Advocates for Informed Choice (AIC) is the first organization in the country using innovative legal strategies to advocate for the civil rights of children born with variations of reproductive or sexual anatomy. Our mission is to engage parents, doctors, attorneys and intersex activists in strategy discussions; stimulate legal dialogue about the fundamental rights of children born with intersex conditions or DSDs; and employ traditional and non-traditional legal tools to ensure justice for children born with intersex conditions or DSDs. These activities are grounded in a sense of respect and compassion for the children, parents, doctors and intersex adults involved.
A number of scientists, bioethicists and patient advocates have recently voiced concerns about treatment of pregnant women who may be carrying a fetus affected with Congenital Adrenal Hyperplasia (CAH) with the steroid dexamethasone.1
It seems that, at a few institutions, large numbers of these pregnant women may be receiving this experimental, ethically questionable, off-label treatment as if they were in a study but without the protection normally given to human subjects of research, and possibly without adequate informed consent.
AIC believes that pregnant women who may be carrying fetuses affected with CAH, as well as fetuses who may have CAH, deserve all the legal and ethical protections normally extended to pregnant women and fetuses who are the subjects of research or experimental treatment. It is not yet clear which doctors and institutions have adequately protected these rights and which have not. However, it is abundantly clear that this treatment has been given to pregnant women for far too long without adequate clinical trials and without addressing the significant ethical concerns it raises.2
Why are doctors giving dexamethasone to pregnant women who may be carrying fetuses with CAH?
CAH is an endocrine disorder that can cause serious and even life-threatening medical problems. In addition to these problems, girls with CAH are often born with a bigger-than-typical clitoris or with “masculinized” genitals. Some doctors have been giving dexamethasone to women who might be carrying a fetus with CAH in order to prevent atypical genitals. Some doctors also think that giving dexamethasone during pregnancy may reduce “masculine” behavior in girls with CAH. Dexamethasone does not prevent the other, serious complications of CAH.
Why is this treatment controversial?
This treatment is controversial for several reasons.3 First of all, there are indications that dexamethasone may cause serious problems. Human studies have demonstrated that prenatal dexamethasone treatment results in detrimental changes to the brains of children. Children exposed to dexamethasone show problems with working memory, verbal processing, and anxiety. Animal studies have also indicated reason to be very concerned about prenatal dexamethasone’s effect on fetal brains. Adverse outcomes in animal studies include low placental weight, low birth weight, small head circumference, cleft palate, adrenal hypoplasia, thymic hypoplasia, hepatomegaly, late-onset hypertension, and impaired glucose tolerance. Some of the problems caused by prenatal dexamethasone treatment may not appear in humans until middle age.4
Secondly, only 1 out of 8 fetuses treated with dexamethasone stand to benefit at all from treatment. CAH is an inherited condition. Generally, women who are advised to take dexamethasone have already had one child with CAH, which means that they and their partners are carriers of the gene for CAH. But even if a couple has already had one child with CAH, there is only a 1 in 8 chance that a future pregnancy will be a female with CAH. To be effective, dexamethasone treatment must start very early in pregnancy, too early to tell if the fetus is an affected female. Since only a female fetus with CAH will develop atypical genitals, 7 out of 8 fetuses subjected to the risks of dexamethasone treatment for CAH have no chance of benefiting from the treatment. Many ethicists and doctors have raised serious ethical concerns about treating 7 unaffected fetuses in order to potentially benefit one.5
Third, some people have questioned whether there is any real “benefit” to this treatment. Surely it is unethical to treat fetuses with a potentially risky drug in order to prevent them from developing “masculine,” or tomboyish, behavior. And many people with atypical genitals have said that they are satisfied and comfortable with their bodies the way they are. Many also think it is not worth the risk of neurological damage to increase the chance that a child is born with typical-looking genitals.
There are some, relatively rare, cases of CAH where genital surgery may be necessary for purely medical reasons. If it were possible to ascertain those rare cases early on in pregnancy, prenatal treatment with dexamethasone might allow avoidance of otherwise necessary surgery. However, as this early detection is not possible, it is still not clear that the risk of harm to the vast majority of exposed fetuses is worth it.
Finally, after more than 25 years of treating pregnant women with dexamethasone, there have not been adequate controlled clinical trials to confirm the safety of this treatment for this purpose. Dexamethasone has not been approved by the FDA for this use for pregnant women. While there have been some small studies, they are inconclusive and the large majority of the women who have been treated do not appear in those studies. Some doctors think the treatment is too risky to recommend. Others are assuring their patients that it is safe. Ethically, there is no good reason to continue such a controversial treatment without studying the long term effects on people who have already received it.
Are doctors who are treating fetuses with dexamethasone to prevent atypical genitals conducting human research?
Certainly, treatment of pregnant women with dexamethasone to prevent the fetus from developing atypical genitals is experimental in the sense that we do not know what the long-term outcomes will be for either the mothers or for children who were treated prenatally. However, doctors are allowed to prescribe medications off-label if there is a good reason to do so. Federal regulations make a distinction between off-label prescription, or “innovative treatment,” and human research.
The difference is the intent of the doctor. If an innovative treatment is done just for the purpose of treating an individual patient, it is not considered research. However, when a doctor prescribes an innovative treatment for the purpose of gathering “generalizable knowledge,” even if it may also benefit the patient, that is research.6 If a doctor treats a number of pregnant women with dexamethasone and then reports on the results of that treatment, it raises a serious question of whether that doctor is conducting research, which would then trigger federal protections for human research subjects. It is not clear now which of the doctors prescribing dexamethasone to pregnant women who may be carrying fetuses affected by CAH are following the protocols for human subject research, but it seems likely that many are not.
What rights do pregnant women who are subjects of human research have?
Human research subjects receive many special protections. One of the most important protections is that research must be approved by an Institutional Review Board, or IRB, which includes scientists, healthcare professionals, and ethicists who are not part of the research team, and who are supposed to ensure that the research is conducted ethically, minimizing risks to the participants.7 There are also special rules for informed consent in the research context, to ensure that human subjects fully understand the risks, potential benefits, and unknowns of the treatment they are receiving.8When the subjects of research are pregnant women or fetuses, there are additional special protections to ensure that these vulnerable populations are not coerced, and that risks are minimized and are justified by the potential benefits.9
Some doctors who are offering this treatment may be uncertain if what they are doing is innovative treatment or research. If the doctor is a researcher and he or she is offering the treatment to large numbers of women whom he or she has actively sought, that would increase the appearance of a research protocol. When doctors enter this kind of “gray area,” it is recommended that they consult an IRB for guidance even if such consultation is not clearly required by law. It is especially important to uphold the highest standards of ethical conduct when using untested treatments on vulnerable populations such as pregnant women and fetuses.
What rights do pregnant women receive when doctors prescribe off-label treatment?
Even if off-label prescription is not considered “research,” pregnant women who receive this treatment have the same rights to informed consent that all patients have. This includes the right to all the information a reasonable person would need to know to make an informed decision about whether or not to undergo treatment. AIC believes that means pregnant women who are prescribed dexamethasone to prevent the fetus from developing atypical genitals have the right to know:
- That the FDA has not approved use of this drug for this purpose;
- That some studies have indicated there may be serious risks to the fetus, including neurological risks, and what these risks are;
- That there are known risks for the mother, and what these risks are;
- That there is at least a 7 in 8 chance that the fetus they are carrying is not a female affected by CAH;
- That even if the fetus is a female affected by CAH, the treatment does not always prevent atypical genitals;
- That there is no evidence that atypical genitals are harmful to a child’s psychosocial development.
If doctors are not providing this information, they are not giving their patients the full story, and this may violate generally accepted standards of informed consent.
Why are you calling for an investigation of Dr. Maria New’s treatment of pregnant women with dexamethasone at Mt. Sinai Medical Center and anywhere else she may have conducted such treatment?
AIC, along with several prominent researchers and bioethicists, is submitting letters of concern to the Food and Drug Administration, the National Institutes of Health, the Department of Health and Human Services Office for Human Research Protections, and the IRB’s at Mount Sinai Medical Center and any other institutions where she may have conducted such treatment, requesting an investigation of Dr. New’s treatment of pregnant women who may be carrying fetuses affected by CAH with dexamethasone. While we have concerns about other physicians’ use of this drug, Dr. New has been one of the chief clinical researchers in this regard and one of the leading proponents of this treatment.
As of 2003, she had treated over 600 pregnant women.10 She is the principal investigator in an ongoing study of children who were treated prenatally with dexamethasone years ago, to discover whether and how these children were harmed by treatment.
We are not claiming that there are any problems with this follow-up study. It appears to have proper IRB oversight. However, at the same time she is researching possible long-term adverse effects, Dr. New’s clinic appears to be continuing to prescribe this experimental medical treatment to pregnant women. We understand from attendees at a medical conference where Dr. New presented her work that she publicly resisted questions about how she ensures her pregnant patients give fully informed consent, and her institution, Mount Sinai Medical Center, has so far not answered questions from a concerned group of bioethicists about whether she has IRB approval for this ongoing experimental treatment. (See more on this at www.fetaldex.org.)
It is not clear at this time that Dr. New or her clinic have done anything that violates the law. However, AIC believes that anyone providing such untested and controversial treatment to pregnant women should be completely transparent and make every effort to meet the highest ethical standards as well as legal standards. Whether or not it is legally required, these pregnant patients deserve the protection of IRB oversight, and the public has a right to know that such protections are in place. Furthermore, enrolling these patients in a properly regulated clinical trial would at least ensure that any adverse effects will be reported to the FDA and that scientific findings will be obtained from this experimental use. If neither Dr. New nor her institutions will tell us how these vulnerable patients are being protected, then the appropriate authorities should step in and investigate.
What else is AIC calling for?
We support an immediate halt to the off-label use of dexamethasone on women suspected of carrying a female fetus with CAH.
All women and children who were exposed to this treatment must be studied by a team of independent researchers. This includes the 87.5% of women treated who we now know were not in the target population, and the 87.5% of the children who were not in the target population.
If this experimental treatment is resumed–assuming the unlikely, namely that the establishment of medical necessity, probable risk, harm, and benefit indicates that such experimental treatment is found by the medical community to be reasonably warranted–it should only be resumed within highly controlled clinical trials in which there are full protections provided for human subjects of research.
Any clinician-researchers who have repeatedly, knowingly subjected pregnant women to this off-label treatment without consideration for their rights as human subjects of research should be formally investigated by their institutions as well as the applicable federal agencies for violations of human subjects research ethics.
Women who have been subjected to these treatments without the benefit of IRB oversight should be immediately contacted and advised of what has happened to them, and should be advised of their rights to pursue compensation in the event they or their children have been harmed.
What liability do doctors and hospitals face if they have treated pregnant women with dexamethasone without adequately protecting their rights?
Doctors and hospitals who have conducted human subject research without proper oversight may be subject to federal and state sanctions.11 Additionally, whether or not their treatment constituted research, doctors who administered dexamethasone to pregnant women to prevent the fetus from developing atypical genitals may face liability in court if they did not ensure adequate informed consent. Since the harmful results of prenatal dexamethasone treatment may not appear for decades, this liability may extend for a very long time.
What should I do if I think that I or my child may have been harmed by experimental treatment with dexamethasone?
If you think that you or your child may have been harmed by experimental treatment of CAH with dexamethasone, you may want to contact an attorney. You can also contact AIC for more information.
AIC contact information:
Anne Tamar-Mattis, J.D., Executive Director
Cotati, CA 94931
2Walter L. Miller, Dexamethasone Treatment of Congenital Adrenal Hyperplasia in Utero: An Experimental Therapy of Unproven Safety The Journal of Urology, Volume 162, Issue 2, August 1999, Pages 537-540.
3Sytsma S. “The Ethics of Using Dexamethasone to Prevent Virilization of Female Fetuses,” in Ethics and Intersex, Sytsma S., ed. (Springer 2006).
645 CFR 46.102(d).
745 CFR 46.103.
845 CFR 46.116-117.
945 CFR 46.201-204.