Cambridge scientists have identified a key protein that could act as a predictor for pre-eclampsia and fetal growth restriction, two of the major causes of stillbirth and of sickness among mothers and newborns.
The discovery helps explain why placental cells fail to properly 'invade' the uterus in these two related conditions and could lead to the development of tests to help identify those at greatest risk and new treatments for the conditions.
Pre-eclampsia affects around one in 20 pregnancies worldwide and is a leading cause of maternal and fetal health complications, contributing significantly to mortality rates of mothers and babies worldwide.
Fetal growth restriction, where a baby does not reach its biological growth potential in the womb, affects roughly 3% to 10% of pregnancies in high-income countries and up to one in five pregnancies globally. It is a leading cause of complications in the womb and in newborns, including stillbirth.
Both of these conditions are known to be linked to problems with the placenta not developing properly early in pregnancy, in particular a failure of specialised placental cells known as the extravillous trophoblast (EVT) to invade the mother's womb and establish a healthy blood supply.
Professor Gordon Smith, Head of the Department of Obstetrics and Gynaecology, University of Cambridge, said: "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.
"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."
To better understand this process, Professor Smith and colleagues from the Department of Obstetrics and Gynaecology and The Loke Centre for Trophoblast Research at the University of Cambridge analysed serum samples taken from pregnant women at around week 12 of their pregnancies who had been recruited to the Pregnancy Outcome Prediction Study (POPS) at the Rosie Hospital, part of Cambridge University Hospitals NHS Foundation Trust.
The researchers looked retrospectively for 'red flags' present in those women whose pregnancies went on to be affected by pre-eclampsia or fetal growth restriction. Their findings are published today in Nature Medicine.
The researchers found that low circulating levels of a protein known as isthmin-2 (ISM2) around three months into the pregnancy was the strongest indicator that the pregnancy would go on to face problems with pre-eclampsia or fetal growth restriction.
ISM2 and its associated mRNA – a molecule that carries instructions from DNA to the part of the cell that makes proteins – are produced almost exclusively in the placenta and, within the placenta, ISM2 mRNA is found in greatest abundance in EVTs.
To test whether this association was likely to be a cause of the problems, the team used a laboratory technique to switch off or greatly reduce production of ISM2 in human trophoblast stem cells. The trophoblast is the outer layer to the early-stage embryo, and these stem cells can normally develop into the outer layer of the placenta. However, although the cells still survived and grew normally in the absence of ISM2, they failed to turn into invasive EVT cells.
In 3D cellular models known as placental organoids – essentially, 'mini-placentas' – the cells stopped spreading into surrounding material, which was mimicking the uterus. In other words, without ISM2, the cells lose their ability to become the type of cells that burrow into the womb and establish blood flow.
Remarkably, when human kidney cells – which do not normally make the protein – were forced to make ISM2, they became more invasive in cell culture.
Professor Smith, who is also a consultant in maternal and fetal medicine at The Rosie, added: "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.
"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."
Professor Steve Charnock-Jones, from the Department of Obstetrics and Gynaecology, said: "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. 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 researchers identified the protein by studying a sample of more than 200 women who subsequently experienced pre-eclampsia and/or fetal growth restriction and more than 200 women with normal pregnancies. The findings were validated by studying samples from Swedish pregnant women, including more than 100 cases and 200 controls.
The research was largely funded by Wellcome Leap, with additional support by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Cambridge and the Medical Research Council.
Reference
Miao, R, Gong, S, Sovio, U & Aye, ILMH et al. Isthmin-2 is essential for extravillous trophoblast invasion and is a first trimester predictor of preeclampsia and fetal growth restriction. Nat Med; 1 Sept 2026; DOI: 10.1038/s41591-026-04573-6
