For years, severe preeclampsia has been viewed primarily as a placental disease. A new study suggested that the disorder extends beyond the placenta, involving coordinated changes in maternal tissues and the immune system.

Published on July 24 in Science Advances, the study used advanced genomic techniques to create one of the most detailed cellular maps of severe preeclampsia to date, identifying pathways that could become targets for future therapies.

“This is a landmark mechanistic study that substantially advances our understanding of severe preeclampsia,” said Abdulla Al-Khan, MD, vice chair and co-director of the Division of Maternal-Fetal Medicine & Surgery at Hackensack University Medical Center in Hackensack, New Jersey, who was not involved in the study.

“It moves us one step closer to precision therapies that target the underlying biology of the disease rather than simply treating its clinical manifestations. However, these findings require validation before they can influence clinical care,” he added.

Preeclampsia affects an estimated 3%-8% of pregnancies worldwide and remains a major cause of maternal and fetal illness. Although clinicians can usually manage complications, delivery remains the only definitive treatment.

Mapping the Fetal-Maternal Interface

To better understand the underlying mechanisms, researchers from University College London (UCL) and University College London Hospitals analyzed tissue samples collected from 20 pregnancies, including 10 complicated by severe preeclampsia and 10 gestational age-matched control participants. Pregnancies ranged from 25 to 37 weeks’ gestation and included both early- (≤ 34 weeks) and later-onset disease.

Using single-cell RNA sequencing and spatial transcriptomics, techniques that show which genes are active in individual cells and where those cells are located within tissues, the researchers mapped nearly 293,000 cells across the fetal-maternal interface and identified 27 distinct cell populations.

“By studying all the tissues at the fetal-maternal interface, we could see how cells behaved in different compartments, how they communicated with one another, and whether the molecular signatures were shared across tissues or unique to a particular location,” Sara Hillman, MB ChB, PhD, University College London Hospitals NHS Foundation Trust and UCL in London, England, told Medscape Medical News.

Al-Khan said the study’s major strength was its use of single-cell and spatial transcriptomic approaches, which allowed researchers to examine individual cell populations rather than whole tissue.

Placenta Under Stress

Some of the earliest changes were seen in the placenta, particularly in early-onset disease. Extravillous trophoblasts, the fetal cells that normally invade the uterus and remodel spiral arteries that improve blood flow to the placenta, were reduced and failed to reach deeper uterine layers, which likely impaired placental blood flow.

Other placental trophoblasts, the fetal cells that form the placenta and support oxygen and nutrient exchange, showed molecular signs of hypoxia, altered metabolism, and tissue injury, indicating that the placenta was under stress.

The placenta also showed signs of angiogenic imbalance, a hallmark of preeclampsia in which signals controlling blood vessel growth become disrupted. In particular, expression of FLT1, a gene associated with abnormal regulation of blood vessel development, was increased, especially in early-onset disease.

Metabolic changes were observed in both early- and later-onset disease, including increased expression of leptin, a hormone involved in energy regulation. Researchers also identified changes in fibrosis-related genes, suggesting that the placenta was undergoing a stress-related injury response.

“We expected to see well-recognized features such as placental hypoxia,” Hillman said. “What surprised us were several pathways that emerged in severe preeclampsia, particularly leptin signaling and mitochondrial dysfunction across the fetal-maternal interface.”

Changes Beyond the Placenta

Beyond the placenta, the researchers identified widespread changes in maternal immune cells. Immune cells in tissues surrounding the placenta showed signs of mitochondrial dysfunction and oxidative stress, particularly in early-onset disease.

Researchers also identified increased type I interferon signaling in monocytes and macrophages. This immune pathway, best known for its role in antiviral defense, was also detectable in maternal blood. “This interferon signature we identified in blood needs further exploration but potentially adds a new marker in the detection of severe preeclampsia,” Hillman said.

Macrophages, which help regulate inflammation and clear damaged tissue, also behaved differently depending on their location. Those within placental tissue showed gene activity linked to cell death and fibrosis, while those in the uterine muscle and fetal membranes displayed a more anti-inflammatory, tissue-repair profile.

The findings also suggest that leptin produced by placental trophoblasts may signal to maternal immune and endothelial cells, providing one possible mechanism linking placental dysfunction with the inflammation and vascular abnormalities seen in severe preeclampsia.

What Comes Next

Although some of these are early findings, they provide a more complete picture of how severe preeclampsia develops and identify biological pathways that may be explored for future therapies.

However, Al-Khan cautioned that the study included only 20 pregnancies, lacked external validation, and did not account for treatments commonly given to women with severe preeclampsia, including corticosteroids, antihypertensive medications, and magnesium sulfate, all of which could influence gene expression.

“We need larger, multicenter studies before these findings can be translated into clinical practice,” he said.

Hillman said the team’s next priorities are to test these pathways in functional models and determine whether existing therapies can be repurposed to reverse the disease process.

“If successful, we may be able to identify a new, already existing, treatment for severe cases where the highest burden and mortality lies for this extremely challenging condition of pregnancy,” she said.

The research was funded by the Medical Research Council, the National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, and the UCL Hospitals Biomedical Research Centre. The authors reported no additional relevant financial disclosures.