Why isn't there more research into improving pregnancy conditions?

Sponsors shy away from this population

Experts say there may be some opportunities missed in research with pregnant women. Despite some concerted government efforts that have succeeded in increasing research in this area, major industry sponsors shy away from this population.

"Clearly, this is a critical area where you want to have the best studies you can to advise pregnant women and their families as to what their options are," says Catherine Spong, MD, branch chief of pregnancy and perinatology branch of the National Institute of Child Health and Human Development (NICHD) in Rockville, MD.

"Unfortunately, because of the special circumstances, it's more difficult to get these studies done and to get people interested in doing a study," Spong says. "You have two patients to look at, and you have to take the interest of both the mother and developing child into consideration."

This is why there are many drugs that are not labeled for use in pregnant women, and why obstetricians must make decisions based on limited research and their own common sense, Spong adds.

Pregnant women and even women who could become pregnant have been excluded from research for a long time, says Karen J. Schwenzer, MD, FCCM, an associate professor of anesthesiology and critical care medicine at the University of Virginia (UVA) School of Medicine in Charlottesville, VA.

"Go back two decades and women of childbearing potential were excluded completely from research until the late stages of drug development," Schwenzer says.

While the industry's attitude toward women of childbearing age has changed in the past 10 years, there hasn't been a lot of change among research involving pregnant women, Schwenzer says.

"I think there's still a fear among the industry and investigators about doing studies involving pregnant women," Schwenzer says. "We do have some studies at UVA, but these primarily are studies that have a direct benefit to the mother with minimal risk to the fetus."

For example, one study looks at the management of labor pain using different types of labor epidurals. Another addresses bladder disease in pregnancy and the development of gallstones, she says.

"So I am seeing studies like that coming through from our investigators," Schwenzer says. "But these are investigator-initiated studies; I have not seen a study sponsored by the industry that targets pregnant women."

Also, many of the studies are retrospective analyses and are not as specific as a randomized trial, she notes.

Even commonplace pregnancy health issues are little studied, Schwenzer says.

For instance, high blood pressure is common among pregnant women, but most drugs used to treat the condition have not been studied in pregnant women, she says.

"That leads doctors and obstetricians to choose a drug that may not have enough research evidence that it's safe," Schwenzer explains. "Clinicians have to use their best estimates, and it's a judgment call on what the best treatment would be, based on evidence in nonpregnant individuals."

Most of the studies involving pregnant women that Schwenzer has seen are those that provide a direct benefit to the woman and pose minimal harm to the fetus, she says.

"We see retrospective studies that have no risk, obviously," Schwenzer adds.

NICHD has a 20-year-old program called the Maternal Fetal Medicine Unit Network, that has sought to increase research knowledge about pregnant women, Spong says.

Fourteen network sites across the United States tackle important problems and critical issues in pregnancy with the goal of developing evidence-based practice, Spong says.

"What we've done is identify practices in place that were not really beneficial to pregnant women and their children," Spong says.

"One example is previously there were studies that had shown a condition called bacterial vaginosis (BV) or Trichomonas vaginalis that is associated with pre-term birth," Spong explains.

Two studies had shown that women at high risk for pre-term delivery could have this risk reduced through treatment for BV, she adds.

This led to obstetricians treating every woman who had this condition.

The network chose to study the treatment and recruited asymptomatic pregnant women who were screened for BV. They were randomized to antibiotic treatment or placebo, but the trial was stopped early, Spong says.

"The women with Trichomonas who were treated had a higher rate of pre-term delivery," she says.

As a result of the clinical research, obstetricians were advised to stop screening every pregnant woman for the infection.

"If they're symptomatic, then treat it, but if they're not complaining, then there's no reason to treat," Spong says. "Whatever the flora is for that person may be more beneficial than what takes over when you eradicate the flora."

This example demonstrates why clinical research in pregnant women can lead to better and safer practices.

In another example, the network demonstrated through research a treatment for preventing pre-term delivery, Spong says.

"It's the number one cause of neonatal death and long-term morbidity for children," Spong says.

One of the network sites screened high-risk pregnant women who had already delivered a pre-term baby and evaluated them to see if they were interested in a trial using progesterone to prevent pre-term delivery, Spong explains.

The women received weekly progesterone, and the trial produced such positive results that the data safety monitoring board (DSMB) decided it would be unethical to continue to randomize patients. The study found that weekly progesterone, started in the 16th to 20th weeks, prevented pre-term deliveries of less than 32 weeks, 35 weeks, and 37 weeks, Spong says.

"We were questioned quite harshly after the progesterone trial about whether it was safe," Spong recalls. "But no one questions giving progesterone to women [treated for infertility], and they're given it at a more vulnerable time during the first trimester."

The problem is that clinical trials involving pregnant women are needed to guide future studies with pregnant women, Spong says.

"The opportunities for pregnant women to participate in clinical trials are limited, despite a push from the Food and Drug Administration and others," Schwenzer notes.

Also, IRBs and investigators should consider the ethics of removing women from typical adult clinical trials when the women become pregnant, Schwenzer says.

"Is that ethical to deny treatment to a woman that she couldn't get otherwise?" she says.

On the other hand, there are clinical trials involving drugs that are known to be harmful to a fetus, such as the thalidomide trials for cancer, and so the ethical concerns are not just theoretical.

"Suppose there's a trial where the potential for therapeutic benefits for a woman is there, and so you enroll women knowing there is the potential of their getting pregnant," she says. "You give separate consent forms, detailing the type of risk that's involved and the type of birth control that needs to be used to avoid pregnancy."

These types of trials often require women to use two types of birth control, and they're given a pregnancy test, Schwenzer says.

"Sponsors won't use pregnant women in trials involving some potentially helpful drugs because of the risk," Schwenzer adds.

However, the NICHD network has made some important contributions to the scientific world's collective knowledge about pregnancy.

The Maternal Fetal Medicine Unit Network currently is enrolling 10,000 pregnant women in a preeclampsia prevention trial that involves the use of vitamin C and vitamin E, Spong says.

"Clearly, preeclampsia is a condition we need better understanding of, and we need to develop therapies," Spong says. "This is the largest trial we've ever done."

Ideally, pharmaceutical sponsors and more investigators would do research with pregnant women because the potential benefit to society could extend far, Spong says.

Pre-term delivery and low birth weights are associated with health problems that may occur even decades after the baby is born, she adds.

"I would love to have more people do research in pregnant women," Spong says. "If you could improve the uterine environment and improve outcomes, then we'd have less disease, strokes, heart attacks, and other health problems."

[Editor's note: For more information about the Maternal Fetal Medicine Unit Network, see the Web site: www.bsc.gwu.edu/mfmu.]