Low levels of a protein called isthmin-2 (ISM2) could be an early warning sign for pregnancy complications such as pre-eclampsia and fetal growth restriction, new research has found. The Cambridge-led team hope the discovery could lead to new predictive tests and treatments.
Pre-eclampsia and fetal growth restriction are major causes of stillbirth and of sickness among mothers and newborns. Pre-eclampsia affects around 1 in 20 pregnancies, while fetal growth restriction – where an unborn child grows more slowly than expected – affects around 1 in 5 pregnancies, particularly in lower-income countries.
The findings are published today in Nature Medicine and are based on analysis of data collected from over 400 women who participated in the pregnancy outcome prediction study (POPS), which ran at the Rosie Hospital, part of Cambridge University Hospitals NHS Foundation Trust (CUH), from 2008 to 2012.
In both pre-eclampsia and fetal growth restriction, the placenta fails to fully develop and connect with the uterus wall. This results in a poorer connection between the mother’s blood and that of the developing fetus.
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.
Professor Gordon Smith, honorary consultant at CUH and Head of the Department of Obstetrics and Gynaecology, University of Cambridge who led the POPS
The new results focused on samples collected from the blood of pregnant women around 12 weeks into pregnancy and compared those that went on to develop pre-eclampsia or fetal growth restriction against those that didn’t.
The researchers found that low levels of ISM2 in the blood at the 12 week stage was the strongest difference between women that experienced complications and those that didn’t.
ISM2 is produced by cells in the placenta and further lab work using human stem cells, showed that reducing ISM2 levels could limit placenta development, providing a likely explanation the role of ISM2 in pre-eclampsia and fetal growth restriction.
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 Smith
The findings were validated by studying samples from a separate group of pregnant women in Sweden, including more than 100 cases of pre-eclampsia or fetal growth restriction and 200 unaffected pregnancies.
The research was primarily funded by Wellcome Leap, with additional support from the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Cambridge and the Medical Research Council.
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 a major difference to pregnancy outcomes, protecting the health and lives of millions of mothers and their babies every year.
Professor Steve Charnock-Jones, from the Department of Obstetrics and Gynaecology, University of Cambridge