fetaldex.org

Frequently Asked Questions

 

If you have a question about prenatal dex that is not answered by this website, please use the “contact” button above. These FAQs are written by Alice Dreger.


Update, August 2012: In response to media inquiries about our new paper, Mount Sinai spokesperson Ian Michaels has said “the claims are ‘unfounded’ because New’s practices have been previously cleared by federal agencies and that the FDA has waived the need for dexamethasone to be approved as an ‘investigational new drug.’” He has also held up a 2010 AJOB paper as a defense. Our replies:


What about Mount Sinai’s point that we were criticized in the American Journal of Bioethics?

Our new paper shows why the AJOB paper was just plain wrong about the facts. Also note, the lead author of the 2010 AJOB piece works for Mount Sinai but he didn’t disclose his affiliation in the paper, and Mount Sinai is now also not disclosing that he works for them. (Mount Sinai must have one funny conflict-of-interest policy.) The FDA official who did the prenatal dex investigation also works for AJOB. For a complete unpacking of the AJOB connections, see this page.


What is our response to Mount Sinai’s appeal to the FDA IND exemption/waiver?

We don’t understand why Mount Sinai thinks that a letter from 1996 from the FDA which doesn’t even refer to the use of prenatal dexamethasone for the prevention of virilization in female fetuses somehow makes okay everything that’s happened here. We don’t think it does, but we think perhaps Mount Sinai hopes to confuse reporters by waving this document that Dr. New has also waved around. For a complete unpacking of the IND exemption question, go to this page.


What is our response to Mount Sinai’s claim that the feds cleared New’s practices?

We believe that to say that New’s practices have been cleared by federal agencies constitutes a gross misstatement of the OHRP and FDA responses. What the OHRP and FDA actually concluded was that they could see no grounds to proceed in terms of regulatory action. As we show in our Journal of Bioethical Inquiry paper, their conclusions were based on an inadequate investigation and a narrowly legalistic reading of the matter. It is at this point difficult for us to understand how the feds could look at the information we’ve now seen and have come to the conclusion that there was nothing more that could be done to protect these vulnerable patients/subjects.

According to the OHRP letter of September 2010 (download here), which appears to be based on MSSM’s 2010 response to the OHRP’s inquiries, “Since her arrival at MSSM [Mount Sinai School of Medicine] in 2005, Dr. New has conducted one study related to the use of dexamethasone in pregnant women at risk of carrying a female fetus with CAH that enrolled human subjects. This project, which was initially reviewed by a MSSM IRB in 2004, involved cognitive testing and outcomes follow-up on patients who either had or had not been treated with dexamethasone during the prenatal period. According to the protocol, the decision as to whether a pregnant woman was treated or not treated was not part of the study. We find nothing justifying a conclusion that the actions of the clinicians in treating those [pregnant] women should have been considered part of a clinical trial and subjected to IRB review. Dr. New was not the physician at MSSM for any of the cases included in her [follow-up] study.”

Yet via FOIAs of Dr. New’s NIH grant materials, she seems pretty clearly to speak of diagnosis and treatment on fetuses using prenatal dexamethasone for prevention of masculinization in females at Mount Sinai as part of her research program. For example, in her 2006 research progress, she reported, to the NIH, 27 diagnosed and/or “treated” fetuses at Mount Sinai (download that document here: 2006 grant progress galloping ahead.pdf).

We also found, via FOIA, a letter from the head of Mount Sinai’s IRB telling the NIH in 2004 that Mount Sinai had cleared New for a project called “Prenatal Diagnosis and Treatment” (Silverstein to NIH 2004 on New IRB approval.pdf). The suggestion has been that this was for an outcome study. But note that this IRB protocol’s title. It isn’t called “Long-term Outcomes of Prenatal Dexamethasone Treatment” or something like that. The fact that the title mentioned diagnosis seems to suggest it referred to a pregnancy study. The accompanying materials appear to confirm this.

See our paper for details on the grant claims regarding numbers of subjects of “prenatal diagnosis and treatment,” including one claim by New of 2,144 human subjects in that category. As we note in our paper, New periodically used the fact that “we are the only group in the U.S.A. routinely carrying out prenatal diagnosis and treatment of CAH” as a major reason why the government should fund her studies on the “large population of prenatally-treated infants” she had “accumulated.” This particular statement was made while she was still at Cornell, but once out Mount Sinai a decade later, she was still telling the NIH that her clinic was drawing patients from all over the United States.


This concludes our August 2012 update. Here are general FAQs on this issue:


What is CAH?

Congenital adrenal hyperplasia (CAH) is a serious endocrine disease that occurs in both males and females and typically requires lifelong hormonal management. Newborns are commonly screened for CAH because it can be a debilitating or even fatal disease in extreme forms if not treated. CAH causes the adrenal glands to be in high gear and to put out lots of androgens, which are sometimes called “masculinizing” hormones. The form of CAH that is at issue here is called 21-hydroxylase deficiency. (You can learn more about CAH at the CARES Foundation website.)


What else does CAH involve?

In females, some forms of CAH, including 21-hydroxylase deficiency, increase the likelihood that a girl will be “masculinized.” This means she may be born with atypical genitals (for example, a larger than usual clitoris). Girls with this form of CAH are also more likely to be tomboyish, and studies have shown they are more likely than the general population of females to be lesbian or bisexual and to be interested in traditionally male hobbies and occupations. They also, on average, have less interest in having children.


Why are some doctors interested in using dexamethasone to target these females prenatally (while they are fetuses in their mothers’ wombs)?

Some doctors advise women who are “at risk” for having a girl with 21-hydroxylase deficiency CAH to take dexamethasone prenatally. This intervention does nothing to prevent or cure CAH. The primary goal is to prevent the development of ambiguous genitalia in girls. Prenatal dex also may prevent the development of a confluence of the urethra and vagina (a urogenital sinus), a medical problem that occurs in some cases. Read more about that here. Some doctors have also suggested that prenatal dex might prevent these girls from being lesbian, tomboyish, male typical in their interests, and disinterested in being wives and mothers. Read about that here. This is an off-label use of a pregnancy category C drug that has been used starting as early as the second week of pregnancy.


What else has dexamethasone been used for?

Dexamethasone is also used for, and has been approved for, some post-birth uses. It has also been used sometimes prenatally for other uses, such as to help reduce risks associated with premature birth, but in that case, the dexamethasone is given much later in pregnancy when the brain is more mature and theoretically less vulnerable. Dexamethasone is not a “female hormone” as some have erroneously reported.


So what are your concerns?

Please see our “issues” page to understand our multiple concerns.


Isn’t prevention of ambiguous genitalia a legitimate medical issue?

A big clitoris or a small penis isn’t dangerous physiologically. It makes sense intuitively that having “ambiguous genitalia” might increase psychosocial risk of harm. But studies have not shown that, and indeed the evidence we have from people who have grown up with their atypical genitals intact suggest there is not an increased risk. (See this page for more.) It’s also important to understand that in the last 5 years, there has been a dramatic movement away from “corrective” genital surgery among physicians. See this major medical consensus as evidence. In other words, doctors now acknowledge that the supposed “need” for prenatal dex is not as great as they used to think.

Some girls born with CAH are born with a urogenital sinus, or a confluence of the urethra and vagina. These girls may require surgery to remain healthy in terms of urination, sexual function, and reproduction. It appears that prenatal dex can mitigate this problem for some females.  But not all girls with 21-hydroxylase deficiency are born with this problem, and it isn’t even clear that all those who are will need surgery.

Moreover, a urogenital sinus is not such a serious condition that it automatically justifies using a risky drug as early as the second week of pregnancy, especially given the number of fetuses treated who don’t even have the condition. Over 90% of the children exposed to prenatal dex in the first trimester for this purpose will derive no benefit, and all will be exposed to all the risks. Expert pediatricians we have spoken with have indicated that it would be highly surprising if the FDA Office of Pediatric Therapeutics were ever to decide that the risks of prenatal dex are justified simply by the offsetting of risk of urogenital sinus.

It’s important to understand that dex is a risky drug for both mothers and children exposed in utero. It isn’t at all clear to many doctors that prevention of ambiguous genitalia and a urethral-vaginal confluence is worth the serious risks of dex. It is also important to note that it is not known how successful dex is in preventing a urethral-vaginal confluence; we lack good data on the effectiveness of dex even for this purpose.


But don’t some doctors describe prenatal dex for CAH as safe and effective?

If so, especially at this point (since the Task Force findings and the Swedish outcomes report), we would be surprised and concerned. Again and again, expert medical societies have said that this off-label use of dexamethasone is risky and remains experimental. This consensus has only gotten more visible. You can read many examples of that here.


So what are the risks and unknowns of prenatal dex?

The Swedish study group -- the only group to ever study this intervention in a prospective controlled manner -- now reports that approximately 1 in 5 children exposed prenatally have suffered a serious adverse event. In a journal article detailing outcomes on 43 children treated in Sweden and Norway during 1985-1995, when compared to controls,

[i]n general, treated children were born at term and were not small for gestational age. As a group, they did not exhibit teratogenous effects/gross malformations, although eight severe adverse events were noted in the treated group, compared with one in the control group. Three children failed to thrive during the first year of life; in addition, one had developmental delay and hypospadias; one had hydrocephalus; two girls were born small for gestational age, and one of these girls was later diagnosed with mental retardation; and one child had severe mood fluctuations that caused hospital admission. In the control group, only one child was admitted because of Down’s syndrome.


How is it the Americans haven’t found an adverse effect rate of approximately 1 in 5? Probably because they haven’t looked. American physicians, under the guidance of Maria New, have done this intervention outside prospective controlled long-term studies, in spite of all the calls from all the medical groups over the years NOT to do it outside these kinds of studies.

As for the cognitive and behavioral outcomes, the Swedish team admits, “the small sample size, relatively high refusal rate, and the retrospective study design limited the conclusiveness of the results” of their follow-up of the behavioral development in 40 Swedish children treated prenatally. Nevertheless, they did find that:

[a]n adverse effect was observed in the form of impaired verbal working memory in CAH-unaffected short-term-treated cases [i.e., the children who were not the intended targets of the intervention]. The verbal working memory capacity correlated with the children’s self-perception of difficulties in scholastic ability, another measure showing significantly lower results in CAH-unaffected, DEX-exposed children. These children also reported increased social anxiety. In the studies on gender role behavior, we found indications of more neutral behaviors in DEX-exposed boys.

Remember that, according to a recent article in Endo Daily reporting on the Task Force that produced the latest consensus to label prenatal dex experimental, dexamethasone “crosses the placental barrier and may affect the fetal hypothalamic-pituitary-adrenal axis. Prenatal use of the drug is associated [with] low birth weight, central nervous system effects, cleft palate, liver enlargement, a decrease in fetal beta cells and other negative outcomes in animals. The human literature suggests that prenatal dexamethasone carries a 1.7 odds ratio for orofacial clefts and decreases birth weight by about 0.5 kg.”

The Endo Daily article continues: “because dexamethasone prenatal treatment is relatively new, no offspring have yet reached middle age where many problems can be expected to present.”

The Task Force’s report is cited here.


Why is there so little data on outcomes, when thousands of children have likely been exposed to this prenatal intervention?

Of 1,083 studies reviewed by a major medical task force in 2009-2010, only four of those studies were good enough to provide any meaningful scientific data. That is because Dr. Maria New and her collaborators have not been studying this drug use as they should have, in prospective, controlled, long-term clinical trials from start to finish. Instead, they’ve been describing the drug as safe, recruiting hundreds if not thousands of pregnant women with this claim of safety, and then studying mothers and children years later with questionnaires to see if the drug really was safe.

New’s chief collaborator in the follow-up reports, Heino Meyer-Bahlburg of Columbia University, admits that over half of those treated have not responded to requests for follow-up questionnaires. (What if the families not answering are not answering because they believe they were already harmed by these clinical researchers?) This is no way to study a drug specifically aimed a changing the bodies of fetuses. In the post-thalidomide, post-DES world, this is grossly irresponsible. And the American Academy of Pediatrics has said so.

Now we know, from the Swedish report, just how worried we need to be about what really happened to all those exposed.


Who were the members of the 2010 Task Force?  Was it comprised of radical activist groups?

Not unless you consider all the following co-sponsors “radical”: the American Academy of Pediatrics, the Lawson Wilkins Pediatric Endocrine Society, the Society of Pediatric Urology, the European Society of Endocrinology, the European Society for Pediatric Endocrinology, the Androgen Excess and PCOS Society, and the CARES Foundation. New’s chief collaborator, Heino Meyer-Bahlburg, is one of the authors on the paper. The lead author has also collaborated with New on papers about prenatal dexamethasone.


So all these pregnant women in the U.S. really were being used as experimental subjects without being told that?

This use of prenatal dexamethasone for CAH is off-label, which means it has NOT been determined by the FDA to be safe or effective for this use. Doctors can legally prescribe drugs off-label. But if they are running an experiment with an off-label drug, they must do so with Institutional Review Board (IRB) oversight to protect the research subjects. The women given the drug must also be advised that they are in an experiment, and advised of their rights and of the risks.

It appears that nearly all medical experts have agreed that this drug use is experimental and should only be done in controlled clinical trials with IRB oversight. The contrarian in this case has been Dr. Maria New, who has for many years described this use as “safe for mother and child” both at her own website and at the CARES website.

Please notice at both of those pages, Dr. New says she has “treated” over 600 women and says that she plans to follow them up to see what happened to them in the treatment. This suggests she sees them as research subjects. Indeed she has published papers about her “personal experience” with hundreds of these women and babies. Yet so far as we can ascertain, she was not enrolling these hundreds of pregnant women in clinical trials in which safeguards would have been in place to protect them and their babies.  She appears to have done a small clinical trial in the mid-90s (we’re still waiting for a response to our FOIA request to the OHRP to see what happened), but such a small trial would not account for the hundreds of women and babies New actually treated and studied later to see if prenatal dex had, in fact, hurt them.

Dr. New got federal funding to do the follow-up studies. She had IRB approval for the follow-up studies, which is not surprising because IRBs see little harm in follow-up questionnaire studies. But did she have IRB approval and patients’ informed consent to actually treat these hundreds of pregnant women with this experimental drug, while she was apparently telling these women the drug was “safe for mother and child”? (See the Time article for just two examples of women who seemingly were not informed that the drug was experimental and carried risks; we’ve run into more.)


Why did you and your colleagues contact the FDA Office of Pediatric Therapeutics and the federal Office for Human Research Protections?

Because we were extremely alarmed that Dr. New (and perhaps also non-expert clinicians misled by her statements?) is apparently working against a very clear consensus of experts, apparently treating women with this drug outside of IRB-approved clinical trials, promoting the drug as “safe for mother and child,” and loosing track of most of the patients before we even know what happened to them.

Ellen Feder of American University and I (Alice Dreger) contacted the OHRP, the FDA, and the relevant institutions in early February of 2009, along with 30 of our colleagues in bioethics and allied fields. I set up this website to triage information for those involved in working on this. You can read the various letters of concern and formal complaints at our correspondence page. That page also shows responses to letters of concern and complaints.


What other actions have you taken?

We have been working to figure out what happened here, so that researchers, regulators, and patient advocates can understand more about how systems designed to protect may fail. You can read some of the findings of our FOIA requests at our FOIA page. (We are still awaiting results of additional FOIA requests and appeals, and I have now sued the government over its failure to respond to our FOIA requests and appeals. We are awaiting the judge’s ruling on the case.) At the page on disseminating the truth about standards of care, you can read about what we’ve done to try to make sure health care professionals know the status of prenatal dex for CAH. We’ve also been publishing work on this.


Where do things stand with the OHRP and the FDA?

An excellent summary is available here. Also read our paper in the Journal of Bioethical Inquiry.


Do you really think such a prestigious individual at such a prestigious institution would put patients and science at risk like this?

You can read here about a prior investigation by the OHRP of Weill Cornell. Note that Dr. New was one of the researchers shown to be in violation of IRB regulations. You can read here about the $4.4 million fraud case settlement Dr. New was involved in, brought by the NIH, shortly before Dr. New left Weill Cornell. The case is described further here, referencing New’s NIH grant number 5M01RR006020: CornellGovernmentComplaint_000.pdf. Grant abstract here.

You can read at the following link about New’s request for salary support from the NIH, in which we learn “her circumstances changed abruptly this year when she had to relinquish the chairmanship of the Department of Pediatrics and the directorship of the Children’s Clinical Research Center at Weill-Cornell Medical School and the salaries entailed in these positions”: 7.02 NIH recommends salary support.pdf

Amazingly, it appears that New lost her position and salary at Cornell following a case of alleged fraud involving her NIH grant (which was settled, as noted above), and then she turned around and asked the NIH to help her out because she’d had to relinquish her salary (see this: 2.03 New requests salary support.pdf), and they apparently decided to give her money as a Merit Award (see this: 4.03 date WCMC salary stopped.pdf).


Why has Dr. New apparently told reporters she was not interested in preventing lesbianism?

We don’t know. See this page for lots of examples from her own publications, presentations, and grants.


Why has Dr. New apparently told reporters she had IRB approval and informed consent?

Dr. New has had approval to do follow-up studies, which consist, for example, of phone surveys. Few IRBs have a problem with phone surveys. But it appears she did not have IRB-monitored informed consent to treat hundreds and hundreds of pregnant women with the drug itself, which is much more serious.

It’s like this: Imagine a doctor tries a cardiac drug off-label on you, a drug use that the rest of the medical establishment says is dangerous and risky and should never be attempted outside IRB-approved clinical trials, if it should be attempted at all. (That’s what the medical establishment has been saying for years about prenatal dex for CAH.) Your doctor doesn’t tell you (and the hundreds of other patients he’s solicited through his private research foundation with claims that the off-label use is “safe”) that this is, in fact, generally understood to be very experimental and risky. Later the doctor calls you up, with the IRB’s permission, to say “Would you like to participate in a phone survey study where I ask you how you’re feeling now?”

Not OK. You have the right to know from the start that you’re being experimented on, to know the risks, and to be protected with the IRB from the start.

Why would Dr. New bother to arrange IRB approval and oversight for the phone studies? Doing so allowed her to publish the data she had collected. Otherwise many journals wouldn’t let her publish what she had found. She told them she had IRB approval. And she did. For the phone studies. But we don’t think she enrolled into IRB-monitored studies the hundreds (or thousands?) of women and children she later studied in the follow-ups. Needless to say, giving the drug is the much, much more dangerous (and ethically problematic) part of the process. And we know she never ran a proper prospective, controlled, long-term study like the Swedish team did.

Reporters are not finding women who knew they were essentially in an experiment. On the contrary, they’re finding women who had no idea. Discussion boards of parents and email I’m receiving also indicates more pregnant women who had no idea they were being given a risky, poorly studied, experimental off-label treatment.


What do you want to see done?

We want all the women offered prenatal dex for CAH to know that this drug is experimental; we want them to know the risks and unknowns before they agree to take the drug; like the medical establishment, we do not want to see them offered this drug outside of IRB-approved and IRB-monitored, controlled, prospective, long-term clinical trials.

We want all the women already treated with this drug for this use to be advised by our government of what happened to them and to be advised if their rights were violated.

We want to know what really happened to the brains and bodies of the children exposed in utero.

We want to see anyone (individual or institution) who violated these women’s rights to be held accountable.

We want to see that this never happens again, with any drug or procedure. If people are being experimented upon, they need to know that and to have their rights protected.


How did this all unfold?

Late in 2009, clinicians who felt impotent to stop what they saw as ongoing abuse contacted me and asked me to help. (“You’re an ethicist; do something.” I didn’t bother to explain this isn’t what ethicists do.) I took a look--not too hard for me to do quickly, since I started work in this field 15 years ago and know the lay of the land. As I looked at the medical literature, at the Web, and made calls to doctors and researchers who know their stuff, I was increasingly stunned and alarmed. I also reviewed some of the journal articles with my mate, a physician and medical educator, and he was equally alarmed. I dropped everything and called in my colleagues, and we did what we could to make sure “at risk” women and their children were being protected.

Our first concern was what appeared to be improper experimentation, and we worked immediately on that. As we worked on the project, Ellen Feder of American University, Anne Tamar-Mattis of Advocates for Informed Choice, and I became aware of two related issues which have garnered far more media attention, namely “clitoral sensory testing” being done on little girls by Cornell surgeon Dix Poppas, and suggestions by Dr. New and her colleagues that prenatal dex could be used to prevent lesbianism, low maternal interest, interest in traditionally-male occupations, etc. These issues are organized here.


Have you been criticized for speaking out like this?

Interestingly, we have only been openly criticized for our actions by clinicians who have engaged in these practices and in one “ethics” paper that appears at first glance to be led by independent critics, but isn’t. The lead author of that paper, Laurence McCullough, only mentioned in the paper his affiliation with Baylor College of Medicine. He did not disclose in the paper that he also works for Weill-Cornell and for a Bioethics Program that is funded by the Mount Sinai School of Medicine, the two institutions most implicated in our criticisms. Dr. McCullough also misrepresented to us the situation of the paper’s second author, Frank Chervenak, who works in and for the administration of Weill-Cornell. We found out some of the truth about Chervenak’s association with New through a FOIA request. Read about that here.


Who has funded your work?

Ellen Feder and I are funded by our universities (American University and Northwestern University, respectively) to do whatever work we deem appropriate to our appointments. I am effectively also funded by my mate, because he lets me work part-time so that I can do highly reactive, research-intensive work like this. The work of Anne Tamar-Mattis is funded in part through Advocates for Informed Choice.


Are things getting better for people with sex atypicality, in spite of what we’re reading about here?

I think so. If you’d like to read more about reforms happening within the medical system around issues of sex atypicality, go to the website of Accord Alliance.