Researchers Are Discovering How to Predict – and Maybe Treat — Pregnancy Complications Early On.
Katie Love wishes there was some way she could have been prepared. But there was no way to know, early in 2020, that her pregnancy would lead to terrifyingly high blood pressure and multiple hospital visits, ending in induced labor and a 56-hour-long, “nightmare” delivery at 37 weeks. Love, a social media strategist in Pittsburgh, had preeclampsia, a poorly understood and potentially deadly pregnancy complication that affects 1 in 25 pregnant women in the United States. But there was no blood test, no easy diagnostic marker to warn Love that this might happen. Even on her first visit to the emergency room, with sky-high blood pressure, doctors could not be certain preeclampsia was the cause.
In fact, the primary but imperfect indicators for preeclampsia — high blood pressure and protein in the urine — haven’t changed in decades. The Preeclampsia Foundation calls a simple, rapid test to predict or diagnose the condition “a key component needed in the fight.”
Another common pregnancy complication is preterm birth, which affects 1 in 10 U.S. pregnancies, but there are few options to predict that might happen, either.
“The best tool that obstetricians have at the moment is still a tape measure and a blood pressure cuff to diagnose whatever’s happening in your pregnancy,” says Fiona Kaper, a vice president at the DNA-sequencing company Illumina in San Diego.
The hunt for such specific biomarkers is now taking off, at Illumina and elsewhere, as scientists probe maternal blood for signs that could herald pregnancy problems. These same molecules offer clues that might lead to more specific treatments. So far, it’s clear that many complications start with the placenta, the temporary organ that transfers nutrients, oxygen and waste between mother and fetus, and that these problems often start well before symptoms arise. Researchers are using the latest stem-cell technology to better understand the causes of complications and test treatments.
Pressing Need
Obstetricians aren’t flying completely blind; medical history can point to high or low risk for pregnancy complications. But ultimately, “everybody who’s pregnant is at risk for preeclampsia,” says Sarosh Rana, chief of maternal-fetal medicine at University of Chicago Medicine and an advisor to the Preeclampsia Foundation. And the symptoms of the condition include problems like headache and swollen feet that overlap with those of pregnancy in general, complicating diagnoses.
The “holy grail" would be early, first-trimester biomarkers. If obstetricians and expecting parents could know, in the first few months of pregnancy, that preeclampsia is a risk, a pregnant woman could monitor her blood pressure at home and take-low dose aspirin that might stave it off.
There are a couple more direct tests physicians can turn to, but these are imperfect. For preterm labor, fetal fibronectin makes up a sort of glue that keeps the amniotic sac, which cushions the unborn baby, attached to the uterus. If it’s not present near a woman’s cervix, that’s a good indicator that she’s not in labor, and can be safely sent home, says Lauren Demosthenes, an obstetrician and senior medical director of the digital health company Babyscripts in Washington, D.C. But if fibronectin appears, it might or might not indicate preterm labor.
“What we want is a test that gives us a positive predictive [signal],” says Demosthenes. “I want to know, if I get it, is it really going to predict preterm birth, or is it just going to make us worry more and order more tests?” In fact, the fetal fibronectin test hasn’t been shown to improve pregnancy outcomes, and Demosthenes says it’s fallen out of favor in many clinics.
Similarly, there’s a blood test, based on the ratio of the amounts of two different proteins, that can rule out preeclampsia but not confirm it’s happening. It’s approved in many countries, though not the U.S.; studies are still ongoing. A positive test, which means “maybe preeclampsia,” still leaves doctors and parents-to-be facing excruciating decisions: If the mother’s life is in danger, delivering the baby can save her, but even a few more days in the uterus can promote the baby’s health. In Ireland, where the test is available, it’s not getting much use, says Patricia Maguire, director of the University College Dublin Institute for Discovery.
Maguire has identified proteins released by platelets that indicate pregnancy — the “most expensive pregnancy test in the world,” she jokes. She is now testing those markers in women with suspected preeclampsia.
The “holy grail,” says Maguire, would be early, first-trimester biomarkers. If obstetricians and expecting parents could know, in the first few months of pregnancy, that preeclampsia is a risk, a pregnant woman could monitor her blood pressure at home and take-low dose aspirin that might stave it off. Similarly, if a quick blood test indicated that preterm labor could happen, doctors could take further steps such as measuring the cervix and prescribing progesterone if it’s on the short side.
Biomarkers in Blood
It was fatherhood that drew Stephen Quake, a biophysicist at Stanford University in California, to the study of pregnancy biomarkers. His wife, pregnant with their first child in 2001, had a test called amniocentesis. That involves extracting a sample from within the uterus, using a 3–8-inch-long needle, for genetic testing. The test can identify genetic differences, such as Down syndrome, but also carries risks including miscarriage or infection. In this case, mom and baby were fine (Quake’s daughter is now a college student), but he found the diagnostic danger unacceptable.
Seeking a less invasive test, Quake in 2008 reported that there’s enough fetal DNA in the maternal bloodstream to diagnose Down syndrome and other genetic conditions. “Use of amniocentesis has plunged,” he says.
Then, recalling that his daughter was born three and a half weeks before her due date — and that Quake’s own mom claims he was a month late, which makes him think the due date must have been off — he started researching markers that could accurately assess a fetus’ age and predict the timing of labor. In this case, Quake was interested in RNA, not DNA, because it’s a signal of which genes the fetus’, placenta’s, and mother’s tissues are using to create proteins. Specifically, these are RNAs that have exited the cells that made them. Tissues can use such free RNAs as messages, wrapping them in membranous envelopes to travel the bloodstream to other body parts. Dying cells also release fragments containing RNAs. “A lot of information is in there,” says Kaper.
In a small study of 31 healthy pregnant women, published in 2018, Quake and collaborators discovered nine RNAs that could predict gestational age, which indicates due date, just as well as ultrasound. With another set of 38 women, including 13 who delivered early, the researchers discovered seven RNAs that predicted preterm labor up to two months in advance.
Quake notes that an RNA-based blood test is cheaper and more portable than ultrasound, so it might be useful in the developing world. A company he cofounded, Mirvie, Inc., is now analyzing RNA’s predictive value further, in thousands of diverse women. CEO and cofounder Maneesh Jain says that since preterm labor is so poorly understood, they’re sequencing RNAs that represent about 20,000 genes — essentially all the genes humans have — to find the very best biomarkers. “We don’t know enough about this field to guess what it might be,” he says. “We feel we’ve got to cast the net wide.”
Quake, and Mirvie, are now working on biomarkers for preeclampsia. In a recent preprint study, not yet reviewed by other experts, Quake’s Stanford team reported 18 RNAs that, measured before 16 weeks, correctly predicted preeclampsia 56–100% of the time.
Other researchers are taking a similar tack. Kaper’s team at Illumina was able to classify preeclampsia from bloodstream RNAs with 85 to 89% accuracy, though they didn’t attempt to predict it. And Louise Laurent, a maternal-fetal medicine specialist and researcher at the University of California, San Diego (UCSD), has defined several pairs of microRNAs — pint-sized RNAs that regulate other ones — in second-trimester blood samples that predict preeclampsia later on.
Placentas in a Dish
The RNAs that show up in these studies often come from genes used by the placenta. But they’re only signals that something’s wrong, not necessarily the root cause. “There still is not much known about what really causes major complications of pregnancy,” says Laurent.
The challenge is that placental problems likely occur early on, as the organ forms in the first trimester. For example, if the placenta did a poor job of building blood vessels through the uterine lining, it might cause preeclampsia later as the growing fetus tries to access more and more blood through insufficient vessels, leading to high blood pressure in the mother. “Everyone has kind of suspected that that is probably what goes wrong,” says Mana Parast, a pathologist and researcher at UCSD.
To see how a placenta first faltered, “you want to go back in time,” says Parast. It’s only recently become possible to do something akin to that: She and Laurent take cells from the umbilical cord (which is a genetic match for the placenta) at the end of pregnancy, and turn them into stem cells, which can become any kind of cell. They then nudge those stem cells to make new placenta cells in lab dishes. But when the researchers start with cells from an umbilical cord after preeclampsia, they find the stem cells struggle to even form proper placenta cells, or they develop abnormally. So yes, something seems to go wrong right at the beginning. Now, the team plans to use these cell cultures to study the microRNAs that indicate preeclampsia risk, and to look for medications that might reverse the problems, Parast says.
Biomarkers could lead to treatments. For example, one of the proteins that commercial preeclampsia diagnostic kits test for is called soluble Flt-1. It’s a sort of anti-growth factor, explains Rana, that can cause problems with blood vessels and thus high blood pressure. Getting rid of the extra Flt-1, then, might alleviate symptoms and keep the mother safe, giving the baby more time to develop. Indeed, a small trial that filtered this protein from the blood did lower blood pressure, allowing participants to keep their babies inside for a couple of weeks longer, researchers reported in 2011.
For pregnant women like Love, even advance warning would have been beneficial. Laurent and others envision a first-trimester blood test that would use different kinds of biomolecules — RNAs, proteins, whatever works best — to indicate whether a pregnancy is at low, medium, or high risk for common complications.
“I prefer to be prepared,” says Love, now the mother of a healthy little girl. “I just wouldn’t have been so thrown off by the whole thing.”
Bivalent Boosters for Young Children Are Elusive. The Search Is On for Ways to Improve Access.
It’s Theo’s* first time in the snow. Wide-eyed, he totters outside holding his father’s hand. Sarah Holmes feels great joy in watching her 18-month-old son experience the world, “His genuine wonder and excitement gives me so much hope.”
In the summer of 2021, two months after Theo was born, Holmes, a behavioral health provider in Nebraska lost her grandparents to COVID-19. Both were vaccinated and thought they could unmask without any risk. “My grandfather was a veteran, and really trusted the government and faith leaders saying that COVID-19 wasn’t a threat anymore,” she says.” The state of emergency in Louisiana had ended and that was the message from the people they respected. “That is what killed them.”
The current official public health messaging is that regardless of what variant is circulating, the best way to be protected is to get vaccinated. These warnings no longer mention masking, or any of the other Swiss-cheese layers of mitigation that were prevalent in the early days of this ongoing pandemic.
The problem with the prevailing, vaccine centered strategy is that if you are a parent with children under five, barriers to access are real. In many cases, meaningful tools and changes that would address these obstacles are lacking, such as offering vaccines at more locations, mandating masks at these sites, and providing paid leave time to get the shots.
Children are at risk
Data presented at the most recent FDA advisory panel on COVID-19 vaccines showed that in the last year infants under six months had the third highest rate of hospitalization. “From the beginning, the message has been that kids don’t get COVID, and then the message was, well kids get COVID, but it’s not serious,” says Elias Kass, a pediatrician in Seattle. “Then they waited so long on the initial vaccines that by the time kids could get vaccinated, the majority of them had been infected.”
A closer look at the data from the CDC also reveals that from January 2022 to January 2023 children aged 6 to 23 months were more likely to be hospitalized than all other vaccine eligible pediatric age groups.
“We sort of forced an entire generation of kids to be infected with a novel virus and just don't give a shit, like nobody cares about kids,” Kass says. In some cases, COVID has wreaked havoc with the immune systems of very young children at his practice, making them vulnerable to other illnesses, he said. “And now we have kids that have had COVID two or three times, and we don’t know what is going to happen to them.”
Jumping through hurdles
Children under five were the last group to have an emergency use authorization (EUA) granted for the COVID-19 vaccine, a year and a half after adult vaccine approval. In June 2022, 30,000 sites were initially available for children across the country. Six months later, when boosters became available, there were only 5,000.
Currently, only 3.8% of children under two have completed a primary series, according to the CDC. An even more abysmal 0.2% under two have gotten a booster.
Ariadne Labs, a health center affiliated with Harvard, is trying to understand why these gaps exist. In conjunction with Boston Children’s Hospital, they have created a vaccine equity planner that maps the locations of vaccine deserts based on factors such as social vulnerability indexes and transportation access.
“People are having to travel farther because the sites are just few and far between,” says Benjy Renton, a research assistant at Ariadne.
Michelle Baltes-Breitwisch, a pharmacist, and her two-year-old daughter, Charlee, live in Iowa. When the boosters first came out she expected her toddler could get it close to home, but her husband had to drive Charlee four hours roundtrip.
This experience hasn’t been uncommon, especially in rural parts of the U.S. If parents wanted vaccines for their young children shortly after approval, they faced the prospect of loading babies and toddlers, famous for their calm demeanor, into cars for lengthy rides. The situation continues today. Mrs. Smith*, a grant writer and non-profit advisor who lives in Idaho, is still unable to get her child the bivalent booster because a two-hour one-way drive in winter weather isn’t possible.
It can be more difficult for low wage earners to take time off, which poses challenges especially in a number of rural counties across the country, where weekend hours for getting the shots may be limited.
Protect Their Future (PTF), a grassroots organization focusing on advocacy for the health care of children, hears from parents several times a week who are having trouble finding vaccines. The vaccine rollout “has been a total mess,” says Tamara Lea Spira, co-founder of PTF “It’s been very hard for people to access vaccines for children, particularly those under three.”
Seventeen states have passed laws that give pharmacists authority to vaccinate as young as six months. Under federal law, the minimum age in other states is three. Even in the states that allow vaccination of toddlers, each pharmacy chain varies. Some require prescriptions.
It takes time to make phone calls to confirm availability and book appointments online. “So it means that the parents who are getting their children vaccinated are those who are even more motivated and with the time and the resources to understand whether and how their kids can get vaccinated,” says Tiffany Green, an associate professor in population health sciences at the University of Wisconsin at Madison.
Green adds, “And then we have the contraction of vaccine availability in terms of sites…who is most likely to be affected? It's the usual suspects, children of color, disabled children, low-income children.”
It can be more difficult for low wage earners to take time off, which poses challenges especially in a number of rural counties across the country, where weekend hours for getting the shots may be limited. In Bibb County, Ala., vaccinations take place only on Wednesdays from 1:45 to 3:00 pm.
“People who are focused on putting food on the table or stressed about having enough money to pay rent aren't going to prioritize getting vaccinated that day,” says Julia Raifman, assistant professor of health law, policy and management at Boston University. She created the COVID-19 U.S. State Policy Database, which tracks state health and economic policies related to the pandemic.
Most states in the U.S. lack paid sick leave policies, and the average paid sick days with private employers is about one week. Green says, “I think COVID should have been a wake-up call that this is necessary.”
Maskless waiting rooms
For her son, Holmes spent hours making phone calls but could uncover no clear answers. No one could estimate an arrival date for the booster. “It disappoints me greatly that the process for locating COVID-19 vaccinations for young children requires so much legwork in terms of time and resources,” she says.
In January, she found a pharmacy 30 minutes away that could vaccinate Theo. With her son being too young to mask, she waited in the car with him as long as possible to avoid a busy, maskless waiting room.
Kids under two, such as Theo, are advised not to wear masks, which make it too hard for them to breathe. With masking policies a rarity these days, waiting rooms for vaccines present another barrier to access. Even in healthcare settings, current CDC guidance only requires masking during high transmission or when treating COVID positive patients directly.
“This is a group that is really left behind,” says Raifman. “They cannot wear masks themselves. They really depend on others around them wearing masks. There's not even one train car they can go on if their parents need to take public transportation… and not risk COVID transmission.”
Yet another challenge is presented for those who don’t speak English or Spanish. According to Translators without Borders, 65 million people in America speak a language other than English. Most state departments of health have a COVID-19 web page that redirects to the federal vaccines.gov in English, with an option to translate to Spanish only.
The main avenue for accessing information on vaccines relies on an internet connection, but 22 percent of rural Americans lack broadband access. “People who lack digital access, or don’t speak English…or know how to navigate or work with computers are unable to use that service and then don’t have access to the vaccines because they just don’t know how to get to them,” Jirmanus, an affiliate of the FXB Center for Health and Human Rights at Harvard and a member of The People’s CDC explains. She sees this issue frequently when working with immigrant communities in Massachusetts. “You really have to meet people where they’re at, and that means physically where they’re at.”
Equitable solutions
Grassroots and advocacy organizations like PTF have been filling a lot of the holes left by spotty federal policy. “In many ways this collective care has been as important as our gains to access the vaccine itself,” says Spira, the PTF co-founder.
PTF facilitates peer-to-peer networks of parents that offer support to each other. At least one parent in the group has crowdsourced information on locations that are providing vaccines for the very young and created a spreadsheet displaying vaccine locations. “It is incredible to me still that this vacuum of information and support exists, and it took a totally grassroots and volunteer effort of parents and physicians to try and respond to this need.” says Spira.
Kass, who is also affiliated with PTF, has been vaccinating any child who comes to his independent practice, regardless of whether they’re one of his patients or have insurance. “I think putting everything on retail pharmacies is not appropriate. By the time the kids' vaccines were released, all of our mass vaccination sites had been taken down.” A big way to help parents and pediatricians would be to allow mixing and matching. Any child who has had the full Pfizer series has had to forgo a bivalent booster.
“I think getting those first two or three doses into kids should still be a priority, and I don’t want to lose sight of all that,” states Renton, the researcher at Ariadne Labs. Through the vaccine equity planner, he has been trying to see if there are places where mobile clinics can go to improve access. Renton continues to work with local and state planners to aid in vaccine planning. “I think any way we can make that process a lot easier…will go a long way into building vaccine confidence and getting people vaccinated,” Renton says.
Michelle Baltes-Breitwisch, a pharmacist, and her two-year-old daughter, Charlee, live in Iowa. Her husband had to drive four hours roundtrip to get the boosters for Charlee.
Michelle Baltes-Breitwisch
Other changes need to come from the CDC. Even though the CDC “has this historic reputation and a mission of valuing equity and promoting health,” Jirmanus says, “they’re really failing. The emphasis on personal responsibility is leaving a lot of people behind.” She believes another avenue for more equitable access is creating legislation for upgraded ventilation in indoor public spaces.
Given the gaps in state policies, federal leadership matters, Raifman says. With the FDA leaning toward a yearly COVID vaccine, an equity lens from the CDC will be even more critical. “We can have data driven approaches to using evidence based policies like mask policies, when and where they're most important,” she says. Raifman wants to see a sustainable system of vaccine delivery across the country complemented with a surge preparedness plan.
With the public health emergency ending and vaccines going to the private market sometime in 2023, it seems unlikely that vaccine access is going to improve. Now more than ever, ”We need to be able to extend to people the choice of not being infected with COVID,” Jirmanus says.
*Some names were changed for privacy reasons.
What causes aging? In a paper published last month, Dr. David Sinclair, Professor in the Department of Genetics at Harvard Medical School, reports that he and his co-authors have found the answer. Harnessing this knowledge, Dr. Sinclair was able to reverse this process, making mice younger, according to the study published in the journal Cell.
I talked with Dr. Sinclair about his new study for the latest episode of Making Sense of Science. Turning back the clock on mouse age through what’s called epigenetic reprogramming – and understanding why animals get older in the first place – are key steps toward finding therapies for healthier aging in humans. We also talked about questions that have been raised about the research.
Show links:
Dr. Sinclair's paper, published last month in Cell.
Recent pre-print paper - not yet peer reviewed - showing that mice treated with Yamanaka factors lived longer than the control group.
Dr. Sinclair's podcast.
Previous research on aging and DNA mutations.
Dr. Sinclair's book, Lifespan.
Harvard Medical School