New Blood Biomarker Predicts May Predict Preeclampsia and Fetal Growth Restriction

Preeclampsia and fetal growth restriction are major drivers of stillbirth and serious maternal morbidity, yet clinicians still lack reliable early predictors to guide targeted surveillance. Both conditions often stem from impaired placental development, particularly inadequate invasion of the uterus by specialized trophoblast cells. New findings show that a placenta-derived protein measured early in pregnancy may help predict these outcomes while also clarifying mechanisms of trophoblast invasion.

University of Cambridge researchers identified the circulating protein isthmin-2 (ISM2) as a candidate first-trimester biomarker for preeclampsia and fetal growth restriction. ISM2 and its messenger RNA (mRNA) are produced almost exclusively by the placenta, with highest expression in extravillous trophoblasts (EVTs), the cells that invade the uterine wall to establish maternal-fetal blood flow. In maternal serum collected around 12 weeks’ gestation, low circulating ISM2 was the strongest indicator that a pregnancy would later be complicated by either condition.

Image: Findings show that low circulating ISM2 around 12 weeks gestation was the strongest indicator of later pregnancy complications (Image Credit: Adobe Stock)

Mechanistic studies supported a functional role for ISM2 in extravillous trophoblast (EVT) biology. When investigators suppressed ISM2 in human trophoblast stem cells, the cells survived and proliferated but failed to differentiate into invasive EVTs. In three-dimensional placental organoid models that mimic uterine interactions, ISM2 deficiency reduced cellular spread into the surrounding matrix. Conversely, ectopic ISM2 expression made human kidney cells more invasive in culture, further linking the protein to invasion capacity.

The analysis used samples from the Pregnancy Outcome Prediction Study (POPS) at the Rosie Hospital, part of Cambridge University Hospitals NHS Foundation Trust, including serum collected around week 12 of pregnancy. Researchers examined early “red flags” in women whose pregnancies later developed preeclampsia or fetal growth restriction. More than 200 such cases and more than 200 uncomplicated pregnancies were assessed, with validation in a Swedish cohort that included more than 100 cases and 200 controls. 

The study was published on September 1, 2026, in Nature Medicine and involved the University of Cambridge Department of Obstetrics and Gynecology and the Loke Centre for Trophoblast Research.

“This has major implications for care in pregnancy. Early-pregnancy maternal levels of isthmin-2 are much better at predicting complications than existing tests, so it could enable us to develop better ways of identifying pregnancies at greatest risk. It also gives us a potential way to prevent these conditions from happening, if we can find a way to stimulate production of ISM2 in the placenta. Not only that, but blocking it might prevent the need for surgery for complications in which the placenta has implanted in the wrong place, such as ectopic and Cesarean scar pregnancies,” said Gordon Smith, head of the Department of Obstetrics and Gynecology at the University of Cambridge.

“Every pregnancy carries with it a risk of preeclampsia and fetal growth restriction, and this is even more the case in low- and middle-income countries. Now that we know what goes wrong, we may be in a better position to make a major difference to pregnancy outcomes, protecting the health and lives of millions of mothers and their babies every year,” added Steve Charnock-Jones, from the Department of Obstetrics and Gynecology, University of Cambridge.

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