Decoding preeclampsia

The deadly pregnancy condition has baffled humanity for millennia. Is medicine finally catching up?

My friend Deena Shakir thinks her husband jinxed their third pregnancy.

As they brought their baby home from the hospital, he marveled it was her easiest delivery yet. By contrast, Deena’s last two deliveries were “dramatic.” But this time she had a straightforward C-section, got back on her feet quickly, and was even discharged from the hospital early.

A few days later, as her husband assembled the stroller for their first walk, Deena developed a thundering headache. Always a planner, she fished out the blood pressure cuff that she kept around, just in case. The reading shocked her.

“I had never had a high blood pressure reading in my life. Not before pregnancy, not during pregnancy,” she told me. “As someone with no clinical training, I didn't understand that the pain I was feeling in my head was because there was fluid in my brain.” But she understood that something was gravely wrong.

A call to her doctor’s office might stall out with the answering service. She needed advice about what to do right away. So she called me instead.

As an obstetrician, I’m used to fielding questions from pregnant friends and family. I delight in being helpful with the mundane–is this or that safe to eat, etc. But I could tell from Deena’s tone that this was not mundane.

Her blood pressure was in the severe range. Her headache was a precursor to seizure and possible brain damage. The clinical signs were clear, I told her: she needed to get to an emergency room immediately.

“In the 15 minutes it took to drive from my house to the hospital, I was leaving voice notes for my kids. I was going over my will with my husband. I thought I might not make it,” she remembers tearfully.

A familiar stranger

At the hospital Deena was given STAT IV medications to drop her blood pressure, and she was placed on a magnesium sulfate drip to suppress her central nervous system. Less than a week after first leaving the hospital she was readmitted for supportive care and observation. Ultimately, she emerged shaken, but unscathed.

Deena is aware that it doesn’t always turn out that way and talks often about how lucky she is. She is a partner at Lux Capital, a Maven board member, and one of the most informed people I know. She was the type of pregnant person who would read scientific articles herself and text me detailed, nuanced questions to ensure she and her baby would be as healthy as possible. But despite all of her connections and her savvy, neither she, nor I, nor her doctors, had a way of seeing preeclampsia coming.

For the whole of my career, that is just how it’s been. Preeclampsia, while all too familiar, is also shrouded in mystery. We struggled to understand why it envelops the body in the first place, let alone why it rages in some people while smoldering in others. The only known “cure” is to deliver the baby and placenta–except (perplexingly) when it isn’t. In Deena’s case the onset occurred days after her baby was born.

Although it is a condition unique to pregnancy, it often presents as a Frankenstein of systemic disorders, from cardiovascular disease to chronic kidney and liver disease. It can rapidly shut down an assortment of vital organs. And it can be fatal.

Although it is a condition unique to pregnancy, it often presents itself as a Frankenstein of systemic disorders, from cardiovascular disease to chronic kidney and liver disease. It rapidly shuts down an assortment of vital organs. And it can be fatal.

Preeclampsia has always been with us. Mesopotamian and Egyptian texts describe convulsions in pregnancy that were likely eclamptic seizures. Throughout the centuries physicians developed colorful language to describe it’s harbingers. Early modern literature refers to “dropsy,” the swelling from fluid that builds up in the limbs, and also sometimes the lungs. My medical textbooks refer to “toxemia” of pregnancy, based on the 19th century hypothesis that toxins from the placenta were poisoning the mother.

The 20th century brought the formalization of obstetrics as a discipline within medicine. Early obstetricians were so confounded by preeclampsia that to this day, the entire prenatal schedule of visits is based on catching it before it’s too late. Women are typically advised to go to the doctor every month at the beginning of pregnancy. But then in the third trimester it becomes every three weeks, and then every two, and then every week at the very end, lest a missed blood pressure fail to detect preeclampsia toxemia creeping in.

Because doctors are always on our back foot in managing preeclampsia, it remains one of the leading causes of maternal and infant mortality, accounting for one in six deaths globally. Approximately 5-8% of pregnant women in the United States will develop it. Megan Markle, Beyonce, and Kim Kardashian all had preeclampsia.

In almost all cases, the difference between surviving preeclampsia and suffering its worst consequences is a matter of responding to its onset on time. Yet until recently, efforts to get ahead of the disease have been elusive. As recently as the 1980s and 1990s, debunked medical theories attributed preeclampsia to parasitic worms and sperm allergies (for which doctors prescribed sperm exposure and desensitization).

As Dr. Benjamin Sachs, the former chief of obstetrics and gynecology at Beth Israel Deaconess Medical Center told the New Yorker in 2006, “Every academic obstetrician would love to find the cause of preeclampsia.” And yet, for a long time, nobody had.

Sherlockian cells

When I was a medical student, Dr. Sarosh Rana both frightened and fascinated me. She was completing her advanced fellowship training in maternal fetal medicine and I was only just starting to understand the rhythms of the hospital. As a student, my job (as I understood it) was to hop after her, chasing her down the wards as she briskly strode from one sick pregnant patient to the next.

Sarosh never walked, or talked, without purpose. She arrived at the hospital before the sun came up and often left after the sun went down. She went the extra mile for every patient with extreme attention to detail. And she was an encyclopedia of information, seemingly knowing everything there was to know.

One day, during a rare lull, she asked me if I could be any cell in the human body, what would I pick? Having never considered the question I paused for her to share her ready answer.

“I would be a syncytiotrophoblast,” she told me confidently.

I vaguely understood that these cells form the outermost layer of the placenta, serving as the border between maternal and fetal blood. That somehow, like sentinels, they dictate what is allowed to come in and out–nutrients yes, toxins no.

The hospital schedule was punishing, requiring overnight shifts and weekends, often exceeding 80 hours a week. Yet after work, between stretches of service and being on call, Sarosh would drive an hour up I-95, from the hospital Providence to a lab in Boston. This lab proved to be the lynchpin in unraveling preeclampsia’s mysteries.

During the first weeks of pregnancy, these trophoblast cells invade the inner lining of the mother’s uterus and remodel the mother’s arteries to support exponentially higher blood flow. It is a radical transformation that ensures both the maternal tissue and the developing fetus are adequately perfused with oxygen and nutrients. Sometimes, however, it goes horribly wrong. The remodel fails, resulting in a layer of delicate blood vessels that, as one doctor put it, look like “spiderwebs torn apart.”

But when he submitted the results of his studies on soluble FLT to Nature, they rejected it—after all, many had tried to solve the disease before, and many were skeptical that a one-off study had cracked it.

The lab that Sarosh spent every chance she could working in was led by a humble physician named Dr. Ananth Karumanchi, who found that preeclampsia is closely associated with elevated levels of a protein called soluble FLT, which sludged up other proteins and blocked their ability to nourish the remodeled blood vessels. His research ended up proving that patients who developed mild preeclampsia had 2x more soluble FLT in their blood, and those with severe preeclampsia had 5x more.

Ananth isn’t an obstetrician—he’s a nephrologist. His interest was piqued nonetheless by the concept of a vascular disease that didn’t originate in the kidneys yet ultimately ended up there. And remarkably, on his first try looking into the disease, he discovered the key protein. “We lucked out,” he told me when we caught up last week.

He submitted the results of his studies on soluble FLT to Nature only to have it rejected—after all, many had tried to solve the disease before, and many were skeptical that a one-off study had cracked it. Fortunately, Ananth’s work was ultimately accepted elsewhere. Today it is the most highly cited preeclampsia paper of all time.

The myth of one disease

Ananth’s seminal paper was published in 2003, but it would take another 18 years for him to finally garner FDA approval for the first molecular test for preterm preeclampsia—even after it was approved across Europe a decade earlier. For reference, he tells me eight new tests for Crohn’s disease (which has roughly the same population prevalence) have been approved in that same period.

But he continued to work furiously. He detected additional proteins that are instrumental in the formation of preeclampsia. He published more landmark papers, shaped obstetric practice guidelines, and became a pioneer in aligning molecular insights with drug development, helping pave the regulatory path—termed the “FDA door-opening”—toward new targeted therapies.

Ananth also activated many physicians and scientists with his belief that preeclampsia is a disease that we can not only predict but stop in its tracks. Sarosh went on to join Ananth’s lab as an investigator, ultimately becoming faculty at Harvard Medical School. A few years later, I completed my training and joined her at the same hospital.

I found myself reflecting on this legacy as I met with the founders of Mirvie last month. Mirvie is an astonishing platform that promises to predict pregnancy complications months before they occur, even among those with no apparent risk factors—all with a simple blood test. When I read their first paper published in a 2022 issue of Nature, the data looked almost too good to be true.

Mirvie’s technology builds on Ananth’s work, as well as several decades of cancer detection research. They find strong evidence that signs of preeclampsia can be tracked through tiny bits of free-floating placental mRNA in the bloodstream.

For otherwise low risk women, the test is 91% sensitive in predicting those who will develop the disease. Those who test negative can also be confidently reassured – it correctly identifies those who will not develop the disease 99.7% of the time.

“What is pretty exciting is that the molecular signal, the placenta driven signal, is particularly strong in the moms who do not have any preexisting high risk factor, like diabetes or chronic hypertension.” In other words, he says, “The area where we have the greatest unmet clinical need is also where the molecule performs the strongest.”

Furthermore, their data indicate that preeclampsia is actually multiple distinct disorders–not a single condition. In other words, there are different types of preeclampsia, with different sources and thus different possible treatments. When I ask the team about Deena’s case, their CEO and cofounder Maneesh Jain tells me rather than regarding it simply as a rare case, it may actually be a “totally different condition than preterm preeclampsia.”

This insight is foundational in reducing the likelihood of patients and doctors of the future will get blindsided. As Jain tells me, “What is pretty exciting is that the molecular signal, the placenta driven signal, is particularly strong in the moms who do not have any preexisting high risk factor, like diabetes or chronic hypertension.” In other words, he says, “The area where we have the greatest unmet clinical need is also where the molecule performs the strongest.”

Consistency meets innovation

Sarosh grew up in Uttar Pradesh, India, which has one of the highest maternal and infant mortality rates in the world. As a student, she vividly remembers seeing woman after woman arriving at the hospital, convulsing in eclamptic seizures, often with tragically demised babies that had to be delivered with forceps. It was those memories that motivated her to schlep from the hospital in Providence to the lab in Boston during her fellowship, and to help Ananth chase down the molecular origins of preeclampsia.

Before long, Sarosh became a high profile rock star in her own right and was recruited to the University of Chicago as their Section Chief of Maternal Fetal Medicine. There, on the impoverished South Side, a large proportion of her patient population were Black women, who paid for their care through Medicaid.

The disparities in outcomes were wrenching. Largely due to barriers in access, Black women in the United States are 5x more likely to die from preeclampsia than their white counterparts. It was immediately apparent to Sarosh that the greatest opportunity for impact was at the system level rather than the molecular level.

“I literally looked at every protocol for hypertension,” she said, and then retrained her staff on how to administer magnesium, labetalol, and other medication. “We reduced the severe maternal morbidity for Black moms at the hospital just by making sure that medications were administered optimally,” she told me. Then she turned her attention to making sure every pregnant person could access a higher standard of monitoring and care, which required extending her reach beyond the hospital walls.

Over the last decade Sarosh has developed the nation’s leading program for remote hypertension monitoring and management, called STAMPP Hypertension. The brilliance of the program is in its simplicity: after giving birth, all patients at risk of hypertensive disorders are sent home with a blood pressure cuff, and told to take their reading twice a day in an app.

If their reading exceeds the normal baseline, or if they report feeling a headache, shortness of breath, or chest pain, they are automatically escalated and called by a nurse. The program is cheap, scrappy, and predicated mostly on discipline. “Our rates of follow up increase from 30% to 84%,” she said.

Today STAMPP has enrolled over 6000 people, and has been replicated by health systems in 11 states. And now, Sarosh is once again turning her attention to a new opportunity for impact. Next month she will become Chair of Obstetrics and Gynecology at the University of Nebraska, a state where pregnant mothers and their families routinely drive several hours to get to a hospital that can deliver their baby. It is a place where programs like STAMPP, and tests like Mirvie, will massively extend access to life-saving care.

In discussing her future plans, Sarosh’s commitment is as palpable today as it was when I was a new medical student–a trait she shares with Deena, whose own lived experience deepened her commitment as an investor in women’s health.

And Ananth, the original optimist, tells me, “In the next decade, we will have a molecular therapy that hopefully will be a single dose of srRNA you can inject.” He envisions a near future that would transform preeclampsia once and for all from a deadly specter to a trackable, treatable condition we can finally see coming.

What my team is reading, considering, and building against:

• Nearly two decades ago, Dr. Karumanchi’s discovery (and the long history of preeclampsia that preceded that discovery) was beautifully chronicled in this piece for the New Yorker. It is well worth a read, both to marvel at what has (and what hasn’t!) changed.

• A film I’m proud to be part of, Aftershock, describes how delays in detecting and responding to preeclampsia contributed to the tragic death of Amber Rose Isaac. It portrays an uplifting story of how Amber’s family and community band together to bring reforms to hospitals across the country. The film went on to win the Special Jury Prize at the Sundance Film Festival, the Peabody Award in journalism, and a nod from the Emmies. You can stream it on Hulu and also read my conversation with the director, Tonya Lewis Lee here.
  

• ICYMI, Allyson Felix (the most decorated athlete of all time) wrote a rousing call to action after her teammate Tori Bowie’s death from preeclampsia two years ago for TIME. It is not only a reminder of how much work there is to be done, but also of the many remarkable people we have lost to this disease. You can read my conversation with Allyson here, about all she has done since to advocate for mothers. Her work is also chronicled in a buzzy, forthcoming film She Runs the World, executive produced by the very same Tonya Lewis Lee.
  

• While scientists and clinicians have ushered in much of this progress, none of it would be possible without survivors busting down doors. My friend Eleni Tsigas lost her first child to preeclampsia, and as she told me when we recently connected, “My second pregnancy and the doctor and the care plan and everything we went through benefited from the tragedy of the first pregnancy. But nobody should have to learn how to do pregnancy and how to do obstetrics care because of a tragic outcome.” Over the last decade, Eleni has devoted her life to prevention and education as CEO of the Preeclampsia Foundation. You can read her powerful story here.