issue: reasonable experiment?


There is a clear medical consensus that prenatal dex for CAH remains a risky experimental treatment, one which should be conducted, if at all, only in IRB-approved clinical trials. You can read about that consensus at this page. But should IRBs (Institutional Review Boards) really approve these clinical trials?

Let’s review the facts:

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 will still be born with CAH and will still need lifelong endocrine management to stay safe.

So why is prenatal dexamethasone used, if it does nothing to cure CAH? There is one legitimate medical issue that prenatal dexamethasone can help prevent in CAH, namely the development of a joined urethra and vagina (a urogenital sinus). 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 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 class C pregnancy drug as early as 4 weeks 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 indication 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 ever decided that the risks of prenatal dex were justified simply by the offsetting of risk of urogenital sinus.

In other words, it doesn’t look like prevention of urogenital sinus is worth the risks of giving pregnant women a drug intended to cross the placental barrier, intended to change the fetus’ body in significant ways at such a delicate stage of fetal life. (You can presume that if prenatal dex has a dramatic effect on the development of the genitals, it is likely to also have some effect on other organs and on the brain. Indeed, we already know it has effects on the brain.)

Now, the truth is that prevention of a urogenital sinus is not the major reason prenatal dexamethasone is prescribed. The 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. 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.

Yet ambiguous genitalia are not a medical problem; they don’t cause physiological problems, they just look different. A big clitoris is not a medical problem. Nor do we even have any evidence that ambiguous genitalia increases psychosocial risk; there’s just an assumption they do, in spite of lots of evidence that people have fared reasonably well with ambiguous genitalia. So can we honestly conclude that the substantial risks of dex are worth taking for prevention of ambiguous genitalia?

Troublingly, it looks from some of the medical literature and some presentations to parents groups like some clinicians are hinting that prenatal dexamethasone may also be used to 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.

You can read more about New’s interest in using prenatal dex to present homosexuality and tomboyism here.

So, is prevention of lesbianism and interest in male-typical toys, hobbies, and occupation a reason for IRBs to approve experimentation with prenatal dex? Um, I don’t think so.

So should IRBs approve experimentation with prenatal dex for CAH?

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.”

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. Again, 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 there aren’t data to 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.

Again, we acknowledge that prenatal dexamethasone appears to sometimes prevent the development of a urogenital sinus. 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.

To quote Dr. Miller (which we do with his permission), “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.”

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(Written by Alice Dreger; copyright Alice Dreger, 2010)