Bioethics Forum Essay
Prenatal Dex: Update and Omnibus Reply
Our Bioethics Forum essay from a little over a month ago has already spawned three further essays. So we’ve asked the editors to indulge us in this single reply and update.
To recap, in early February, we called upon scholars in bioethics and allied disciplines to join with us in expressing concern over the possible experimentation on pregnant women involving the administration of dexamethasone without IRB oversight. Some physicians have used dex on women suspected of carrying a fetus with 21-hydoxylase deficiency. This form of congenital adrenal hyperplasia (CAH) has been shown in females to increase the likelihood of ambiguous genitalia, persistence of a urogenital sinus postnatally (explained below), tomboyish behavior, aggressive behavior, low maternal interest, and lesbianism.
We have specifically raised concerns about the work of New York-based pediatric endocrinologist Maria New, who claims to have provided dex prenatally to more than 600 women “at risk” for carrying a girl with CAH. Since treatment starts before diagnosis can be certain, seven out of eight women started on prenatal dex will not even be carrying the type of child targeted. All mothers and children will be exposed to the harms and risks of dex, however, which are significant enough that treatment of fetuses without CAH is stopped as soon as those fetuses can be identified.
It appears that in the vast majority of cases, New did not enroll these women in an IRB-approved treatment trial of prenatal dex. Indeed, in spite of many admonitions from colleagues to undertake this risky, experimental treatment only under IRB oversight (if at all), New seems for many years to have promoted the off-label use of this Class C drug to pregnant women as safe and effective, and to have simultaneously sought and obtained NIH funding to study these women and children after birth to see if the drug was, in fact, safe and effective. (The follow-up studies have had IRB approval, but those overseeing the follow-up studies should have been asking where all these exposed subjects were coming from.) The American Academy of Pediatrics, the European Society for Pediatric Endocrinology, and the Lawson Wilkins Pediatrics Endocrine Society have been among those specifically arguing that this powerful steroid should not be employed for this use outside IRB-approved prospective studies.
In February, 32 researchers in bioethics and allied disciplines signed letters of concern to New’s institutions, to the FDA Office of Pediatric Therapeutics, and to the HHS Office for Human Research Protections. Companion letters were filed by 11 adults born with mixed markers of sex and by the legal rights group Advocates for Informed Choice. Ellen Feder and Alice Dreger subsequently also advised other implicated institutions of the concerns.
The FDA has stated that it is reviewing these concerns. (In general, the FDA has recently shown more interest in pushing back on inappropriate promotion of off-label usages.) Meanwhile, the Office for Human Research Protections has indicated that they have sought and received “preliminary reports on this matter” from Weill Cornell Medical College and Mount Sinai School of Medicine and that they “are awaiting follow-up reports from the institutions.” Since the “OHRP evaluates, at its discretion, substantive allegations of noncompliance involving human subject research projects,” its response suggests that it found significant reason to wonder whether these women have been used in an experiment that was not appropriately treated as an experiment from the outset.
In the first published response to our Bioethics Forum essay, Emi Koyama castigated bioethicists in general for not acting to defend the rights of vulnerable persons, leaving us to wonder why our sustained and substantial action was seized as an opportunity to complain about non-action. While we share Ms. Koyama’s concerns about the medical-industrial complex’s take-over of women’s bodies, we rather doubt her postmodern feminist language would have moved the feds the way we have moved the feds. Pardon our pragmatism.
In the second response, John Lantos waxed poetic about the loss of the term “hermaphroditism.” Actually, our experience indicates that plenty of people continue to use the term to describe themselves, but that these are people with no known sex atypicality who use their adopted identity to pursue people with actual sex atypicality to satisfy their own paraphilic interests. This is one reason some patient advocates and clinicians moved to abandon the term in favor of “disorders of sex development” (DSD). (There were plenty of other reasons, too.) In addition, Lantos confuses “ambiguous genitalia” with “DSD,” the latter being an umbrella term for all congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.
Lantos correctly argues that it is worth taking into account whether the person whose genitals are being cut is likely to benefit from the cutting aimed at genital normalization. But he incorrectly states that we don’t have evidence of how people with atypical genitalia fare. We do, and although it is weak, the evidence suggests that genital normalization is not medically necessary. The burden of proof for medical necessity remains on surgeons, as the doing of harm continues to go first.
Lantos commits a common error when he suggests the only way to know how people would fare if left with atypical genitalia intact would be through a randomized, controlled trial. In fact, many such people already exist, and interested researchers have pretty much ignored them (except for John Money and a few social scientists, including Dreger, Katrina Karkazis, Sharon Preves, and Elizabeth Reis). Why? We don’t know.
Dreger has been asking the medical establishment for over a decade for evidence that ambiguous genitalia constitute an increased psychosocial risk. Her question has usually been met with silence, or at most with the assurance that surgeries are better today. Lantos says that “nobody except medical historians will even remember the clumsy and barbaric things that we once did,” but we remember enough history (from Tuskegee to Johns Hopkins) to have sounded an alarm now on prenatal dex. If we really must wait for the historians to get some good perspective, well, good news—a medical historian is here. And she sees cause to change the course of the history being written now.
Lantos notes that there is a paucity of data on the outcomes for fetal dex. He’s right. What’s more, there should be far more data, given the numbers New claims to have treated. Lantos says there should be informed consent. Right again: and New’s explicit refusal to answer multiple questions about informed consent, when asked by medical professionals, is exactly what ignited this whole firestorm in January. Lantos asks that “information [be put] out there on Web sites.” Okay, fine, but what do we do when the very officious and supportive-looking CARES Foundation site and The Maria New Children’s Hormone Foundation site recruit women with the claim that this drug has been shown to be safe, when it hasn’t? What actions should we take when we know that informed consent is being actively subverted? (We answered that question by calling the feds.)
The third response comes from medical professionals associated with Harvard. We are grateful to see this group of clinicians and research administrators responding by calling for much better informed consent, ethics oversight, and outcomes research than what we think we’ve seen so far (although we do lift an eyebrow when, in a piece for the Bioethics Forum, they write, “ethical issues and potential side effects to mother and fetus notwithstanding . . . ”). We also thank the Harvard group for pointing out something critical: girls with 21-hydroxylase deficiency may be born with a urogenital sinus, and prenatal dex may prevent this. The postnatal urogenital sinus is a birth anomaly that involves the confluence of the urethra and vagina and can result in urinary, sexual, and reproductive problems.
The reason we did not pay enough attention to this point is explained by our focus on New’s work on prenatal dex, which appears after much review to stand out as atypical. In her promotion of prenatal dex to “at risk” women, New emphasizes the prevention of ambiguous genitalia as the most important aim of intervention. This has implied that ambiguous genitalia represent some kind of medical problem in and of themselves.
Obviously it would be good if medically necessary interventions (for example, surgery to correct a severe urogenital sinus) could be made unnecessary through prevention, as some interventions for neural tube defects have been prevented through increasing fertile women’s intake of folic acid. That said, we remain extremely concerned about the way that prenatal dex is being promoted and administered, and we do not see the potential for a postnatal urogenital sinus as a license to do what has been done.
At least 90 percent of the children whose mothers are given prenatal dex will not benefit, and all will be exposed to risk. The risks are very concerning, particularly considering animal modeling on primates, possible epigenetic effects, and what few outcome studies we do have. New’s latest presentation on outcomes, in Miami, appeared to be missing data on over two-thirds of those treated. What’s the truth about prenatal dex’s effects on the mothers, girls, and boys exposed? We are nowhere near knowing.
We are also very concerned with the use of the CARES Foundation as a vehicle for promotion of this treatment as safe. The CARES Foundation seems to have benefited financially from participating in research (it also obtains some of its funding from pharmaceutical firms) and thus CARES seems to have a conflict of interest that may not be obvious to those women coming to their website for information. (The foundation will be honoring New with a “Pioneer Award” this week.)
Then there is the question of what women have been told as they’ve been given this drug. We do not see reason to be confident that informed consent has been consistently observed. The involved institutions have not responded to our inquiries, and their silence gives us yet more reason to worry.
The Harvard group correctly notes that “there are many drugs taken by pregnant women for which we have limited long-term data about the possible harmful effects on fetuses,” but they go on to list drugs that are given to help mothers with the mothers’ own ongoing medical problems. We do not think there is any excuse for the failure to actively (and ethically) collect the maximum data on women given a drug explicitly aimed at engineering their fetuses, and there is surely no excuse for not telling women how experimental and risky this drug is known to be.
We hope the Harvard group will move with us to ensure that adequate protections are in place for families affected by DSDs so that their human rights are fully respected. We also hope that the Harvard group and others will pursue a national registry for all DSD conditions, so that if DSD-affected individuals must continue to be subjected to experimental treatments, we can at least find out something about what works, and we can be honest about the seriously experimental nature of much of the treatment. A national registry might also finally push many institutions to enact the team care of which so many speak, to provide meaningful psychosocial care for parents and children, and to provide care into adulthood for those affected.