Today we are joined by BBI member Dr. Swati Shree, Assistant Professor in Maternal Fetal Medicine in the Department of Obstetrics and Gynecology at the University of Washington.
BBI: Please tell us about your journey to medicine.
Dr. Shree: I sort of always had a natural affinity to Obstetrics and Gynecology. In medical school, I scheduled it to be my last rotation, because I wanted to make sure I gave all other options due diligence. Once I got to Obstetrics, I realized it was my passion. Ultimately, I decided to pursue a fellowship in Maternal Fetal Medicine because I was interested in the interplay of pregnancy being a normal and joyful experience with one that can be layered with extreme complications. As Maternal Fetal Medicine specialists, we deal with a broad range of relatively common complications like high blood pressure and diabetes, and more rare complications like managing pregnancy in patients who have had organ transplants or who are managing cancer while pregnant.
BBI: What draws you to including research into your work as a clinician seeing patients?
Dr. Shree: I am fascinated that pregnancy is usually a normal, healthy condition in which the human body tolerates a new organ growing inside it that is 50% genetically different from our own bodies. The human placenta is far more invasive than is found in other species. Chickens lay eggs, and there is really no sharing of material between mother and offspring during pregnancy. The human placenta is designed to be invasive because the fetus relies on the mother for everything from oxygen and nutrients to expulsion of waste. How does a mother’s body tolerate exposure to foreign antigens for so many months? The immunological underpinning of pregnancy is fascinating and unique, with many questions still unanswered.
I became interested in looking at the detailed cellular communication between mother and fetus. Clinicians in the field have previously documented exchange of cells between baby to mother and vice versa, and finding that these cells can persist for decades is really incredible. My mentor Dr. Hilary Gammill opened my eyes to this world of molecular communication between fetus and mother, and how those communications can change in various obstetrical settings.
We ask questions about what obstetrical scenarios can alter that transfer in either direction, and what that can tell us about the underlying complication.
BBI: Tell us more about your most recent work applying these questions to preeclampsia.
Dr. Shree: Preeclampsia is currently diagnosed clinically. There is no specific blood test that can make a diagnosis. It can profoundly change how the rest of a pregnancy is managed. It can mean the difference between needing to be in the hospital for the rest of a pregnancy versus being able to be home. Or the difference between needing an emergent preterm delivery versus being able to stay pregnant longer. Preeclampsia is an area ripe for precision medicine because we do not yet have a precise way to diagnose this very common and impactful pregnancy complication.
For purposes of background, we know the placenta is incredibly important in preeclampsia. Abnormalities in placental implantation or development earlier in gestation progresses in some individuals to preeclampsia, usually in the second or third trimester. We know that cell free DNA (cfDNA) shed from the placenta is regularly detected in maternal circulation as early as 10-11 weeks in pregnancy. This biology has been used for over a decade in prenatal screening for chromosomal abnormalities. This led us to ask, could cfDNA be leveraged to give us insight into a mother’s risk for preeclampsia or its complications, or even give us a tool for a potential diagnosis? We investigated changes in cfDNA from maternal plasma in the setting of preeclampsia compared to normal pregnancy, leveraging the same low-pass whole genome sequencing currently used for prenatal screening.
We found stark differences between the two groups. The amount of cfDNA shed in the circulation of individuals with preeclampsia was 9 to 10-fold higher than in individuals at the same gestational ages, but with normal pregnancies. We know that preeclampsia is a condition that can impact multiple organ systems in the mother. It is not surprising that more cfDNA would be found in the circulation when there is injury to multiple organs like the kidney and liver. When we were able to measure what fraction of that cfDNA is coming from the placenta, interestingly the proportion of cfDNA coming from the placenta was about the same in both groups. This tells us that there is a large amount of maternal injury in preeclampsia.
BBI: Where does the work potentially go from here?
Dr. Shree: First, there is good potential for further study that could lead to a test that helps make diagnosis of preeclampsia easier. Second, understanding tissue of origin in the cfDNA could change management for the mom. For example, it is well established that women who experience preeclampsia have a greatly increased risk of cardiovascular disease later in life. Better understanding this process could impact how we provide care for these women even long after their pregnancy is completed. With more research completed, I could see a scenario in which I say to a patient experiencing preeclampsia, “Based on our assessment of the cell-free DNA in this pregnancy, you are experiencing kidney injury. We are not yet seeing it in your labs, but we can see it in the shed DNA.” That patient could potentially get placed on a protective pathway for her kidneys, even without having elevated creatinine or high blood pressure. Maybe one would consider interventions like a low-dose ACE-inhibitor to decrease the risk for potential complications.
We certainly aren’t there yet with the data, but these are types of scenarios that I think could evolve from this work. The implications of these findings are going to lead to more work to understand the tissues of origin when cfDNA is increased in a mom’s blood, and how to interpret that data to improve their care during the pregnancy, and potentially afterward.