Researchers rank 11 preeclampsia therapies as top candidates for further development

A global review of the preclinical pipeline highlights 11 leading candidates, while exposing major gaps in evidence quality, disease models, and therapeutic diversity.

Study: The global preclinical research and development landscape for pre-eclampsia and eclampsia therapies. Image Credit: Dasha Petrenko / Shutterstock

In a recent article in press in the journal Communications Medicine, researchers identified and ranked potential prevention and treatment candidates for preeclampsia and eclampsia in the preclinical pipeline for further research.

Among the candidates, 11 were ranked as high-potential, while 32 candidates across the broader pipeline were proposed to reduce soluble fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, or to influence pathways regulating its release. Since many candidates relied on the same biological pathway and animal models cannot fully replicate the anatomical and physiological complexity of human pregnancy, further preclinical and, where justified, clinical research is required. High-quality and well-controlled preclinical studies, followed where appropriate by clinical trials, could strengthen the evidence for their safety and efficacy and support the development of new therapies for preeclampsia and eclampsia, which are among the most serious hypertensive complications of pregnancy.

Preeclampsia affects approximately 4 million women each year across the globe. The condition is a hypertensive disorder of pregnancy that can involve maternal organ dysfunction and impaired placental function and can lead to adverse pregnancy outcomes, including maternal mortality, stillbirth, and newborn death. Nevertheless, only a few medications are available for its prevention and management. Moreover, the authors note that all were originally repurposed from treatments developed for non-pregnant individuals.

To date, delivery of the baby and placenta remains the only definitive cure. Scientists are therefore actively trying to identify new drug targets and design strategies to improve preeclampsia care. Several candidates have shown promising preclinical findings. If validated through stronger preclinical evidence and subsequent clinical research, they could expand treatment options and reduce the global burden of the disease.

About the Study

In the present study, researchers analyzed and ranked 83 potential candidates in the preclinical maternal health drug development pipeline spanning 2000 to 2025 for preeclampsia and eclampsia. The study excluded candidates that lacked primary or publicly available preclinical data, were reported only in abstracts, or were associated with serious adverse effects, including fetal loss or reabsorption. New chemical entities that had progressed to clinical development, with planned or incomplete trials, were described separately rather than ranked using the matrix.

The team then assessed these candidates across the domains of evidence quality, product development stage, and implementability. The assessment considered the needs of women during pregnancy, healthcare providers, and health systems in low- and middle-income countries (LMICs). They also identified the molecular targets and underlying mechanisms of these candidates.

The researchers developed a prioritization matrix drawing on existing assessment tools. They assigned numerical values to the answer options for all the matrix questions based on their importance and summed these values to rank potential candidates. Questions related to evidence quality and safety carried greater weight. Two reviewers independently scored each candidate, with disagreements resolved by a third reviewer. Maternal health experts from the Accelerating Innovation for Mothers (AIM) team reviewed and refined the matrix before ranking the candidates.

Evidence quality questions were informed by criteria from the Quality Assessment Tool for In Vitro Studies (QUIN) and the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) frameworks. The Technology Readiness Levels (TRL) tool evaluated product maturity. The researchers used selected Target Product Profile criteria to assess implementability.

Results

Among 83 candidates analyzed, 11 were identified as high-potential, 63 as medium-potential, and 9 as low-potential. Only 26 candidates were considered active, while 57 had no published activity since 2023. The 83 candidates included dietary supplements, biologics, and drugs for the prevention or treatment of preeclampsia. Overall, 55.4% could be administered orally, while 51.8% required cold-chain transport and storage. Other candidates used injected routes, including intravenous or subcutaneous administration.

The high-potential candidates included repurposed drugs, such as cyclosporin A, gefitinib, azathioprine, and sufentanil. Other high-potential candidates included the repurposed biologic etanercept, repurposed dietary supplements including puerarin, mangiferin, and L-ergothioneine, and new chemical or biological entities such as rhPlGF, MZe786, and SynB1-ELP-p50i. Several of these candidates had received limited attention in previous reviews. However, nearly half of the identified candidates were novel chemical or biologic compounds, with the entire pipeline spanning 37 distinct molecular targets. These findings indicate that the search for new therapies extends beyond repurposing existing drugs, with several novel candidates offering additional avenues for investigation.

Interestingly, among the preclinical candidates, 32 candidates were proposed to reduce soluble fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, or influence pathways that regulate its release. Among the high-potential candidates, only gefitinib was identified as having a documented safety concern during pregnancy because it also inhibits the epidermal growth factor receptor (EGFR), which plays an essential role in placental development. No adverse effects were observed in the gefitinib study included in the analysis, although the absence of identified concerns for the other candidates does not establish their safety during pregnancy. The researchers also noted that most preclinical studies carried a moderate risk of bias, suggesting that the current evidence should be interpreted with caution.

Bullseye diagram of preclinical candidates for pre-eclampsia. Each ring represents a different technology readiness level (TRL), with the outermost ring at TRL 3 and the innermost at TRL 5. The diagram is split into the different target binding sites for each candidate. The developer of each candidate is classified as an academic (red), pharmaceutical (yellow), or academic/pharmaceutical (blue) enterprise. Asterisks denote a binding target related to the sFlt-1 signaling pathway.

Conclusions

The findings identified several promising preclinical candidates for preventing or managing preeclampsia and eclampsia. The researchers suggest that the highest-ranked candidates should be prioritized for further investigation. However, limited diversity in therapeutic targets and the use of inappropriate or insufficiently representative animal models remain key barriers to their development.

Looking ahead, researchers will need to overcome regulatory hurdles in preeclampsia drug development, including limited industry engagement, widespread off-label medication use, and reluctance to conduct clinical trials among pregnant women.

They will also need to use better-matched animal models of preeclampsia or organ-on-a-chip systems that can more accurately model disease pathophysiology and drug pharmacokinetics to develop more targeted treatments. Because sFlt-1-mediated disease may represent only a subset of preeclampsia, future research should also investigate a broader range of therapeutic targets, particularly for late-onset or term disease.

Development should also better reflect the needs of LMICs, where most preeclampsia-related illness and mortality occur. Combined with multidisciplinary collaboration, these efforts could accelerate the progression of suitable candidates toward clinical trials and help bring effective therapies into routine care, ultimately improving outcomes for mothers and babies.