Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction
Preeclampsia and fetal growth restriction (FGR) are major causes of global morbidity and mortality. Both conditions are associated with impaired invasion of the uterus by extravillous trophoblast (EVT). We performed proteomics in maternal serum obtained at ~12 weeks 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.
Authors
- Emma Cook (ORCID: https://orcid.org/0000-0002-6142-4443)
- Peter Conner (ORCID: https://orcid.org/0000-0002-9246-3277)
- Ylva Carlsson (ORCID: https://orcid.org/0000-0002-1414-7279)
- Anna Sandström (ORCID: https://orcid.org/0000-0003-2879-4271)
- D. Stephen Charnock‐Jones (ORCID: https://orcid.org/0000-0002-2936-4890)
- Irving L.M.H. Aye (ORCID: https://orcid.org/0000-0003-3400-5005)
- Marius Kublickas (ORCID: https://orcid.org/0000-0002-1875-0745)
- Ulla Sovio (ORCID: https://orcid.org/0000-0002-0799-1105)
- Stephanie N. Rogers (ORCID: https://orcid.org/0000-0002-4563-1899)
- Alice Zancanaro (ORCID: https://orcid.org/0000-0002-8362-6572)
- Susanne Lager (ORCID: https://orcid.org/0000-0003-3556-065X)
- Sungsam Gong (ORCID: https://orcid.org/0000-0001-5796-4423)
- Paul Kirk (ORCID: https://orcid.org/0000-0002-5931-7489)
- Jacqueline Güttler (ORCID: https://orcid.org/0000-0002-8141-5712)
- Giulia Avellino (ORCID: https://orcid.org/0000-0002-7413-0217)
- Gordon C. S. Smith (ORCID: https://orcid.org/0000-0003-2124-0997)
- Ruoyu Miao
- Stefan R. Hansson (8129772)
- Anders Larsson
- Lina Bergman
- Peter Lindgren
- Anna-Karin Wikström
- Ana Toribio
Institutions
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Uppsala University Hospital (SE)
- Lund University (SE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Stellenbosch University (ZA)
- Sahlgrenska University Hospital (SE)
- Karolinska Institutet (SE)
- MRC Biostatistics Unit (GB)
- Skåne University Hospital (SE)
- NIHR Cambridge Biomedical Research Centre (GB)
- The Loke Centre for Trophoblast Research (GB)
- University of Gothenburg (SE)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Medicine
- Published
- 2026-09-01
- DOI
- https://doi.org/10.1038/s41591-026-04573-6
- Primary Topic
- Pregnancy and preeclampsia studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- UK Research and Innovation
- National Institute for Health and Care Research
- Department of Health and Social Care
- Vetenskapsrådet
- Uppsala Universitet
- Svenska Läkaresällskapet
- Science for Life Laboratory
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre