Galileo's Middle Finger (25 page)

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 and 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:

Now one of the biggest breakthroughs, and I think one of the most satisfying things I’ve done in my scientific life, was to participate in the program of prenatal diagnosis and treatment of congenital adrenal hyperplasia. I didn’t start it. It was pioneered by a wonderful scientific investigator in Lyon, France, by the name of Maguelone Forest. She is the one who started the idea that it might be possible to treat the fetus by treating the mother. And what we did in New York is simply to refine it, advance it, and make it more feasible. . . . I’ll give you some slides to buttress what I’m saying, [but] the conclusion is, it’s effective and it is safe. Notwithstanding any people who criticize me for what I’m doing, I think it’s one of the
nicest
things I can do for my patients, which is to prevent ambiguity of the genitalia, so that these children, when they’re born, do not have confusion of sex assignment—nobody can call it a boy when it is really a girl, and nobody has to undergo very difficult surgical procedures, the surgery for which is only
done well in very few centers
.

In making this presentation, Dr. New revealed that she herself is a carrier for CAH, a fact that probably explained how she got into this field of research. The message to the parents would have been clear: I am one of you, and I want only what is best for your children. And good news: “The conclusion is, it’s effective and it is safe.”

What is dexamethasone? A potent synthetic steroid, dexamethasone is actually used for a wide variety of medical purposes. Doctors ordinarily prescribe it for children and adults to treat inflammation, like the kind you might get with some eye or skin diseases, and to treat various autoimmune diseases, like psoriasis and lupus. Dexamethasone has sometimes also been given in the second or third trimester to pregnant women at risk of
giving birth prematurely
; that’s because some of the steroids known as glucocorticoids—the drug class that includes dexamethasone—can cross the placenta and push a fetus’s lungs to mature faster, giving the fetus a better chance at survival if born too soon.

But the prenatal use of dexamethasone at issue in the intersex story aims not at second- or third-trimester fetuses who might otherwise
die
; instead it aims at
first-trimester
female fetuses who might otherwise develop in
sexually atypical
ways. In fact, it’d be more accurate to say the CAH-related use of prenatal dexamethasone is aimed at
embryos
. Humans start to differentiate into male and female types really early, by the seventh week of development. If you want to reengineer human genital development, you have to hit an embryo—through its pregnant mother—with dexamethasone pretty much as soon as you know the mother is pregnant. Usually the parents are identified before pregnancy because they’ve already had a child born with CAH, but additional “at-risk” parents are picked up because they’ve decided to undergo preconception genetic screening, and the screening picks up that both parents are carriers. Through the CAH care networks, CAH-affected
families steadily learned
over the years to start a woman on dexamethasone the moment a pregnancy with CAH risk was confirmed.

The prenatal use of dexamethasone for CAH has always been “off-label,” meaning that, while dexamethasone has been approved by the FDA for some specific medical uses (like treatment of inflammation), this has never been one of them. In fact, the FDA has for years classified dexamethasone in
pregnancy category C
, those drugs for which “animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans.” Why then would doctors still be allowed to use it in pregnant women? Because, as the FDA notes for category C drugs, “potential benefits may warrant use of the drug in pregnant women
despite potential risks
.” Some doctors, like Maria New, decided that the “potential benefit” of intersex prevention justified potential risks.

But one would expect such doctors to be terribly careful with a first-trimester sex-engineering attempt, particularly since
the DES disaster
. Starting in the late 1930s, physicians sometimes gave pregnant women diethylstilbestrol (DES), a synthetic estrogen, generally to prevent miscarriage. A controlled, blinded
study published in 1953
in the
American Journal of Obstetrics and Gynecology
actually showed that DES didn’t work for this use; women who were given DES did
not
end up with healthier pregnancies. Nevertheless, obstetricians kept pushing DES on pregnant women, perhaps unaware of the study, perhaps disbelieving it, perhaps thinking DES couldn’t hurt. With no good evidence of efficacy or safety, about 5 to 10 million fetuses were exposed to DES by the time this use finally came into
serious question in 1971
. It was then that clinicians in Boston realized that girls and young women who had been exposed to DES in utero were developing a rare and often
fatal vaginal cancer
at an alarmingly high rate. They realized the DES link to this strange cancer cluster only because a woman named
Penny Stone
, a mother of a teenage girl with this rare vaginal cancer, insisted that researchers consider as a possible cause the DES she had taken when pregnant with her daughter Sheila. A few months after the Boston group made its findings known, facing intense pressure from a Congressional investigation, the FDA issued an alert, and the intervention eventually tapered off among obstetricians. Since then, researchers have linked prenatal DES exposure to increased risk of many
reproductive cancers
, as well as to major fertility problems in prenatally exposed males and females.

The negative effects of DES did not present themselves in obvious ways at birth, which is part of the reason they took so long to be recognized. But as the medical profession learned the hard way, when a drug given during pregnancy is studied unscientifically, even
dramatic
birth defects may not be tied to the drug until thousands of babies are harmed. In the middle of the twentieth century, the widespread use of thalidomide, a sedative and antinausea drug for adults, led to babies exposed in utero being born without limbs or in some cases with flipperlike limbs. It was only in the early 1960s when
Frances Oldham Kelsey
, a scientist at the FDA, pushed very hard to collect and analyze data that the disaster of thalidomide came to be widely recognized. By that point, about
ten thousand children in Europe
had already been born with shocking birth defects because their mothers had taken thalidomide when pregnant with them, typically to deal with morning sickness. Yet, until a prominent
Washington Post
article about Kelsey’s scientific efforts emerged, the buzz had continued to be that thalidomide was a safe and effective sedative and antinausea medication.

Everybody working in medical research knows that there are lots of formal protection systems in place to prevent another DES or thalidomide. For example, researchers who want to experiment on pregnant women and fetuses are supposed to jump through extraordinary regulatory hoops before being allowed to proceed. There’s also supposed to be a kind of
cultural
protection in place from the conventional wisdom developed in response to DES and thalidomide, a conventional wisdom that says you don’t mess with fetuses pharmacologically unless you absolutely must, unless, for example, you think the fetus will otherwise die, as in the deployment of steroids for premature birth. Even then, you are supposed to proceed with profound trepidation and enormous scientific care if you know the drug crosses the placental barrier and affects the fetus. DES and thalidomide showed us how many cases of harm it can take, if you’re not scientifically careful, to start to learn what effects you’re really having when you’re exposing fetuses to pharmaceuticals.

So imagine how careful you should be when you’re exposing embryos to a drug
with the intention of changing how their tissues will develop
.

And how often does a pharmaceutical intervention have in all cases
only
the effect intended?