Fertility clinics across the U.S. are prescribing a medication with a seriously concerning safety profile and no proven benefits.
When Susan Manning, a 39-year-old woman just a few weeks into her first pregnancy, wrote to tell me she had been put on the steroid dexamethasone to prevent a miscarriage--and to ask whether she should be worried about taking this drug--at first I could not even process what she was saying. Dexamethasone is known to cross the placental barrier and impact fetal development, so the very idea of first trimester exposure sets off warning bells. Besides, dexamethasone is not known to help in preventing miscarriage. Susan's story sounded too crazy to be true.
It also sounded too close to the history of DES (diethylstilbestrol). From the 1940s through the 1970s, some doctors gave pregnant women DES, a synthetic estrogen, to try to prevent miscarriage. In spite of clinical evidence that it didn't work as intended, millions of fetuses were exposed in utero before doctors discovered that prenatal DES exposure could lead to infertility and deadly cancers. Just last week, Eli Lilly & Co. settled a suit brought by four sisters who believe their breast cancers were caused by prenatal DES exposure.
But as it turns out, Susan (a pseudonym) had it right. Women like her, pregnant by virtue of in vitro fertilization (IVF), are today routinely put on dexamethasone for miscarriage prevention at some IVF clinics. Susan is being treated abroad at a high-profile clinic, but some American infertility clinics also advertise this off-label use of dexamethasone as if it is the standard of care.
I inquired about this with Dr. Geoffrey Sher, Executive Medical Director of the Sher Institutes for Reproductive Medicine, a high-profile infertility practice with offices across the country. He confirmed in an email that, "We recommend 0.5 mg - 1.0 mg. [of dexamethasone] orally daily (dosage varies based upon individual patient needs) from the time of initiating the [IVF] cycle through to the tenth week of pregnancy." He could not point to studies showing that dexamethasone helps prevent miscarriage, but argued, "Since there are so many other variables that are involved" in IVF pregnancies, studies "would virtually be impossible to do."
In essence, doctors using dexamethasone for miscarriage prevention are working from a physiological hunch. The hunch is that some women who seek out IVF have immune problems that cause their bodies to reject pregnancies. If dexamethasone suppresses a woman's immune system, maybe it will help her maintain a pregnancy. But, again, there's no scientific evidence that dexamethasone prevents miscarriage, and no evidence that this drug--a drug known from animal and human studies to have the potential to change fetal development--is safe to use in this way.
Surprisingly, it appears that even women like Susan, with no diagnosable immune disorder and no history of recurrent miscarriage, are being put on dexamethasone for miscarriage prevention by some IVF specialists.
I asked Dr. Ralph Kazer, Chief of the Division of Reproductive Endocrinology and Infertility at Northwestern University's Feinberg School of Medicine, to give me his thoughts on this use of dexamethasone. (We work at the same medical school, although Dr. Kazer and I have never communicated before this.) Dr. Kazer expressed concern, saying, "The extent to which early [pregnancy] losses are due to immunological problems is controversial, but it is almost certainly a relatively rare problem."
I asked Dr. Kazer if he knew of studies of efficacy or safety of this off-label (non-FDA-approved) use. The answer was no. "This is not complicated," Dr. Kazer wrote. "In the absence of good evidence for efficacy or a very specific medical condition, a drug like dexamethasone should not be given to pregnant women in the first trimester."
He explained why: "Dexamethasone is a Category C drug, which means that there are concerning animal data [about safety] but no good data in humans regarding teratogenicity [i.e., birth defects caused by a drug]. Such drugs should only be used when potential benefits outweigh potential risks. There is currently no good evidence that this criterion is fulfilled for typical IVF patients. Dexamethasone does cross the placenta, so at the very least, it reaches the fetus."
At Brown University's Alpert Medical School, Dr. Philip Gruppuso is a pediatric endocrinologist with research interests in the fetal origins of adult health and disease. When I told Dr. Gruppuso about this use of dexamethasone, a steroid in the class of drugs called glucocorticoids, he responded, "Regardless of the rationale, the first trimester use of glucocorticoids should be viewed as an experimental treatment that could have long-lasting untoward effects. Evidence from animal studies raises the possibility that glucocorticoids can alter the fetal epigenome." In other words, prenatal synthetic glucocorticoid exposure could permanently change the way a person's genetics will operate over his or her lifetime.
In fact, the reason Susan had found me was because I have been tracking the history of a case in which prenatal dexamethasone has been used with the specific intention of permanently altering the course of fetal development: some doctors have been using dexamethasone on pregnant women at risk for having a child with Congenital Adrenal Hyperplasia (CAH). An endocrine disorder, CAH can cause female fetuses to develop ambiguous genitals and other atypical sex anatomy. "Dex" is believed to be effective at reducing the odds that a female fetus with CAH will be born virilized.
The off-label use of dex for CAH has been very controversial--and not only because it may impact a developing child's body permanently in unpredictable and unintended ways. (Rarely does a drug do only what you want it to do.) Because the intervention has to start before fetal genitals differentiate into male or female types, doctors have had to expose fetuses before they could know whether the fetus really is a female with CAH. As a result, almost 90% of the fetuses exposed via their genetic-carrier mothers' ingestion of dex have not even been females with CAH.
Medical societies' consensus statements on the matter have consistently concluded that this use should be restricted to prospective, long-term, controlled trials, with full ethics board oversight. But this use of dexamethasone has occurred almost entirely outside the kinds of clinical trials that could establish whether it is safe and effective.