Ellen Feder of American University and I are grateful that people are concerned about the issues we’ve raised regarding the prenatal use of dexamethasone for CAH. But we’re disturbed that some news reports and blogs have the facts wrong. Here are the facts. We also recommend you read the Time magazine report by Catherine Elton because it is extremely well researched.
What is CAH?
Congenital adrenal hyperplasia (CAH) is a serious endocrine disease that occurs in both males and females and 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 in the current media buzz is called 21-Hydroxylase Deficiency.
What else does CAH involve?
In females, this form of CAH increases 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 prenatally on these females?
Some doctors advise women who are “at risk” for having a girl with 21-hydroxylase deficiency CAH to take dexamethasone prenatally. The 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 medical problem that occurs in some cases. If a girl is born with the urethra and vagina joined together, she may suffer infections and will have problems later with intercourse. Prevention of that confluence is a clear legitimate medical use of prenatal dex for CAH. But only some (not all) girls with 21-hydroxylase deficiency develop this urogenital problem.
A large number of pregnant women and their offspring are being exposed to the risks (including the unknowns) of this drug compared to the number of girls who obtain a real medical benefit. This is why clinicians have expressed serious reservations about the risk/benefit ratio.
It isn’t enough to say “we want to prevent problems.” You have to think about what problems you might accidentally be introducing in the process of attempting prevention. Remember DES? Pregnant women were given DES for over three decades with the goal of increasing their offspring’s survival. Saving babies: an admirable goal. Yet DES turned out, in hindsight, to cause tremendous medical problems, including cancer in thousands of women.
It’s notable that in 2001, a committee of the American Academy of Pediatrics warned Dr. Maria New that she ought to be very careful with prenatal dex for CAH, and they specifically admonished her to remember the history of DES and thalidomide. The AAP committee understood how long it took before doctors realized the disasters of DES and thalidomide. We already know prenatal dex is powerful enough to have effects on the brain, lungs, and genitals of fetuses. This suggests a serious consideration of whether the goals intended are worth the risks, including what we don’t know about this drug’s effect so early in pregnancy. (It’s no wonder that on the blog sites, women who were exposed to DES in utero are commenting with dismay and fury at uncontrolled experiments with prenatal dex.)
Isn’t prevention of ambiguous genitalia a legitimate medical issue?
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. There has been a movement away from “corrective” genital surgery among physicians. See this major medical consensus as evidence.
More importantly, 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.
The following is also critical to understand: prenatal dex does nothing to treat the disease that is CAH. Many children who have CAH will need lifelong endocrinological management, and prenatal dex does nothing to change that. This use of prenatal dex is primarily aimed at preventing ambiguous genitalia in girls with CAH.
And the prevention of lesbianism?
A very few clinician-researchers have suggested that prenatal dex could prevent lesbianism, bisexuality, tomboyism, relatively low maternal interest, and interest in traditionally-male hobbies and occupations. Some of these researchers, notably pediatric endocrinologists Saroj Nimkarn of Weill Cornell Medical College and Maria New of Mount Sinai Medical School and Florida International University, have constructed these “masculine” behaviors as abnormal, and have suggested prenatal dex could prevent those “abnormalities”:
In a 2010 article in the Annals of the New York Academy of Medicine, Nimkarn and New write:
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“Gender-related behaviors, namely childhood play, peer association, career and leisure time preferences in adolescence and adulthood, maternalism, aggression, and sexual orientation become masculinized in 46,XX girls and women with 21OHD deficiency [CAH]. These abnormalities have been attributed to the effects of excessive prenatal androgen levels on the sexual differentiation of the brain and later on behavior.” Nimkarn and New continue: “We anticipate that prenatal dexamethasone therapy will reduce the well-documented behavioral masculinization . . .."
Do they really think girls who might grow up to be straight and not want babies need to be “fixed”?
Please read the article that started this whole buzz, the one we wrote with Anne Tamar-Mattis of Advocates for Informed Choice. Click here to read it.
Is this your main concern?
We are certainly concerned about anyone trying to use drugs to make children fit outdated gender norms. But we came to this over a much greater concern: We have reason to believe most of the women who have been given this drug did not know they and their babies were part of an experiment, did not have their rights as research subjects protected, and may not have told about all the risks of this drug.
This drug is experimental?
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 (in apparent violation of FDA regulations) 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. Yet apparently she never enrolled them in clinical trials in which safeguards would have been in place to protect them and their babies. Dr. New also got federal funding to study these women years after their pregnancies. Did she tell them when she treated them with the drug that they were in a big experiment?
What makes you think this drug is experimental and not standard of care?
The medical profession (except for Dr. New) has been fairly unequivocal that this use of prenatal dex is risky and should only be done (if at all) through IRB-approved trials. You can read here our letter to the CARES Foundation outlining many of the times physicians said this over the last ten years. Those stating this opinion include the woman who developed this treatment (Forest), and consensus committees of the Lawson Wilkins Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, and the American Academy of Pediatrics.
In 2001, the American Academy of Pediatric committee stated about this use of prenatal dex:
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“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.”
This opinion has persisted and only grown stronger. A new consensus statement, to be published in August, states the following:
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“We recommend that prenatal therapy continue to be regarded as experimental, and be pursued only through research protocols approved by the local Institutional Review Boards at centers capable of enrolling a sufficiently large number of participants in such protocols—alone or in collaboration with other centers—to yield precise findings.” (emphasis added)
This statement is endorsed by the American Academy of Pediatrics, the Lawson Wilkins Pediatric Endocrine Society, the Lawson Wilkins Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the Society for Pediatric Urology, the Androgen Excess and PCOS Society, and the CARES Foundation.
Why are they all worried?
Because, no matter what Dr. New says, this drug has not been shown to be safe. For this use, it is being given as early as the fifth week of pregnancy, when fetuses are extremely vulnerable to damage by drugs. Moreover, because doctors have to give the drug before they can know if a woman is really carrying a female fetus with CAH, seven out of eight of the children who have been exposed through this prenatal treatment don’t even have the condition at issue. The potential effects on the mothers are non-trivial, too. The AAP had to remind Dr. New that her own work showed that.
So 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 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. (Her chief collaborator in the follow-up reports, Heino Meyer-Bahlburg of Columbia University, admits that over half of those treated don’t respond to their requests for follow-up data collection. The paper in which this admission appeared has now disappeared online; I have a copy of it.)
We contacted the OHRP, the FDA, and the relevant institutions in early February of this year, along with 30 of our colleagues in bioethics and allied fields. I set up the website fetaldex.org to triage information for those involved in working on this.
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. (Explains her departure, maybe?)
Why did Dr. New tell Roxanne Palmer at Nature that she had IRB approval and informed consent?
Dr. New has apparently 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 approval to treat 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. 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, and to be protected with the IRB from the start.
Why would Dr. New bother to get IRB approval 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 had it for the drug administration, the much, much more dangerous part of the process.
We hope we’re wrong about all this, and that all women offered prenatal dex for CAH have had their rights appropriately protected. But if we were wrong about the failure of IRB to protect people here, and wrong about the lack of informed consent, we think we would know by now. Frankly, Cornell and Mount Sinai’s lawyers almost certainly would have told us we were wrong (and told us to shut up), and so would have the Feds. Instead, Cornell and Mount Sinai refuse to comment six months in, and the feds continue their investigations, because they found cause to investigate following our letters.
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; we do not want to see them offered this drug outside of IRB-approved, controlled, 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 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.
Are you saying this could be happening in other instances (experimenting on people without their knowledge)?
Yes. In the midst of all this, we uncovered what we think is another example of a research abuse of this population, also at Weill Cornell, and wrote about it here. We have every reason to fear this is happening all over medicine as some clinician-researchers take advantage of IRB lapses of oversight.
This concludes the major points we want all reporters and bloggers to understand. The following section explains more details for those who want to learn more.
How did this all unfold?
Late last year, clinicians who felt impotent to stop what they saw as ongoing abuse contacted me and asked me to help. 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.
You can read about those two related issues here and here.
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 less vulnerable.
Dexamethasone is not a “female hormone” as some have erroneously reported.
Is there really reason to worry about this use of dex?
Yes. Dex is already classified by the FDA as a category C drug for pregnancy. That means it has already been determined to be seriously worrisome, even before this “innovative” use. Most of the previous uses for prenatal dex in humans have occurred much later in pregnancy, and even those later uses caused doctors to be worried about using dex prenatally. This use of dex for CAH is so early in pregnancy, when the fetal organs (including the brain and sex organs) are especially fragile.
Who has funded this work?
Ellen Feder and I are funded by our universities 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 work like this. (I purposely left a traditional tenured academic job with lots of obligations so that I could do this kind of social justice work.) Anne Tamar-Mattis’s work is funded through donations to Advocates for Informed Choice. (So if you care, donate!) The Hastings Center, which has published our work on this, is the premier independent non-profit bioethics and public policy institute. (You can also donate to them if you want to support this kind of social justice work in bioethics.) The Hastings Center does not pay us for our publications, and we do not pay them to publish our work. (You can find a complete list of my 30 columns for Bioethics Forum here.) I do personally donate to both AIC and the Hastings Center.
Are things getting better for people with sex atypicality, in spite of what we’re reading about in terms of the practices by Drs. New and Poppas?
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.
