Ahead of time

Predicting who will deliver a baby prematurely

Purnima Gaddam remembers a day in May 2012 when everything seemed to be going just right. Three months pregnant with her first child, she walked home from a long day at work and lay down on the family-room sofa to joyfully contemplate her life.

Purnima Gaddam, with her son Arcadius, and Jishnu Menon, with Seetha, were referred to high-risk obstetrics.

“We had made all these plans that seemed like they would come to fruition so naturally,” Gaddam says. She and her husband, Jishnu Menon, were ready to become parents: Both had jobs they loved, her pregnancy was going smoothly and they were preparing for a kid-friendly house remodel. They were choosing a pediatrician, considering baby names and reading up on cloth vs. disposable diapers.

“I was so happy and so content,” Gaddam says. She pauses. “It’s a feeling I was never able to recapture.”

On July 14, 2012, Gaddam and Menon’s eldest son was born just over halfway to his due date, after 22 weeks and five days of what should have been a 40-week pregnancy. He lived only a few hours.

His parents were blindsided. They grieved and they felt deeply frustrated. Gaddam, then 32, was perfectly healthy. She had gone to every prenatal check-up, taken her vitamins and followed her obstetrician’s advice. How could such an ideal pregnancy have ended in disaster?

An intractable problem

It’s a question that occupies hundreds of scientists at Stanford Medicine and across the country. The nation’s preterm birth rate began rising in the early 1980s, peaking in 2006, when one in every eight babies arrived at least three weeks early. Nearly half a million families across the country are still affected each year, and although most U.S.-born preemies survive, many have lifelong disabilities. In about half of premature deliveries — including Gaddam’s — doctors never learn why the baby came early. And while some early births are necessary to protect the health of the mother or child, in many cases continuing the pregnancy to term would be better.

“Preterm birth remains an intractable problem, and one that is very poorly understood,” says David Stevenson, MD, principal investigator of the March of Dimes Prematurity Research Center at Stanford University.

Yet the need to understand it is urgent. Prematurity recently surpassed infectious disease to become the No. 1 cause of death in young children around the world.

“That’s the bottom line,” Stevenson says. “It is now the main killer of kids through age 5.” In the United States, the most common causes of preemies’ deaths are extreme immaturity, breathing problems, brain injury, infections and the bowel disease necrotizing enterocolitis. About 40 percent of these deaths occur in the first 12 hours of life; 95 percent happen before the baby is 3 months old. In less-developed countries, where preemies’ chance of survival is far worse, they die for lack of basic medical care such as adequate warmth, breastfeeding help for their mothers, low-tech respiratory support and antibiotics. Providing such measures could save three-quarters of these infants, the World Health Organization estimates. But predicting who is likely to have a preterm baby and preventing early labor would be even better.

Stanford’s prematurity research center, founded in 2011 with a 10-year, $20 million grant from the March of Dimes, was the first of five such centers now in operation across the country that are working to illuminate the biology of preterm birth. The foundation wants to unite scientists from many disciplines to answer one of the most basic questions about childbirth.

“It’s a very simple question,” says Joe Leigh Simpson, MD, March of Dimes’ senior vice president for research and global programs. “What causes labor? The embarrassing fact is that we don’t know.”

The human birth process is unusual, rendering animal models of labor mostly useless. In most mammals, a drop in the pregnancy-maintaining hormone progesterone precedes and triggers labor, whereas in humans, whose babies are relatively immature at birth, progesterone levels are at their highest at delivery. But new scientific tools, including several noninvasive techniques emerging at Stanford, are finally giving researchers safe ways to ask what brings human pregnancy to a conclusion. Stevenson and his colleagues hope their discoveries will help predict and prevent preterm deliveries.

'There was really nothing we could do'

On the morning of July 13, 2012, Gaddam felt fine. By afternoon, something was off.

“I’d had a stressful week at work, and I thought it was my body telling me it had had enough,” she recalls. Her back ached. She felt vaguely unwell. “I thought, ‘I’ll rest and I’ll be OK.’”

That evening at home, she tried sitting and lying down in different positions, taking a shower, relaxing. Nothing helped.

“Throughout the night, the feeling of not feeling well intensified, but I never had anything that felt like a contraction,” she says. “I thought I was just having a hard moment in my pregnancy.”

The next morning, Gaddam and Menon went to their local hospital in Mountain View, California, so she could be checked. “I was 4 centimeters dilated,” she says. “There was really nothing we could do at that point.”

Their baby boy was born that afternoon, arriving two days before what doctors call the threshold of viability, the 23-week pregnancy milestone generally considered the earliest a baby can survive premature birth.

Gaddam and Menon both held their son before he died, as did their parents and Gaddam’s brother, all of whom rushed to the hospital.

‘When I think back to holding our baby, knowing he was barely alive, it just didn’t feel real. It felt like it was happening to us rather than anything we were participating in.’

The loss was so intense it was almost impossible for the bereaved couple to take in.

“When I think back to holding our baby, knowing he was barely alive, it just didn’t feel real,” Gaddam says. “It felt like it was happening to us rather than anything we were participating in.”

“It was horrifying but also very hard to believe that it actually happened,” Menon says. In the months afterward, they leaned heavily on family and friends for support.

“I didn’t force myself to get over it,” Menon says. “There’s a part of me that doesn’t really want to.”

Gaddam’s thoughts often returned to the most consoling words she heard on the day of her son’s birth and death.

“My father said, ‘He’ll come back.’” Her voice breaks as she recalls her dad’s clear faith. “Even though I’m not very religious, it was a really comforting feeling to think that our baby would come back.”

But that meant Gaddam and Menon would have to face another pregnancy.

Who delivers early

When Stanford’s prematurity research center launched in 2011, one early goal was to better understand women’s risk factors.

Some were well-known, including pregnancy during the teen years or after age 40, African-American ethnicity, carrying twins or other multiples, certain infections, poverty, stress and lack of prenatal care. Maternal illnesses such as diabetes, high blood pressure and the obstetric complication pre-eclampsia raise prematurity risk, too. But there were others.

Stanford’s first new findings appeared in 2014 when a team led by Gary Shaw, DrPH, professor of pediatrics, used a database of nearly 1 million California births to learn that maternal obesity substantially raised the risk of delivery before 28 weeks of pregnancy.

Soon after, researchers from Stanford and the U.S. Department of Veterans Affairs reported a connection between preterm delivery and maternal post-traumatic stress disorder. The researchers studied 16,000 births, including about 1,900 to women who had PTSD diagnosed in the prior year. This group’s risk of spontaneous preterm delivery was elevated by 35 percent.

Patients with PTSD do have high rates of other psychiatric conditions and unhealthy behaviors that other studies have associated with preterm delivery, notes the study’s senior author, Ciaran Phibbs, PhD, associate professor of pediatrics. “But we found that the effect of PTSD was independent of, and much larger than, these other factors,” he says.

In August 2015, a team led by David Relman, MD, professor of medicine and of microbiology and immunology, found another striking relationship, a pattern of vaginal bacteria linked to preterm births. Among the 49 pregnant women in their study, the researchers observed four low-risk patterns of vaginal bacteria, all dominated by lactobacillus, a bacterial genus previously associated with health in women. But a fifth pattern, characterized by more bacterial diversity and different predominant bacteria — such as such as gardnerella and ureaplasma — raised the risk of preterm birth. The longer a woman had the pattern, the greater her chance of delivering early.

The researchers were also intrigued to learn that the high-diversity pattern appeared in nearly all women after they gave birth, and persisted for as long as a year, possibly explaining why closely spaced pregnancies increase prematurity risk.

Encouragingly, the vaginal microbiome may be amenable to treatment during pregnancy. “It’s still total speculation,” Relman cautions. But he hopes for a future in which the expectant mom’s microbiome is tracked the way a park ranger keeps tabs on an ecosystem, “monitoring for invasive species, pruning them away, ensuring the environment gets the right nutrients.”

A matter of trust

“It’s really hard to trust your body again when it’s failed in such an immense way,” Gaddam says.

After their son’s death, she and Menon were referred to high-risk obstetrician Jane Chueh, MD, at Lucile Packard Children’s Hospital Stanford. They still wanted a child, and they wanted to know how they might get through another pregnancy.

Chueh explained the treatments that could help reduce the chance of another premature delivery: progesterone supplements starting at 16 weeks of pregnancy, frequent monitoring and a minor surgical procedure called cerclage to temporarily stitch Gaddam’s cervix closed midway through gestation. (The cervix, the muscular opening of the uterus, must stay tightly closed until near delivery. Some very premature births may be due to a weak cervix, which doctors try to support with cerclage until near the due date.)

Gaddam, who manages business development for the global literacy program at the nonprofit Benetech, and Menon, associate general counsel and head of legal at Mozilla, felt somewhat reassured. “Dr. Chueh, from the very beginning, was sure that she could help us have a healthy baby,” Menon says. “She would never promise, but her attitude was so amazing. It changes the way you feel about the process, because even getting pregnant again was scary.”

But Chueh’s well-honed bedside manner masked her vexation over the fact that the techniques for predicting and preventing preterm labor have not improved in decades. Similarly, when women come to the hospital in premature labor, doctors’ tools are rudimentary: drugs that only sometimes, temporarily, stop contractions — maybe buying enough time for a few doses of other medications that temper the effects of prematurity on the baby’s brain and lungs.

Gaddam thought a lot about the possibility of a second tragedy. “It was really hard, knowing it was likely that my body wouldn’t be able to sustain a pregnancy to term, to be aware that it was my responsibility to gauge what was happening internally and communicate it to the medical team,” she says. “I felt like I had no idea what was happening in the first pregnancy, and it was hard for me to believe that I would be able to tell if something happened again.”

Asked about her wish list for preventing prematurity, Chueh is succinct: She wants tools that reduce the guesswork for expectant moms and their doctors. “It would be really nice to have a test we could use in the first part of pregnancy to identify people at risk for prematurity,” she says. “And we would love to have an etiology, something we could treat.”

The role of inflammation

Several scientists are trying to understand the exact molecular path connecting risk factors such as maternal obesity or PTSD to early contractions of the uterus. Their working hypothesis: While myriad genetic and environmental factors play into prematurity risk, one major biologic mechanism must translate these into a delivery trigger. Mounting evidence suggests inflammation is key.

“Think of pregnancy as a state of immune tolerance that suppresses inflammation,” says Martin Angst, MD, professor of anesthesiology, perioperative and pain medicine. As long as the mother’s immune system accepts the immunologically foreign fetus, the pregnancy continues. “But at some point, her body is no longer immune-tolerant; instead it’s now more in a pro-inflammatory state.”

Inflammation is the immune system’s and body’s way of getting rid of potentially harmful material. It’s also associated with obesity, stress, infections and diabetes — a litany of prematurity risk factors.

Angst and his collaborators published a study comparing immune cells from the blood of mothers who had preterm deliveries against similar cells from mothers who had full-term pregnancies. The researchers used a relatively new technique, called cytometry by time-of-flight mass spectrometry, to test the inflammatory response of specific immune cell subsets. The technique lets scientists take a simultaneous look at all immune cell subsets represented in blood. They wanted to see if, under lab conditions, immune cells taken from women who had had a preterm birth were more sensitive to an inflammation trigger.

Indeed, immune cells called monocytes from women who had given birth prematurely responded differently when the researchers induced inflammation in the lab. In particular, certain components of the toll-like receptor 4 pathway, which acts like the stone that starts the avalanche of the inflammatory response, were more readily activated in these mothers’ monocytes.

“There is a change in the immune disposition of these people and we can see it,” Stevenson says. A future in which at-risk women receive targeted immunotherapy to block the pathways involved in preterm birth now seems possible, he adds. “We can probably understand not just the biomarkers of preterm birth but also the associated changes in gene expression — it’s a really interesting story.”

Stevenson is alluding to work by another Stanford researcher, Stephen Quake, PhD, professor of bioengineering and of applied physics, whose team has developed a technique to track RNA in the maternal blood that may function as a “molecular stethoscope” to detect the signature of impending prematurity. RNA, the message genes send as they act, is released in tiny amounts by dying cells. Quake’s team now has the ability to read these signals not just from the mom’s cells but also from the fetal cells that make their way into the mother’s blood. They can detect physiological changes in the tissues and organs of both the mother and the baby, and hope to use this information to measure genetic programs of distress that they think will accompany premature delivery.

“It gives you this unparalleled window into the whole process of pregnancy, from the point of view of the pregnancy and also of the mom,” Quake says. “There is exquisite specificity to what you’re measuring.”

RNA, microbial, immune and other biomarkers will soon, the researchers hope, give obstetricians the specific predictive and preventive tools they now lack. “The goal is to try to find a simple blood test to alert us to which women are at risk so they can be appropriately cared for,” Quake says. “Hopefully that will give them a safer and more comfortable pregnancy, both physically and psychologically.”

Happy outcomes

Purnima Gaddam had two pregnancies after her premature son’s death. They were neither physically nor psychologically comfortable, but they did have happy outcomes. Gaddam and Menon’s second son, Arcadius, was born in August 2013, about four weeks early, and is now a healthy 2-year-old. His little sister, Seetha, arrived in August 2015, only 2½ weeks before her due date; Gaddam felt signs of labor a few weeks earlier, but quickly went to the hospital, where medications stopped her contractions.

Now that they are past the difficult wait through Gaddam’s pregnancies, the couple is enjoying their children. Menon relishes the new perspective they’ve brought him: “As an adult, you’ve seen, say, a car over and over,” he says. Arcadius, however, thinks cars are exciting, and his excitement is infectious. “Even the most basic things become great again in a new way.”

Gaddam, an avid reader, jokes that Arcadius managed to start a book club before she did: At his small day care, he makes the other children sit and look at books with him, becoming upset if they lose interest too quickly. “There’s one other baby who always follows him around, and while he turns pages and babbles on, she will stay,” she says, laughing. “He has one really devoted attendee.”

In a more serious vein, she reflects on how the death of her first child changed her outlook. “When you’ve been lucky enough to have things happen the way you hoped, you feel agency and control — that if you work hard you can get what you’re working for,” she says. “But when something like this happens, it makes you realize that nothing is ever promised.”

After her loss, a different, bittersweet promise was realized: her father’s belief that her son would return. “We did have a son,” she says. “We always have felt he was coming back to us.”

Erin Digitale is the pediatrics science writer for the medical school’s Office of Communication & Public Affairs. Email her at digitale@stanford.edu.

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