Work being carried out at the Irish Centre for Foetal and Neonatal Translational Research (Infant) in Cork could result in the world's first accurate predictive screening test for pre-eclampsia. At present, more than half a million infant deaths worldwide are attributed to the disease each year. It affects up to 5 per cent of first-time mothers and is a leading cause of maternal death. Yet despite being known of for thousands of years there are no effective treatments for it.
"Pre-eclampsia is known as the disease of theories," says Infant director Prof Louise Kenny. "There are literally hundreds and hundreds of theories out there in relation to it. It was described by Hippocrates almost 2,500 years ago; Japanese woodcuts hundreds of years old show women having seizures as a result of it; and a member of Rembrandt's school painted a picture depicting a woman with pre-eclampsia attending a doctor in 1732. It has been known about throughout history but we haven't been able to do anything about it."
The problem is that by the time a mother-to-be develops pre-eclampsia at about 37 weeks it is already far too late to do anything about it. What is needed is a test that will predict at a much earlier stage of pregnancy which women will develop it. “Success is developing a test will trigger the development of new therapies for it,” Prof Kenny notes. “One of the things holding us back has been that we don’t know what to study in terms of looking for a treatment.”
Kenny’s search for an accurate predictive test began some years ago when she was working as a post-doctoral researcher at the same time as practising as a doctor and took her into the field of metabolomics.
Metabolomics compares the relative differences between biological samples based on their metabolite profiles. Metabolites are the products of metabolic processes and can indicate the presence of disease and other conditions.
Kenny says it is rather like the study of the genome but much more dynamic. “Genomics is the science of looking at the genome while proteomics is the science of looking at gene messages. Metabolomics looks at the metabolome which is made up of the products of the metabolism. But the genome is very stable and we are born and die with the same set of genes. The metabolome changes hourly and reacts to what we eat among many other things such as our disease status; it is very dynamic.”
She decided to try to identify specific metabolites which would be predictive of pre-eclampsia. But the problem was finding what to look for among millions of molecules. And this is where metabolomics differs from other research approaches – you don’t necessarily have to know what you’re looking for when you start out.
“Metabolomics is pretty much the Antichrist of the scientific method,” Kenny says. “It is a hypothesis-free approach. The research leads to the hypotheses.”
What she and her team did was recruit 7,000 expectant mothers across six European countries and take blood samples from each of them at 15 weeks. It was then a case of waiting to see which of the women developed pre-eclampsia and analysing their samples to see what they had in common and how they differed from those of the women that didn’t develop the disease.
“A little over 200 of the expectant mums developed pre-eclampsia and we were able to look at the samples we had in the freezer. We found more than 400 biomarkers which were statistically deranged. It didn’t matter what the differences were in the women concerned – the biomarkers were the same if they had developed pre-eclampsia. We ran the tests again after that to make sure the results were correct.”
Having found that she was on the right track in the search for a screening test it was a question of deciding on the next move. This has involved the development of a prototype test with funding support from the EU and ongoing research at the Science Foundation Ireland-funded Infant research centre which was established late last year.
“We have developed an algorithm to analyse a blood sample which is taken at 15 weeks. This takes into account the woman’s age, her blood pressure, her body mass index, and the presence and levels of certain metabolites to predict their chances of developing pre-eclampsia later on. We are running a clinical trial of the test involving 5,000 first-time mums in six EU countries at the moment and we should have the results of that in about 18 months’ time. Once we have those results it will take a further six months or so to go through the data and we will know then if the test works or not.”
Success could bring huge benefits to women at risk of pre-eclampsia. “There is already good research evidence to indicate that women who take aspirin from before the 16th week of pregnancy can significantly reduce their risk of developing pre-eclampsia,” Kenny points out. “However, in the post-thalidomide-era pregnant women are naturally very reluctant to take any drugs, particularly if their chances of developing pre-eclampsia are between 3 per cent and 5 per cent. I think there would be a much higher chance of them taking a drug if they were told their chances were 30 per cent or higher.”
The test would also enable new avenues of research into treatments for the disease with huge potential benefits for mothers, babies, and the health system. “One in five babies in neonatal intensive care units at the moment is there as a result of pre-eclampsia, foetal growth restriction and spontaneous preterm birth.
“Having a test like this will enable us to tell a mother at an early stage that she can go home and relax and enjoy her pregnancy and to help the small number who are at risk of pre-eclampsia. And because there are no effective treatments at the moment it has been estimated that the cost of caring for mothers up until birth is $45 billion (€32.6bn) a year in the developed world alone.”
These benefits mean that the test could be a real game-changer. “We will be releasing the test into an absolute vacuum where there is an overwhelming need for it. It can open up new avenues of research and we may finally be able to develop effective treatments for this disease.”
