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Purpose: This website seeks to raise awareness regarding the prenatal use of dexamethasone, a Class C steroid, which is sometimes given to pregnant women to attempt to prevent female fetuses from developing genitals that are more in-between the male and female types and (among some clinicians, we think) to also prevent female fetuses from being psychologically “masculnized,” i.e., tomboyish, more aggressive than average girls, and ultimately lesbian in sexual orientation. Our major concern is that women given this drug may have been experimented upon without their knowledge and without human research protections.
Which fetuses are targeted: Prenatal dexamethasone is recommended by some physicians to pregnant women who are believed to be “at risk” for having a female fetus with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia (CAH). In CAH, the adrenal glands produce abnormally high levels of androgens, which are sometimes called “masculinizing” hormones. This form of CAH can result in a girl being born with genitals that look in-between the male and female types (e.g., she may have a large clitoris) and with a confluence of her urethra and vagina (which can cause medical problems for her). Studies have also indicated that these girls’ brains are “masculinized” in the womb, meaning that, on average, they are also more likely than other girls to be tomboyish and to grow up to be lesbian in sexual orientation.
What is the purpose of the prenatal dexamethasone treatment? Importantly, CAH is a serious endocrine disease (a hormone imbalance) which prenatal dexamethasone does absolutely nothing to cure. A child with CAH who was treated with prenatal dexamethasone is still born with CAH and must have lifelong endocrine management to be safe.
So why is prenatal dexamethasone used? There is one legitimate medical issue that prenatal dexamethasone can help prevent in CAH, namely the development of a joined urethra and vagina. Girls with that type of development can have problems with infection and problems with sexual intercourse. But not all girls with 21-hydroxylase deficiency are born with this problem, and this does not appear to be the major reason prenatal dexamethasone is prescribed. Most clinicians who support its use speak of it as being used to prevent the development of “ambiguous genitalia,” including the development of a big clitoris, which has not been shown to be a medical problem.
And it looks from some of the medical literature and some presentations to parents groups like some clinicians are hinting that prenatal dexamethasone may also prevent daughters who are tomboyish or lesbian. For example, Claude Migeon of Johns Hopkins University has noted that prenatal dexamethasone “would eliminate the need for plastic surgery as well as the poor results often observed after [surgical] reconstruction of the genitalia. It could also avoid the masculinization of the fetal brain which [...] might be related to an unusual sexual behavior of some subjects.” He noted that doctors can’t yet be sure prenatal dexamethasone will prevent lesbianism: “Despite these early encouraging results, we do not have any appreciation of long range effects on the intellect of these children. Nor do we know whether the psychosexual orientation of the adult patients will be different from that reported in our survey of CAH women.”
Heino Meyer-Bahlburg of Columbia University has written that “Long term follow-up studies of the behavioral outcome will show whether dexamethasone treatment also prevents the effects of prenatal androgens on brain and behavior and thereby put the psychoendocrine assumptions [about gender and sexual orientation] to a test.” This does not mean Meyer-Bahlburg is suggesting homosexuality be prevented, but he is suggesting it might have a preventable component. In the same paper, Meyer-Bahlburg notes, “CAH women as a group have a lower interest than controls in getting married and performing the traditional child-care/housewife role. As children, they show an unusually low interest in maternal play with baby dolls, and their interest in caring for infants, the frequency of daydreams or fantasies of pregnancy and motherhood, or the expressed wish of experiencing pregnancy and having children of their own appear to be relatively low in all age groups.”
In a 2001 presentation to parents at a CARES Foundation meeting, of which we have obtained a videotape, Maria New (then of Weill Medical College of Cornell University) told parents, “the challenge here is [...] to see what could be done to restore this baby to the normal female appearance which would be compatible with her parents presenting her as a girl, with her eventually becoming somebody’s wife, and having normal sexual development, and becoming a mother. And she has all the machinery for motherhood, and therefore nothing should stop that, if we can repair her surgically and help her psychologically to continue to grow and develop as a girl.”
In the same presentation, Kelly Leight, then director of CARES, asked New, “isn’t there a benefit to the female babies [treated in utero with dexamethasone] in terms of reducing the androgen effects on the brain?” And New answered, “You know, when the babies who have been treated with dex prenatally get to an age in which they are sexually active, I’ll be able to answer that question,” i.e., whether they “benefitted” from dex by turning out heterosexual.
So what are the issues here? Why all the fuss? This use of prenatal dexamethasone is not FDA approved, and yet Dr. Maria New has (against FDA regulations) long described this drug to prospective, vulnerable patients as “safe for mother and child.” In fact, this drug is recognized by many major medical societies as being extremely risky, full of unknowns, and highly experimental. Yet Dr. New has recruited hundreds of women to this treatment with the claim that it is safe, and then studied them later to see if it really is safe. This appears to violate ethics rules in place to protect human research subjects, especially pregnant women. It isn’t clear that any human research oversight board (IRB) would even allow this drug to be tested experimentally if she or other researchers asked to be allowed to do so, because it is so risky compared to the benefits, and because so many unaffected fetuses end up treated, because the drug must be given before a doctor can know if a woman is really carrying a fetus who is affected.
There would also be an ethical problem here if doctors are suggesting the use of this drug to prevent “conditions” which are not medical problems (e.g., tomboyism, lack of interest in having babies and getting married, lesbianism, and big clitorises).
Why controlled clinical trials exist, especially for pregnant women: It appears to be universally understood, since the thalidomide travesty, that pregnant women who are subject to pharmaceutical experimentation aimed at treating their pregnancy, or treating their fetuses via them, should be enrolled in formal clinical trials with IRB (Institutional Review Board) oversight. Such clinical trials ensure that; (a) these pregnant women are given the protections afforded to human subjects of research by the federal government and local institutions; (b) researchers can quickly become aware of adverse affects to mothers and babies, so that, if necessary, they can stop the experiment before others are harmed; and (c) the maximum amount of scientific data can be gathered from the treatments, so that those mothers and babies whose health and lives are put at risk for medical science at least can rest assured that the methods being used will maximize the scientific learning which may then benefit others.
The off-label use of dexamethasone at issue: Dexamethasone, a Class C steroid, is administered in the U.S. “off label” by some clinicians in an effort to stop the possible “masculinization” of the genitalia of female (46,XX) fetuses who have the form of congenital adrenal hyperplasia (CAH) known as 21-Hydroxylase Deficiency. As noted above, this indication is not approved by the FDA. Dr. Phyllis Speiser of Schneider Children’s Hospital in New York, who has published a “pro” statement of this treatment, says these girls suffer from “disfiguring genital ambiguity,” such that consideration of the off-label treatment is warranted. The central goal of at least some prominent clinicians using fetal dex appears often to be to end up with a girl who is born with female-typical genitalia and a female-typical brain.
Yet, to our knowledge, in the vast majority of cases, the off-label prenatal dexamethasone treatment for CAH, which is widely recognized as experimental and is specifically aimed at engineering the bodies of fetuses, has apparently not been occurring in the U.S. under the structure of formal clinical trials. If this is the case, most if not all of the women being given this drug are being denied the protections of the regulations designed to safeguard the lives of human subjects of clinical trials. These pregnant women appear to be being used as experimental subjects without being granted the rights accorded experimental subjects.
We hope we are wrong about this. But we started making noise and formal complaints about this almost six months ago, and no one has shown us proof that we are wrong, nor has the major institution involved, Weill Medical College at Cornell University, told us to shut up, as we would expect them to if we were wrong.
What if dex is being administered prenatally for CAH outside of clinical trials? This situation would be a concerning enough situation even if every woman treated were actually carrying a female fetus with CAH. It would mean pregnant women are essentially being experimented on without being told. But because the prenatal dex treatment must begin before the doctor can be sure if a woman is even carrying a female fetus with this form of CAH, doctors are administering the steroid dexamethasone to many women who are not even carrying affected fetuses.
Researchers all seem to agree that 87.5% (7 out of 8) of those women and fetuses whom clinicians are exposing to dexamethasone are not even in the affected population. Dr. Walter Miller, Distinguished Professor of Pediatrics and the Chief of Endocrinology at UCSF, a critic of this treatment, has concluded “it does not seem ethical to submit 7 of 8 fetuses to any risk whatsoever when the treatment cannot benefit them.”
In fact, the treatment only achieves its aim about 80% of the time even among the affected population, meaning that, in reality, over 90% of the women and children being exposed to prenatal dexamethasone for CAH will experience absolutely none of the intended “benefit” from the treatment, although they are all being exposed to all of the harms and risks. (Click here to see the calculation.)
It appears unlikely that a drug (like this one) specifically used to alter a fetus’s body for these purposes would be unlikely to ever be approved by the FDA for use in pregnant women, even for experimental purposes, even if the baby were at-risk for something much more serious, when, by necessity, the great majority of pregnant women given the drug would not even be carrying a child affected with the condition being targeted.
Perhaps this explains why this use may be going on outside of clinical trials--because such clinical trials would probably never have been approved by Institutional Review Boards (which safeguard the rights of human subjects)?
Is there even a medical necessity to preventing ambiguous genitalia? Even beyond the question of why so many women and children are being treated when they can gain no benefit (a question of efficacy), we need to ask whether there is any medical need to prevent genital virilization (a question of necessity), which seems to be the main reason clinicians recommend prenatal dex. Although common sense might lead us to assume girls born with atypical genitalia are at an increased risk for psychosocial harm if left to grow up with atypical genitalia, many clinicians admit that they are unaware of data that evidence that. Anecdotal and historical data suggest that, if there is an increased risk to these girls, it is low. In other words, there is, as of yet, not even evidence for the medical necessity of this primary reason named for this treatment. Those who advocate this experimental treatment say that girls who benefit from it will avoid the risks and harms of elective surgery, seeming to ignore that the surgery is elective and not shown to be necessary for a girl’s health. They also seem to be unaware of the major pediatric endocrinology consensus from 2006 which called for fewer surgeries in these cases.
We do want to acknowledge that prenatal dexamethasone appears to sometimes prevent the development of a confluence of the vagina and urethra, which can cause infections and problems with sexual intercourse. However, not all affected females are even born with this problem, and this doesn’t seem to be the main reason prenatal dex is recommended by those who recommend it. Nor does prevention of this problem give any clinician or researcher an excuse to do whatever she or he wants with this patient population.
Curiously, those who advocate the use of prenatal dexamethasone for CAH in order to circumvent surgeries have historically also assured parents and the public that genital surgeries on girls with CAH are safe and effective. If the surgeries are in fact safe and effective, why are these physicians bothering to put so many unaffected women and children needlessly at risk through the use of prenatal dex on all of them?
To quote Dr. Miller (which we do with his permission), who believes the surgeries are safe and effective, “it seems to me that the main point of prenatal therapy is to allay parental anxiety. In that construct, one must question the ethics of using the fetus as a reagent to treat the parent, especially when the risks are non-trivial.”
So the necessity of prenatal dex is very much in doubt.
The efficacy of the treatment is also in doubt when over 90% of those exposed gain no benefit. Indeed, if the drug is designed to reduce a psychosocial risk compared to what would be the control, and we have no real data on the control group, we can say nothing about the efficacy of this drug. We don’t even know if there really is a risk here, so we cannot know if the risk is being reduced.
Is there a medical necessity to preventing tomboyism, lesbianism, and low interest in marrying men and having babies? Um, you’re kidding, right?
What about the safety? Most clinicians and researchers familiar with this drug appear to be seriously worried about it. That will be made clear again in a forthcoming consensus statement from the American Academy of Pediatrics, the European Society of Endocrinology, the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the Society of Pediatric Urology. You can read an early draft of their work here. You’ll notice the Task Force assigned with coming up with the statement from these groups says prenatal dexamethasone is risky and should only be used for CAH in controlled clinical trials with ethics oversight in place.
Dr. Miller, who has been raising red flags on this practice since 1998, has noted that prenatal dexamethasone treatment results in male and female children being exposed, in utero, to a level of glucocorticoids 60-100 times normal levels. Animal studies have long established that abnormally high levels of glucocorticoids are neurotoxic, meaning that they result in the death of nerve cells, including in the brain, in the fetal period.
Human studies show that this prenatal dex treatment may result in detrimental changes to the brains of children given the drug in the womb, including the over 90% of children who receive no benefit from the treatment. Children exposed to dexamethasone have been shown to be at higher risk for problems with working memory, with verbal processing, and with anxiety. This is not a benign treatment by any means.
Dr. Miller has concluded, reasonably we think, that “this experimental treatment is not warranted and should not be pursued, even in prospective clinical trials.” Nearly all other clinicians who have weighed in have said that if it’s used, it should be in prospective clinical trials, not as standard of care the way Dr. New promotes it.
Studies at the tail end but not from the start? It appears that some researchers, notably Dr. New’s team, may be administering prenatal dex treatments to pregnant women, off-label and outside any clinical trials or human subjects research protections, even while they are concerned enough to be studying the mothers and children after the birth. In other words, these clinician-researchers consider the off-label use of this drug questionable enough to study its long-term safety, yet not questionable enough to manage as formal clinical trials during pregnancy?
For example, the National Institutes of Health Office of Rare Diseases has recently funded a long-term follow-up study of children who were treated with dexamethasone to prevent atypical genitalia. This study seeks to discover a few aspects of how these children and also their mothers may have been harmed. Again, the principle investigator of this study is Dr. Maria New, of Mt. Sinai Medical Center in New York.
Dr. New, a major proponent of the prenatal dex treatment, therefore seemingly admits that this is an experimental treatment that involves serious risk to children. Yet, to our knowledge, she and several of her colleagues are still currently recommending the non-FDA-approved treatment to pregnant women without enrolling them in any study and without protecting them with IRB oversight. We have been unable to find conclusive evidence in her published work or any evidence at clinicaltrials.gov that Dr. New has been administering dex to pregnant women as part of a clinical trial. Dr. New and the director of the IRB at Mt. Sinai have not yet answered our questions about whether Dr. New has had IRB approval to run clinical trials of dex on pregnant women. (Dr. New is now claiming, in response to our noise-making, that she only wrote one prescription for prenatal dexamethasone, but this does not explain why she boasts of having treated over 600 women with this drug.)
Again, we hope we are wrong. But it appears (and we will certainly change this website immediately if we learn otherwise) that Dr. New and some of her colleagues are admitting to these mothers, ten years down the line, that this treatment to engineer their children was done experimentally. For the long-term study, they get these mother’s approval to study them and their dex’ed children. The long-term study group has IRB (Institutional Review Board) human subjects research protections oversight for their subjects. However, these clinician-researchers have not been, to our knowledge, protecting pregnant women at the outset by enrolling them in IRB-approved clinical trials that would protect them as human subjects of clinical pharmaceutical research while they are pregnant.
How has the CARES Foundation played a role in this? According to a promotion of Dr. New’s dex work published by the CARES Foundation, “Dr. Maria New has treated over 600 pregnant women at risk for the birth of a CAH-effected child.” That was as of 2003. Dr. New has continued to promote this off-label use, and has continued essentially to solicit patients (or should we say subjects?), including through the CARES Foundation, since that time. We may safely assume the number of women and children exposed is now substantially higher than 600 women and 600 children.
The New York Times recently reported the FDA’s move to stop clinicians from promoting off-label uses of drugs for cosmetic purposes as “safe and effective.” We invite you to look at this article to judge for yourself whether the off-label use of prenatal dex has been promoted as safe, effective, and even necessary to a vulnerable population of pregnant women. We also invite you to look at Dr. New’s own foundation’s page on the treatment.
Clinician-researchers to whom we have expressed our concerns about this treatment have assured us they are trying to get the doses of dexamethasone as low as possible, to minimize risk. This means they know there is risk and that that risk is probably associated with dosage. But it is unclear how they can ascertain dose-response without controlled clinical trials. This practice thus seems to be ethically questionable also in terms of using human subjects without a reasonable methodology for obtaining maximum knowledge with minimum harm to subjects.
Is there informed consent in this drug use? When Dr. New was asked by Dr. Eric Vilain of UCLA at a conference in Miami, in January 2010, what kind of informed consent she was obtaining from the pregnant women to whom she is recommending this treatment (one would like to know, what exactly is she telling these women about the necessity, risk, harm, and benefits, and is she explaining that this is experimental and off-label?), she refused to answer Dr. Vilain’s question, indicating she thought his question about informed consent was out of line. We do not believe questions about informed consent are ever out of line.
According to corroborated reports, Dr. New did assure attendees in Miami that, as a mother, she would never harm other mothers and children, and she assured her audience that this treatment was not accidentally making treated boys gay, an outcome she seemed to imply would be a strike against using the treatment.
What actions have we taken to follow up on our concerns? We have organized a group of professional researchers in Bioethics and allied fields to file formal letters of concern regarding the use of prenatal dexamethasone on pregnant women “at risk” for carrying a 46,XX fetus with CAH. We have also worked with Advocates for Informed Choice, who has also sent letters of concern. These letters have been sent to:
the FDA Office of Pediatric Therapeutics;
the HHS Office for Human Research Protections;
Mount Sinai Medical Center (Dr. New’s current institution);
Weill Medical School of Cornell University (from which much of this treatment appears to have been administered, under Dr. New’s guidance);
Florida International University (where Dr. New is Associate Dean for Clinical Research).
We are organizing additional letters when it appears more are necessary to make sure that women who were given dexamethasone during pregnancy for possible CAH are advised of what may have happened to them without their fully informed consent.
You can see the letter from the Bioethicists here.
You can see the letter from Advocates for Informed Choice here.
So far: The FDA response indicating investigation here; the Office of Human Research Protections response indicating investigation here. Florida International University has acknowledged our communications and indicating they are looking into our concerns. We have received not even so much as an acknowledgement of our concerns from Weill-Cornell and Mount Sinai.
***TIME MAGAZINE and NATURE reports now available online.***
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