The Other Drug Moms

Becky Jensen is an experienced traveler in a medical no man’s land.

Four years ago, problems with her pregnancy led doctors to prescribe numerous medications--such as hormones and antibiotics--none of which, Jensen noted with alarm, had been tested for safety in pregnant women.

Having miscarried five times previously, Jensen became so distraught over her dilemma--either lose her baby or take drugs that might harm the baby--that she followed her doctor’s advice to take yet another medication: a mild tranquilizer so she wouldn’t miscarry due to stress.

The Arcadia woman finally reached her emotional breaking point the day her husband went to a pharmacy to pick up some baby aspirin, which Jensen’s doctor told her would help increase blood supply and circulation to the fetus.

“The pharmacist knew I was at home pregnant. He told my husband, ‘Oh, no, Becky can’t take this because she’s pregnant! These are contraindicated because they will cause bleeding in the fetus.’ I called my obstetrician to complain and he assured me that I should take them. But it was a month before I @could swallow a pill. It said right there on the package insert: Do not take if you are pregnant.”

The no man’s land where Jensen resided for seven months--eventually giving birth to a premature but healthy son--is also known as the field of maternal-fetal toxicology. It is the place where a few dozen gutsy researchers confront a hushed-up reality: An estimated half of all pregnant women consume medications despite the fact that there is almost nothing known about most drugs’ safety during pregnancy.

Even dissected into smaller pieces, the issues confronting researchers in this field are overwhelming:

* Which drugs--legal, illegal, prescription or over-the-counter--can harm a fetus?

* Which drugs are safe for pregnant women who need treatment for an illness or relief from suffering?

* How do you answer these questions when it’s considered unethical to test new drugs on pregnant women?

On the 25th anniversary of the removal of thalidomide from the marketplace, there is a consensus building that these hard questions can no longer be ignored. Thalidomide was the medication for morning sickness prescribed to thousands of pregnant women in the 1950s that was later linked to severe birth defects.

That disaster, experts say, undercut legitimate efforts to better understand medication in pregnancy. Gradually, however, there is a recognition that ignorance is not bliss.

Research from a few respected maternal-fetal toxicology research programs in North America has whetted the thirst for more knowledge. And earlier last month, the U.S. Centers for Disease Control and Prevention launched a five-year, six-center project to collect data on possible factors relating to birth defects, with a special focus on medications.

Perhaps most significantly, the pharmaceutical industry is dipping a cautious toe into the testing of drugs in pregnant women before products move to the marketplace, a concept once considered an ethical quandary--pitting a woman’s health against her fetus’ welfare--that defied a solution.

“There is this huge tension between the need for authoritative information and this big, black hole,” says Dr. Gideon Koran, a Toronto-based researcher at the forefront of maternal-fetal toxicology. “Since the thalidomide disaster, the general gestalt of the community is that every drug is a potential thalidomide and women should not take medications while pregnant. But what is happening now is the larger community, both lay people and medical professionals, is beginning to understand the risk of not doing anything about these issues.”

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The fact is, say experts in the field, pregnant women are, for a variety of reasons, taking drugs.

“Legal drugs are widely used during pregnancy,” says Dr. Allen Mitchell, director of the Birth Defects Study at the Slone Epidemiology Unit at Boston University. “I think what people don’t appreciate is that the most commonly used drugs are probably the least studied.”

The patterns of drug usage in pregnancy usually fall into one of three categories: illicit drug use, especially of alcohol; use of medications--often over-the-counter drugs--that women unwittingly take in the first month or two of pregnancy before they realize they are pregnant; and the use of medications to treat illness, disease or suffering.

“More than half of all pregnancies are unplanned, so millions of women use medications because they were not planning to become pregnant. We estimate than more than 1 million babies, in the United States and Canada, are exposed to drugs in the first or second month of pregnancy,” Koren says.

Mitchell says the majority of pregnant women take acetaminophen (such as Tylenol) while pregnant, while as many as one in five take ibuprofen (i.e. Advil), and one in seven take pseudo-ephedrine, the active ingredient in many decongestants, such as Sudafed. Women may assume these drugs are safe during pregnancy because they are available without a prescription.

But, he says, “Drugs go over-the-counter when the Food and Drug Administration says they are safe to obtain without a prescription. . . . It may be safe for the mother but pose a risk to the fetus. We know little, if anything, about the risks or safety of these over-the-counter drugs.”

Besides concern for the fetus by avoidable drug use, researchers are also increasingly frustrated with the lack of knowledge on how to safely administer medication to pregnant women who need it.

“We are trying to identify drugs that cause problems to the baby. But the flip side is, we are trying to see if some drugs are safe for some women to take. The latter is what we’d really like to be able to do,” says Dr. Kenneth Lyons Jones, director of the California Teratogen Information Service and Research Program at UC San Diego. The program, which features a counseling hotline, fields about 1,100 calls a month from obstetricians and patients.

More women in their late 30s and early 40s, who may have already developed some of the common illnesses or chronic conditions of adulthood, are having babies now, notes Koren, whose program, Motherisk, handles about 140 inquiries a day. Moreover, women who decades ago wouldn’t have considered pregnancy are today starting families.

“Women with kidney disease, transplant recipients, cardiac patients, who were not even supposed to think about conceiving, now are encouraged to start a family. This means there are thousands of women on medications who are getting pregnant,” he says.

But they are getting pregnant on blind faith because there is very little scientific information about the medications they are using, experts acknowledge.

“This is a very difficult area,” Mitchell says. “I don’t envy the physician. They have to operate in an area of ignorance.”

Women, too, suffer the anxiety of having to take drugs without knowledge of how their fetuses will be affected.

Jensen, who has a heart defect in addition to her tendency to miscarry, berated herself unmercifully over decisions that would have stumped Socrates.

“I told myself that I was no better than the mom taking street drugs, only mine were legal,” she recalls. “I had visions of my baby coming out shaking from withdrawals.”

At one point, Jensen had to intervene between her cardiologist’s desire to protect her heart and her perinatologist’s wish to avoid premature labor. The perinatologist wanted to prescribe a drug to halt Jensen’s pre-term labor that would have threatened her heart. Jensen refused the medication.

“I had to be my own advocate,” she says. “But then I thought, ‘Are you being selfish? Don’t you care about your baby?’ ”

The golden rule that drugs should not be taken during pregnancy leads many women to panic when they are faced with a decision about medication, says Candace Hurley, founder of Sidelines, a nonprofit Laguna Beach counseling service for women with complicated pregnancies.

“The pendulum has swung so far to the notion that if you even take an aspirin during pregnancy, your baby will have some terrible disability,” she says. “Women are so frightened about taking anything during pregnancy that there is almost a hysteria about it.”

When Carol Kennan of San Dimas went into labor in her 25th week of pregnancy, there was little time to ruminate about whether to take a drug to stop the labor. Medication was administered in the emergency room, Kennan’s labor was halted and she went home.

But at home, Kennan felt qualms about her doctor’s order to continue taking the drug, terbutaline. Like most medications prescribed to pregnant women, terbutaline was approved for marketing by the FDA for an entirely different purpose--asthma.

“I had been so careful that I would even watch my caffeine intake,” Kennan says. “And now I was faced with taking a medication for 11 or 12 weeks of pregnancy. You begin to wonder if you’re doing the right thing. But the benefits outweighed the risk. It made sense to me to take the terbutaline.”

Women like Hurley and Kennan are backing efforts for more research on maternal-fetal toxicology. In September, Hurley joined Rep. Pat Schroeder (D-Colo.) in Washington to introduce Schroeder’s Safe Motherhood Act, which would create better reporting of complications in pregnancy and fund more research to counteract the widespread belief, Hurley says, that “nothing can be done” for pregnant women who are ill. The legislation will be carried next term by Rep. Cynthia McKinney (D-Ga.).

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When it comes to saving the baby, it’s easier to choose medication, despite the risks. But many pregnant women face muddier choices.

For example, Koren says, about 50,000 U.S. women are hospitalized each year due to pernicious vomiting and nausea during pregnancy. The anti-nausea drug Bendectin became available to women beginning in 1965. But in 1983 it was yanked from the marketplace by its manufacturer, Marion Merrell Dow, when charges were made that the drug caused birth defects.

Subsequent analyses of more than 20 epidemiological studies, however, show that women who took Bendectin did not have an increased rate of malformed babies, Koren says. The drug is now back on the market in Canada, manufactured by Duchesnay Inc. under the name Diclectin. It remains unavailable to U.S. women even though it is considered the only effective treatment for nausea in pregnancy, and the costs of doing nothing for these patients is high. One study at Brigham and Women’s Hospital in Boston found that about 10% of women with the condition undergo abortions to escape the unrelenting vomiting.

“Women with severe vomiting have a terrible psychological morbidity,” Koren says. “One cannot believe that this is happening in 1996.”

Two studies found the rate of hospitalization for women with severe vomiting in pregnancy tripled after Bendectin was withdrawn, he adds: “What is the cost of that? Millions? But Bendectin is an example of hysteria driving a drug out of the market and exposing many women to the risks and unpleasantness of morning sickness. It’s easy to tell a woman, no, you can’t take a drug. But then they suffer and their families suffer.”

Some women are barred from compassionate medical treatment because of doctors’ fears of malpractice should a baby be born with a problem, experts admit. This is especially true in cases where women’s lives are generally not threatened if they discontinue or don’t receive medication during pregnancy.

Scores of women with mental illnesses are thought to be affected by this dilemma, says Jones, who, along with Mitchell, has made psychotropic medications a priority in his research. As many as 10% of women of child-bearing age suffer depression, while many thousands are stricken during this time of life with bipolar disorder, schizophrenia, panic disorder or obsessive-compulsive disorder.

“Lithium is the best studied, but for most psychotropic drugs, and particularly for the newer ones, there is very little information,” Mitchell says. “We do not have a full assessment of risks versus benefits.”

The information is of intense interest. When Jones published a paper in the New England Journal of Medicine in October on the effects of Prozac in pregnant women, it created a national stir. He found that the drug can cause fleeting problems in the newborn, such as jitteriness and breathing problems, but that it was not associated with a higher rate of miscarriage, premature birth or major birth defects.

“With Prozac, we have found problems. But they are not life-threatening and can be dealt with. Therefore, for women who have to take the drug, our data are pretty optimistic. But if you can get by without it, then the data would suggest you should try to get by without it,” he says.

But, Mitchell notes, even a finding of such relatively mild impact could be viewed as alarming.

“There was real concern in the mental health community that [due to the study] the drug would be dropped in favor of no treatment or alternative treatments about which we know less or worry about more,” he says.

The Prozac study is an example of how many decisions in maternal-fetal toxicology rest on the delicate balance between risks versus benefits, Jones says.

“I think legal ramifications relate to not providing facts. We are sitting down with the doctor and the patient and saying, ‘Here are the pros and cons. Do you want to take the risk?’ If you involve a woman and her husband and they make the decision, I don’t see a liability problem with that.”

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The kind of epidemiological fieldwork performed by Jones and his colleagues, however, is a far cry from the concrete, detailed data available to every non-pregnant adult who consumes an FDA-approved medication.

New drugs are typically rigorously tested over seven to 10 years, first in lab animals then in large numbers of human subjects. The experiments in lab animals are virtually the only way drug manufacturers might learn of a possible teratogen--an agent that causes a birth defect--before the drug moves to the marketplace, says Dr. John Siegfried, deputy vice president for regulatory and scientific affairs at the Pharmaceutical Manufacturers Assn., the industry trade group in Washington.

But the realization that animal studies are far from perfect--thalidomide, for example, produced no anomalies in pregnant lab animals--and that “pregnant women end up being their own guinea pigs,” has prompted some soul-searching among manufacturers, Koren says.

Siegfried agrees: “Usually companies just say, ‘This drug has not been tested in pregnant women’ and leave it at that. This is true for lots of drugs they know that pregnant women will take, and it is a dilemma. If you know the drug is going to be used by pregnant women, it would be reasonable to test it in pregnant women to have that information. But that has not been done as aggressively as it might have.”

The industry has been nudged ahead in this gamble, however, by the FDA. In 1993, the agency canceled its long-standing policy of preventing women of child-bearing age to enter clinical trials. The policy was established to avoid the potential for harm to a fetus should a research subject become pregnant. But the rule also meant that virtually no data on the effects of various medications in women were collected.

While the vast majority of all drug trials still only admit women who are using birth control, the industry is also beginning to design drug trials on pregnant women, Siegfried says.

Drug manufacturers can also see dollar signs in the relaxation of the rules, he says: “If you can come onto the market with a drug that has been tested and proven safe for pregnant women and your competitor hasn’t done that, you have just opened the cash register drawer.”

Nevertheless, there is no real rush to sign up pregnant women to test new medications. The field is fraught with potential bombshells. Just ask executives at Marion Merrell Dow. Thirteen years later, the manufacturer of Bendectin is still fighting lawsuits that its product caused birth defects.

“Safety has to be the first priority,” Siegfried says. “And at this point, as a scientific community, we don’t have a lot of tools to know what happens with a drug. How much of a drug is transported to the fetus? How much of a barrier is the placenta? What is the physiology and metabolism of the drug in the fetus? Is it the same as an adult woman?

“We don’t have good research techniques to have that information. There is a heck of a lot we need to know. It’s a tremendous Catch-22. Women have every right to have the information. But the current techniques to get that information--risk-free--are not good.”