you earlier regarding concerns about the CARES Foundation’s role in the promotion of prenatal dexamethasone for the prevention of ambiguous genitalia. I presume you shared that information with your Board of Trustees. I write today to you and your board on behalf of myself and Ellen Feder, Ph.D., Associate Professor and Acting Chair of Philosophy and Religion at American University.


To review, on February 3, 2010, thirty-two professional researchers in Bioethics and allied fields formally raised an alarm about the use of prenatal dexamethasone to prevent genital ambiguity. We communicated our concerns to: (1) the FDA Office of Pediatric Therapeutics; (2) the HSS Office for Human Research Protections; (3) Mount Sinai School of Medicine (Dr. Maria New’s home institution); (4) Florida International University (Dr. New’s secondary institution); and (5) Weill Medical School of Cornell University (where most of the work we are about to describe was based). Dr. Feder has served as our corresponding author on those letters.


We expressed our concerns regarding multiple aspects of this treatment, including most especially that hundreds of women and their fetuses (now children) may have been administered this risky Class C steroid off-label in what appears to have been a large human experiment but without the benefit of human research protections oversight from Institutional Review Boards (IRBs).


IRBs are meant to protect the rights of human research subjects, including the right to fully informed consent to participate in an experiment. IRBs also are designed to prevent experiments that researchers themselves do not realize are too dangerous or unnecessary to pursue. IRBs are also supposed to make sure that the maximum amount of scientific knowledge will be obtained from experiments on humans.


You should also know that IRBs tend to be especially concerned about experimentation on pregnant women since the DES and thalidomide travesties. You can safely assume the people who gave pregnant women DES and thalidomide never intended to harm them or their babies.


We want to be clear that we are not questioning the intentions of the prenatal dexamethasone researchers. They may very well have had nothing but the best of intentions. But it is out of the realization that “the road to hell is paved with good intentions” that IRB oversight has come to be required when humans are to be the subjects of medical experiments.


My colleagues and I have continued reviewing the papers published on the use of prenatal dexamethasone to prevent genital ambiguity. It continues to appear to us that the Cornell-affiliated group working under Dr. Maria New did not have IRB approval to run a treatment trial of prenatal dexamethasone, at least not in the vast majority of the many hundreds of cases. This means that hundreds of mothers and babies, many of them potentially recruited under the auspices of the CARES Foundation, may have been subjected to a risky experiment without being told that they were part of an experiment and without having proper ethics protections in place to safeguard their wellbeing and their rights.


There is enough ambiguity in the paper by Cerame, et al.1 that we think that that study may have involved IRB approval for a treatment trial of prenatal dexamethasone for CAH. The rest of the papers do not seem to indicate any IRB approval for a treatment trial of this drug during pregnancy. 


It appears that the Cornell-affiliated group may have had IRB approval at times to do various procedures around the prenatal dexamethasone treatment, for example, CVS, DNA analysis, and follow-up studies. Indeed, under Dr. New’s leadership, researchers published many times on the results, drawing systematic and generalizable conclusions.2-9


This suggests they should have gotten IRB approval to do the intervention at the center of this research, namely the off-label administration of this Class C steroid to pregnant women. It also suggests they should have known they should have gotten IRB approval to give pregnant women dexamethasone.


By 1999, through the Cornell-affiliated group lead by Dr. New, it appears there were at least 403 instances of diagnosis and treatment;7 by 2001, at least 532;8 by 2003, at least 600.10 There seems to have been a consistent pattern here of gathering data on the drug's effects and publishing on that data. All of this looks like a prospective treatment trial, which would of course require IRB approval and oversight. But, again, we don't see evidence of IRB approval and oversight for treatment trials of prenatal dex involving over 600 pregnant women and their fetuses. We believe their rights may therefore have been violated.


We are also alarmed by what appears to be the active promotion by Dr. New of this off-label use as “safe for mother and child.”10, 11 Some of this promotion has occurred specifically through the CARES Foundation. As we understand it, in response to our concerns, the FDA is now looking into this promotion. We have sent them the CARES Foundation material as part of our concerns about what has happened to these women and their babies.


We suppose a researcher like Dr. New might wish to argue that the drug use was not, in fact, experimental. That would seem to be belied by the substantial research and publication by Dr. New and her colleagues on the individuals treated via Dr. New2-9 which suggests New, et al. understood this to be highly experimental, at least for purposes of grants and publications. We recommend you see also the recent claim made by Dr. New, now at Mount Sinai, to the NIH: “The long-term effects of this treatment, however, have not been evaluated.”12 This suggests she knows this drug has not been shown to be “safe” since she is still asking for funding to find out whether or not it is safe. We must ask why, then, she is telling the CARES Foundation mothers that this drug has been shown to be safe.10, 11


Any argument that this drug was not experimental is also belied by the views of other prominent clinician-researchers as we summarize here chronologically. As you read the following statements, you must keep in mind that researchers’ call for “prospective” trials means they believe that the experiment must be understood to include the giving of the drug. Trials of this sort require active human subjects research protections (IRB oversight) designed to protect these women and their babies during the pregnancies, something that Dr. New does not appear to have secured.


1997, Secle and Miller: “we recommend that it be subject to prior approval and regulation by appropriate institutional review boards (IRBs).”13


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.”14


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.”15, 16


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.”17


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.”18


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.”20


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.”21


2008, Speiser: “The long-term safety of gestational dexamethasone should be monitored prospectively.”22


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.”23


The group working under the leadership of Dr. New seems to have been alone in considering this drug use on a very large number of pregnant women and their babies not experimental enough to run as a prospective treatment trial with IRB protections in place for these families, but experimental enough to follow quite extensively in studies, grants, and publications.


What has happened here appears to be a de facto treatment trial on many hundreds of pregnant women, without IRB oversight, at least some of whom appear to have been recruited via CARES with claims of safety and efficacy10 that we believe are inappropriate ethically, scientifically, and legally in terms of FDA regulation. This is very serious indeed. We hope we are wrong.


We are very disturbed, since we have reviewed a videotape of a 2001 presentation made by Dr. New to CARES, that Dr. New was using CARES to promote this drug as safe and effective when she knew that animal studies had not shown the drug to be safe or effective for this use. Her own papers had documented this.5 In that 2001 presentation, she assured the audience that rat studies had indicated problems in rats that had not yet been found in the human babies. But she did not mention what studies on primates (i.e., monkeys, much closer to our body types) had shown in terms of serious risks,24 even though she had reviewed that harm shown to monkeys in her own published papers by that time.5


Nor did she mention, in that 2001 presentation, that her own follow-up studies at that point had already shown harms to these children. Harms would later be confirmed by other researchers, including negative effects on verbal processing, memory, and anxiety levels.25


If we are correct in our understanding of what has happened, there are important ethical questions raised by the use of this population of mothers and children for the follow-up studies, particularly follow-up studies done by the New-affiliated group (which often have Dr. Heino Meyer-Bahlburg as a lead author). It may be ethically problematic to now use these women and their children as human subjects for follow-up studies of prenatal dexamethasone if these families became part of this “interesting” population by being misled or ill informed at the outset about the necessity, safety, and efficacy of this drug administration.


There are also important scientific questions raised by what appears to have been such a poorly controlled trial. If these studies were not run as real scientific trials from the start, as they should have been, then it is very hard to know what really happened during the pregnancies in which women were administered dexamethasone.


We are also very concerned by the disjuncture between what Dr. New advertises on her Foundation's website (“Dr. New maintains contact with all children treated prenatally”11) and the substantial number of patients missing from the follow-up studies on which she is a coauthor. Dr. New has made the same claim about continuity of contact with all patients to the CARES Foundation,10 even though her studies suggest otherwise.


Studies of prenatal dexamethasone give us substantial reason for concern for these mothers' and children's physical and mental well-being, particularly given that this usage is aimed at preventing a cosmetic issue (one not even shown to increase a girl’s psychosocial risk) and that 87.5% of the mothers started on prenatal dexamethasone will not even be carrying a fetus that is 46,XX 21-hydroxylase deficient.23 As mentioned earlier, studies have already shown some concerning adverse effects on exposed children.5, 25, 26


In addition, some researchers have raised concerns about possible epigenetic effects that might even impact the wellbeing of these children's children.25 Epigenetic effects are changes to genes that can be passed from generation to generation. The women given prenatal dexamethasone when pregnant may not have been told that they may even have been putting their grandchildren at risk by using dex during their pregnancy.27 We really don’t know what they have been told. When asked, this past January at a professional conference, by another pediatric endocrinologist, about what informed consent she obtains from pregnant women to whom she offers dex, Dr. New brushed off the question and refused to answer it.


We ourselves do not find evidence that animal studies have shown that prenatal dexamethasone is likely to be safe in humans; on the contrary, studies showing harm to animals exposed prenatally to dexamethasone have been used by the teams associated with Dr. New to try to figure out what defects they might find in the exposed children.9 This certainly looks to us like an improper move to human experimentation on pregnant women of a Class C steroid without satisfactory establishment of safety in animal studies. That this human experimentation may even be done without IRB oversight astonishes us.


Dr. New knows that researchers are not supposed to move to human experimentation until a drug has been shown safe in animal studies. She mentioned this specifically in her 2001 presentation to CARES when seemingly lamenting the NIH’s refusal to let her study gene therapy for CAH until it has been proven safe and effective in animals.


We were especially disappointed to see that, in her 2001 presentation to CARES, Dr. New alluded disparagingly to colleagues who had questioned her use of prenatal dex and apparently did not tell the CARES Foundation that those colleagues included a designated committee of the American Academy of Pediatrics. Just a few months before, that American Academy of Pediatrics committee actually felt the need to unanimously remind Dr. New that her own research had already shown dangers to mothers and children from this procedure.15 Why did she not inform the CARES Foundation about this warning?


We have provided a version of this letter to the other institutions whom we have already asked to conduct investigations, as well as to The Endocrine Society, the Lawson Wilkins Pediatric Endocrine Society, Drs. Phyllis Speiser and Walter Miller (with whom we had prior communication), and Columbia University (the institution of Heino Meyer-Bahlburg, the lead author of many of the follow-up studies). We will also put a copy of this online so that others may aid in this investigation. Many researchers are now already going over the papers to learn more.


We call upon you to join us in asking for the investigation into possible violations of ethical and scientific standards in this off-label promotion and use of prenatal dexamethasone on vulnerable pregnant women. We also ask you to work to immediately ensure that all women who have been exposed to this off-label use during pregnancy now be told what is now known about the risks and harms of prenatal dexamethasone to mothers, children, and non-human animals.


We also call on you to agree publicly with us that this experimental treatment should cease immediately and that extensive follow-up studies on the mothers and children used in this major human experiment should be conducted by researchers independent of Drs. New and Meyer-Bahlburg. We presume we do not need to remind you, as the AAP suggested in their communication, how long it took before the realities of DES and thalidomide became well-known enough to stop their usage. We do not want to see the CAH population go down in history as the DES and the thalidomide populations have.


Finally, we admit to being quite disturbed at the idea of the CARES Foundation giving Dr. New a “pioneer” award in the coming weeks. We ask you to consider your fiduciary responsibility to the CAH-affected population as well to ethical science. It is possible, of course, that you did not know much of this before our letter, but now you know. If you believe that anything we have said here is inaccurate, we would certainly like to know.


Thank you for your consideration of this letter. Please feel free to share this research and communication as you deem necessary.  


Signed:


Alice Dreger, Ph.D. (corresponding author)

Professor of Clinical Medical Humanities and Bioethics 

Feinberg School of Medicine

Northwestern University


Ellen K. Feder, Ph.D.

Associate Professor and Acting Chair

Department of Philosophy and Religion

American University




Notes:


1.Cerame BI, Newfield RS, Pascoe L, et al. Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia. J Clin Endocrinol Metab 1999;84:3129-34.

2.Speiser PW, Laforgia N, Kato K, et al. First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 1990;70:838-48.

3.Karaviti LP, Mercado AB, Mercado MB, et al. Prenatal diagnosis/treatment in families at risk for infants with steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). J Steroid Biochem Mol Biol 1992;41:445-51.

4.Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1995;80:2014-20.

5.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.

6.Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI. Mothers' reactions to prenatal diagnostic procedures and dexamethasone treatment of congenital adrenal hyperplasia. J Psychosom Obstet Gynaecol 1996;17:175-81.

7.Carlson AD, Obeid JS, Kanellopoulou N, Wilson RC, New MI. Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol 1999;69:19-29.

8.New MI, Carlson A, Obeid J, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86:5651-7.

9.Meyer-Bahlburg HF, Dolezal C, Baker SW, Carlson AD, Obeid JS, New MI. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. J Clin Endocrinol Metab 2004;89:610-4.

10.Kitzinger E. Prenatal diagnosis & treatment for classical CAH (at http://www.caresfoundation.org/productcart/pc/news_letter/winter02-03_page_9.htm). In: CARES Foundation Newsletter; 2003.

11.New M. Prenatal diagnosis and treatment of congenital adrenal hyperplasia (at http://www.newchf.org/testing.php). In: The Maria New Children's Hormone Foundation; 2010.

12.New M. Determining the long-term effects of prenatal dexamethasone treatment in children with 21-hydroxylase deficiency and their mothers (at http://clinicaltrials.gov/ct2/show/NCT00617292). In. Mount Sinai Medical Center: NIH Office of Rare Diseases; 2008.

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

14.Miller WL. Dexamethasone treatment of congenital adrenal hyperplasia in utero: an experimental therapy of unproven safety. J Urol 1999;162:537-40.

15.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.

16.Erratum. (at http://pediatrics.aappublications.org/cgi/content/full/107/6/1450). Pediatrics 2001;107:1450.

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

18.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.

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

20.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.

21.Lajic S, Nordenstrom A, Ritzen EM, Wedell A. Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 2004;151 Suppl 3:U63-9.

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

23.Miller WL. Prenatal treatment of classic CAH with dexamethasone (con). Endocrine News (Tri-Point Series) 2008:16-8.

24.Uno H, Eisele S, Sakai A, et al. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav 1994;28:336-48.

25.Lajic S NA, Hirvikoski T. Long-term outcome of prenatal treatment of Congenital Adrenal Hyperplasia. In: WL FCaM, ed. Disorders of the Human Adrenal Cortex. Endocrine Development ed. Basel: Karger; 2008:82-98.

26.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.

27.Drake AJ, Tang JI, Nyirenda MJ. Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease. Clin Sci (Lond) 2007;113:219-32.




Update: On Feb. 23, 2010, the CARES Foundation answers that their board will discuss our concerns.