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Both conditions are associated with impaired invasion of the uterus by extravillous trophoblast (EVT). We performed proteomics in maternal serum obtained at ~12\u2009weeks of gestational age in a prospective pregnancy cohort (Pregnancy Outcome Prediction Study). Here we show that low maternal serum isthmin-2 (ISM2) was the strongest protein signal (out of 2,904) in the first trimester of pregnancy for preeclampsia or FGR. We validated the association in two independent cohorts (Pregnancy Outcome Prediction Study 2 and Improving Maternal Pregnancy And Child ouTcomes study). ISM2 protein and mRNA are almost exclusively produced in the placenta, and, within the placenta, ISM2 mRNA is highly enriched in EVT. Knocking down ISM2 in cultured human trophoblast stem cells profoundly inhibited EVT invasion. Conversely, expressing ISM2 in a cell line lacking endogenous ISM2 (HEK293 cells) promoted migration. We conclude that ISM2 may be causally involved in the early pathophysiology of failed trophoblast invasion and that the protein and its associated pathways are potential targets for the prediction and prevention of preeclampsia and FGR.<\/jats:p>","DOI":"10.1038\/s41591-026-04573-6","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:02:44Z","timestamp":1788253364000},"page":"3351-3358","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-4467","authenticated-orcid":false,"given":"Ruoyu","family":"Miao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5796-4423","authenticated-orcid":false,"given":"Sungsam","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-1105","authenticated-orcid":false,"given":"Ulla","family":"Sovio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3400-5005","authenticated-orcid":false,"given":"Irving L. 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G.C.S.S.\u2019s department has received payment from Roche for a talk given by G.C.S.S. (fetal growth restriction). G.C.S.S. has been a paid consultant to GSK (preterm birth) and has been a member of a Data Monitoring Committee for GSK trials of respiratory syncytial virus vaccination in pregnancy. G.C.S.S. is currently a member of a Data Monitoring Committee for respiratory syncytial virus vaccination in pregnancy (Moderna) and chairs a Data Monitoring Committee for a hyperemesis gravidarum therapeutic trial (NG Biopharmaceuticals). G.C.S.S. and D.S.C.-J. have received nonfinancial support from Illumina. G.C.S.S. and D.S.C.-J. have received support from Pfizer and Sera Prognostics (outside the scope of this work). Cambridge Enterprise (UK) has filed a patent relating to the work described in this paper, with G.C.S.S., D.S.C.-J., P.D.W.K., S.G., R.M., U.S. and I.L.M.H.A. as the named inventors. The patent has been licensed to Medicines360 (San Francisco, USA). G.C.S.S. and D.S.C.-J. are paid consultants to Medicines360. D.S.C.-J. is a paid consultant to GondolaBio. L.B. and A.-K.W. have received reagents for PlGF and\/or sFlt1 from Roche, Perkin Elmer and Thermo Fischer. L.B. has received drugs and placebo for a preeclampsia intervention trial from Merck Damstadt. L.B. consults for DiaMedica and Arraka therapeutics, which are invested in finding new treatments for preeclampsia. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}