Discoveries

Scientific Dream Team Aims to Make Preeclampsia a Relic of the Past

A pregnancy disorder called preeclampsia remains a leading cause of maternal mortality. It can strike like lightning, endangering both mother and child. A dream team of investigators at Cedars-Sinai is determined to render this mysterious disease a relic of the past.

Stork with baby during lightning storm

Illustration: Christina Chung

Lady Sybil of Downton Abbey, a rebel who married the family chauffeur, had just given birth to a healthy daughter when the plot of the popular British television series took a shocking twist. The beloved character suddenly fell into convulsions and died.

She suffered from a severe form of preeclampsia, a pregnancy disorder that begins with high blood pressure and can trigger a cascade of other complications—turning what is supposed to be one of life’s most joyful milestones into a devastating health crisis.

Preeclampsia means “before the lightning” in Greek. As Lady Sybil’s fate illustrates, life-threatening seizures can strike with lightning speed.

Set in the early 1900s, Downton Abbey made headlines on both sides of the pond with this heart-rending episode from 2013. It also called attention to the disturbing fact that preeclampsia can be as dangerous today as it was a century ago. In fact, hypertensive disorders of pregnancy like preeclampsia affect nearly 400,000 women in the U.S. each year.

The only cure for preeclampsia is delivery of the baby—and the placenta, where the disease process begins. But what helps the mother could harm the baby. Preeclampsia is a major cause of preterm birth that can put infants in intensive care for months and lead to long-term health and developmental problems. The condition also is responsible for as many as 500,000 infant deaths and 76,000 maternal deaths across the globe annually.

The United States has the dubious distinction of preeclampsia rates that are three to four times higher than that of other developed countries. And African American women face even higher risk: They are three to five times more likely than white women in the U.S. to suffer from the condition.

But change is coming. A dream team of Cedars-Sinai physicians is aggressively pursuing solutions.

The Dream Team

“Preeclampsia has been talked about for hundreds of years, yet it remains a mystery,” says Sarah J. Kilpatrick, MD, PhD, a nationally renowned expert in maternal-fetal medicine and women’s health, and chair of the Cedars-Sinai Department of Obstetrics and Gynecology.

A physician-scientist who has treated more than 1,000 women for preeclampsia, she says each case requires vigilance because no one knows what course this unpredictable disorder will take. “We don’t know why some patients get it and others don’t, or who will develop severe symptoms,” explains Kilpatrick, the Helping Hand of Los Angeles Chair in Obstetrics and Gynecology.

She is now working closely with two leading preeclampsia investigators: Ravi Thadhani, MD, MPH, and Ananth Karumanchi, MD. Both are kidney specialists who came to Cedars-Sinai in 2017 from different Harvard Medical School training hospitals in Boston, where they had collaborated for nearly two decades.

Thadhani is vice dean of Research and Graduate Research Education and chair of Biomedical Sciences at Cedars-Sinai. Karumanchi is the Medallion Chair in Vascular Biology and director of Nephrology. In recent European studies, they jointly developed a test for early detection of preeclampsia as well as an experimental therapy. They see Cedars-Sinai as the ideal place to validate and build on the promising results.

“This institution fosters a drive to make a difference in human lives,” Thadhani says. “We have the support we need to push this work over the finish line.”

Thadhani and Karumanchi say they are excited to have the opportunity to collaborate with Kilpatrick and others at Cedars-Sinai who are studying links between pregnancy disorders and heart disease later in life. But their first priority is preeclampsia.

The pair joined forces with Kilpatrick to lead a national, 12-site study that aims to win Food and Drug Administration (FDA) approval for a reliable preeclampsia diagnostic test. The study, launched in April, focuses on a critical question: Which patients with preeclampsia are at highest risk of developing severe symptoms that could quickly become life-threatening?

The test could give doctors vital information to guide medical decisions, such as which patients need treatment to prevent seizures, who needs to remain hospitalized before their due date and how long it’s safe to delay delivery. The next step will be to hone a treatment approach that Thadhani and Karumanchi began working on years ago in Boston. They are determined to accelerate progress in a field that has too long been neglected.

Catch-22

Melissa Salama and baby Ruby

Melissa Salama and baby Ruby are both healthy today despite preeclampisa that led to preterm delivery. Photo: Rachael Porter                            

Women with preeclampsia may be hospitalized for weeks so they can be closely monitored for signs of severe disease such as kidney failure, fluid in the lungs and liver damage. During this time, physicians and patients are trapped in a catch-22, trying to manage the health of the woman while protecting her unborn child.

“All we can do is monitor the mother closely, manage symptoms as they arise and try to prolong the pregnancy as long as possible. It’s a delicate balancing act,” Kilpatrick says.

This balancing act can put mothers-to-be on an emotional roller coaster. Melissa Salama, a Los Angeles mother of three, has been there—twice.

The first time was seven years ago, when she gave birth to her first child in New York at age 34. She developed high blood pressure late in the pregnancy, after experiencing uncomfortable swelling and extreme fatigue for weeks. Her daughter, Molly, was born two-and-a-half weeks early. Both mother and child came through with no health problems, although it took a couple of months for Salama’s blood pressure to get back to normal.

Her second child, Ben, now 4 years old, was born a week past his due date at Cedars-Sinai. Salama’s blood pressure was a bit high at the end so she finished the pregnancy on bedrest as a precaution, but preeclampsia did not become a problem.

Then came Ruby. Salama had the same disturbing symptoms as in her first pregnancy, but they were worse this time and started earlier. “I felt so rundown and had an incredibly difficult time focusing on anything. I was anxious about making it to the end of the pregnancy. I knew it could get very bad,” Salama recalls.

Her doctor, Karyn Morse Solky, MD, clinical chief of the Cedars-Sinai Department of Obstetrics and Gynecology, advised her to come to the hospital on a Friday morning last December because her blood pressure had been consistently high and her blood platelet count was falling, putting her at risk for internal bleeding. She was treated with medication for hypertension and magnesium sulfate to prevent seizures. It was a month before her due date.

“My husband and I were very worried that it was too early and there could be lasting effects on our baby,” Salama says. “We were also scared about whether I would be OK. And I was worried about my two kids at home. I needed to get back to them.”

Push for Change

One reason mothers like Salama find themselves in such an agonizing position is because pregnancy has often not kept pace as a focus of medical research. Fear of harming the fetus is a formidable barrier to developing scientific evidence to guide clinical care when mothers-to-be develop complications.

Kilpatrick explains: “Most medications we use during pregnancy are classified as Category C by the FDA, which means we don’t have proof they’re safe during pregnancy because they haven’t been studied in humans—yet the potential benefits may outweigh the risks. I almost always recommend taking the medication for conditions such as hypertension, depression or Crohn’s disease because it’s riskier for the mom to stop it, and we know from experience that the risk to the fetus is small.”

Thadhani says he doesn’t know of any pharmaceutical or biotech firm that has made it their mission to develop treatments for preeclampsia, and women’s health issues in general are not a priority. “We’ve pitched our research to more than 30 companies without success,” he says. “One problem could be that 99.9% of the people making the decisions are men.”

But the biggest obstacle to finding industry partners for this research is most likely a ghost from the past.

In the late 1950s, the drug thalidomide was prescribed to relieve nausea and morning sickness in pregnancy. It resulted in a worldwide tragedy: Thousands were born with severe birth defects such as malformed limbs—only 40% survived. “It is still fresh in people’s minds. It still keeps companies from supporting pregnancy studies that could open them up to a lawsuit,” Karumanchi says.

He notes another deterrent to obtaining industry support: The biology of preeclampsia has not been understood well enough to identify clear targets for drug development. He and Thadhani have made major contributions to advancing this knowledge, while pursuing a path to treatment that would not put the fetus at risk.

Making the Impossible Possible

After years of working at different hospitals five miles apart, Thadhani and Karumanchi no longer have to schedule a time and place to meet. “This is the first time we’ve worked under the same roof,” Thadhani says. “It’s great to be able to butt heads with each other in the same lab every day.”

The two investigators feed off each other’s creative energy. While Karumanchi’s demeanor is casual and laid-back, Thadhani has perfect posture and a polished manner. He stands at a whiteboard in his office and writes key points as the two discuss their work.

But appearances can be deceiving. Karumanchi respectfully describes his longtime research partner as “a bit on the edge.”

“You have to be a little crazy when you’re trying to do what’s never been done before,” he says. “Ravi thinks outside the box. He believes nothing is impossible.”

Thadhani appreciates the way Karumanchi helps him “stay grounded.” He adds: “I’ll see a problem in the clinic and he’ll help explain the biology. This is the yin and yang of our partnership.”

In Boston, they often brainstormed at a Borders bookstore about halfway between Thadhani’s lab at Massachusetts General Hospital and Karumanchi’s lab at Beth Israel Deaconess Medical Center. One afternoon in 2008, they braved a blizzard to meet there. They stayed for hours. And it wasn’t because they were waiting out the storm. They vowed not to leave until they figured out an approach to treating preeclampsia that would help the mother without harming the baby. It turned out to be one of the most productive meetings of their careers.

A Little Bit of Luck

As an expert in vascular biology, Karumanchi became fascinated years ago with growing evidence that preeclampsia damages the cells that form the lining of blood vessels. He figured the cause had to be one or more of the proteins released into the mother’s blood vessel system by the placenta. But which one?

Finding the culprit could have been a daunting, needle-in-a-haystack undertaking. But he got lucky. He was able to use new technology to examine the entire genome of the placenta in a single snapshot, rather than looking at one protein at a time to determine whether it was elevated in preeclampsia patients.

“I was asking the right question at the right time,” he says. “This technology had just come out. Without it, I might have spent 50 years trying to do this.”

The “brightest signal” came from a “bad” protein called soluble fms-like tyrosine kinase 1 (sFlt-1). Also significant was a “good” protein essential to healthy blood vessels: placental growth factor (PIGF). Karumanchi had a hunch that preeclampsia was triggered when the “bad guys” outnumbered the “good guys,” causing blood vessels to constrict instead of relaxing and opening up to support blood flow for a healthy pregnancy.

While Karumanchi was working on this basic biological science, Thadhani was studying high blood pressure in women and caring for preeclampsia patients in the clinic. He found it frustrating not to be able to do more for them. When he heard about Karumanchi’s results, he knocked on his door. The two launched a study using 10,000 tissue samples Thadhani had collected from pregnant women in Boston to validate Karumanchi’s theory.

This led them to the diagnostic tool that is now the focus of a clinical trial at Cedars-Sinai. The study seeks to identify a ratio between the “bad” and “good” proteins that would help identify patients most likely to develop severe symptoms of preeclampsia.

Once they confirmed the role of the “bad” sFlt-1 protein in preeclampsia, they knew they had a critical building block for a treatment as well as a diagnostic test. Anyone who observed them on that stormy day in the bookstore in Boston might have thought they were arguing. “We sat there for hours trying to figure out the best approach. It was a cognitive wrestling match,” Thadhani says.

Their expertise as kidney specialists led them to an answer.

“Our predecessors in nephrology realized that, rather than taking out whole blood, we can tinker with it to take out what’s bad and leave in what’s good,” Thadhani says. “Nephrologists have been pioneers in selective removal strategies.”

A light bulb went on: Instead of developing a drug targeting sFLt-1 that might cross the placenta and damage the fetus, why not remove the offending protein from the mother’s bloodstream?

Three years later, Thadhani and Karumanchi launched their first treatment study in Europe. Using a process similar to kidney dialysis, they modified existing technology to develop a device that removes blood through a catheter, runs it through a machine that eliminates sFLt-1 and then returns the blood to the mother.

Thadhani says they’ve been able to extend pregnancy for about two weeks, a significant period for development of the fetus. The findings of their first pilot study on this potential treatment method were published in 2011 in Circulation. A follow-up study published in 2016 by the Journal of the American Society of Nephrology confirmed the initial findings and set the stage for the next step—validating these results in larger U.S. studies.

A Mother’s Hope for the Future

When Salama was admitted to Cedars-Sinai a month before Ruby’s due date, she knew every day would make a difference in her baby’s health. Fortunately, she was already in a safer zone at 36 weeks than many other mothers-to-be in her situation.

Kilpatrick says standard practice is to deliver at 34 weeks when the mother’s symptoms are severe, because “babies do well after this point.” Decisions get tougher when severe symptoms of preeclampsia appear earlier in the pregnancy.

In Salama’s case, her symptoms were getting worse and time was short. But she was relieved to learn that she would receive a steroid injection to help the baby’s lungs develop, and they would wait 48 hours to induce labor. While her husband, Evan, alternated between supporting her at the hospital and reassuring the kids at home, she did deep-breathing exercises to calm herself.

Five days after Salama entered the hospital, Ruby was born. She weighed 4 pounds, 15 ounces, and was stable enough to be held by her mom for two hours before she began a five-day stay in the NICU. Ruby didn’t have severe problems, but needed to “mature a bit,” Salama says. The only issue that continued after they got home was that Ruby was too weak to nurse. Salama reluctantly stopped breastfeeding far earlier than she had planned.

Overall, dealing with preeclampsia was “an incredibly stressful experience for the whole family,” she says.

“Dr. Solky was very understanding about how nervous we were,” Salama says. “She acted quickly, and we’re thankful it was an excellent outcome. Ruby is healthy and I feel good now.”

‘Don’t Give Up’

In 2006, a lengthy article by Jerome Groopman in The New Yorker featured Karumanchi’s effort to identify the proteins released from the placenta that trigger preeclampsia. Karumanchi says the article helped increase awareness of this disease at a time when it was much less understood than it is today.

However, he adds, “The most important thing that came out of the article was the many emails I received from patients.”

He will never forget the gist of these messages: “Keep going. Please don’t give up.”

Karumanchi and Thadhani have no intention of giving up. They are committed to continuing their work with Kilpatrick and other research partners until they change the trajectory of this disease.

Meanwhile, Kilpatrick continues to deliver an important message to patients: “They may feel they did something to cause this, so I always tell them, ‘It’s not your fault.’ There’s no reason for a woman to feel guilty about getting this disease. It’s just bad luck.”

“This disease keeps you very humble,” Karumanchi says. “Women’s lives are at stake. We have to change that.”

Another Path to Progress in Fighting Preeclampsia

Sometimes the immune system that is supposed to protect us from disease goes haywire and triggers health problems instead of fighting them off. Richard M. Burwick, MD, assistant professor in the Cedars-Sinai Department of Obstetrics and Gynecology, believes this is what happens with preeclampsia.

As he explains, proteins that help regulate the immune system become overactive during pregnancy. “The body starts reacting against the pregnancy by activating these proteins as if there’s a bacterial infection that it needs to fight,” he says. 

He’s preparing to launch a preeclampsia clinical trial this summer to explore the safety and effectiveness of a drug that inhibits these proteins and has been approved by the FDA to treat certain blood disorders. He believes this could be an effective way to prolong pregnancy for preeclampsia patients and to prevent severe side effects such as organ damage and destruction of red blood cells and platelets.

By the Numbers

  • Hypertensive disorders of pregnancy impact an estimated 5–8% of all pregnant women—including 400,000 in the U.S. annually. 
  • Preeclampsia causes as many as 76,000 maternal deaths and 500,000 infant deaths across the globe each year.
  • Preeclampsia typically occurs after 20 weeks of pregnancy, in the late second or third trimester, and postpartum eclampsia may occur up to six weeks after delivery. 
  • At least a third of deliveries involving mothers with preeclampsia occur before babies come to term at 37 weeks.
  • About 25% of preeclampsia cases involve severe symptoms.
  • The average amount of time between diagnosis of preeclampsia and delivery of the baby is seven days.
  • Preeclampsia is on the rise, with incidence in the U.S. increasing 25% over the last two decades—another puzzle for investigators to solve.