Cambridge Scientists Unlock Key Protein That Could Predict and Prevent Devastating Pregnancy Complications

In a breakthrough that could save the lives of millions of mothers and babies, researchers at the University of Cambridge have identified a crucial protein that acts as an early warning system for pre-eclampsia and fetal growth restriction (FGR), two of the leading global causes of stillbirth.

The study, published today in the journal Nature Medicine, reveals that low levels of a protein known as isthmin-2 (ISM2) in the mother’s blood around the 12-week mark of pregnancy are the strongest indicator yet that the pregnancy will face severe complications.

The “Invasion” That Goes Wrong

For a baby to thrive, the placenta must aggressively invade the lining of the mother’s womb to establish a rich blood supply that delivers oxygen and nutrients. Remarkably, humans have the deepest placental invasion of any mammal, a necessity driven by the colossal energy demands of developing the human brain.

However, in pregnancies affected by pre-eclampsia (affecting 1 in 20 women worldwide) and FGR (affecting up to 1 in 5 pregnancies globally), this process fails. Specialized placental cells, called extravillous trophoblasts (EVTs), fail to burrow deep enough, starving the fetus of vital resources and endangering the mother.

Until now, the biological “switch” responsible for this failure remained a mystery.

A Powerful Predictor

Researchers led by Professor Gordon Smith, Head of Obstetrics and Gynaecology at Cambridge, analyzed serum samples taken from pregnant women at around week 12, sourced from the Pregnancy Outcome Prediction Study at the Rosie Hospital.

By comparing women who went on to have healthy pregnancies with those who developed complications, the team made a striking discovery: low circulating levels of ISM2 were the clearest red flag for future illness.

To confirm the link, the team used laboratory techniques to switch off ISM2 production in human trophoblast stem cells. Although the cells survived, they lost their ability to transform into the invasive EVT cells required for a healthy placenta. In 3D “mini-placenta” models (organoids), the cells stopped spreading into the surrounding material mimicking the uterus. Conversely, when non-invasive kidney cells were forced to produce ISM2, they suddenly became highly invasive.

Hope for New Tests and Treatments

The implications of this discovery are twofold.

Firstly, it offers a path to better screening. Professor Smith noted that maternal levels of ISM2 are “much better at predicting complications than existing tests,” which could allow doctors to identify at-risk pregnancies far earlier and monitor them more closely.

Secondly, it opens the door to prevention. “It 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,” Professor Smith stated.

Adding a surprising twist, the researchers noted that blocking ISM2 could one day be used as a non-surgical treatment for dangerous complications where the placenta implants in the wrong place, such as ectopic or caesarean scar pregnancies.

A Global Impact

The findings were validated by cross-referencing them with a separate cohort of pregnant women in Sweden. The research was largely funded by Wellcome Leap, with additional support from the NIHR and the Medical Research Council.

Professor Steve Charnock-Jones, co-author of the study, emphasized the worldwide stakes: “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 team now hopes to develop a clinical test based on ISM2 levels, while simultaneously searching for drugs that can safely boost the protein in the placenta to ensure every baby gets the start in life it deserves.