Low ISM2 at 12 weeks flags preeclampsia risk in Cambridge Nature Medicine cohort

The team assayed first-trimester sera from the Pregnancy Outcome Prediction Study, identifying ISM2 as the strongest predictor of subsequent disease. Women who developed preeclampsia or fetal growth restriction showed markedly lower ISM2; in vitro, ISM2 knockdown prevented extravillous trophoblast differentiation and invasion in both 2D and 3D placental organoids, while forced ISM2 expression increased invasiveness in non-placental cells.

Preeclampsia occurs in roughly 5% of pregnancies and fetal growth restriction in 3-10% in high-income settings; both stem from shallow placentation. Prior biomarker panels have shown modest discrimination; ISM2’s placenta-specific expression and functional necessity provide a mechanistic anchor absent from earlier candidates such as sFlt-1 or PlGF.

The work integrates observational data with targeted loss- and gain-of-function models, yet remains a single-center discovery cohort. Next steps require prospective validation across diverse populations and assessment of whether ISM2 supplementation can restore invasion in organoid or animal systems before any clinical test or therapy can be considered.