For two years, a group of world-class scientists pitched their idea for a hot new biotech company to investors: a start-up focused on a promising therapy for preeclampsia, a serious pregnancy complication that can become life-threatening. It was cutting-edge science, backed by a Nobel laureate, a Harvard kidney specialist, a leading chemist, and a biologist with both expertise and personal experience.
Eventually, they gave up – not on the science, and not on preeclampsia – but on the investors.
“We talked to so many different venture capitalists and other companies. The scientists and doctors would get excited,” said Melissa Moore, a University of Massachusetts Medical School scientist who began working on preeclampsia after she suffered from it in 2003 and was put on bed rest for more than a month, only to give birth seven weeks early to a baby girl who weighed less than four pounds. “But as soon as their lawyers heard ‘sick, pregnant women,’ nothing happened,” Moore said. “There’s such a sense of liability.”
Moore and her colleagues’ experience highlights a persistent problem in medical research. About 10 percent of reproductive-age women become pregnant each year in the United States, but far less research is done into pregnancy than into much less common conditions. The effect of medicines on pregnant women and their fetuses is rarely studied. Basic understanding of pregnancy itself is full of gaping scientific holes, mysteries that include how the placenta forms and what, exactly, controls the timing of birth. Some pregnancy experts call the placenta, an organ that is necessary for all human reproduction, the Rodney Dangerfield of the human body because it gets “no respect.”
The default assumption has long been – and, to a large extent, still is – that it’s essential to protect pregnant women from research, rather than ensure they benefit from its rapid progress. But concerted pressure from scientists and advocates is slowly beginning to change policy and research culture.
In January, an updated federal policy that governs protections for human research subjects went into effect, officially removing pregnant women from being listed as “vulnerable to coercion or undue influence,” alongside children and “mentally disabled” people.
“We all joke about pregnancy brain, but I was still able to make decisions for myself and my fetus,” said Sonja Rasmussen, a pediatrician and clinical geneticist at the University of Florida.
Separately, a federal task force last year recommended that pregnant women’s participation in drug trials that offered benefit to the fetus no longer require the approval of the father of the child as well.
“Once the child is born, only consent of one parent is needed,” said Catherine Spong, chief of maternal-fetal medicine at the University of Texas Southwestern Medical Center, who chaired the task force. “Given the autonomy of pregnant women and the evolution of family structure, we really should align that with parental consent for pediatrics.”
Activists successfully pushed for more women to be included in medical research in the 1990s, but pregnant and lactating women have largely been left behind. Now, another round of activism that began a decade ago is pushing new thinking on pregnancy. High maternal mortality rates in the United States have intensified the focus, and there is a growing awareness that conditions during pregnancy can affect a baby’s risk of developing chronic conditions late in life.
Some researchers note that pregnant women are increasingly being studied in their own right – and not just as the environment in which a fetus develops. Recent evidence suggests that pregnancy complications may predict women’s susceptibility to dementia or heart disease decades later.
“Probably most people think pregnancy is a time-limited experience, and therefore, because it lasts only nine months, we don’t need to invest that many resources in it – because it’ll be over soon,” said Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. “But that’s really a fallacious idea. Pregnancy is a stress test for a woman, and there are these dual opportunities, to both understand what lies ahead for the pregnant woman, but also by doing research that ensures a healthy pregnancy, we’re contributing to the long-term health of the nation.”
Crisis launched regulations
The medical attitude toward pregnancy was shaped more than half a century ago by the thalidomide crisis, when women who took the medication for morning sickness had babies with birth defects. The incident helped launch the modern era of U.S. drug regulation, with requirements to prove the effectiveness and safety of drugs before they could be approved for sale. Pregnant women, however, are typically left out of such research.
One study found that the risks to human pregnancy were “undetermined” in 98 percent of prescription drugs approved between 2000 and 2010. An analysis of historical data showed it took nearly three decades to get more precise risk information. That’s despite the fact that of the 6 million women in the United States who are pregnant each year, 90 percent take at least one medication.
Anne Drapkin Lyerly, a bioethicist and obstetrician at the University of North Carolina at Chapel Hill, said that there is a deep-seated norm to leave pregnant women out of clinical trials, reinforced by policies that have classified them as “vulnerable” and institutional rules that have made it easier to avoid considering the potential risks and benefits altogether.
“If you want to exclude a pregnant woman from research, all you’ve got to do is check the box; she’s excluded, no explanation needed,” Lyerly said. “If you want to include her, there’s a whole slew of paperwork and decisions, and you have to justify your decision.”
Taking women out of the vulnerable category is a long way from changing their access to drug trials or changing the incentives drug companies have to include them, but advocates say it’s a long-overdue start. Last year, the U.S. Food and Drug Administration also released draft guidance on when to include women in clinical trials, laying out the case that there is a “critical public health need” for more information on how to use drugs safely in pregnant women.
“If you don’t do these studies, then you don’t have the data to base your decision, but you’re still making decisions,” Spong said. “You’re providing care in the absence of data.”
During the flu pandemic of 2009, Rasmussen recalled deliberating with other experts on whether the Centers for Disease Control and Prevention should recommend that pregnant women should be given Tamiflu – which it did.
“It’s one of the things I’m proudest of in my career is we looked at that and weighed the risk and benefits instead of the knee-jerk, ‘We can’t let pregnant women have that because the data are limited,’ ” Rasmussen said.
Another teaching moment for the medical community came last year, when an HIV drug called dolutegravir was flagged as potentially causing birth defects through a study that surveilled the use of the drug in Botswana.
“The dolutegravir finding was something that oriented the whole HIV research community toward research in pregnancy, even people who don’t work with pregnant women. It raised questions about how to think about women,” Lyerly said.
Time of unknowns
For people who are pregnant or hope to conceive, the unknowns extend far beyond what drugs women can safely take. The National Institutes of Health, which tracks its research funding on nearly 300 health categories, ranging from rare Batten disease to ubiquitous allergies, only began breaking out its spending on pregnancy, maternal health and breast-feeding in 2017.
Stephanie Hinze, 37, of Atlanta, suffers from spina bifida and has used a wheelchair since she was 8 years old. When she and her husband decided to conceive, there was little information for her to rely on – except for an informal network of other women with disabilities who had already had children. Concerns included whether it was safe to carry a child at all; fertility questions; whether she was gaining weight at the right rate, given that doctor’s offices weren’t equipped with accessible scales; and what to do when she couldn’t feel the baby moving due to a decreased lack of sensation in her abdomen.
Hinze, who has two sons, one of whom is adopted, is now pregnant for the second time. She says she was lucky – her first pregnancy went smoothly and her medical team was supportive, contrasting with anecdotes she has heard from others. But at each step, they were solving new puzzles.
“My doctor, while he was great and very receptive, didn’t know everything to expect. As things happened, during the pregnancy, he’d say, ‘Let’s deal with this issue and let’s figure this out.’ ” Hinze said. “You don’t want to go in and your doctor’s not entirely sure what the solution will be for what’s going on.”
NIH last year partnered with the CDC to survey how disabled women experience pregnancy. The questions they hope to answer include: Are they more likely to develop complications? Does disability affect women’s ability to breast-feed? What is their basic experience of pregnancy like?
“We don’t know,” said Alison Cernich, director of the National Center for Medical Rehabilitation Research, describing the evidence gap around disability and pregnancy that she attributes to a “quadfecta” of barriers for women: Women’s health is often overlooked, many disabled women belong to ethnic groups that do not receive optimal care due to bias, many disabled people experience poverty, and disabilities are often stigmatized.
The basic science of pregnancy, too, is getting a closer look, as NIH has so far funded $76 million in research projects to study the human placenta, the temporary organ that provides oxygen and nutrients to the fetus. The recent discovery that it is possible to grow a miniature version of the placenta in a laboratory setting may help scientists understand fundamental questions about how it develops, in part in response to secretions from the uterus.
“Even in the 21st century, we don’t know what’s in the secretions, we don’t know the composition of them, which the whole of the future of the human species depends on,” said Graham Burton, a professor of the physiology of reproduction at the University of Cambridge.
The placenta is necessary for a successful pregnancy, but it also affects the health of the pregnant woman. Preeclampsia, which causes maternal high blood pressure, is caused in part by proteins released from the placenta that affect the function of blood vessels in the mother. There is no treatment for preeclampsia, which ends only when the woman delivers the baby – and the placenta.
Surendra Sharma, a professor of pediatrics at Brown University, has been trying to tease out the science behind an alarming observation made by other researchers: women with preeclampsia appear to be at increased risk for dementia decades later. Intriguingly, he has found that there are misfolded proteins in the placenta from women with preeclampsia, similar to those found in the brains of patients with Alzheimer’s. Women with preeclampsia are also at increased risk for heart disease and stroke.
The idea that treating preeclampsia could help both mothers and babies adds urgency to the quest of Moore and colleagues, who have been disappointed but not deterred by the lack of investor enthusiasm.
“It was an eye-opener, really, to see how worried drug developers seemed to be about the pregnancy indication, but on the other hand, I don’t think it’s an insurmountable thing,” said Craig Mello, a Nobel laureate and co-founder of the fizzled start-up.
Late last year, Moore and colleagues demonstrated a therapy’s promise in treating a baboon version of preeclampsia. They hope to develop the drug through an unconventional nonprofit model.
Moore’s expertise is rooted in basic biology, a deep understanding of a molecule called RNA that performs a slew of basic functions in cells, including turning instructions written in the genetic code into proteins and regulating the genome. When Moore was pregnant and suffering from preeclampsia, she first met S. Ananth Karumanchi, a Harvard physician who had discovered a protein that was overabundant in women with preeclampsia – and they began talking about using RNA to reduce the level of protein. Translating that insight into an effective drug now depends critically on a UMass Medical School chemist, Anastasia Khvorova.
As relative newcomers to the field of pregnancy, the team is undeterred by history.
“One of the reasons we’ve not had a lot of drugs for pregnant women is the risk is viewed as too high – and that’s really unfortunate,” said Karumanchi, who recently moved to Cedars-Sinai Medical Center in Los Angeles. “I think not doing anything for these pregnant women is not an option.”
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