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Major complications in late pregnancy are the leading cause of illness and death in mothers and infants. But until recently, investment and research into perinatal complications for this cohort was severely lacking, both in Ireland and internationally.
Pre-eclampsia is a complication of late pregnancy and causes 70,000 deaths in women and over 500,000 infant deaths worldwide annually. But what if a simple, predictive blood test for pregnancy complications like pre-eclampsia could be developed, saving countless lives and revolutionising healthcare for mothers and babies? Such a test could be ready for launch in as little as three years, Prof Louise Kenny, Professor of Obstetrics at University College Cork (UCC), Director of the INFANT Centre — the Irish centre for Foetal and Neonatal Translational Research — and Consultant Obstetrician and Gynaecologist at Cork University Maternity Hospital, tells the Medical Independent (MI).
The need for enhanced maternal care services is evident, not only in developing countries where maternal care services are unsatisfactory in many facilities. In Ireland, there is also growing need for better care and resources.
Neonatal mortality rates increased last year in Ireland, despite huge advances in healthcare and a greater focus on improving maternity services here. According to the Central Statistics Office (CSO), 184 neonatal deaths (infants under four weeks of age) occurred in 2014, representing a neonatal mortality rate of 2.7 deaths per 1,000 live births, an increase of 0.3 per cent on 2013.
Internationally, approximately two million children die annually in the first week of life. Up to two-thirds of deaths in newborns could be prevented if proper healthcare was provided at birth and in the first week of life, figures from the World Health Organisation (WHO) show.
Distressing statistics such as these are the reason Prof Louise Kenny has devoted her career to improving healthcare for mothers and babies.
SCOPE for improvement
A leading figure in pregnancy research in Ireland and internationally, Prof Kenny was recently recognised for her work with the international study SCOPE — screening for endpoints in pregnancy — when one of its research areas was declared the top paper for 2014 in the category of clinical science in Hypertension, the journal of the American Heart Association.
“We were thrilled because it’s quite unusual for pregnancy research to reach that journal anyway and to win an award was obviously very exciting indeed,” Prof Kenny commented.
Using the research findings generated by SCOPE, the paper highlighted that known biomarkers for pre-eclampsia are essentially ineffective. Titled Early Pregnancy Prediction of Pre-eclampsia in Nulliparous Women, Combining Clinical Risk and Biomarkers, the paper provided one of the most thorough investigations to date of all putative biomarkers and clinical risk factors for the development of pre-eclampsia. A total of 75 putative biomarkers of interest were investigated.
‘Every baby counts. Every mother counts. Mothers matter’
“We looked at the market leaders that proposed biomarkers for pre-eclampsia and essentially showed that they’re not particularly good. None alone or in any combination could predict all cases of pre-eclampsia with the clinical utility we needed,” Prof Kenny explained.
The SCOPE project aims to develop screening tests to predict and prevent major complications in late pregnancy. It was launched in 2004 and recruitment was completed last year, with almost 6,000 individuals taking part. Some 1,600 Irish mothers and babies participated, while the remaining participants were from New Zealand, Australia and the UK. To date, there have been 53 publications based on SCOPE, which in 2007 received €1.7 million in funding from the Health Research Board (HRB).
This was the largest grant made to a single project in Ireland at the time and marked the beginning of a series of major investments in maternal research.
A follow-on study from SCOPE, called IMPROVED, is currently underway and aims to develop a clinically robust, predictive blood test for pre-eclampsia.
The study is titled Personalised Medicine for Pregnant Women: Novel Metabolomic and Proteomic Biomarkers to Detect Pre-eclampsia and Improve Outcome (Improved Pregnancy Outcomes by Early Detection) and is funded by FP7 Health, the European Union’s research and innovation funding programme for 2007-2013.
The project commenced in 2012 and will last four years, and is currently underway in Ireland, Sweden, Germany and the Netherlands. It has a budget of €7.8 million and is being co-ordinated by UCC. Some 5,000 women will be recruited over two years and a biobank with clinical metadata will be established to help facilitate pregnancy research across Europe.
Clinical information and blood samples will be taken from pregnant women at 11, 15, 20 and 34 weeks.
The researchers hope to “determine whether prototype predictive assays and algorithms translate to the clinical environment”. If successful, the test could dramatically reduce mortality among mothers and babies and provide massive healthcare cost savings.
Prof Kenny explains: “We’ve been working on our own programme to develop new bespoke biomarkers for pregnancy and we’ve been using a technique called metabolomics, which is a scientific technique that involves mass spectrometry in looking at very small molecules present in the blood. We found a panel of biomarkers that are bespoke for pregnancy. They seem to be unique for pregnancy and are very predictive for pre-eclampsia.
“That test is currently in what we call phase 2A trials. So the IMPROVED study is in fact one large 2A study of that prototype. The study will finish in two years’ time. It will take us about a year to look at the data but, theoretically, we could be ready to license or launch a test in about three years.”
Despite the obvious clinical demand in providing accurate risk assessment for expectant women, Prof Kenny acknowledges that there are challenges and requirements to be met before the test can be launched in clinics.
“First we have to prove it works and that’s why we are testing our prototype in the IMPROVED study,” Prof Kenny noted.
“Once we are certain that it works, we need to get regulatory approval in Europe and elsewhere and again, that’s not a small undertaking but we are very cognisant of all the pieces of the process. We are hopeful it will get regulatory approval and then we have to market the test. We have to actually manufacture it and get it out there to the women who need it.”
Another critical factor is cost. Prof Kenny is eager to ensure that the test is inexpensive, as the vast majority of women globally who die from pre-eclampsia do so in low-resource settings. A fixed market price for the test has yet to be determined but the technology has been licensed to a company based in Cork called Metabolomic Diagnostics, which is now partnered with the study in trialling the prototype.
“My overriding mission as a clinician and as a mother myself, as a human being, is to make the test as cheap as possible,” Prof Kenny stated.
“It’s technology I developed but we licensed it to a company purely because I haven’t got time to do it myself. If I did, it would take forever and this test is really clinically needed so we needed to get good commercial champions who could actually take the test through regulatory approval, manufacture it and get it to the clinics.”
The IMPROVED study focuses on complications in late pregnancy, including pre-eclampsia, foetal growth restriction and spontaneous preterm birth. Premature babies are 10 times less likely to survive than full-term infants, are more likely to suffer brain injury, and as adults they are more likely to develop diabetes, high blood pressure and obesity.
“Pre-eclampsia is a complex condition, which we don’t fully understand. I know what pre-eclampsia is but I don’t know why women get it. We have a better understanding now than we have had ever before but we still don’t fully understand it,” Prof Kenny noted.
She explained that the condition remains somewhat forgotten in research, for the same reason that all pregnancy conditions have largely been under-researched and under-resourced.
“I think pregnancy has been perceived as a niche area that only affects young pregnant women, so it’s ‘not a big deal’,” she contended.
“That frustrates me enormously, both as a woman and as a doctor, because everyone is born of a pregnancy. If you’re born small or early or both because you mum is ill with pre-eclampsia, you’re more likely to die in utero or be stillborn. You’re more likely to die in the neonatal period and if you survive, you’re much more likely to get complications in adult life like type 2 diabetes, obesity and hypertension.
“I think we’re better now. I think we are realising, fortunately, that pregnancy is not a niche area and that mothers matter. I use that phrase all the time. Every baby counts. Every mother counts. Mothers matter. There has been a big push towards perinatal funding from lots of Government funding agencies and also the WHO. We’re not where we should be, but we’re definitely in a better place than we were.”
Another source of frustration for Prof Kenny is the lack of services to adequately deal with the growing number of women in Ireland with gestational diabetes.
Gestational diabetes is the most common medical disorder in pregnancy and affects 12 per cent of women. As reported by MI last month, gestational diabetes services in Ireland are inadequate, with many at-risk pregnant women going unscreened, against a backdrop of a significant rise in the numbers affected in the last decade.
Prof Kenny is very alarmed that the needs of mothers and babies are not being met in this regard.
“It’s a concern that they’re not. We are seeing an exponential increase in obesity and the type of problems that go with that, like type 2 diabetes. We’re not fully equipped to cope with it, not just in Ireland — they have a similar problem in a lot of well-resourced, non-European countries,” she said.
“But we are very poorly equipped to deal with the increase in type 2 diabetes and gestational diabetes. It concerns me as a clinician. I think we need to do far more to appropriately screen and treat women. We also need to invest a lot more in prevention.”
Women in Ireland and many European countries are now older giving birth and are more likely to be overweight or obese, which is perhaps why small increases in the incidence of pre-eclampsia are occurring, Prof Kenny suggested.
‘My overriding mission as a clinician and as a mother myself, as a human being, is to make the test as cheap as possible’
However, she does not believe that these changes have fuelled recent investments in maternal research and innovation. The main driver, in her view, is the realisation among Governments and funding agencies that “mothers matter and pregnancy counts”. Agencies are slowly realising that investment would have a major impact in reducing healthcare costs and the global disease burden, she believes.
“Equitable investment in pregnancy would alleviate 3 per cent of the global disease burden in a decade. That’s an astonishing statistic, if we had equitable funding for just a few years,” Prof Kenny outlined.
“We only attract a fraction of the funding that things like cancer and cardiovascular disease do. Yet perinatal disease, pregnancy and neonatology [related illness] account for 10 per cent of the global disease burden. If we had equitable funding for just a few years, it would alleviate a significant proportion of that. So it makes economic sense to invest in pregnancy research and I think that’s what’s driving funding agencies now — the fact that the figures add up.”
Despite concerns about a lack of investment in pregnancy research, the HRB has provided approximately €20 million to the area in the last decade.
“Without a doubt, Science Foundation Ireland (SFI) and the HRB have made an incalculable difference to our programme,” Prof Kenny remarked.
“Without the backing of both those funding agencies, we would be nowhere. We wouldn’t have been able to undertake SCOPE without the HRB and we wouldn’t have been able to develop our biomarkers without SFI funding. It’s almost impossible to calculate the difference it’s made. It’s made every difference. Without them we wouldn’t be able to do this.”
Dr Graham Love, Chief Executive of the HRB, is delighted with the progress that projects like SCOPE have made and with the international recognition Prof Kenny’s research is receiving.
“She is effectively leading the way here. It’s fantastic to have somebody like that… She is a superstar,” Dr Love commented.
Dr Love said the HRB’s investment in the area of pregnancy research is on a par with investments in other areas such as neuroscience and cardiovascular care.
“But it’s all relative. This is within the relatively small HRB budget,” he acknowledged.
I think we are realising fortunately that pregnancy is not a niche area and that mothers matter
The HRB annual budget is currently around €40 million, which represents just 0.3 per cent of what is spent on health in Ireland, and State funding is down from around €48 million in 2008. This compares poorly with the UK, where about 2-to-2.4 per cent of its health budget goes into research.
“Ireland is definitely behind. There is simply no other way of putting it. We are below-average spenders. So we have a considerable bit of catching up to do,” he said.
Ireland also needs to use its limited finances more wisely when it comes to innovation and research, Dr Love believes.
“I don’t think we’re getting the best ‘bang for buck’ there and certainly not from the innovation angle and we sure as hell need to, with the demographic explosion coming our way. Whatever pressures are on that €13 billion [current average annual health budget in Ireland] now let’s look at it in 10 years’ time. We need to get much smarter about how we use knowledge and apply it to the services that are there today.”
A lack of funding and the need to apply funds in a more effective way are not the only challenges. Greater collaboration between research projects and the HSE on a practical level is needed, Dr Love maintained.
‘Equitable investment in pregnancy would alleviate 3 per cent of the global disease burden in a decade. That’s an astonishing statistic if we had equitable funding for just a few years’
“We need health research to integrate more tightly into the health service. I think that’s one of the great, shining examples of what we see in the UK,” he said.
“We still have a big step to go to integrate our health research properly into the HSE. We both recognise this, my organisation and the HSE; we need to do a lot more on that front.” Dr Love also believes that research must aim to solve major problems and bottlenecks in our health service.
“It needs to be of use and absorbed by the health service here. It’s not just research for research sake. This is very much needs-driven — it’s got to solve the problem of queuing, of inappropriate attendances at emergency departments, of best choice of drug funding budgets and so on.”
However, with the development of the HSE’s hospital groups and the introduction of the HRB clinical trial networks and the Irish Clinical Research Infrastructure Network, the situation is improving.
Dr Love is similarly enthused by the positive attitude at the Department of Health towards research and innovation.
“I see people like Jim Breslin at the helm in the Department of Health as being very much a person who views research and evidence as very important in defining policies and reforming the health service. I’m noticing that myself already, in terms of our relationship with Hawkins House,” he said.
INFANT: The Centre for Foetal and Neonatal Translational Research
Launched in 2013, Ireland’s first ever Centre for Foetal and Neonatal Translational Research (INFANT) aims to improve health outcomes for mothers and babies through perinatal research.
The Centre, based in Cork, is the brainchild of Prof Louise Kenny and Prof Geraldine Boylan, Professor of Neonatal Physiology, UCC. Despite its relatively short existence, it has tripled in size since its inception. It has come from an initial State investment of just under €6 million and now has an active grant portfolio of about €30 million.
“We have almost 100 researchers working on a variety of research disciplines including nutrition, therapeutics, monitoring, devices and screening. We encompass a large array of research domains across several interconnected thematic areas, all to do with improving outcomes for mothers and babies,” Prof Kenny remarked.
“The figures would suggest we haven’t finished growing yet. We haven’t plateaued. We are still continuing to expand.”
The INFANT brand and awareness about its mission have attracted significant attention. Many large and small- to medium-sized companies are making contact to see if opportunities exist for collaboration.
“Sometimes they’re attracted to the skill set or they have a particular project in mind, but some companies are attracted to the general ethos of what we’re trying to do and want to be involved with it. It’s not an uncommon thing,” Prof Kenny commented.
“We’re very much open for business with industry for the sole purpose of getting our innovations out and into the clinic. The reason why we get up in the morning is to make a difference. Ideas that stay locked on a shelf in our research centre are not going to do that.”
In addition to its involvement in the development of a screening test for pre-eclampsia, the INFANT Centre is involved in many other strands of ground-breaking research, including:
The LEANBH research project, launched last week, is a pilot test to provide remote healthcare monitoring to expectant mothers in order to improve the detection and treatment of hypertension and pre-eclampsia during pregnancy. The vision for LEANBH is to manage care for hypertension and pre-eclampsia in the patient’s home, using remote monitoring of the medical data. It aims to reduce the number of unnecessary follow-on hospital visits, lowering the additional stress and cost of visits, both to the patients and the healthcare system.
At INFANT, remote monitoring will be combined with predictive analytics that can enable faster responses and a higher quality of care through automated alerts to doctors. It also aims to help improve data-sharing among the healthcare team members and offer the ability to integrate with electronic healthcare records. Healthcare researchers will be able to use predictive modelling, trending and scoring to anticipate patient outcomes and evaluate the potential effects of early interventions.
The research data from the pilot study will also provide capabilities to the Centre for devising new predictive models of perinatal healthcare monitoring, which can be used to identify and improve the outcome of pregnancy for both mothers and their babies.
Partly taking its name from the condition hypoxic-ischaemic encephalopathy (HIE), where the brain is deprived of oxygen, the project is examining at-birth blood biomarkers to identify babies at risk so that they can receive early intervention.
A diagnostic test based on the measurement of blood biomarkers in the delivery room will be developed. Such a test does not currently exist and researchers at INFANT hope that when developed, it will dramatically reduce brain injury and disability in babies worldwide.
Babylink aims to exploit new technologies to detect fits and seizures in newborns by analysing neonatal EEGs. INFANT has developed algorithms to identify seizures and is working to implement them in healthcare settings using cloud-computing technology. Researchers teamed up with IBM to develop a solution to allow EEG data to be sent from monitors to a cloud for analysis. Alerts can then be easily transmitted back to the monitor.
The study will help to provide critical expert assistance to healthcare workers in settings where specialist input is required in monitoring the care of babies, but is not always to hand in neonatal intensive care units.
The study is Ireland’s first longitudinal birth cohort study where babies will be observed and monitored in the womb. Detailed analysis of babies from before birth will be recorded and at birth, blood samples will be taken for analysis. Stemming from SCOPE, the study will record information about babies’ diet, growth, development and health. It will also look at mothers’ health, lifestyle and environment.
Recruitment of mothers is currently taking place at Cork University Maternity Hospital, and children will be assessed at two, six, 12 and 24 months. Key players include the Department of Paediatrics, in collaboration with the Departments of Obstetrics and Gynaecology, and Food/Nutritional Science, UCC, and the Department of Dermatology, Trinity College Dublin.
HRB Ireland Perinatal Clinical Trials Network
In May, the HRB announced an investment of €10 million into four new clinical trial networks. One of the networks, the HRB Ireland Perinatal Clinical Trials Network, is co-led by Prof Kenny and Prof Fergal Malone, Master of the Rotunda Hospital and Chairman of the Department of Obstetrics and Gynaecology, RCSI.
The network is a major unit of 200 multidisciplinary researchers examining research questions surrounding pregnant women and newborns.
- Its work programme includes five specific trials looking at:
- Preventing pre-eclampsia in women with diabetes.
- Babies with breathing difficulties.
- Aspirin in pregnancy.
- A new testing method for pre-eclampsia.
- Viagra for babies in the womb with growth difficulties.