Isthmin-2 Predicts Preeclampsia and Fetal Growth Restriction

Low maternal serum isthmin-2 emerged as a first-trimester predictor of preeclampsia and fetal growth restriction in a prospective proteomics study published in Nature Medicine.

Investigators analyzed maternal serum obtained at approximately 12 weeks of gestation in the Pregnancy Outcome Prediction Study. Among 2,904 measured proteins, isthmin-2 was the strongest overall signal associated with preeclampsia, fetal growth restriction, or their composite. The association was subsequently validated in 2 independent pregnancy cohorts.

In the discovery cohort, the 12-week analysis included 242 control samples, 72 cases of preeclampsia alone, 126 cases of fetal growth restriction alone, and 25 cases in which both outcomes occurred. Isthmin-2 ranked first for 3 outcomes and second for the fourth, producing a rank sum of 5; the next-highest protein had a rank sum of 88.

Placental analyses showed that isthmin-2 protein and messenger RNA were produced almost exclusively in the placenta, with messenger RNA highly enriched in extravillous trophoblasts. Knocking down isthmin-2 in cultured human trophoblast stem cells inhibited invasion, while expressing it in a cell line without endogenous isthmin-2 promoted migration.

The findings link a reproducible early serum signal to a plausible placental mechanism. However, the analyses focused on northern European cohorts, and the investigators said further studies should assess the association in other populations.

Source: Miao R, Gong S, Sovio U, et al. Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction. Nat Med. Published online September 1, 2026. doi:10.1038/s41591-026-04573-6