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.”
Two-and-a-half year-old Huckleberry, a blue merle Australian shepherd, pulls hard at her leash; her yelps can be heard by skiers and boarders high above on the chairlift that carries them over the ski patrol hut to the top of the mountain. Huckleberry is an avalanche rescue dog — or avy dog, for short. She lives and works with her owner and handler, a ski patroller at Breckenridge Ski Resort in Colorado. As she watches the trainer play a game of hide-and-seek with six-month-old Lume, a golden retriever and avy dog-in-training, Huckleberry continues to strain on her leash; she loves the game. Hide-and-seek is one of the key training methods for teaching avy dogs the rescue skills they need to find someone caught in an avalanche — skier, snowmobiler, hiker, climber.
Lume’s owner waves a T-shirt in front of the puppy. While another patroller holds him back, Lume’s owner runs away and hides. About a minute later — after a lot of barking — Lume is released and commanded to “search.” He springs free, running around the hut to find his owner who reacts with a great amount of excitement and fanfare. Lume’s scent training will continue for the rest of the ski season (Breckenridge plans operating through May or as long as weather permits) and through the off-season. “We make this game progressively harder by not allowing the dog watch the victim run away,” explains Dave Leffler, Breckenridge's ski patroller and head of the avy dog program, who has owned, trained and raised many of them. Eventually, the trainers “dig an open hole in the snow to duck out of sight and gradually turn the hole into a cave where the dog has to dig to get the victim,” explains Leffler.
By the time he is three, Lume, like Huckleberry, will be a fully trained avy pup and will join seven other avy dogs on Breckenridge ski patrol team. Some of the team members, both human and canine, are also certified to work with Colorado Rapid Avalanche Deployment, a coordinated response team that works with the Summit County Sheriff’s office for avalanche emergencies outside of the ski slopes’ boundaries.
There have been 19 avalanche deaths in the U.S. this season, according to avalanche.org, which tracks slides; eight in Colorado. During the entirety of last season there were 17. Avalanche season runs from November through June, but avalanches can occur year-round.
High tech and high stakes
Complementing avy dogs’ ability to smell people buried in a slide, avalanche detection, rescue and recovery is becoming increasingly high tech. There are transceivers, signal locators, ground scanners and drones, which are considered “games changers” by many in avalanche rescue and recovery
For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
A drone can provide thermal imaging of objects caught in a slide; what looks like a rock from far away might be a human with a heat signature. Transceivers, also known as beacons, send a signal from an avalanche victim to a companion. Signal locators, like RECCO reflectors which are often sewn directly into gear, can echo back a radar signal sent by a detector; most ski resorts have RECCO detector units.
Research suggests that Ground Penetrating Radar (GPR), an electromagnetic tool used by geophysicists to pull images from inside the ground, could be used to locate an avalanche victim. A new study from the Department of Energy’s Sandia National Laboratories suggests that a computer program developed to pinpoint the source of a chemical or biological terrorist attack could also be used to find someone submerged in an avalanche. The search algorithm allows for small robots (described as cockroach-sized) to “swarm” a search area. Researchers say that this distributed optimization algorithm can help find avalanche victims four times faster than current search mechanisms. For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
An avy dog in training is picking up scent
Sarah McLear
While rescue gear has been evolving, predicting when a slab will fall remains an emerging science — kind of where weather forecasting science was in the 1980s. Avalanche forecasting still relies on documenting avalanches by going out and looking,” says Ethan Greene, director of the Colorado Avalanche Information Center (CAIC). “So if there's a big snowstorm, and as you might remember, most avalanches happened during snowstorms, we could have 10,000 avalanches that release and we document 50,” says Greene. “Avalanche forecasting is essentially pattern recognition,” he adds--and understanding the layering structure of snow.
However, determining where the hazards lie can be tricky. While a dense layer of snow over a softer, weaker layer may be a recipe for an avalanche, there’s so much variability in snowpack that no one formula can predict the trigger. Further, observing and measuring snow at a single point may not be representative of all nearby slopes. Finally, there’s not enough historical data to help avalanche scientists create better prediction models.
That, however, may be changing.
Last year, an international group of researchers created computer simulations of snow cover using 16 years of meteorological data to forecast avalanche hazards, publishing their research in Cold Regions Science and Technology. They believe their models, which categorize different kinds of avalanches, can support forecasting and determine whether the avalanche is natural (caused by temperature changes, wind, additional snowfall) or artificial (triggered by a human or animal).
With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides.
With data from two sites in British Columbia and one in Switzerland, researchers built computer simulations of five different avalanche types. “In terms of real time avalanche forecasting, this has potential to fill in a lot of data gaps, where we don't have field observations of what the snow looks like,” says Simon Horton, a postdoctoral fellow with the Simon Fraser University Centre for Natural Hazards Research and a forecaster with Avalanche Canada, who participated in the study. While complex models that simulate snowpack layers have been around for a few decades, they weren’t easy to apply until recently. “It's been difficult to find out how to apply that to actual decision-making and improving safety,” says Horton. If you can derive avalanche problem types from simulated snowpack properties, he says, you’ll learn “a lot about how you want to manage that risk.”
The five categories include “new snow,” which is unstable and slides down the slope, “wet snow,” when rain or heat makes it liquidly, as well as “wind-drifted snow,” “persistent weak layers” and “old snow.” “That's when there's some type of deeply buried weak layer in the snow that releases without any real change in the weather,” Horton explains. “These ones tend to cause the most accidents.” One step by a person on that structurally weak layer of snow will cause a slide. Horton is hopeful that computer simulations of avalanche types can be used by scientists in different snow climates to help predict hazard levels.
Greene is doubtful. “If you have six slopes that are lined up next to each other, and you're going to try to predict which one avalanches and the exact dimensions and what time, that's going to be really hard to do. And I think it's going to be a long time before we're able to do that,” says Greene.
What both researchers do agree on, though, is that what avalanche prediction really needs is better imagery through satellite detection. “Just being able to count the number of avalanches that are out there will have a huge impact on what we do,” Greene says. “[Satellites] will change what we do, dramatically.” In a 2022 paper, scientists at the University of Aberdeen in England used satellites to study two deadly Himalayan avalanches. The imaging helped them determine that sediment from a 2016 ice avalanche plus subsequent snow avalanches contributed to the 2021 avalanche that caused a flash flood, killing over 200 people. The researchers say that understanding the avalanches characteristics through satellite imagery can inform them how one such event increases the magnitude of another in the same area.
Avy dogs trainers hide in dug-out holes in the snow, teaching the dogs to find buried victims
Sarah McLear
Lifesaving combo: human tech and Mother Nature’s gear
Even as avalanche forecasting evolves, dogs with their built-in rescue mechanisms will remain invaluable. With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides. (Humans in comparison, have a meager 12 million.) A new study published in the Journal of Neuroscience revealed that in dogs smell and vision are connected in the brain, which has not been found in other animals. “They can detect the smell of their owner's fingerprints on a glass slide six weeks after they touched it,” says Nicholas Dodman, professor emeritus at Cummings School of Veterinary Medicine at Tufts University. “And they can track from a boat where a box filled with meat was buried in the water, 100 feet below,” says Dodman, who is also co-founder and president of the Center for Canine Behavior Studies.
Another recent study from Queens College in Belfast, United Kingdom, further confirms that dogs can smell when humans are stressed. They can also detect the smell of a person’s breath and the smell of the skin cells of a deceased person.
The emerging avalanche-predicting human-made tech and the incredible nature-made tech of dogs’ olfactory talents is the lifesaving “equipment” that Leffler believes in. Even when human-made technology develops further, it will be most efficient when used together with the millions of dogs’ smell receptors, Leffler believes. “It is a combination of technology and the avalanche dog that will always be effective in finding an avalanche victim.”
Living with someone changes your microbiome, new research shows
Some roommate frustration can be expected, whether it’s a sink piled high with crusty dishes or crumbs where a clean tabletop should be. Now, research suggests a less familiar issue: person-to-person transmission of shared bacterial strains in our gut and oral microbiomes. For the first time, the lab of Nicola Segata, a professor of genetics and computational biology at the University of Trento, located in Italy, has shown that bacteria of the microbiome are transmitted between many individuals, not just infants and their mothers, in ways that can’t be explained by their shared diet or geography.
It’s a finding with wide-ranging implications, yet frustratingly few predictable outcomes. Our microbiomes are an ever-growing and changing collection of helpful and harmful bacteria that we begin to accumulate the moment we’re born, but experts are still struggling to unravel why and how bacteria from one person’s gut or mouth become established in another person’s microbiome, as opposed to simply passing through.
“If we are looking at the overall species composition of the microbiome, then there is an effect of age of course, and many other factors,” Segata says. “But if we are looking at where our strains are coming from, 99 percent of them are only present in other people’s guts. They need to come from other guts.”
If we could better understand this process, we might be able to control and use it; perhaps hospital patients could avoid infections from other patients when their microbiome is depleted by antibiotics and their immune system is weakened, for example. But scientists are just beginning to link human microbiomes with various ailments. Growing evidence shows that our microbiomes steer our long-term health, impacting conditions like obesity, irritable bowel syndrome, type 2 diabetes, and cancer.
Previous work from Segata’s lab and others illuminated the ways bacteria are passed from mothers to infants during the first few months of life during vaginal birth, breastfeeding and other close contact. And scientists have long known that people in close proximity tend to share bacteria. But the factors related to that overlap, such as genetics and diet, were unclear, especially outside the mother-baby dyad.
“If we look at strain sharing between a mother and an infant at five years of age, for example, we cannot really tell which was due to transmission at birth and which is due to continued transmission because of contact,” Segata says. Experts hypothesized that they could be caused by bacterial similarities in the environment itself, genetics, or bacteria from shared foods that colonized the guts of people in close contact.
Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent.
In Italy, researchers led by Mireia Valles-Colomer, including Segata, hoped to unravel this mystery. They compared data from 9,715 stool and saliva samples in 31 genomic datasets with existing metadata. Scientists zoomed in on variations in each bacterial strain down to the individual level. They examined not only mother-child pairs, but people living in the same household, adult twins, and people living in the same village in a level of detail that wasn’t possible before, due to its high cost and difficulties in retrieving data about interactions between individuals, Segata explained.
“This paper is, with high granularity, quantifying the percent sharing that you expect between different types of social interactions, controlling for things like genetics and diet,” Gibbons says. Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent. And at least half of the mother-infant pairs shared 30 percent of their strains; the median was 12 percent among people in shared households. Yet, there was no sharing among eight percent of adult twins who lived separately, and 16 percent of people within villages who resided in different households. The results were published in Nature.
It’s not a regional phenomenon. Although the types of bacterial strains varied depending on whether people lived in western and eastern nations — datasets were drawn from 20 countries on five continents — the patterns of sharing were much the same. To establish these links, scientists focused on individual variations in shared bacterial strains, differences that create unique bacterial “fingerprints” in each person, while controlling for variables like diet, demonstrating that the bacteria had been transmitted between people and were not the result of environmental similarities.
The impact of this bacterial sharing isn’t clear, but shouldn’t be viewed with trepidation, according to Sean Gibbons, a microbiome scientist at the nonprofit Institute for Systems Biology.
“The vast majority of these bugs are actually either benign or beneficial to our health, and the fact that we're swapping and sharing them and that we can take someone else's strain and supplement or better diversify our own little garden is not necessarily a bad thing,” he says.
"There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” says Sean Gibbons, a microbiome scientist at the Institute for Systems Biology.
Everyday habits like exercising and eating vegetables promote a healthy, balanced gut microbiome, which is linked to better metabolic and immune function, and fewer illnesses. While many people’s microbiomes contain bacteria like C. diff or E. coli, these bacteria don’t cause diseases in most cases because they’re present in low levels. But a microbiome that’s been wiped out by, say, antibiotics, may no longer keep these bacteria in check, allowing them to proliferate and make us sick.
“A big challenge in the microbiome field is being able to rationally predict whether, if you're exposed to a particular bug, it will stick in the context of your specific microbiome,” Gibbons says.
Gibbons predicts that explorations of microbe-based therapeutics will be “exploding” in the coming decades. “There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” he says. Rather than taking a mass-marketed probiotic, a precise understanding of an individual’s microbiome could help target the introduction of just the right bacteria at just the right time to prevent or treat a particular illness.
Because the current study did not differentiate between different types of contact or relationships among household members sharing bacterial strains or determine the direction of transmission, Segata says his current project is examining children in daycare settings and tracking their microbiomes over time to understand the role genetics and everyday interactions play in the level of transmission that occurs.
This relatively newfound ability to trace bacterial variants to minute levels has unlocked the chance for scientists to untangle when and how bacteria leap from one microbiome to another. As researchers come to better understand the factors that permit a strain to establish itself within a microbiome, they could uncover new strategies to control these microbes, harnessing the makeup of each microbiome to help people to resist life-altering medical conditions.