Ruth Faden

“There has been progress in people’s appreciation of the evidence gap —but there are still reticence, concern, dogma and hard issues that remain unresolved.” 

In mid-January 2016, Beth Ann Bovino and her husband were looking forward to a “babymoon” in Mexico before the birth of their son in the spring. Three days before their trip, Bovino’s husband called her at work to say he’d just heard the Centers for Disease Control and Prevention was about to announce a warning: Pregnant women should avoid traveling to Mexico due to Zika. The mosquito-borne virus had recently been linked to microcephaly in babies born to infected women.

Bovino’s first thought? “I’ll just put on bug spray.” However, the couple soon changed their plans and spent their vacation in Hawaii instead—a decision for which Bovino is now deeply grateful.

“I’m sure if we had gone to Mexico, I never would have left the hotel room,” says Bovino, a New Yorker who works as U.S. chief economist for Standard and Poor’s and is now mom to a healthy baby. “I would have been terrified, especially when you’ve seen that what Zika does to a fetus and baby is so tragic, and I certainly wouldn’t want that risk.”

Bovino is hardly alone in trying to navigate the personal impact of Zika. While doctors and scientists know some basic information about the illness—it can be spread through sexual contact as well as by mosquitoes, and it can be passed from mother to baby during pregnancy or delivery—far more remains unknown: How likely is it that a pregnant woman exposed to Zika will become ill? Or that Zika will pass to her fetus? What are the odds an infected fetus will develop birth defects? Are women and fetuses more vulnerable to Zika during certain phases of pregnancy?

With so many unanswered questions, women around the world and their doctors are left to make decisions without hard data.

And—as with other conditions that affect pregnant women and fetuses—scientists face larger-than-typical obstacles in answering those questions and in developing prevention and intervention protocols. That’s due to long-standing concerns about including pregnant women in clinical research trials for medications and vaccines.

“The Zika epidemic is highlighting a longtime problem in medical research—the exclusion of the interests of pregnant women from the research agenda,” says Ruth Faden, who just stepped down as founding director of the Johns Hopkins Berman Institute of Bioethics after serving in the role for 21 years.

It’s long been a Catch-22 of medical research: For decades, including pregnant women in drug and vaccine trials was considered unethical. So how do we know which drugs and vaccines are safe for them and their developing fetuses?

Historically, physicians, scientists and scientific institutions like the Food and Drug Administration and CDC have leaned heavily toward precaution, striving to protect pregnant women from exposure to anything with the slightest potential for ill effects.

But many scientists say this well-intentioned approach has caused more harm than good: In the absence of evidence-based research about the safety and efficacy of most medications during pregnancy, pregnant women may be undertreated for a multitude of conditions, such as asthma, depression, diabetes and HIV, leaving them and their fetuses even more vulnerable to disease.

Now, in a step to narrow this knowledge gap, Faden and an interdisciplinary team of scholars (including several Johns Hopkins researchers) are exploring the ethics of research during pregnancy through a grant from the Wellcome Trust, awarded last April. The team will begin with the Zika crisis and expand to more general public health research, spending two years developing guidance for conducting research with pregnant women in the midst of a public health crisis.

“I think there has been progress in people’s appreciation of the evidence gap with regard to pregnant women, and many more people are working on trying to fill that gap. That’s the good news,” Faden says. “But there are still reticence, concern, dogma and hard issues that remain unresolved.”

A Moral Quandary

Back in the 1990s, recognition began to grow that women in general were underrepresented in clinical trials and other investigations of health concerns. In response, the National Institutes of Health launched the Women’s Health Initiative, a long-term study to prevent heart disease, cancer and osteoporosis in women.

In addition, in 1993, Congress passed the NIH Revitalization Act, requiring that NIH-funded studies include representative samples of subpopulations unless their exclusion can be justified for reasons unrelated to cost. In the last decade, the FDA has been actively emphasizing the need to include pregnant and nonpregnant women in clinical trials, issuing industry guidance on pregnancy registries and on conducting studies in pregnant women.

Slowly but surely, those new regulations are helping to change the default from exclusion to inclusion of pregnant women in drug and vaccine trials, says obstetrician Jeanne Sheffield, who specializes in maternal-fetal medicine. Today, the FDA won’t approve most new drugs—especially antimicrobials and vaccines—until they’ve been tested in pregnancy, says Sheffield.

Still, years will pass before enough information is available to patients and doctors. Ironically, though physicians were initially the ones to lobby the FDA for more data about possible medications for their pregnant patients, Sheffield says some physicians now represent something of a roadblock to research. They can be reluctant to subject their patients to potential health and ethical risks by enrolling them in trials. “Change comes slow,” she says.

The ethics are complicated on several fronts. For one thing, researchers can’t ask a fetus for his or her consent to enroll in a study. Concerns that medication and maternal health factors can irreversibly affect a growing fetus are very real. And while the interests of mother and baby might be separate—the drug in question might be targeted toward one more than the other—their physical beings are very much connected, raising questions about the value of gaining information about one of them at the potential expense of the other.

Meanwhile, according to a 2011 study in the American Journal of Obstetrics & Gynecology, about 90 percent of women take at least one medication during pregnancy—and most such drugs have not been tested in mothers-to-be.

Making the Call

Brook Johnson had just entered her second trimester of pregnancy in 2011 when she was hit hard by flu. Unable to keep anything down for 36 hours, she went to the hospital and met up with her obstetrician, who told her she was severely dehydrated and asked if she wanted medication.

Johnson, who was planning an unmedicated labor and delivery, first declined, but then accepted a dose of Zofran, which quickly alleviated her nausea. Aware of television ads listing birth defects as a possible side effect of the drug, as well as the fact that the ads’ accuracy had not been medically proven, Johnson says she weighed the pros and cons with her OB and determined that her illness and dehydration—which can cause complications, including low amniotic fluid—posed a greater risk to her baby.

“It was my balancing act between not wanting a lot of medication, and also not being pigheaded and almost stupid and refusing intervention when I really needed it,” says Johnson, a Baltimore social worker and ballet teacher. Today she is the mother of a 5-year-old and an infant, both healthy.

It helped that Johnson had already built a strong relationship with her OB and trusted her guidance in a situation marked by unknowns and uncertainties. But not every mother-to-be is so lucky.

When Baltimore filmmaker Dina Fiasconaro decided in 2012 to have her first child, she began researching whether to stay on the medications she was taking for anxiety and quickly found there were no clear-cut answers to her questions. So she decided to document her own process of pregnancy and decision-making, along with those of several other pregnant women experiencing anxiety and depression.

Her film, Moms & Meds: Navigating Pregnancy and Psychiatric Medication, features interviews with women describing how they weighed their choices about staying on, getting off or changing their medications at various points during their pregnancies and after their babies were born. What she discovered, she says, was that while the moms all wanted to do what was best for their babies—whether staying on drugs for their own stability or getting off them to reduce risk to the fetus—accessing information about those choices was very challenging.

“It seemed very clear to me that everybody really cared and just wanted to do the right thing. But one of the main issues was that nobody really knew what the right thing was,” Fiasconaro says. “Because either their doctors were being dismissive, or two of their doctors would give them conflicting information. And who was right?”

Without available data, many specialists are exceedingly cautious about prescribing medication to pregnant patients.

At Johns Hopkins, Sheffield says she’s often on the receiving end of calls from providers—ranging from cardiologists to dentists—asking if a drug they would typically prescribe for a patient without a second thought is safe for a patient who is pregnant.

Sheffield makes it her business to keep up with developments in FDA categorization of drugs. So while she may be unable to provide definitive answers, she can usually provide well-researched ones. She can review information about how the drug performed in animal models, for example, or what issues may or may not have appeared in registries tracking observational studies (reports by physicians of outcomes experienced by patients already taking a drug before realizing they were pregnant, for example, or using the drug “off label”).

“It all comes down to: If you stop a medication, what’s going to happen, or if you continue it, what’s going to happen?” Sheffield says. “So it’s a pure risk-benefit thing. That’s one of the things we’re trained to do. Nothing’s perfect.”

A Measure of Safety

Whether a new drug is undergoing testing at a pharmaceutical company or an academic medical center, federal regulations require a series of tightly controlled tests involving approval at each level.

Before a pregnant woman can be enrolled in a trial, for example, the drug must first have to pass through an in vitro lab trial, then an animal trial, then a trial in nonpregnant humans and then a trial in pregnant animals. Research at universities is also subject to an internal Institutional Review Board (IRB), providing another layer of oversight.

When Sheffield arrived at Johns Hopkins last December from the University of Texas Southwestern Parkland Memorial Hospital, she was impressed by the clinical trial approval process here. Johns Hopkins’ two tiers—the main IRB as well as an obstetric review board—ensure acceptable risk for both moms and babies, she believes.

Given such safeguards, she’s found that pregnant women are often eager to participate in studies that help other mothers-to-be better understand the potential impact of medications. For example, when she wanted to test whether giving the antiviral drug acyclovir at 36 weeks would decrease herpes lesions—and therefore decrease neonatal herpes in the baby—women willingly enrolled.

“With pregnant women, if you can say that the due diligence has been done, a lot of them are very willing,” Sheffield says.

Increasingly, researchers are realizing the importance of understanding how the immunologic and metabolic changes that occur during pregnancy affect how a drug is processed and used by the body, and how a disease progresses.

In the first trimester, concerns center on possible structural damage to the fetal brain, heart and other organs, Sheffield says. By the third trimester, with the organs more fully developed, the concerns shift toward growth and maturation—though Zika represents an exception, as it can damage the brain in the third trimester. That is also the time that the woman’s blood volume has increased by 50 percent, and her kidneys are processing high volumes of fluid, so medication dosages and frequencies may need to be adjusted.

Pregnancy also may change how illness manifests itself. The potentially fatal tuberculosis, for example, can more readily progress from latent infection to disease during pregnancy. It’s also known to cause worse pregnancy outcomes, and TB in pregnancy further poses risk of congenital TB to the baby, says infectious disease specialist Kelly Dooley. The risks and benefits of treating latent TB to prevent TB disease in pregnant women compared with nonpregnant adults, though, are unknown.

In addition, some TB has become resistant to standard treatment. The safety and drug concentrations of the new and existing medications available to treat those drug-resistant strains have not been tested explicitly in pregnant women.

“It doesn’t make sense. If someone has TB, you must treat it whether or not that person is pregnant; you cannot wait,” says Dooley. “There are standard treatment regimens recommended by the World Health Organization for patients with drug-sensitive or drug-resistant TB. It is important to have a good understanding of the safety and drug levels of these medications in pregnancy so that they can be used properly. And this information is best collected in the context of clinical trials, wherein rigorous follow-up and testing for safety are standard practice.”

In this regard, she and colleagues at Cornell and multiple trials sites around the world are preparing for a clinical trial of isoniazid and rifapentine, a drug combination that is currently labeled for prevention of TB disease in children and adults with latent TB. They are hoping to test it in pregnant women to characterize its safety in the population and will measure drug levels to determine appropriate dosing over the continuum of pregnancy.

On the Horizon

Sara Goldkind, who spent more than a decade as the first bioethicist at the FDA’s Office of the Commissioner, believes that education and advocacy are needed now to ensure that lasting improvements are made on an institutional and sponsor level, taking into consideration the needs of both women and the fetuses they carry. That is, clinicians, IRB members, investigators and sponsors must all recognize the continued dearth of evidence-based pharmaceutical therapies for pregnant women, she says.

“There also needs to be a lot more education of clinicians, investigators, sponsors and IRB members about the importance of enrolling pregnant women in clinical research—that this research can be done in an ethical manner—and how to protect [these women] once they are enrolled,” says Goldkind, today an independent bioethics consultant.

Specifically, Goldkind says federal agencies like NIH, the U.S. Department of Health and Human Services, and the FDA could catalyze public discussions through advisory committee meetings and public hearings on how to conduct research in pregnant women in a scientifically sound and ethical manner that meets regulatory requirements. Ideally, one result would be policy statements that describe acceptable standards for designing and conducting trials in pregnant women.

In addition to ethics and potential research-associated risks, one major obstacle to progress—cited by Goldkind and others—is cost.

The preclinical reproductive and juvenile toxicology studies that researchers must complete before a pregnant woman is enrolled in a clinical trial are very expensive, so typically they are done very late in drug development. In many cases, drug companies prefer to forego the “preclinical tox package” and accept a designation of “unknown safety” for pregnant women.

Dooley argues that without incentives or other supports, drug companies will continue to exclude pregnant women from licensing studies of investigational drugs.

“So then the question is how the government can help with incentivizing having those packages ready earlier so pregnant women can participate in research trials,” Dooley says. She also advocates changing post-marketing labeling requirements to require testing during pregnancy for any drug that may reasonably be expected for use in pregnant women, similar to requirements for testing drugs in children or other special populations.

Meanwhile, researchers at Johns Hopkins and other research centers are working to develop a Zika vaccine. But since this would be a live, attenuated vaccine—known to be unsafe for fetal development—many of these efforts across the country are focusing on women before they become pregnant and on men.

Knowing that any vaccines developed might not target pregnant women, and recognizing the uncertainties of how Zika unfolds for both moms and babies, Faden says the Wellcome-funded initiative will look at what other approaches to the virus make the most sense ethically. The initiative will also consider the larger question of when—and under what conditions—pregnant women can be involved in clinical trials.

Whatever the results for Zika specifically, the discussion it has sparked can only help with future public health threats—from bioterrorism to new pathogens to the re-emergence of existing pathogens, Faden says.

By identifying the conditions that would make it ethically permissible to involve pregnant women in specific phases of the research-and-development response to the event, she says, we can be better prepared to protect all members of the population from future threats.

—Sarah Richards contributed to this article.

Jeanne Sheffield

Sheffield has found  that pregnant women are often eager to participate in studies that help other mothers-to-be better understand the potential impact of medications.