SALT LAKE CITY — Sarah Mancoll was visiting her parents in Florida when she came down with a cold, which wouldn’t have been a big deal except for one thing: She was pregnant with her first child.
Mancoll wanted to take medicine to relieve her symptoms, but wasn’t even sure if it was OK to take a cough drop. She asked a pharmacist, who said he couldn't advise her. “It was ridiculous and so frustrating,” she remembers, five years later.
Now a mother of three who lives in Takoma Park, Maryland, Mancoll takes a medication much more potent than cough drops for an autoimmune disease that causes her hair to fall out. And she supports a movement to increase the number of pregnant and nursing women who take part in clinical studies that evaluate the safety of drugs and supplements despite the ethical challenges such research presents.
Mancoll spoke last year before a task force charged with making recommendations to the Department of Health and Human Services about the practice.
The task force submitted its report in September, strongly advocating for the expansion of research in pregnant women and nursing mothers. Among its suggestions: that potential liability to researchers be reduced, and that consent from the unborn child’s father no longer be required.
Although pregnant women are not banned from taking part in drug research, they are considered a “vulnerable class” and typically excluded. A review of 558 clinical trials sponsored by pharmaceutical companies found that 95 percent did not accept pregnant women, the 388-page report said.
Supporters of expanded research say the exclusion is unfair to pregnant women and new mothers, who need evidence-based information about the risks that drugs present to their babies, particularly as increasing numbers of women of child-bearing age take medication for anxiety and depression.
Research could also enable the development of new drugs and vaccines to help both mother and child, proponents say. But while the parents must give what's called "informed consent," their baby cannot, and if things go wrong, the effects of a drug could affect the child throughout his or her life.
Is it unethical to expose pregnant women and their babies to risk in medical research? Or, is it unethical to deny them the opportunity to take part and to potentially benefit from the findings? Those are some of the questions Health and Human Services Secretary Alex Azar must confront as he considers what to do with the task force's report, and whether to allow the panel's work to continue.
And if the government takes action that will expand research, the next generation of expectant mothers will have to ask themselves if helping to test a new treatment is something they should do to benefit society, or if it's too great a risk.
The task force was authorized by the 21st Century Cures Act and formed, in part, because of the efforts of Maggie Little, director of the Kennedy Institute of Ethics at Georgetown University, who has been advocating for expanded research in pregnancy for more than a decade.
Little and two friends — Anne Lyerly of the University of North Carolina, and Ruth Faden of Johns Hopkins University — in 2009 founded the Second Wave Initiative to develop and advance “ethically and scientifically responsible solutions for increasing our knowledge base” of how drugs affect pregnant women.
It's not illegal to test drugs on women who are pregnant or breastfeeding, but it's rarely done even though all research involving human subjects is highly regulated and subject to approval from an institutional review board.
Although more than 6 million American women become pregnant each year, the FDA does not require pregnancy-specific data before drugs can be approved.
The safety of drugs and supplements is now largely assessed through studies that examine medication use before women knew they were pregnant, and through pregnancy exposure registries that collect information volunteered by women who take medication while they are pregnant. (There are 109 such registries currently listed by the FDA.) Research has also been conducted during pregnancies that were later ended through abortion.
While pharmaceutical companies stand to benefit from research that could help them market or develop drugs for pregnant women, the liability risk makes them reluctant to include expectant mothers in research, Little said.
Their concerns are not unwarranted. In 1983, the manufacturer of a drug called Bendectin, prescribed for morning sickness, withdrew the drug because of lawsuits related to birth defects, although the FDA did not say it was not safe. Bendectin later returned to the market under another name, Dislegis, but the case serves as a cautionary tale to other drugmakers whose products could be linked to any number of fetal problems.
“Right now, pharma has no incentives (to conduct research with pregnant women), and it has disincentives, and the result is pretty predictable,” Little said.
Without clinical research that could suggest culpability in the event of injury or death, liability is generally limited to the prescribing physician, not the manufacturer of the drug, she added. The product warnings of many over-the-counter drugs say something similar to Tylenol’s disclaimer: “If pregnant or breast-feeding, ask a health professional before use.”
But if two of the panel's key recommendations are adopted — eliminating consent by the father and limiting liability — two significant barriers to fixing the "knowledge gap" will be removed, Little said.
“I think this is a watershed moment in the medical care of pregnant women. What the report makes clear, and what many of us have been urging for 15 years, is that the evidence base for treating pregnant women is sorely lacking and that harms both women and the children they bear,” she said.
Why this matters
Expectant women haven’t always been left out of research, nor have they always been discouraged from taking drugs during pregnancy.
In fact, the current dearth of information can be attributed, in part, to the horrific outcome of two drugs being prescribed freely in the middle of the 20th century: thalidomide, which caused birth defects in more than 8,000 children between 1958 and 1962, and diethylstilbestrol, or DES, which was prescribed in the 1940s and 1950s to prevent miscarriage, but was later linked to cancer in the daughters of women who had taken DES.
Those high-profile tragedies weren’t part of research, but with heightened public concern about studies like the Tuskegee Syphilis Study, in which African-American men were deprived of drugs that could have healed them of the disease, the government began issuing new rules for research in the 1970s. One guideline that still exists categorizes pregnant women, children and prisoners as “vulnerable populations" that needed extra protections.
In 1977, the FDA advised that women “of childbearing potential” be excluded from early drug trials, with the exception of life-threatening diseases. While this was useful in preventing abuses of previous decades, it went too far, said Rebecca Dekker, founder of the website Evidence Based Birth.
“Before we had appropriate ethical guidelines in place, pregnant women were frequently included in studies without their knowledge or consent,” said Dekker, a registered nurse who has a doctorate in nursing.
“Thankfully, research ethics subsequently moved in the opposite direction to require and emphasize consent and human subject protections. However, in the process, a disincentive to do research on pregnant people developed," Dekker said.
According to the report, the use of medications by pregnant women or lactating women is "widespread and growing" despite the dearth of information that exists about the effects during and after pregnancy.
About 90 percent of American women take at least one medication during pregnancy, and 70 percent take at least one prescription medicine while they are pregnant, a 2011 study found. “Between 1976 and 2009, prescription medicine use in the first trimester of pregnancy increased by over 60 percent,” the report says.
The risk of unintended side effects continues after childbirth for the 81 percent of new mothers who breastfeed their children, since substances the mother consumes can be transferred to the baby through breast milk. About half of women take at least one medication postpartum, and many women stop breastfeeding because of their need to take medication, the report said.
The Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gyncecologists have both endorsed the report. In a letter of support, Dr. Hal Lawrence III, executive vice president and CEO of ACOG, specifically urged the government to drop the description of pregnant women as a "vulnerable population" and for the National Institutes of Health to only require a mother's consent for research, instead of the mother and the father, as is the policy for pediatric studies.
"In the absence of a few specific scenarios, requiring consent from a woman's intimate partner prior to initiating research is neither warranted nor ethically justified," Lawrence wrote.
'We're worth studying'
Mancoll, the Maryland mother of three who was afraid to take a cough drop in her first pregnancy, had a bigger issue once her cold subsided. In 2003, she had been diagnosed with alopecia areata, an autoimmune skin disease that causes hair on the body — to include eyelashes and eyebrows — to fall out.
While there is no FDA-approved treatment for the disease, in some cases drugs that have been approved for other illnesses can help a person's hair regrow. But she couldn’t have taken a drug for her condition during pregnancy since there has been no testing to ensure that the medication she would take is safe.
Her children are now 1, 3 and 5, and she has decided against having a fourth child, in part, because she was afraid the window would close in which treatment for alopecia areata would be effective. She acknowledges that many women with a life threatening or mental illness have no choice in whether they should take a drug during pregnancy. "But they have no idea what the effect of these drugs would be,” she said.
Even though Mancoll testified before the task force to urge more research in pregnant women, she is also an example of the challenge facing researchers if more studies are allowed. She said she can’t say for certain she would participate in a clinical trial, that it would depend on “the study and the drug and its importance.”
“I don’t know how I would respond unless I was in the situation,” she said.
Similarly, Stephanie Eagleson, a mother of two in Elizabethtown, Pennsylvania, who is five months pregnant, said she doesn’t think she would feel comfortable participating in a trial, but it would depend on the circumstances.
“I might consider it, depending on the drug, if I really found myself in need of a particular medication during pregnancy, and if there was good reason to think any effects on the baby would be relatively benign," Eagleson said.
Proponents of the change don’t believe hesitation on the part of pregnant women will limit research once other barriers are lifted.
“The key will be a cultural shift related to the presumption of inclusion,” said Kathryn Schubert, chief advocacy officer for the Washington, D.C.-based Society for Maternal-Fetal Medicine.
“This will require a multipronged approach. We will need to ensure that those conducting trials are including pregnant women and lactating women along with educating and making women aware of the opportunities for inclusion in research,” Schubert said.
A study recently listed on the website Clinicaltrials.gov seems to back that up. The drugmaker Novavax says it recruited about 4,600 pregnant women for a trial involving a vaccine given to pregnant women that could potentially benefit the child by passing on a resistance to RSV, a respiratory illness that is the No. 1 cause for babies being hospitalized in the first year of life. At least 3,000 women received the vaccine, the company said in a news release. The results of the trial will be released sometime in 2019.
Even though Mancoll doesn't plan to have any more children, she cheers the conversation that the task force and its work has started.
“Regardless of what comes from it, it says that we, as a population — pregnant women — matter, and we’re worth studying,” Mancoll said.