Drugs are rarely tested on expectant mothers because pregnant women are considered a vulnerable population. But during late nights as the attending physician in the University of Pittsburgh Magee-Womens Hospital labor and delivery ward, Catherine Chappell often meets expecting mothers who have tested positive for the hepatitis C virus (HCV), which is commonly passed from mother to child during pregnancy.
Like hepatitis B, HIV, and certain other infections, HCV spreads via bodily fluids and infected needles. HCV cases have tripled from 2010 to 2016 because of the opioid epidemic, according to the US Centers for Disease Control and Prevention.
Many of Chappell’s patients also struggle with combinations of opioid addiction, poverty, and mental health issues—all factors that make them less likely to seek health care when not pregnant. In 2015, Chappell realized her patients’ pregnancies offered a window of opportunity: Could she treat the mothers with antivirals for hepatitis C, thus curing two patients at once? Although the antiviral drug combination of ledipasvir and sofosbuvir had been approved since 2014 to treat four of the six viral strains that cause HCV, it had never been systematically tested in pregnant women.
In a Phase I trial, Chappell and her colleagues treated nine women with the medication during their pregnancies. All nine were cured of the infection and their babies born virus-free, with no adverse effects noted. The team presented the results at the 2019 Conference on Retroviruses and Opportunistic Infections in Seattle and now plans to extend the study to a newer antiviral that targets all six strains of the virus. Jyoti Madhusoodanan spoke with Chappell about the need for expanding drug testing during pregnancy.
▸ Hometown: Odessa, Texas
▸ Current position: Assistant professor; obstetrics, gynecology, and reproductive sciences; University of Pittsburgh
▸ Education/Degrees: BA, Biology and Chemistry, Southwestern University, 2003; MD, University of Texas Southwestern Medical School, 2007; MSc, Clinical Research, University of Pittsburgh, 2015
▸ Professional highlights: Conducting the first prospective study of hepatitis C treatment in pregnant women
▸ Biggest challenge with this trial: “Recruitment. We recruited for 2 years and got nine patients.”
▸ Best professional advice received: “Be flexible, and allow yourself to be drawn to the most interesting and impactful science.”
▸ One drug you wish was better studied in pregnancy: “Coffee! Many of my pregnant patients quit coffee cold turkey. The data around caffeine and risks of miscarriage or low birth weight in infants is mixed. I wish we had better data, so pregnant women wouldn’t have to live without coffee without a solid reason.”
▸ Hobbies: Hiking, biking, and an occasional triathlon
How did you get interested in conducting clinical trials in pregnant women?
Working in women’s health as an obstetrician, I see the burden women have when they’re pregnant. It’s a time when clinicians, obstetricians, and other doctors are very reticent to use any extra medicines, especially if they haven’t been studied during pregnancy. So pregnant women who have health issues that require medicines are left high and dry, without good research to really direct them on what medicines are safe. They’re constantly told, “You can’t do this or can’t eat that,” and it’s not really based on a lot of evidence.
One of the reasons that pregnant women have effectively been protected from research that could improve their health is because we thought we were protecting the mom and the baby from harmful research. But really, we also “protected” them from getting new and improved treatments that can improve maternal health and also consequently improve the health of the fetus.
As of now, how do we know whether a drug is safe for use during pregnancy?
Pregnant women are not usually included in the studies done for FDA approval. What is generally done instead is that we give the medications at higher doses to pregnant animals and see if there are any problems with that. Then manufacturers say the drugs may be safe in pregnancy, but human studies should be done. What usually happens is that maybe 10 years down the line there are enough pregnant women that had exposure to the drugs, so we can say something meaningful. It really leaves pregnant women and obstetricians without any good data to make decisions on newer drugs.
There are also a lot of problems with what we call recall bias, which happens when information is collected after an event. If there’s a negative thing that happens, the pregnant women and doctor may see a correlation. But if nothing bad happens, she might not even remember, or the doctor might not recall giving that medication.
Have any trials been conducted in pregnant women?
In many ways, HIV trials led the way. ACTG 076, a clinical trial launched in 1991, was the first study of the antiretroviral drug AZT to prevent HIV transmission from the mom to the baby. That and other trials in pregnant women led to therapy regimens designed for pregnancy. At that time—before we had really good antiretrovirals for treatment—HIV infection was basically a death sentence. That made people really want to prevent perinatal transmission.
Why not use the same strategy for other medications?
HIV is a chronic infection that does not have a cure. In that way it differs from hepatitis C. The mantra for a long time was: Why would you want to treat a woman with hepatitis C during pregnancy? Is that risk worth it when you can cure her after pregnancy and also treat the baby if needed? But for us, it’s very practical. When a woman comes in for prenatal care, we can test her for hepatitis C, treat her, and also prevent perinatal transmission at the same time.
How do you talk with women about the choice to participate in the study?
Research participation in pregnancy is not for everyone. Some women will not even take a Tylenol during pregnancy, and these women would be uncomfortable participating in research during pregnancy. We discuss the potential risk and benefits at length with all of our participants and how we have designed the study to reduce these risks, by starting medications after organogenesis is complete around 16 weeks’ gestation and by doing preclinical studies on animal models. We make sure that the participant understands that we cannot predict what might happen with the infant, but we have reduced the risk as much as possible.
What should the criteria be for testing drugs in pregnant women?
Drugs for any infection during pregnancy that causes significant maternal or neonatal issues should be prioritized. Next would come drugs for chronic conditions like diabetes or hypertension.
It’s common practice to take pregnant women off certain medications because they’re untested during pregnancy and put them on older medications that have more data. But we shouldn’t be fearful of doing the studies necessary to determine that the newer treatments are safe and effective during pregnancy.
Jyoti Madhusoodanan is a freelance writer. A version of this story first appeared in ACS Central Science: cenm.ag/chappell. This interview was edited for length and clarity.