Galileo's Middle Finger

by Alice Dreger

  As if by providence, at that moment—just as I was feeling tremendous clarity about what activism should and shouldn’t look like—a small group of my old intersex-rights allies, including a couple of clinicians with whom I’d remained close, called me to ask me to help with an ongoing travesty of justice. The crux of the matter was this: A major clinician-researcher in the intersex field (someone we all knew well) had been promoting a high-risk drug regimen to pregnant women who, along with their mates, were genetic carriers for a particular intersex condition, one caused by elevated levels of androgens in female children. The idea behind the intervention was this: If, through genetic screening, a clinician identified a woman as being at risk of having a daughter with this condition, then as soon as the woman got pregnant, a doctor would start dosing her with the steroid dexamethasone. If all went as planned, the dexamethasone would dampen the effect of the androgens, preventing intersex development in the daughters.

  The major proponent of this fetal intervention, Dr. Maria New—a distinguished member of the National Academy of Sciences and a charismatic pediatric endocrinologist still actively working in her eighties—was going directly to the support groups for families with this condition to strongly recommend the intervention to them. She was selling parents on this “treatment” by claiming that “with nearly 20 years’ experience, the treatment has been found safe for mother and child.” This wording made it sound as though the Food and Drug Administration (FDA) had approved this use, when the FDA hadn’t. While doctors are allowed to prescribe drugs “off-label,” i.e., for uses the FDA has not approved, doing so means acting without the benefit of extensive FDA review of a use. In fact, the medical-scientific literature was utterly devoid of well-controlled studies of efficacy and long-term safety of prenatal dexamethasone for intersex prevention. Doctors didn’t know what the intervention really did in the long term, although many were very worried; dexamethasone was being used specifically because it had the power to cross the placenta and permanently alter the course of fetal development. Indeed, lab-based studies of prenatal dexamethasone exposure in animals, including nonhuman primates, suggested that dexamethasone exposure could shift fetal development in deeply unpredictable ways, including by changing brain development.

  It got worse. Even while Dr. New was describing this use as safe and effective, openly taking credit for having gotten over six hundred pregnant women to follow this prenatal regimen, and boasting that she had at Mount Sinai School of Medicine in New York “the only clinic in the United States which routinely provides this service,” she was at the same time taking National Institutes of Health (NIH) funding to study, retrospectively, what had really happened to children and mothers who had been exposed. To get the NIH funding, Dr. New told the agency something very different from what she said in her public promotions of prenatal dex: “The long-term effects of dexamethasone on the children who received it as fetuses and on mothers who were exposed to it while they were pregnant have not been determined.” She told the NIH that her large “accumulated” clinical population of exposed women and children made her especially well positioned to do this research.

  Telling pregnant women a fetus-altering drug is “safe and effective” and then using them to get grants to see if it really is safe or effective? The failure of ethics in this case seemed so appalling and so obvious to me that it seemed a perfect case study of how to spot and stop a true and significant case of abuse of research subjects. And it involved the very issue around which most of my work had revolved: the often-harmful, non-evidence-based medical quest to “normalize” children. Here again was a situation where doctors, motivated by not-unreasonable fears of social stigma, were driving forth an unscientific and even unethical system of treatment—in this case, risking the health of pregnant women and their babies, completely outside of modern scientific standards for pharmaceuticals. Indeed, after I did a little more reading and investigating, the situation seemed so clear that I thought we could and should use this as a demonstration of evidence-based social justice protest—a model of how you appropriately use evidence, the press, and the Internet to reign in abusive research. This case could serve to show scientists why activists were very reasonable to still be vigilant about ethics violations—because terrible abuse really was happening to some vulnerable subjects—and to show activists why and how we should work to push for better evidence. Moreover, because the researchers calling for my help were calling me in as an activist, I thought this would be a great example of collaborative work between the two camps.

  Yes, it would be relatively easy! The source of our outrage, the reason for our collaboration across the researcher-activist divide—it would all be obvious to everyone. The press, the universities, and the government would do what they’re supposed to do. People weighing in on the Internet would behave well. Everyone would see that this is how you do it: You push together for the truth.

  Looking back, I’m guessing I was high on cough medicine. That said, even if I hadn’t been, I would have taken on this cause. It was too important to say no. This was one quest for pediatric “normalization” run completely amok. And although this work—which I guessed at the outset would take only three months—ended up consuming the next three years of my life, nearly crushing my reputation and my spirit, it did end up teaching me the last things I needed to learn from my long journey: how badly most people want simple stories of male and female, nature and nurture, good and evil; how the Internet has gutted the Fourth Estate; how the government is made up of fallible and occasionally disappointing humans; and why, more than ever before, democracies must aggressively protect good research.

  • • •

  AT THIS POINT in my intellectual development, after witnessing the personal consequences to individuals attacked for controversial research, to say that I was reluctant to call out a single researcher would have constituted a substantial understatement. But after my colleagues brought this case to my attention, I poked around and could quickly see why they were focusing specifically on Maria New. Dr. New, I realized uncomfortably, had made herself the eight-hundred-pound gorilla of prenatal dexamethasone for intersex prevention. She really stood alone. There had been a number of major pediatric researchers, including prominent physicians with whom I had for years argued over intersex care, trying to put a stop to her misleading promotion of this intervention as having been found safe and effective. A quick search confirmed why they were a bit frantic: There remained a complete absence of any properly controlled scientific studies demonstrating efficacy or safety in humans. There hadn’t even been any animal modeling of this use published. The animal studies that had looked at prenatal dexamethasone were designed simply to find adverse effects of prenatal exposure to dexamethasone in general; no animal studies had been published specifically looking at whether you really could stop intersex development via prenatal dosing with steroids. The number-one rule of pharmaceutical research? Before you touch a human, see if the intervention works in animals. This was especially true for fetal experimentation. Yet such animal modeling hadn’t been done, and New’s retrospective sampling methodology suggested that the results of her NIH-funded study would be of low scientific quality. While what she was doing didn’t appear to be illegal according to FDA prescribing rules, ethically it was extremely problematic.

  Meanwhile, alarming data were emerging from a Swedish research team that had been tracking children there carefully from the start of prenatal dexamethasone exposure straight through later childhood. The Swedish data suggested that prenatally exposed children were showing increased rates of problems with memory and with social anxiety—signs that the intervention might have adverse brain effects. And the rest of their bodies? The Swedish group had found cases of growth failure and of delayed psychomotor development among the children prenatally exposed, suggesting unintended effects on the rest of the body as well.

  Dr. New had not been studying the effects of exposure nearly as careful
ly as the Swedish team, even though she had taken credit for exposing well over fifteen times as many mothers and children. I did the math to figure how many pregnant women per month might be getting sucked in to this unethical cycle of ill-informed “treatment” and federal follow-up research grants, knowing the frequency of the condition at issue (somewhere between 1 in 10,000 and 1 in 15,000 births) and knowing that New’s clinic drew patients from around the world. It could be a dozen per month. Then I mentally put myself in the position of these pregnant women, most of whom would know only what was told to them by the intervention’s reassuring promoter. Then I thought about what New was doing—telling the families the intervention had been found safe while using previously exposed families to get NIH funding to see if it was safe.

  Then I went back to my friends’ central question: What should we do?

  You’d think that if anybody was qualified to answer the question How do you stop a scientific researcher?, it would’ve been me at that moment. The problem was that my work had only uncovered all the wrong ways to do it. What the hell was the right way?

  • • •

  TO UNDERSTAND HOW my colleagues and I were processing this scene, one needs first to know a little biochemistry, a little developmental biology, and a little history.

  In spite of what popular culture might lead you to believe, males and females usually make the same types of hormones. In addition to making the hormones usually associated with their sexes, male bodies also make the “female hormone” estrogen and female bodies also make the “male hormone” testosterone. What determines male and female biology is, in part, the different levels of sex hormones that usually occur in males and females during sex development. Being estrogen-heavy will usually make you more female-typical, while being testosterone-heavy will usually make you more male-typical.

  Ovaries equal more estrogen, and testes equal more testosterone. That’s why most females are feminine and most males are masculine. But again contrary to pop culture’s representations of sex, the ovaries and testes aren’t the only organs in the human body that produce sex hormones. Some sex hormones are also made by our adrenals, a pair of glands that sit just above our kidneys. These glands make androgens, a group of hormones sometimes called masculinizing hormones: androgens can push the development of sex differentiated-tissues (like genital tissue, breast tissue, and some brain cells) in a more male-typical direction during sex development, even if you have ovaries. Perhaps you already see where this is going: There exists a condition called congenital adrenal hyperplasia (CAH) that results in higher-than-normal levels of androgens. If CAH occurs in a genetically female fetus, in spite of the fact that the fetus has XX chromosomes, ovaries, and a uterus, the higher-than-normal level of androgens can lead that fetus to be born masculinized in terms of genital appearance. CAH is, in fact, the most common cause of congenital ambiguous genitalia in genetic females.

  The reason it’s impossible to know the efficacy of prenatal dexamethasone for CAH without a blinded, controlled drug treatment trial—something that has never been done—is because there is actually substantial natural variation in genital formation of CAH-affected females, ranging all the way from nearly typical female to nearly typical male. The natural variation among XX children with CAH means that a child with the condition may be born with a typical clitoris, a large clitoris, or in very extreme cases even one that has the urethra running part or all the way through it, just like a penis. The labia majora may be separated in the typical female fashion or may be joined at birth, looking much like a male scrotum. The XX child with CAH may have a normal vagina, may have a vagina that will not allow normal menstruation and vaginal intercourse, or in very rare cases may be essentially missing a vagina altogether. Sometimes a CAH-affected XX child will have something called a urogenital sinus, wherein the urethra and vagina develop in such a way that they meet, creating the potential for urine and menses backwash and subsequent infections.

  Like genitals, brains are also shaped by prenatal androgens, so it should not surprise us that many CAH-affected girls’ and women’s behaviors and interests show what researchers call behavioral masculinization. Although there is a lot of variation in this population, CAH-affected girls are more likely than average girls to be interested in boy-typical toys, like cars and trucks, than in girl-typical toys, like baby dolls. They’re more likely to want to play with boys and are more interested in rough-and-tumble play. CAH-affected women are more likely to be bisexual or lesbian, and less likely to be interested in becoming mothers. A sizable percentage of genetic females with CAH—as much as 5 percent—ultimately identify as male in terms of their gender identities. The behavioral outcomes in this population strongly suggest that gendered behaviors and sexual orientation have a biological inborn component, and in CAH, females are skewed in a male-typical direction.

  CAH can actually show up in both males and females, but only in the females can it cause intersex development. (Extra androgens in a developing male won’t make his sex ambiguous.) Notably, in both males and females, CAH can be a dangerous endocrine disease. Because the adrenal glands are responsible for the body’s response to physiological stress, having CAH can mean a poor response to infections and traumatic accidents. In the most extreme forms of CAH, a newborn baby who isn’t diagnosed and treated promptly with steroids can go into an adrenal crisis and die within a few days of birth. The potential seriousness of CAH is why all fifty states now employ newborn screening for CAH. If prenatal dexamethasone could prevent or cure CAH—not just prevent intersex development—that would require a recalculation of the ethical equation of using (and pushing) this intervention. Unfortunately, the endocrine disease that is CAH can’t be prevented, nor can it be cured. No matter what you do to a CAH-affected fetus prenatally, the medical dangers of CAH will have to be managed postnatally with monitoring and medication. This means that even if prenatal dex prevents intersex development, an exposed child will still face the serious health consequences of CAH.

  CAH is a recessive genetic condition, which means that if both parents are carriers for the condition, each of their children will have a one-in-four chance of having CAH. Prenatal screening of a fetus in the second trimester has been used for many years to reveal to parents whether a fetus has CAH. Some couples have historically opted to abort. But in the early 1980s, in France—where, perhaps not coincidentally, by the time you could diagnose a fetus with CAH, an abortion would have been illegal—clinicians figured out that dampening down androgens in utero might prevent prenatal atypical sex development in CAH-affected females. A 1984 paper by these French clinicians published in the Journal of Pediatrics showed apparent success in one case using a prenatal course of dexamethasone, and after that documentation of assumed success in just one human case, “at-risk” mothers-to-be throughout the world started being offered prenatal dexamethasone.

  Right around the time of the French group’s publication, Dr. Maria New began making the intervention available at her Cornell University Medical College–based clinic in New York City. (This was years before she landed at Mount Sinai School of Medicine, across town.) Dr. New had become internationally known in medicine and among the CAH-affected population for having improved the health and fertility of countless patients through her research and clinical care. She was the top specialist in CAH care. It was therefore easy for her to reach out and recommend this intervention to large numbers of CAH-affected families and their personal physicians. And she did so with gusto.

  But why would anyone take such risks with fetuses? To understand this, you have to understand what a strong revulsion and/or pity some people feel toward a person who is born with a body that falls smack-dab between male and female. Maria New was not alone in feeling that intersex should be prevented if at all possible; many of her colleagues had long had the same general philosophy, knowing as they did that, historically, in most cultures, people have been expected to adhere to one of two sex types, in body a
nd behavior. Although in the younger generation, clinicians have changed their thinking about intersex, homosexuality, and transgender, Maria New, born in 1928, had been working consistently from a very traditional, very conservative approach to sex and gender. Here, for example, is Dr. New speaking to a group of CAH-affected families at a support-group meeting in 2001 recorded on video. The audience sees, on a screen beside Dr. New, the masculinized genitals of a baby girl born with CAH—a large clitoris, fused labia. The genitals look pretty male. Dr. New tells the families:

  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 [internally] 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.

  The message is clear: Genetic females are supposed to have petite clitorises, grow up to see themselves as typical girls, and become wives and mothers. Since the baby shown in the slide was already born, Dr. New was suggesting to the audience that this particular child would have to have her femininity saved by normalizing genital surgeries. From Dr. New’s point of view, better still would be the clinical approach of ensuring a sex-typical girl right from the start of development—with prenatal dexamethasone. Dr. New encouraged the parents at the meeting to see this and to understand how personally motivated she felt to recommend prenatal dexamethasone: