Monday, August 10, 2009

The quest to conquer pre-eclampsia

The act of giving life can be a perilous one for thousands of women worldwide. Globally, pre-eclampsia is a leading cause of maternal and infant illness and death, claiming the lives of more than 100,000 women and at least 500,000 infants every year. Experts agree that this potentially deadly disorder could be prevented with the development of a test that identified women who are at greatest risk, but a screening tool for pre-eclampsia in early pregnancy remains as elusive, thus far, as the Arthurian Holy Grail.

This quest to conquer pre-eclampsia, however, has acquired renewed momentum lately with the arrival on the field of an Irish research team based in University College Cork, who have embraced this challenge with crusade-like vigour and are backed by the world’s largest medical research charity. Developing a predictive test for pre-eclampsia will, of course, secure a place in the annals of medical history for the successful team, but that is not the driving force behind this concerted push to identify a simple, clinically accurate and affordable assay. Research leader Professor Louise Kenny – an obstetrician in Cork University Maternity Hospital – puts it simply: “it’s about saving the lives of young mothers and their babies, that’s why we get up every morning, that’s why this is so important.”

Louise is a dark-haired poster girl for obstetrics research; a PhD graduate - her study of abnormal vascular responses in pre-eclampsia is award winning – most days Louise can be found in the laboratory with her research team and, later, by the bedside delivering babies, and in both worlds she radiates youthful energy, positivism and acumen.

These qualities, coupled with a promising research proposal, were pivotal in convincing the prestigious Wellcome Trust to invest close to a million Euro in her search for an early pregnancy pre-eclampsia test. Despite an attack of nerves while awaiting to deliver her pitch for funding at the Trust’s London office, Louise and her co-principle investigator Professor Phil Baker, Director of the Manchester Biomedical Research Centre, UK, must have presented a very convincing case as their study was awarded a massive grant of €800,000 earlier this year.

This landmark study is being carried out by Louise’s team at the Anu Research Centre of the Department of Obstetrics and Gynaecology, UCC, in collaboration with Baker, her former professor, and his group at the Maternal and Foetal Research Centre.

Louise is acutely aware that the task ahead is a daunting one: there is a lot of money and expectation riding on them to develop the world’s first effective and affordable screening tool for pre-eclampsia, which would undoubtedly transform the future of antenatal care worldwide.

“The Welcome Trust Translational Award is really quiet prestigious award, they’re difficult to get, because what they’re focused on is taking good quality science that is worked up to a certain level and then trying to translate it into something that’s clinically useful; Bench to bedside. We had to physically go to the Wellcome Trust in London and basically convince them that the science we had is good enough and they could take a risk and give us their money: A lot of money. Winning one of these awards is a bit like going into the Dragon’s Den actually because the pressure is now on to produce results,” she adds.

This Wellcome Trust award is built on the Health Research Board (HRB) funded Screening for Pregnancy Endpoints (SCOPE) Project, currently based at Cork University Maternity Hospital and also led by Louise. Essentially, this project is a unique, international collaboration to create a pregnancy biobank that can be used to discover new ways to predict and prevent health problems in late pregnancy, including pre-eclampsia, fetal growth restriction and spontaneous preterm birth.

Ireland’s involvement in this eight-centre international initiative commenced in 2007 with a HRB grant of €1.7 million - the largest award ever made to a single project in Ireland for obstetrics and gynaecological research. SCOPE Ireland is the largest single contributor to the project biobank with samples from more than 3,000 women.

A key ambition of SCOPE is to develop predictive tests that offer first time mothers an accurate, personalised risk rating for each disease. Louise’s focus is pre-eclampsia. And already Louise and her team have identified biomarkers in the blood of women in early pregnancy that they then used to predict the subsequent development of pregnancy complications, particularly pre-eclampsia. It was this exciting finding that clinched the Wellcome Trust award.

“We found the biomarkers by identifying particular metabolites in the blood – these are small molecules which are involved in normal growth, development, and reproduction. We have been collaborating with Manchester - one of the leading centres of metabolomic discovery in Europe for several years - and this award will enable UCC to establish a key role in taking this research forward.”

The work ahead involves confirming that the metabolites they’ve identified can be used to reliably screen for the development of pre-eclampsia. To do this, they will carry out a targeted screening of 3,000 low-risk women.

“The next phase will be to combine clinical information and metabolites to develop the most effective system for predicting problems in pregnancy. The final step is to turn this into a prototype blood test which is suitable for commercial use,” says Louise, her tenor infectiously optimistic. “The award will make a tremendous difference to our work, and hopefully mothers and babies should benefit from the new screening test within the next five to ten years.”

There is currently no clinically useful test for pre-eclampsia, which affects 5 percent of first time mothers. Each year, the number of maternal deaths from pre-eclampsia is equivalent to the loss of 170 jumbo jets of pregnant women. Compounding this tragic statistic is the fact that a quarter of the babies born to mothers with pre-eclampsia are growth restricted and a third are premature. A recent report of the Confidential Enquiry into Stillbirth and Death in Infancy (CESDI) revealed that one in six stillbirths and one in six sudden infant deaths occurred in pregnancies complicated by maternal hypertension.

“Developing a test for pre-eclampsia would make an enormous difference to women and their unborn babies all over the world,” Louise explains. “What we currently use is a combination of clinical risk factors such as personal history, but the vast majority of women who get pre-eclampsia, however, don’t have any history and they certainly don’t have it in their first pregnancy – and 55 per cent of the antenatal population is in their first pregnancy.”

She outlines several decisive criteria governing the success of a predictive test; firstly it has got be effective in early pregnancy; “developing a screening test in late pregnancy is useless, we really have to know at the start of the pregnancy or as early as possible what someone’s risk factor is”.

“There are two reasons for that,” she continues, “firstly it’s because there are some interventions that we can institute that may actually reduce risk and, even if there aren’t many now, given the pace of medical discovery we’d hope that there would be more coming along very shortly.

“But everything we know about this condition tells us that in order for any intervention to work it has to be started early prior to the disease, and preferably as early in pregnancy as possible. So we need a test to tell us who’s at risk because obviously we don’t want to expose every pregnant woman to drugs that she doesn’t need.

“Even in the absence of a very good intervention, the second reason for such a test is because we are then able to tailor antenatal care to women depending on their risk assessment. In this age where we very much try to offer holistic and patient-focused care to women in pregnancy – and one shoe does not fit all - knowing if someone is actually low risk is almost as valuable as knowing that they’re high risk because it mean they can avail of a different package of antenatal care. They could predominantly have their antenatal care based in the community so they don’t have to come into our already overcrowded and under resourced hospitals. There are both patient and health economic benefits all round for the development of this test," she emphasises.

Of course, critically, the screening tool has to be clinically accurate – there are lots of tests out there that have been proposed and have been binned because clinicians found that they’re next to useless.

“So it has to be early pregnancy, it has to be good and, ultimately, it does have to be affordable because the majority of women who die from this condition do so in the developing world,” Louise points out. “And in the developing world more than anywhere else it will probably have the biggest impact. We, in Ireland are a very resource strapped nation anyway and we struggle to offer adequate antenatal care to all the women in our country, as in other European countries, and we are essentially the developed world. Imagine the widespread benefit if we had a cheap simple test that could predict risk in early pregnancy? And in the developing world, you could be sure it would have a massive impact on how they distribute their very limited resources.”

Certainly the kudos for whoever develops a screening tool for pre-eclampsia would be immense and the commercial potential could prove stratospheric. Screening for cervical cancer using the Pap test, for example, is one of the greatest successes of screening and has immortalised its inventor Dr George Nicholas Papanicolaou. Louise graciously tolerates probing questions about her interest in such fringe benefits, even confiding that her thoughts have occasionally drifted down that alluring path of accolade and profit, but it is quite apparent that these are not motivating factors for her work.

“The commercial potential is quite interesting and you can get carried away with being first with this great test but I always try to not forget is that a pregnant woman dies of pre-eclampsia somewhere in the world every third minute. So in the time that we’ve been chatting a handful of young, previously healthy women at the start of their adult life, usually in their first pregnancy, will have died of a disease. But we still don’t have a screening test for it or an effective treatment,” she emotes.

Louise has been researching this disease since the mid ‘90s, soon after her graduation from Liverpool Medical School in the UK. In 2001, while based at the University of Manchester’s Maternal and Fetal Health Research Centre, she embarked on an innovative collaboration with the University’s School of Chemistry to investigate the use of metabolomic technology in the development of a pre-eclampsia screening test.

“These are two disciplines that normally wouldn’t collide through the system, and we’ve been working on that collaboration ever since. The link with SCOPE is that in order to actually identify biomarkers, yes you need quite complex discovery programmes, but they are absolutely crucially dependent on access to patients or samples. That’s where the SCOPE study comes in.”

There are several big research groups internationally working on developing a predictive test for pre-eclampsia, but in recent years some of these teams have joined forces and are now working together in SCOPE to progress this goal.

“The principal investigators in SCOPE, and there are five or six of us, basically just put down the weapons, as it were, over the past decade and decided to join forces and not work in competition. Most of us have been friends and colleagues for many years and we all met through our common interest in pre-eclampsia. I think it’s fair to say that we are all working together now and not in competition, and we found that it has speeded up the rate of discovery massively. A problem shared in a problem halved, and sharing knowledge is everything, we’re not really that bothered about protecting what we know or publishing results first.”

In fact, Louis discloses that they are in the process of assembling data for their first major publication that will detail the 75 biomarkers of interest they have identified, of which 15 potentially hold the key to a screening test. This groundbreaking study will be published before the end of the year.

“Inevitably with anything that is commercially as lucrative as a potential screening test there are other interests, as it were, but the primary focus of both the Wellcome Trust and the SCOPE consortium is in getting a test to the bedside that can actually make a difference.

“Most of us have direct contact with patients. I have a PhD and I work as a scientist but I’m also clinically trained and I work as a doctor. I spend half my time with patients, and that’s really what gets me out of bed in the morning, it’s the idea of developing a test that will make a difference in that portion of our working day.

“In the 21st century, when we’ve made so many breakthroughs in other branches of medicine - and we really have made tremendous medical progress in so many different areas in the last two decades or so - things have stood still in obstetrics research. But with so many people now working together towards a common goal, I think that is about to change.”

The Baseline Study:

One aspect of obstetric research that has always frustrated Prof Louise Kenny is that it usually finished with the baby. The minute the baby was out, obstetrics dissevered interest.

“But we now know that the nine months in utero have a profound effect on how babies grow and develop, not just in infancy but into adult life. It’s a whole concept called foetal programming, and we know, for example, that babies who are born small as a result of pre eclamptic pregnancies are much more likely to grow into adults who develop diabetes and heart disease and hypertension,” she explains.

In 2006, Louise moved from Manchester to Cork to take up key role in the development of the new Anu Research Centre at Cork University Maternity Hospital. “I was lucky that when I arrived in UCC and was setting up the SCOPE study, Deirdre Murray, who was a newly appointed paediatric colleague, and Jonathon Hourihan, who is the head of the Department of Paediatrics, were incredibly enthusiastic about establishing a study on the back of SCOPE that would follow the progress of these babies into childhood, so we set about writing grant applications.”

Funding of €800,000 was secured from the Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, enabling the BASELINE (Babies After Scope: Evaluating the Longitudinal Impact Using neurological and Nutritional Endpoints) study to commence.

BASELINE is the first Irish birth cohort study, which will look at why some children develop common childhood diseases while others remain healthy. In August 2008 the first mothers recruited to the SCOPE pregnancy study in Cork began to deliver, and the first BASELINE baby arrived at the clinic in November last year.

“Initially the research will concentrate on the effects of poor growth in the womb, the incidence and prevalence of food allergy and eczema in early childhood and the incidence and effects of maternal and infant vitamin D status on the growth and health of Irish children.

“We have funding to follow the babies up for the first two years, and obviously we’re very much hoping that that funding will be extended, or will attract funding from other agencies, that will allow us to follow these babies through their childhood and into adult life,” says Louise.

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