Photo: Precious Ann Fortes, and her newborn baby, Magnolia. Fortes was a participant in the UCLA study on predicting adverse pregnancy outcomes. (Image courtesy of Precious Ann Fortes)
Pregnancy is a transformative experience – and many of those life-altering changes begin on a molecular level.
A new UCLA study is harnessing the power of those tiny transformations in a way that could help more accurately predict pregnancy complications, such as gestational diabetes and preeclampsia, before symptoms arise.
In modifying a blood test used to detect DNA-level changes that could point to fetal abnormalities, this research is the first to tie potential pregnancy complications to the presence of cell-free nucleic acids – free-standing genetic material – shed from the placenta into the mother’s blood.
To Sherin Devaskar, MD, physician-in-chief at UCLA Mattel Children’s Hospital and lead author on the study, this blood test is the first step in addressing at-risk pregnancies.
“Most often in medicine, we're fixing a problem after it occurs,” Dr. Devaskar says. “If we are able to detect some of these pregnancy disorders before they happen and if we can prevent them, that will be phenomenal.”
New information paired with early detection will lead to better outcomes for mothers and their babies, she says. Mothers will be forewarned, and therefore better able to work with their doctors on making the necessary diet, medical and behavioral changes to stave off pregnancy complications.
Diving into the DNA and RNA
The placenta provides oxygen and nutrients to the baby, produces hormones, and acts as a barrier, keeping out toxic materials and infections. However, there’s a lot we still don’t know about this temporary and mysterious organ, which is “like the internet,” Dr. Devaskar says, in the vastness of the genetic information it holds.
Because of its crucial role in connecting mother and baby, the placenta has become a key figure in the field of epigenetics, which studies interactions between environment and gene. The research that Dr. Devaskar and her team undertook, made possible with funding from the National Institute of Child Health and Human Development (NICHD), a program of the National Institutes of Health (NIH) as part of the Human Placenta Project, aimed to further understanding of the role the placenta plays in fetal development.
Between February 2017 and January 2019, the study team examined a group of expectant mothers and tested their blood periodically through the duration of their pregnancies.
To isolate cell-free nucleic acids shed from the placenta into the blood, the interdisciplinary team used state-of-the-art imaging, mathematical algorithms and modeling with the aid of Kyung Sung, PhD, associate professor in the department of radiological sciences, bioengineering and Biomedical Physics; Xianghong Zhou, PhD, professor in pathology and laboratory medicine; Wenyuan Li, associate adjunct professor in the division of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA; Qingjiao Li, professor at The Eighth Affiliated Hospital at Sun Yat-Sen Univiersity in Shenzhen, China; and Matteo Pellegrini, PhD, professor in the division of molecular cell and development biology.
Giorgia Del Vecchio, a post-doctoral researcher in the department of pediatrics at the David Geffen School of Medicine at UCLA, analyzed the cell-free DNA from samples of maternal plasma taken during the first, second and third trimester of pregnancy and also at delivery.
Del Vecchio explains that since the plasma is circulating in the body, it can collect DNA produced by any organ. Using a new algorithm developed by collaborators from Dr. Zhou’s laboratory, researchers were able to identify how much of the isolated DNA was coming from the placenta.
“We found that in patients who developed gestational diabetes later in pregnancy, the percentage of DNA coming from placenta in the first trimester was higher compared to the patients with pregnancies that didn’t have complications,” Del Vecchio says.
In most cases, gestational diabetes shows no symptoms — but the effects can lead to early or complicated delivery, and the baby developing low blood sugar or jaundice. The disorder is typically diagnosed with a glucose tolerance test at 24-28 weeks, but with the blood test developed by UCLA researchers, it is detectable during the first trimester, between 10-12 weeks.
The research team was also able to develop a model to predict preeclampsia with up to 86% accuracy by isolating and sequencing cell-free RNA to identify whether certain preeclampsia-indicating genes were at play. Preeclampsia is a condition which typically begins after 20 weeks of gestation and causes high blood pressure in mothers, with potential to cause issues in the kidneys and other organs.
“The thing about preeclampsia that makes it so dangerous is that it's so unpredictable,” says Carla Janzen, MD, maternal fetal medicine specialist at UCLA.
According to Dr. Janzen, the only cure for preeclampsia is delivery. That may not always be the best option: the longer preeclampsia develops, the more profound an impact it has on mothers and babies.
It can restrict blood flow to the placenta, which could delay fetal growth and cause preterm birth. Women who develop diabetes or preeclampsia during pregnancy also have a higher chance of developing cardiovascular disease later in life, and their babies are at risk for developing hypertension and diabetes.
“These conditions could really affect the entire trajectory of a baby into adult life,” Dr. Devaskar says.
Dr. Janzen says the team is hopeful the research will guide the further development of tests to help diagnose pregnancy disorders earlier. Right now, “these conditions are currently diagnosed once they have already influenced the health of the mother and developing baby,” she says.
Empowering mothers
Determining the likelihood that a pregnancy will develop these complications is like putting together a million-piece jigsaw puzzle.
For instance, incidences of preeclampsia and gestational diabetes are impacted by social factors such as access to health care, education, income and race and ethnicity. The stressors some mother face “predisposes them to these conditions,” Dr. Devaskar says.
But if a blood test can improve the predictions of whether these disorders might appear during pregnancy, mothers might be able to make lifestyle changes in their first and second trimesters to lessen the chances of developing symptoms: maintaining a healthy weight, regular physical activity, incorporating a nutrient-dense diet and drinking enough water. And if medical interventions are needed to head off pregnancy complications, mothers can work with their obstetricians to introduce those interventions on an earlier timeline.
Precious Ann Fortes, a then second-year medical student at the David Geffen School of Medicine at UCLA, was one of the 200 expectant mothers who consented to participate in this study.
She says the effort to advance knowledge on the placenta and maternal health spoke to her interests in a deep way, at both the macro-level of public health and “on a microscopic level, being able to see the different changes that occur during pregnancy.”
“All of that really empowered me,” Fortes said.
Inspired by this work and its potential for impact on mothers – including herself – Fortes said she was motivated to pursue a future in pathology. Now a physician resident in pathology at UCLA, she is excited for the results of the study to bear fruit.
Dr. Devaskar is hopeful that through early, noninvasive methods, mothers like Fortes can be more effective agents in their own health care, and in determining the future health of their babies.
“Knowledge is power,” she says. “And patients have the right to knowledge and to be powerful in their own care.”
