Low circulating levels of isthmin-2 in early pregnancy were associated with later complications and outperformed existing predictive markers, researchers report.
Researchers at the University of Cambridge have identified a key placental protein that could serve as a predictive biomarker for pre-eclampsia and fetal growth restriction, according to a study published in Nature Medicine.
Pre-eclampsia affects approximately one in 20 pregnancies worldwide, serving as a primary driver of maternal and neonatal morbidity and mortality, according to the University of Cambridge. Fetal growth restriction affects between 3% and 10% of pregnancies in high-income countries and up to 20% of pregnancies globally, representing a leading cause of stillbirth and neonatal complications.
Both conditions are linked to early placental dysfunction, specifically when specialized placental cells known as extravillous trophoblasts fail to adequately invade the uterine lining and establish normal maternal blood supply, the authors note.
“As part of normal development, the placenta invades into the tissues of the mother’s womb. Of all mammals, humans have the deepest placental invasion, which reflects the massive demands of oxygen and nutrients required to manufacture the most complex machine ever known, the human brain,” says Gordon Smith, PhD, head of the Department of Obstetrics and Gynaecology at the University of Cambridge, in a release. “When this process goes wrong and specialist placental cells fail to adequately invade the uterus, it results in a placenta and fetus that are deprived of nutrients and oxygen, leading to pre-eclampsia and fetal growth restriction. But until now, the reason for this failed invasion has been obscure.”
Analyzing First-Trimester Serum Biomarkers
To isolate the biological mechanisms of failed invasion, researchers from the Department of Obstetrics and Gynaecology and The Loke Centre for Trophoblast Research at the University of Cambridge retrospectively evaluated serum samples collected around week 12 of pregnancy from participants in the Pregnancy Outcome Prediction Study at the Rosie Hospital.
The investigation revealed that low maternal circulating levels of isthmin-2 (ISM2) at approximately three months of gestation served as the strongest indicator of subsequent pre-eclampsia or fetal growth restriction. ISM2 and its messenger RNA are produced almost exclusively in the placenta, showing highest expression levels within extravillous trophoblasts.
The research team evaluated more than 200 women who later developed pre-eclampsia or fetal growth restriction alongside more than 200 women with uncomplicated pregnancies. The diagnostic findings were subsequently validated in an independent Swedish cohort comprising more than 100 cases and 200 control subjects.
Mechanisms in Cellular and Organoid Models
To evaluate causality, investigators suppressed ISM2 expression in human trophoblast stem cells. While the stem cells remained viable and proliferated normally, they failed to differentiate into invasive extravillous trophoblasts. In three-dimensional placental organoids mimicking uterine tissue, cells lacking ISM2 ceased spreading into the surrounding matrix. Conversely, inducing ISM2 expression in non-expressing human kidney cells increased cellular invasiveness in culture.
“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 those pregnancies at greatest risk,” says Smith, who is also a consultant in maternal and fetal medicine at The Rosie, in a release. “It also gives us a potential way to prevent these conditions from happening, if we can find a way to stimulate production of IMS2 in the placenta. Not only that, but blocking it might prevent the need for surgery for complications where the placenta has implanted in the wrong place, such as ectopic and caesarean scar pregnancies.”
“Every pregnancy carries with it a risk of pre-eclampsia and fetal restricted growth, and this is even more so the case in low- and middle-income countries,” says Steve Charnock-Jones, PhD, professor in the Department of Obstetrics and Gynaecology at the University of Cambridge, in a release. “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.”
The study was supported by Wellcome Leap, the National Institute for Health and Care Research Biomedical Research Centre: Cambridge, and the Medical Research Council.
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