Beyond Second Opinions "d0e276"

Benefits, Risks, Unknowns

Even before she began trying to have a child, Anna thought she might have trouble. She knew from gynecologic exams that her cervix was "like a pinprick hole," rather than an elongated lower segment opening into her uterus. Anna's abnormal cervix was a legacy of medication her mother took while pregnant—DES. The synthetic hormone DES, intended initially to prevent miscarriage and then prescribed for a wide range of pregnancy problems, proved to be neither effective nor safe. Its side effects reached all the way to the next generation, exposed before birth. Thus, Anna was reluctant to take any drug while trying to conceive. "I just didn't want to take anything," she recalls. "It seemed rather ironic, being a DES daughter. I'm having problems because my mother took a pregnancy medication. And then it turns out I may have to do the same thing."

Anna's gynecologist did first test whether she ovulated regularly. However, the results—which can never unequivocally confirm a completed ovulation—were ambiguous. She probably did ovulate, but it was not clear how regularly: perhaps not each month or perhaps without a normal hormone response. So her doctor suggested she try Clomid. In answer to Anna's questions about safety, he cited the many years Clomid has been used without serious problems. He would check her ovaries each month to be sure they were not enlarged by cysts, the most common hazardous side effect. He did not mention that there are few good follow-up studies or other mechanisms for reporting problems with Clomid. He did not mention that no one knows just how this chemical affects the human body. Doctors do agree on one fact: while Clomid stimulates ovulation in some women, the resulting pregnancy rate is surprisingly low. Beyond its effect of lowering the quality of cervical mucus, journal articles speculate that clomiphene may alter the delicate hormonal balance required for conception and embryo implantation into the uterine lining or that the drug may impair blood flow to the uterus just as the lining's intricate vascular build-up prepares for an embryo.^[7] Some studies suggest subtle damage to the egg or embryo may lessen chances for a pregnancy.^[8]

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Anna's concerns about safety extended beyond her own health. If she did conceive after taking this drug, could there by any effects on the fetus? For her doctor, these concerns were remote. He assured her that Clomid has a short half-life—that is, much of the drug would be out of her body in a matter of days, before she ovulated. What her doctor did not say—and might not have known—is that some scientists do worry about that other "half," particularly after repeated treatment cycles and increased dosage.^[9] Some quantity of drug does linger and can build up over months of use. Animal studies suggest possible harmful effects on an embryo during the earliest weeks, those weeks most crucial for normal development. No one has studied health effects on human offspring born after clomiphene-treated cycles except to check for observable birth defects in newborns. Though present information indicates that long-term health problems seem unlikely in children of women who took clomiphene before conceiving, the possibility that this drug might have effects on the developing fetus is something physicians have not conveyed to patients.

Anna and Tom might well have decided to try Clomid even if they had learned of a possible long-term risk, since the sparse hints of harmful effects on offspring have been limited to experimental animal models. But they might have decided the drug's benefits were not certain enough to take any chance, even if risks are minimal or only "theoretical." For Anna and other patients, potential harm—the unknowns—must join known risks weighed against the benefits provided by a treatment. This type of decision is highly individual, depending on personal views about having a baby and about taking risks with one's own health or a baby's. This decision requires full airing of the possibilities, their likelihood, the strength of existing evidence. In Anna's case, risks as well as benefits of Clomid fell heavily among the unknowns; the balance would not tip easily toward a certain direction. However, the risks her doctor did describe—side effects she might experience during the months she took Clomid—did not seem to outweigh the possible benefits. Anna decided, though with reluctance, to take the drug.

After several months on Clomid—months with mood swings her doctor had not warned her about but with no pregnancy—Anna faced the next questions. How long should she continue? Should she take a higher dose? Should they be trying something else? To counteract the deleterious effect of Clomid on cervical mucus, her doctor suggested they try adding estrogen, the female hormone that normally enhances mucus quality at the time of ovulation. To support an embryo in its earliest stages, even before a pregnancy test, they could try adding progesterone, another female hormone with a crucial role immediately following

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ovulation. Unfortunately, there is no good evidence that administering these hormones increases the likelihood of pregnancy. At this point, then, her doctor was ready to move beyond Clomid, but the desire to "do something" was outstripping reasons to think the something would do any good.

And what of the potential for harm? No one can say whether taking estrogen posed special risks for Anna, exposed in utero to the synthetic estrogen DES; however, scientists who study long-term effects of hormones have expressed concern about prescribing hormonal drugs to DES daughters.^[10] Even more compelling to Anna was that her doctor's suggestions sounded rather like the DES regimen her mother was given, the pregnancy treatment that brought Anna to this point in the first place. She remained concerned about effects all of these medications might have on a developing fetus if she did conceive and decided against taking additional hormones.

Questions about Risks

Questions about risks for women taking Clomid and other fertility drugs emerged publicly in 1993, with reports of a possible link to ovarian cancer. One epidemiological study of women diagnosed with ovarian cancer suggests that use of Clomid for more than one year may increase an individual's chances of later developing this disease.¹ Pointing out the large proportion of women in the study who took Clomid even though they did not have ovulation problems, Dr. Robert Jaffe cautioned, "If additional carefully performed and controlled studies also point to the possibility of increased risk of ovarian malignancies in infertile women who undergo repeated attempts at ovulation induction, clinicians should be circumspect in their use of [fertility drugs]. At the very least, the sometimes thoughtless, profligate, and often prolonged use of clomiphene citrate, particularly in women with normal ovulatory cycles, should not be perpetuated."² By the mid-1990s, fertility specialists were more commonly recommending that women try Clomid for not more than three to four treatment cycles, perhaps alternating months with no treatment.

Lack of knowledge about how Clomid affects the human body extends further than a woman's reproductive tract. In 1994, an ophthalmologist reported on a woman taking clomiphene citrate who developed a dark area in one eye; her vision was seriously impaired and had only partially improved months after stopping the drug. Noting that Clomid, like other hormonal drugs, can reduce blood flow to the eye and that vision problems are common with Clomid, he cautions that this medication should be stopped and a patient's eyes examined if she experiences any changes in vision.³ While only a case report, it does raise questions: first, whether gynecologists read and pay attention to an eye doctor's cau-

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tions, and second, whether they inform women who are deciding whether to take Clomid about this potential side effect.

Another interesting case report, given patients' common reports of moodiness or depression while taking Clomid, describes psychotic symptoms in a woman shortly after she started treatment. The authors suggest that clomiphene—in combination with the physical and psychological stress of undergoing fertility treatment—may trigger such a reaction in some women. They recommend that physicians inform patients "in detail about the possible psychological effects of clomiphene"; if a patient has previously experienced psychiatric illness, ovarian stimulants such as Clomid should be prescribed "with particular care."⁴

1. Rossing, Daling, and Weiss 1994.

2. Jaffe 1995a.

3. Lawton 1994.

4. Seidentopf et al. 1997, 707.