CHALLENGES FOR PREGNANT AND LACTATING PERSONS
Sarah Mancoll shared her perspective as a mother and advocate for including pregnant and lactating persons in research. Mancoll has alopecia areata, a chronic autoimmune condition for which there is no cure and no particularly effective treatment.1 She described how, prior to becoming pregnant, she was able to keep her hair loss to a minimum through bimonthly corticosteroid injections. Although this process was painful and disruptive to her workday, it was relatively successful in limiting disease progression and spurring hair regrowth. At age 30, having had alopecia areata for 8 years, Mancoll consulted her obstetrician/gynecologist (OBGYN), dermatologist, and primary care physician about the possibility of continuing intralesional corticosteroids when she became pregnant. While each doctor told her that it was “probably fine,” there was no clinical evidence to inform their shared decision-making. She added that none of her providers were comfortable giving definitive guidance. Feeling “deeply frustrated,” Mancoll decided to stop corticosteroid injections for the duration of her pregnancy and lactation and, as a result, she lost all of her hair. She started intralesional corticosteroids 5 years later, after having her last child, but the treatment was no longer effective for her. Today,
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1 Mancoll noted that just days prior to the workshop FDA approved the first systemic treatment for alopecia areata.
at age 40, Mancoll is participating in a clinical trial for a new medication designed to treat alopecia areata. She considers trial participation as a way to give back to the alopecia community, and as a policy professional for a scientific society, she feels strongly about advancing knowledge to improve human wellbeing. Mancoll concluded, “When a person decides to have a baby, they should have access to information that can help them make well-informed medical decisions. Like other Americans who are not pregnant or lactating, they too should benefit from knowledge gleaned from clinical research studies.”
Additional patient perspectives were provided via a video of prerecorded statements. Like Mancoll, these individuals faced difficult decisions about whether or not to take necessary medications in the absence of any clinical trial evidence. Danielle Askin described making the decision of whether to continue medication for psoriatic arthritis during her pregnancies and while breastfeeding as a lose-lose situation. Her rheumatologist, who was also a mother, reviewed potential medications with her and explained there had been no studies done in pregnant or lactating persons and potential adverse effects for her children were unknown. She observed that whether she stopped treatment or continued taking medication, “either I would have negative side effects for myself, or my children would have negative side effects, or both of us.”
Melissa Gorman suffered a medical complication during her first pregnancy, and she and her husband found themselves having to decide whether or not she should take a medication while pregnant and then while breastfeeding. “I was shocked to find there wasn’t a lot of information available.” As a nurse, she said she found it frightening to have to make a medical decision for herself and her child without any scientific evidence on which to base that decision.
Ciarra Covin, who has been living with HIV for nearly 14 years, described feeling disheartened when she learned that her medication was not recommended for people who were pregnant. As a program manager at the Well Project, a nonprofit serving women living with HIV, Covin emphasized the need for clinical research to include parents with HIV who are pregnant or breastfeeding.
Amber Griffith, a postdoctoral fellow at the Washington University School of Medicine in Saint Louis, was pregnant during the ongoing COVID-19 pandemic and said, “The vaccine and how it affects pregnant women was really important to me at that time.” As a researcher, she emphasized that doctors need to have conversations with their patients to explain, “We’re not just…pulling things out of thin air and…giving it to people. There’s a process.”
CHALLENGES FOR CLINICIANS
David Haas, the Robert A. Munsick Professor of Obstetrics and Gynecology at Indiana University and a practicing OBGYN, described the challenges of discussing the risks and benefits of treatments with pregnant patients in the absence of sufficient information about the risks and benefits specific to pregnancy or lactation.
“There is no such thing as no exposure,” Haas said. Many people who become pregnant have existing conditions that require treatment or develop pregnancy-related conditions that can be treated, and there are risks if these conditions are left untreated. In the absence of data to inform treatment decisions, most clinicians will take a “start low and go slow” approach, which he said results in the undertreatment of many pregnant and lactating people. Haas pointed to mental health conditions and pregnancy as an example. He said that selective serotonin reuptake inhibitor (SSRI) antidepressant drugs have been well studied and are not associated with obstetric complications, but there is a “small but inconsistent risk” of birth defects with certain SSRIs. While there have been some issues affecting newborns, these issues have been transient and seem to have no effect on long-term neurodevelopment outcomes. In contrast, untreated depression in pregnant people has been associated with pregnancy complications, increased risk and severity of postpartum depression (affecting mother–infant bonding, ability of the mother to care for self and newborn), and long-term neurodevelopmental outcomes and mental health outcomes in the child.
Polypharmacy is also a concern given that many people take multiple medications during pregnancy. Haas concluded that data are needed—not only about the safety and efficacy of drugs used individually—but also about the interactions of drugs when taken simultaneously during pregnancy.
Haas stated that relatively little is known about the effects of drugs on pregnant individuals in the immediate postpartum period, when many physiological changes occur. Data are also needed on potential long-term implications for the child, said Haas. He also emphasized the need to maintain well-phenotyped mother–child cohorts to monitor the health of the mother and the developing baby well after delivery.
Haas expressed optimism that some progress has been made. He mentioned as examples the work done by the PRGLAC Task Force; studies such as the Pharmacokinetics and Safety of Commonly Used Drugs in Lactating Women and Breastfed Infants (CUDDLE) study by the Pediatric Trials Network;2 and the Centers for Excellence in Therapeutics, which are
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2 See https://clinicaltrials.gov/ct2/show/NCT03511118 (accessed September 12, 2022).
being established by the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub of NICHD.3
Thomas Hale, university distinguished professor of pediatrics and assistant dean of research at Texas Tech University School of Medicine, agreed that it is critically important to treat patients for ongoing conditions while pregnant and lactating. He agreed that polypharmacy in pregnancy is common, noting that he routinely receives calls about pregnant persons who are taking up to 10–15 medications.
Hale discussed the need for better data on the pharmacokinetics of drugs in pregnant and in lactating persons. From a pharmacology perspective, the kinetics of a given drug may fluctuate over time (e.g., there may be variation during the 9 months of pregnancy, variation during the first few hours postpartum, and variation over the course of lactation). Additionally, drug kinetics may fluctuate based on location within the body (e.g., there may be variation between the placenta of a pregnant person compared to the alveolar apparatus in the breast of a lactating person). He emphasized that pharmacokinetic studies in pregnant and lactating persons are essential to ensure patient safety. He explained that lactating rodent models of pharmacokinetics are not by themselves useful for determining appropriate dosing regimens for pregnant and lactating persons, and added that patients may be at increased risk when dosages are based on rodent data alone.
There are persistent misconceptions about the ability to conduct trials in pregnant and in lactating persons, Hale said. Researchers may avoid doing these studies for fear of litigation should there be adverse events. However, there are ways to mitigate risk in clinical trials. In some trials in lactating persons, for example, mothers can pump milk prior to dosing and the baby can be fed for several hours to a day or more with pumped milk. Hale suggested that federal support is needed to incentivize clinical studies in pregnant and lactating persons and ensure liability protection for researchers and clinicians.
Ajoke Sobanjo-ter Meulen, vice president medical affairs and policy at Icosavax, pointed out that the lack of clinical evidence on the safety and efficacy of drugs in pregnant and lactating persons is part of a larger “gender data gap” issue that spans disciplines and sectors worldwide. Progress has been made by pioneering stakeholders and organizations, such as the development of a vaccine candidate for group B Streptococcus and several candidates for respiratory syncytial virus (RSV), which are currently being evaluated in clinical trials in pregnant persons. She noted that these are the first novel vaccines being developed solely for an indication for use in pregnancy. The U.S. Food and Drug Administration
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3 See https://mprint.org (accessed September 12, 2022).
(FDA) has been a leader globally in guidance and policy development to enable the inclusion of pregnant persons in clinical research. And there are scientific experts, advocates, and champions developing policy recommendations. However, there is much more to be done, she said.
OUTCOMES OF EXCLUSION
One of the outcomes of the exclusion of pregnant and lactating persons from COVID-19 vaccine clinical trials is that these populations lack confidence in these vaccines, said Zsakeba Henderson, senior vice president of maternal child health impact and the interim chief medical officer at March of Dimes. Although the Centers for Disease Control and Prevention (CDC) has recommended that all pregnant people be vaccinated for COVID-19 (CDC, 2022), misinformation persists and one in four women who are pregnant or are planning to become pregnant think that pregnant women should not get a COVID-19 vaccine, according to a recent Kaiser Family Foundation poll (Sparks et al., 2022). Data from the Louisiana Pregnancy-Associated Mortality Review indicate that many of the maternal deaths from COVID-19 were individuals who had chosen not to be vaccinated for COVID-19 because there were insufficient data for this population. Similarly, many maternal deaths from cancer were in individuals who did not proceed with their cancer treatment while pregnant, said Veronica Gillispie-Bell, associate professor, senior site lead and section head of obstetrics and gynecology, director of quality for women’s services at Ochsner Health System, and medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review for the Louisiana Department of Health. “Including pregnant and lactating individuals in clinical trials…is literally a conversation about life or death,” she said.
As another example of both the potential risks of not taking a drug or vaccine and the importance of long-term follow-up, Ebony Boyce Carter, associate professor and chief of clinical research in obstetrics and gynecology at Washington University School of Medicine in St. Louis, Missouri, cited a recent study showing that exposure to COVID-19 infection in utero was associated with adverse neurodevelopmental outcomes in infants at 1 year of age (Edlow et al., 2022). A key lesson from the COVID-19 pandemic, Henderson summarized, is that “including pregnant women in clinical trials as soon as ethically possible allows for better data, early intervention, and early dissemination of public health messaging that dispels myths and misinformation.”
There are also inherent risks for patients with chronic conditions who become pregnant, and outcomes are affected by the lack of data on use of medications during pregnancy. Brittany Bettendorf, clinical assis-
tant professor and rheumatologist at the University of Iowa, said that patients with rheumatologic conditions (e.g., lupus, rheumatoid arthritis, vasculitis, inflammatory myopathies) can be at risk for preterm labor, preeclampsia, newborns small for gestational age, and increased morbidity and mortality for mother and baby. Her goal for her patients is to have their condition well controlled for 3 to 6 months before they become pregnant, using a therapeutic regimen they can continue throughout pregnancy. Preconception counseling4 is a challenge, however, as many of the medications used for rheumatologic conditions have not been studied during pregnancy and lactation. In addition, switching a patient to a different medication can lead to a flare of disease that must be brought under control before they try to become pregnant. Over the past couple of decades there has been a focus on developing novel biologic therapeutics for chronic diseases, which Bettendorf said are improving patient quality of life and reducing morbidity and mortality. However, many of these treatments still have unknown safety profiles in pregnancy and lactation.
WILLINGNESS OF PREGNANT AND LACTATING INDIVIDUALS TO PARTICIPATE IN CLINICAL TRIALS
Leyla Sahin, deputy director for safety in the Division of Pediatrics and Maternal Health at the Center for Drug Evaluation and Research (CDER) at FDA and session moderator, said FDA often receives questions and comments about whether pregnant and lactating persons actually want to participate in clinical research. From her perspective as a patient, Mancoll said she believes she would have been open to the idea of enrolling in a clinical trial while pregnant, in part because she is personally a strong advocate for science. She added that her condition is not life threatening or life shortening, and she speculated that patient willingness might depend on the condition they have while pregnant. Gorman (via prerecorded video) discussed participating in a clinical study being conducted by her neurologist during her second pregnancy (on the safety of seizure medications during pregnancy and lactation). She described this as “a wonderful opportunity for me for several reasons.” In particular, she said wanted to help other pregnant individuals in the situation she was in during her first pregnancy.
Haas grouped potential studies enrolling pregnant participants into two general categories: (1) opportunistic studies in which the participant
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4 The American Congress of Obstetricians and Gynecologists recommends preconception counselling to review an individual’s medications and any necessary treatment modifications. See https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2019/01/prepregnancy-counseling (accessed November 2, 2022).
is already taking the study medication for a condition they currently have, and participation will basically involve some extra bloodwork (e.g., for pharmacokinetics studies or longer-term outcome studies); and (2) studies in which participants receive a drug they are not already taking (i.e., trial participants are healthy or are not yet being treated for a given condition). He said that, in his experience conducting clinical trials, there is wide variability in willingness to enroll in a trial among pregnant persons, and many pregnant individuals have a distrust of clinical research and may be hesitant to enroll in a trial. Haas remarked that increased public awareness about the importance of clinical trials is needed, and attention is required to build trust in the clinical research enterprise.
Hale said clinical trials that include lactating individuals often fall into the opportunistic category discussed by Haas. Hale is the founder and director of the Infant Risk Center, a national call center for pregnant and breastfeeding persons. The center receives around 100 phone calls and 10,000 visits to its website each day from people with questions about medications, and it actively recruits from this population. Lactating persons taking a drug are asked to register to receive a follow-up call about enrolling in a clinical trial. He said that around 90 percent of people who register are willing to enroll. The challenge is that many do not follow through with sending breast milk samples. The center has found that providing a debit card for reimbursement of expenses has helped.
Sobanjo-ter Meulen discussed how trial participation among pregnant persons is influenced by factors such as the burden and the severity or mortality of a given disease and whether or not a disease is preventable. As an example, she mentioned that in the 1980s there was minimal hesitancy among pregnant women for receiving the tetanus vaccine because people saw firsthand how infants died of tetanus. Engaging pregnant persons in vaccine trials for a disease such as group B Streptococcus, a bacterial infection, is more complicated, Sobanjo-ter Meulen said. It requires raising awareness of the severe impact this maternal infection can have on the fetus in utero (e.g., stillbirth, preterm birth) and on the neonate, especially in the first 72 hours of life. In the United States, prevention of infection that occurs during the birth process can be accomplished with intrapartum intravenous antibiotics; however, this treatment is not available in most low- and middle-income countries.
Sobanjo-ter Meulen added that, in her experience, there is a willingness on the part of pregnant and lactating people to participate in vaccine clinical trials if they are aware that the intervention might preserve their pregnancy and prevent severe disease in their infant. Raising awareness requires significant education and understanding on the part of the pregnant person as well as their health care providers (e.g., physicians, nurses, and midwives).
Geeta Swamy, associate vice president for research, vice dean for scientific integrity, and professor of obstetrics and gynecology at Duke University, emphasized that, “pregnant and lactating people are people who are pregnant or lactating at the time.” These individuals should be considered for trial enrollment the same as nonpregnant people. Elad Sharon of the National Cancer Institute agreed that “pregnant people are also people” and added that some people enroll in a clinical trial and then unintentionally become pregnant. Unfortunately, becoming pregnant is often one of the reasons listed in a protocol for a participant to be discontinued from a study, which, Sharon pointed out, is a missed opportunity to continue to learn from these patients. He noted that during the pivotal clinical trial for the Moderna COVID-19 vaccine there were 13 trial participants who became pregnant over the course of the study (FDA, 2020). These data were publicly presented at the December 2020 FDA advisory committee meeting and subsequently “largely ignored.” He suggested regulators should enable and encourage data collection from persons who become pregnant during a drug trial and include the data in the product label.
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