Global Review Identifies 11 High-Potential Preclinical Candidates for Preeclampsia, Exposing Gaps in Evidence Quality and Therapeutic Diversity
Key Insights
A global analysis of 83 preclinical candidates for preeclampsia (search) and eclampsia (search) ranked 11 as high-potential for further development, including repurposed drugs like cyclosporin A, gefitinib, and etanercept.
Among the candidates analyzed, 32 were proposed to reduce the anti-angiogenic factor sFlt-1 or influence its regulatory pathways, highlighting a narrow focus on a single biological mechanism.
Most preclinical studies carried a moderate risk of bias, and animal models used cannot fully replicate the anatomical and physiological complexity of human pregnancy.
A comprehensive global review of the preclinical pipeline for preeclampsia (search) and eclampsia (search) has identified 11 high-potential therapeutic candidates while exposing significant gaps in evidence quality, disease models, and therapeutic diversity. The findings, published in Communications Medicine, represent the first systematic analysis and ranking of preclinical candidates for these serious hypertensive disorders of pregnancy.
Preeclampsia (search) affects approximately 4 million women each year globally and can lead to maternal organ dysfunction, impaired placental function, and adverse outcomes including maternal mortality, stillbirth, and newborn death. Despite this burden, only a few medications are available for prevention and management—all of which were originally repurposed from treatments developed for non-pregnant individuals. Delivery of the baby and placenta remains the only definitive cure.
"Surprisingly few medicines are available to prevent or manage pre-eclampsia (search), all of which are repurposed from non-pregnant populations and conditions," the study authors note, underscoring the urgent need for new therapeutic options.
Ranking Methodology and Key Findings
Researchers analyzed 83 candidates in the preclinical maternal health drug development pipeline spanning 2000 to 2025. The team developed a prioritization matrix drawing on existing assessment tools, evaluating candidates across three domains: quality of preclinical evidence, product development stage, and implementability. Questions related to evidence quality and safety carried greater weight, and two reviewers independently scored each candidate with disagreements resolved by a third reviewer.
Among the 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 high-potential candidates included repurposed drugs such as cyclosporin A, gefitinib, azathioprine, and sufentanil, as well as the repurposed biologic etanercept. Repurposed dietary supplements including puerarin, mangiferin, and L-ergothioneine also ranked highly, alongside new chemical or biological entities such as rhPlGF (search), MZe786, and SynB1-ELP-p50i.
Notably, 49.4% of candidates analyzed were new chemical or biological entities, 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," the researchers note.
Narrow Focus on sFlt-1 Pathway
A striking finding was the concentration of candidates around a single biological mechanism. Among the preclinical candidates, 32 were proposed to reduce soluble fms-like tyrosine kinase-1 (search) (sFlt-1), an anti-angiogenic factor, or to influence pathways that regulate its release. The researchers caution that sFlt-1-mediated disease may represent only a subset of preeclampsia (search), and future research should investigate a broader range of therapeutic targets, particularly for late-onset or term disease.
Safety Considerations and Evidence Limitations
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 (search) (EGFR), which plays an essential role in placental development. However, no adverse effects were observed in the gefitinib study included in the analysis. The researchers emphasize that the absence of identified concerns for other candidates does not establish their safety during pregnancy.
The study also revealed that most preclinical studies carried a moderate risk of bias, suggesting that current evidence should be interpreted with caution. Furthermore, animal models used in preclinical research cannot fully replicate the anatomical and physiological complexity of human pregnancy, limiting the translatability of findings.
Practical Considerations and Path Forward
In terms of administration and logistics, 55.4% of candidates could be administered orally, while 51.8% required cold-chain transport and storage—a significant consideration for implementation in low- and middle-income countries (LMICs), where the assessment framework placed particular emphasis.
Looking ahead, the researchers highlight several barriers that must be addressed: limited industry engagement, widespread off-label medication use, reluctance to conduct clinical trials among pregnant women, and the need for better-matched animal models or organ-on-a-chip systems that can more accurately model disease pathophysiology and drug pharmacokinetics.
"High potential candidates should be prioritised for further development, but progress is restricted by current mechanisms of action and animal models," the authors conclude. "Increased investment is essential to advance pre-eclampsia (search) therapies into clinical trials."