Can Precision Pregnancy Save More Mothers?

Tall, slender, and seemingly extremely fit, she was at one time the fastest woman in the world and an Olympic champion. But she died at home, alone, during labor, in the world’s richest country.

How could this happen?

“Tragic,” “heartbreaking,” and “totally preventable,” is how experts describe the death of 32-year-old American sprinter Tori Bowie in early May. But few are surprised that it happened, given the abysmal state of maternal healthcare in the U.S.

According to experts working on new tests and approaches to better manage pregnancy, part of the problem is that we are approaching it backward.

“Most of the attention is later in the pregnancy and during the delivery, of course,” says Evelina Grayver, MD, who heads the Women’s Heart program at Northwell Health’s Katz Institute for Women’s Health, as well as the health system’s cardiovascular obstetrics program. In other words, it’s a classic case of too little too late.

“We need to start providing more care sooner, and carry that on after delivery,” she says. “I’d like to shout that from the rooftops.”

She says more women should undergo preconception counseling and even a stress test before they start families. She points out that between 5% and 7% of maternal mortality during the first year after delivery is from complications of preeclampsia, a hypertensive disease that affects 1 in 25 U.S. pregnancies. It’s estimated that is causes 50,000 maternal deaths and more than 500,000 fetal deaths worldwide per year.

Spontaneous preterm birth can also affect the mother’s health. One study found that women who deliver prematurely face a heightened risk of heart disease over the course of their lives (Crump, C. et al. Ju 2020, JACC). Early delivery also increases risk for high blood pressure, diabetes, high cholesterol, and neurologic symptoms. One in 10 U.S. babies is born prematurely.

“Pregnancy is a stress test,” Grayver points out. “People need to understand that hemodynamic changes take place in the body during pregnancy.”

The problem in some places is getting worse. Experts who’ve studied the issue say that the situation in the U.S. is particularly shameful, considering how much we spend on healthcare. According to a recent study (Hoyert, L., CDC, 2023), the U.S. rate of maternal deaths during pregnancy or within 42 days of being pregnant was 32.9 per 100,000 live births—more than 10 times the estimated rates for other high-income countries such as Australia, Israel, and Spain, which all have between 2 and 3 deaths per 100,000 live births. The U.S. maternal mortality rate actually increased every year from 2018 to 2021 (Harris, E., JAMA, 2023).

There are also notable disparities within the U.S. Pregnant black women, such as Bowie, have nearly triple the maternal death rate of white women. Hispanics and Indigenous women are also at greater risk than white patients. “There are a lot of social and behavioral determinants, but structural racism is part of it,” says Louis J. Muglia, MD, PhD, president and CEO of the Burroughs Wellcome fund and a pioneer in the genetics of preterm birth.

Of course, the problem is much worse in most developing countries, but for different reasons. Some women in these lower-resource settings may receive no care at all. Still, there is widespread agreement that we could easily improve the situation in this country. And new tools that could have global use may be part of the solution.

Earlier, more precise tests

Preterm delivery is the leading direct cause of death in neonates and children under five years of age around the world. As noted above, it can also impact a mother’s long-term health.

Hologic’s fetal fibronectin (fFN) test measures a glycoprotein at the maternal-fetal interface that is usually not detectable in vaginal secretions until later in pregnancy. Its early presence in vaginal secretions is a biochemical indicator of preterm birth risk. The company reports that fFN is the single common biochemical marker for all four mechanisms of preterm birth: activation of the maternal/fetal hypothalamic-pituitary-adrenal axis, inflammation, decidual hemorrhage, and pathological uterine distention. The test received FDA approval in 1995.

Muglia and others are seeking genetic clues that may indicate who is at risk even earlier. He coordinated a landmark study for the March of Dimes Research Center that involved data from more than 50,000 women and pointed to six gene regions that influence the length of pregnancy and timing of birth (Zhang, G, et al. NEJM, 2017).

Two of the gene areas identified, WNT4 and AGTR2, suggest that cells within the lining of the uterus play a larger-than-expected role in the length of pregnancy, indicating a new potential target for medications to help prevent preterm birth.

One of the most ambitious efforts is by Mirvie, which is developing RNA-based early tests for both preeclampsia and preterm birth. RNA messages change over time as a pregnancy progresses. According to a pivotal study of samples from 1,840 women in the U.S., Europe, and Africa (Ramussen, M., et al., Nature, Jan 2022), these transcripts can effectively identify 75% of pregnancies that later develop preeclampsia, months
in advance.

The company is also developing a patient-centered Care Plan designed with the help of medical experts and preeclampsia advocates. The plan includes more than a dozen monitoring, medication and labs, and nutrition and lifestyle steps that improve the chances that a pregnancy will be healthy. This type of patient and physician education is sorely needed in this field, according to Mirvie.

The company published a high-profile study on its preterm birth platform based on tens of thousands of samples from 242 ethnically diverse pregnancies (Camunas-soles, et al, AJOG, 2022). The authors say this test identifies 76% of early preterm birth cases and highlights relevant biological pathways.

“It’s time to treat pregnancy like we do cardiovascular disease and cancer,” says Maneesh Jain, Mirvie’s CEO and co-founder. “It’s estimated that 84% of pregnancy-related deaths are preventable. We have to do something about this.”

The next steps for Mirvie will be getting a product on the market, Jain says experts who’ve studied the issue say that: “It took years to collect and analyze this many samples. It’s time to take it to the clinic.”

Other new tests for preeclempsia, by Thermo Fisher, were approved by the FDA in May. These novel immunoassays are the first and only such tests to receive breakthrough clearance for the disorder. B·R·A·H·M·S PlGF plus KRYPTOR and B·R·A·H·M·S sFlt-1 KRYPTOR biomarker assays can be used with other tests in women deemed at risk to help determine whether they will progress to preeclampsia within the next two weeks.

It’s all in your head

For two common conditions of pregnancy, severe nausea and postpartum depression, there can be the added challenge of stigma. Marlena Fejzo, a geneticist at the University of Southern California Keck School of Medicine, learned this first hand when she developed severe hyperemesis gravidarum (HG) during her second pregnancy.

HG is a form of extreme morning sickness that affects a small number of women, but it can be devastating and may cause thoughts of suicide, termination of wanted pregnancies, dehydration, weight loss, and nutritional deficiencies.

Fejzo couldn’t even drink water, and she lost so much weight she was essentially immobile. She eventually got IV fluids and a feeding tube, but it was too late. She lost the baby. Beyond the heartbreak, pain, and discomfort, there was the added insult that her doctor thought the symptoms were “in her head” and that she was looking for sympathy. It’s a sentiment she still hears today from healthcare professionals.

There was so little known about what caused this condition, or how to treat it, that Fejzo decided she would study it. She has long partnered with the Hyperemesis Education and Research Foundation on such work.

In 2011, she was the senior author on a paper that helped establish a genetic component of HG (Zhang, Y., et al., Am J Obstet Gynecol). Then, in 2022, she was part of a team that used whole-exome sequencing to look for variants associated with HG. The researchers got help from 23&Me to collect samples, and Regeneron offered to do the sequencing. One gene stood out: GDF15. Notably, the gene’s product is part of a pathway that causes vomiting in nonhuman primates, chemotherapy­induced nausea and vomiting, and cancer cachexia. In animals, inhibiting it is an effective treatment, and therapeutic agents based on these findings are in development.

Postpartum depression (PPD), meanwhile, is estimated to affect between 10% and 15% of new mothers. It’s thought to be multifactorial. HG is one of the causes, but it is believed that genetics play a role in PPD too.

According to one report, “Evidence is strong for the genetic basis for PPD with approximately a 40% heritability. The heritability is thought to be a mixture of genetic risks for other types of mood disorders and genetic risks that are unique to PPD” (Payne, J.L. Biomarkers of Postpartum Psychiatric Disorders, 2020).

Patients with PPD and/or psychosis are vulnerable to self-harm, suicide, and even infanticide. After an episode, more than half of patients will experience a recurrence.

In a particularly horrific example of how bad this condition can be, a woman in Massachusetts recently strangled her three young children and then jumped out a window, ending up paralyzed from the waist down. Her lawyer reported that she was seeking help for PPD at the time and was prescribed 13 psychiatric medications in just four months. Notably, after the incident, the woman received a lot of support online from others who have experienced PPD.

A new plan for pregnancy management

A major challenge in determining the most useful tests is getting enough samples. Both Muglia and Fejzo’s teams worked with 23&Me, a direct-to-consumer genetics company, to get large numbers.

Muglia also believes artificial intelligence can be a big help with the challenge of preventive maternal health. “There are research efforts to design a precision profile for every woman,” he says. There are also promising avenues of research not yet fully tapped, including the microbiome, transcriptomics, inflammation, fetal-maternal signaling, nutrition, epigenetics, and mitochondria.

It’s hard to tell whether any of this would have helped Bowie. It was reported that she was eight months pregnant when she died, in labor, and possibly had “respiratory distress and eclampsia,” according to People magazine, which obtained a copy of her autopsy. But her longtime agent told the magazine that Bowie said she did not want to give birth in a hospital.

After Bowie’s death, one of her former teammates, Tianna Madison, wrote on Instagram that she had also gone into labor early. It is notable, she said, that “THREE (3) of the FOUR (4) of us [all black] who ran the SECOND fastest 4X100 relay of all time, the 2016 Olympic champions, have nearly died or died in childbirth.”

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