A Cambridge study found low levels of a protein called isthmin-2 early in pregnancy strongly predict pre-eclampsia and fetal growth restriction risk.
Pre-eclampsia affects around one in 20 pregnancies worldwide and is a leading cause of complications for mothers and babies. A related condition, fetal growth restriction, is a leading cause of stillbirth. Both have long been difficult to predict early enough to act. A new discovery from the University of Cambridge could change that.
Cambridge scientists have identified a protein, isthmin-2, that appears to act as an early warning signal for both conditions, detectable through a simple blood test taken around week 12 of pregnancy. The findings, published in Nature Medicine, also help explain the underlying biological failure behind both disorders.
How Common Are These Complications?
Fetal growth restriction, where a baby does not reach its expected growth potential in the womb, affects roughly 3% to 10% of pregnancies in high-income countries and up to one in five pregnancies globally. Both conditions are known to be linked to problems with the placenta failing to develop properly in early pregnancy.
Why the Placenta Sometimes Fails to “Invade” the Womb
Normal pregnancy depends on specialised placental cells, called extravillous trophoblast cells, invading the mother’s womb to establish a healthy blood supply.
Professor Gordon Smith, Head of Cambridge’s Department of Obstetrics and Gynaecology, explained why that process matters so much: “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 that invasion fails, the placenta and fetus are starved of nutrients and oxygen, leading to pre-eclampsia and fetal growth restriction. Until now, exactly why this invasion fails in some pregnancies has been unclear.
Finding the Warning Sign
To investigate, Professor Smith and colleagues from Cambridge’s Department of Obstetrics and Gynaecology and The Loke Centre for Trophoblast Research analysed blood serum samples taken from pregnant women around week 12, drawn from the Pregnancy Outcome Prediction Study at the Rosie Hospital. They looked back at which women went on to develop pre-eclampsia or fetal growth restriction, searching for early biological “red flags.”
Low circulating levels of isthmin-2 turned out to be the strongest indicator that a pregnancy would go on to face one of these two conditions. The protein and its associated genetic instructions are produced almost exclusively in the placenta, concentrated in exactly the trophoblast cells responsible for womb invasion.
Confirming the Protein Actually Causes the Problem
Finding a correlation isn’t the same as proving cause, so the team used a laboratory technique to switch off or sharply reduce isthmin-2 production in human trophoblast stem cells. The cells still survived and grew normally without the protein, but they failed to develop into the invasive cells needed to establish blood flow.
In 3D “mini-placenta” models called placental organoids, cells lacking the protein stopped spreading into the surrounding material meant to mimic the uterus. In a striking reversal, when human kidney cells that don’t normally produce isthmin-2 were engineered to make it, those cells became more invasive too.
Professor Smith, who also treats patients as a consultant in maternal and fetal medicine at The Rosie, said the implications for care are significant: “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 isthmin-2 in the placenta,” he added.
He added that the same discovery might have another use: blocking the protein could potentially help avoid the need for surgery in cases where the placenta implants in the wrong location, such as ectopic pregnancies or caesarean scar pregnancies.
What This Could Mean for Pregnancy Care
Professor Steve Charnock-Jones, also from Cambridge’s Department of Obstetrics and Gynaecology, framed the stakes in global terms: “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,” he said.
The researchers identified the protein using a study group of more than 200 women who went on to develop pre-eclampsia or fetal growth restriction, compared against more than 200 women with normal pregnancies. The findings were then validated in a separate group of Swedish pregnant women, including more than 100 affected cases and 200 controls.
The research was largely funded by Wellcome Leap, with additional support from the National Institute for Health and Care Research Biomedical Research Centre Cambridge and the Medical Research Council.