What do you do if you find out you’re pregnant and could have a girl born with what looks like a small penis? For two decades, expectant mothers in this position have taken a drug that seems to help prevent fetuses at risk of this from developing partly masculinized genitals. But in June, researchers in Sweden, who have conducted some of the most rigorous research on the treatment since the late 1990s, announced that they would no longer enroll new patients for fear of long-term side effects. And last month, the record of the best-known American champion of the drug was questioned when patient advocates charged she’d misrepresented her work to patients and the government. If this gives you a queasy feeling that the use of this drug has far outstripped the research on its safety, you’re right to worry.
Doctors have prescribed dexamethasone since the 1980s to pregnant women whose kids are at risk of the condition congenital adrenal hyperplasia. CAH, which comes in several forms, affects the adrenal glands and can cause severe loss of salt and water in boys and girls. In girls it can also cause the clitoris to resemble a small penis, or the vagina to become partly closed like a scrotum. (This is the most common form and the one I’m talking about.) Prenatal dex doesn’t cure CAH. What the drug does seem to do, however, is reduce the chances that girls with CAH may have genitals that look, for instance, like this or this. The Food and Drug Administration has not approved the drug to head off these effects of CAH, but physicians often prescribe it off-label. Medical references and textbooks for obstetricians often treat prenatal dex as accepted care for fetuses at risk. And expectant parents have been understandably drawn to the promise of a prenatal fix—an early, non-invasive, almost invisible answer to their fears. In 2010, Time magazine described a woman who had had one child with CAH, found out she was pregnant again, and called a leading expert on prenatal dex, “before calling her own mother.”
To be sure, CAH carries risks. When girls’ urethras are partly fused to their vaginas, or when their vaginas remain sealed into a pouch resembling a scrotum, they may be more likely to develop infections. Without a normal vaginal opening, they may have difficulty with heterosexual sex, if that’s their preference (women with CAH are more likely than other women to be lesbians). They may also have difficulty delivering a child. Girls who simply have enlarged clitorises may not face the same medical risks. But parents and doctors still agonize about their futures, worrying that they will be stigmatized, bullied, or sexually troubled, and plenty of data shows that these fears are real, Philip Gruppuso, a pediatric endocrinologist at Brown told me. If girls aren’t treated in utero, they can have surgery later. But the procedures are risky and difficult, with their own potentially serious complications.
And so proponents of prenatal dex have argued that they are sparing girls from an invasive, radical treatment. But this drug is radical, too. Women must start taking dex when they’re only around 6 weeks pregnant, since this is when male and female genitals begin to develop. At this stage, they don’t know whether the embryo has CAH or even whether it’s a boy or a girl. So most of the time—in fact, in 7 out of 8 cases—the drug doesn’t offer even a potential benefit.
Physicians rarely prescribe drugs to pregnant women that are intended to alter fetal development. And the genitals that dex is given to modify form at the same time as the heart, the brain, and other organs. Research suggests that the drug can affect these other systems, as well. When pregnant lab animals take dex, their offspring may be at increased risk for high blood pressure, high blood sugar, impaired memory and learning, and abnormal responses to stress. (These problems may also turn up in adults who take high doses of steroids like dex for inflammatory disorders or asthma, says Gruppuso.)
Small studies in humans suggest some overlapping concerns. Swedish researchers found over a decade ago that in a group of 43 dex-exposed children, eight had severe medical issues: one had a developmental delay, one had “mental retardation” and one had “severe mood fluctuations that caused hospital admission.” In 2007, the Swedes also found that in a small sample of boys and girls ages 7 to 17, those who’d been exposed to dex in utero did not differ from those who had not in terms of IQ, learning or long-term memory. But their verbal working memory was less good and they reported feeling increased social anxiety.
Several medical societies representing endocrinologists have long argued that prenatal dex should be considered experimental and prescribed only in the context of rigorous clinical trials. The decision by the Swedish group in June to stop treating new patients with the drug was based on mounting concerns based on the accumulating medical evidence. While there is no proof that prenatal dex causes complications, “we couldn’t say that dex does not cause complications either,” neuropsychologist Tatja Hirvikoski of the Karolinska Institute in Stockholm told me.
Given the doubts all along, how did this treatment gain such widespread acceptance? The renowned CAH expert, Maria New, now at Mount Sinai in New York, probably did more than anyone else to convince women and doctors of the drug’s value. (The woman who told Time that she called a doctor before her own mom was calling New, who told her “to start taking dexamethasone immediately.”) In 2010, a group of bioethicists, including Alice Dreger of Northwestern University, expressed concern to the government about New’s work. They alleged that she was misrepresenting what was known about the drug’s efficacy and safety, and suggested she may have been conducting research on it without proper oversight. The FDA and federal Office of Human Research Protections did not find wrongdoing, saying that New’s research was conducted under appropriate oversight. However, Dreger and others pressed forward with multiple Freedom of Information Act Request related to New’s grants as well as the federal investigation, and last month published a devastating further critique. They say that New told pregnant women and other doctors that the treatment was shown to be safe even as she was receiving federal research dollars under the claim that the drug’s long-term effects had yet to be established. She also failed to “appropriately collect and publish evidence,” which might have helped to resolve the matter. In other words, in order to do what she probably thought was in the best interests of her patients, she and others conducted “de facto experimentation on fetuses and pregnant women, largely outside of prospective long-term trials and without adequate informed consent,” Dreger writes. Dreger has posted additional documents here. Speaking for New in response, Mount Sinai sent me a statement (read it in full here) saying that New “has been defended by numerous prominent bioethicists” who published an article saying that “the damage done to Dr. New’s reputation by her critics ‘is derived from an illicitly borrowed presumption of scholarly due diligence.’ ”
What’s most distressing is that after all these years, so little good research exists on this intervention. That leaves families facing the uncertainties of CAH in an even more difficult position. How do you weigh what having unusual genitalia might mean to a child’s life against the unclear risks of early treatment? I’m not sure. But whatever fix prenatal dex may seem to promise, the risks look awfully daunting.