Pre eclampsia

Pre eclampsia

PhD Candidates
  • Gabriele Bobek

Pre eclampsia Group

Keywords: preeclampsia, hypertension, pregnancy, MRI, cardiovascular disease  
Collaborators (internal): G. Bobek, T. Stait-Gardner, B. Ghadirian, J. Preis , W.S. Price, J Lind
Collaborators (external): A Makris (HRI), R Nanen (Nepean Hospital)

Research: Research carried out by this group involves the physiological and molecular study of preeclampsia. Preeclampsia is a condition affecting women during pregnancy resulting in hypertension (high blood pressure), proteinuria (protein in urine) and oedema (fluid build up in tissues). Without treatment it can progress to a dangerous condition called eclampsia, leading to convulsions, stroke, kidney failure and maternal and fetal death. It is the most significant and common complication of pregnancy, affecting 5% of all pregnancies. Currently the only treatment is bed rest, administration of hypertensive medications or premature delivery of the baby. 

The placenta is the interface between the maternal and the fetal environments and is vital for the exchange of gases, nutrients and wastes between mother and baby. Altered placenta structure and function has been postulated to lead to the maternal symptoms.  The risk factors for preeclampsia are those which predispose the placenta to immunological insult (lupus, anticardiolipin syndrome, changing sexual partners) or vascular mal-adaptation (chronic hypertension, diabetes). The study of these risk factors and their interaction has been hampered by a paucity of animal models and a lack of linkage between cell experiments and whole animal studies. Defining the sequence of abnormalities of the immune system and its regulation, and the vascular reaction to these immunological changes would greatly enhance our understanding of the underlying mechanisms of preeclampsia and lead to opportunities for definitive treatment other than by urgent delivery of the pregnancy.

Our work in pregnant baboon research over the last 10 years, has shown that the most profound aberrations in maternal outcome have been demonstrated when the cytokine environment of the placenta is altered. Additionally we have identified a relationship between acute reduction in placental blood flow and an increase in the production of placental toxin sFLT-1 (an antagonist of vascular endothelial growth factor VEGF). The timing and tracking of this increase makes it highly likely that it causes elevated maternal blood pressure, and a later increase in urinary protein excretion just as has been demonstrated in human preeclampsia.
We are now currently developing a rodent model where we aim to dynamically follow changes in placental perfusion and structure to elucidate links between cytokine imbalance, shallow placental invasion, placental ischaemia (restricted blood flow), release of sFLT-1 and subsequent maternal hypertensive response.

In collaboration with the Department of Nanotechnology at the University of Western Sydney, (Prof William Price) we have an unprecedented opportunity to use direct imaging of placental blood flow in small pregnant rodents which will allow us to identify the relationship between cytokine imbalance, altered placental structure and blood flow, and the release of placental toxins that lead to the hypertensive maternal response. Placental blood flow is measured by Magnetic Resonance Imaging (MRI) techniques including  BOLD (Blood Oxygen Level Dependent) MRI and DWI (Diffusion Weighted Imaging)  of the embryo-placenta units (EPU). The higher power magnetic field available to this project gives us the power to determine subtle effects in blood flow over relatively small periods of time.

This work aims to elucidate the exact mechanisms of preeclampsia by correlating (i) tissue specific cell-cell interaction studies of invasive potential of placental cells with (ii) physiological changes seen in placental blood flow and (iii) maternal haemodynamics using small pregnant rodents. Defining the sequence of abnormalities of the immune system and its regulation and the vascular reaction would greatly enhance our understanding of the underlying mechanisms of preeclampsia and lead to opportunities for definitive treatment for the mother and baby other than by urgent delivery of the pregnancy.

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Professor Annemarie Hennessy

MD (Medicine, 1985), FRACP (Nephrology, 1991), PhD (Preeclampsia - Cardiovascular Physiology, 1997), MBA (Business Administration, 2003)

Research Interests
Annemarie Hennessy is the Foundation Chair of Medicine at the University of Western Sydney (UWS).  She was the Director of the Hypertensive Disorders of Pregnancy (HDP) Unit at the Royal Prince Alfred Women and Babies (RPAWB) from 1998 until October 2006 and continues in an honorary capacity within the unit.  Annemarie has a half time commitment to medical research in her capacities as Head of Medicine, UWS, The Group leader of the Vascular Immunology Group at the Heart Research Institute and as the Director of the NHMRC Baboon Colony.

Annemarie has 19 years experience in preeclampsia research conducted at RPAWB, the Mater Sydney and Cornell University Medical College, New York and is now extending research activities to Great Western Sydney at the UWS School of Medicine. She is actively involved in molecular and immunology research and directs 2 PhD students in this area at the Heart Research Institute (USYD) and 1 at UWS.

Annemarie has directed research efforts in whole animal physiology using non-human primates. Her experience in baboon pregnancy is internationally recognised. The recent findings linking sFlt-1 to placental ischaemia has won National and International awards and was the subject of an Editorial in the Kidney International (2007) where this was published.  These findings represent some remarkable work with primate pregnancy and a model of preeclampsia highly relevant to the human condition. Annemarie has demonstrated her capacity to direct this complex work at the same time as maintaining clinical involvement with preeclampsia care which will facilitate translation to human studies.

The recent clinical outcomes projects for pregnancy which Annemarie has instigated have been the first to demonstrate sustained improvements in maternity care with benchmarking of outcomes. The results of this program have lead to major changes in clinical practice in the Canadian units with whom she collaborates. It is currently informing clinical practice in NSW and supports a large scale randomised clinical trial in anti-hypertensive choice in pregnancy (CHIPS) study being run out of Canada.

Dr Makris and Professor Hennessy were the first to identify and publish an association between induced placental ischaemia in pregnant primates and the production of the toxic hypertensive molecule sFLT-1.  This is an important finding in light of previously unknown source of sFLT-1 identified to be toxic in human pregnancy.  Their publication in the prestigious Kidney International Journal in 2007, led to an Editorial in that journal and has already been cited 16 times. Comments have been made by practicing and Academic Obstetricians that they can finally see the point of animal studies in preeclampsia in that they identify mechanistic links between physiological changes of preeclampsia and newly discovered candidate proteins.

AM Hennessey Profile (PDF, 20kb)
AM Hennessey Publications current for the past 5 years (PDF, 19kb)

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Gabriele Bobek

Gabriele is a Technical Officer in the School of Medicine, Campbelltown Campus of UWS. She has 13 years experience in research in the fields of Endocrinology and Immunology, encompassing techniques ranging from small animal surgery to tissue culture of immune cells, to protein analysis of antigen complexes to sequencing of immune genes. She has recently joined the preeclampsia group and is undertaking a part-time PhD investigating placental abnormalities in hypertension in pregnancy.

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Dr Angela Makris

Angela is a Nephrologist and Obstetric Physician who completed PhD studies in 2006. She has conducted pivotal research into sFLT-1 in pregnancy at a time when this is emerging as the most significant advance in preeclampsia and hypertension in pregnancy research in the last 25 years.  Her work with baboon placental ischaemia is likely to make a very significant contribution to understanding the patho-physiological signals involved in preeclampsia.

Angela is supported in her role as investigator by the Heart Research Institute, and the Department of Renal Medicine, Royal Prince Alfred Hospital as well as in her collaboration with the University of Western Sydney (Professor Annemarie Hennessy) and the NHMRC Clinical trials Centre (Prof Keech).  She is in active clinical practice at the Liverpool Hospital.

Angela has a remarkable publication record, 16 papers and 30 Abstracts to National and International Meetings. Her work on serial testing in preeclampsia was beaten to publication in the NEJM in 2005, although her work had commenced in 2002.  Her study however, takes a more holistic approach to risk factor assessment and her model has been presented and has won international awards for research excellence (In preparation for Submission at present). Angela's baboon studies were complex and detailed and offer some very important insights into treatment strategies.
Dr Makris and Professor Hennessy were the first clinicians to identify and publish an association between the use of non-steroidal non-selective cyclooxygenase anti-inflammatory analgesics (NSAIDs) and hypertension in the immediate post-partum period. Their publication in the prestigious American Journal of Obstetrics and Gynecology in 2004, led to the Australian Adverse Drug Reaction Advisory Committee (ADRAC) making a National notification warning against the use of NSAIDS in hypertensive women after delivery. As a result of this notification, Angela and Annemarie developed and implemented the Hype RCT which has been underway since late 2004- early 2005.

Presentations:

  • High blood Pressure Research Council of Australia Dec 2007, Adelaide.
  • Australasian and New Zealand Society of Nephrology (ANZSN) 2005 (Wellington): 'sFLT-1 in elevated in women with preeclampsia prior to the diagnosis and is induced by placental hypoxia.'
  • Australasian Society for the Study of Hypertension in Pregnancy (ASSHP) 2005 (Darwin): 'Differences in circulating cytokines, sTRAIL and sVEGFR-1 in women with preeclampsia.'

Awards and Prizes Received:
2007 - Basic Science Award, High blood Pressure Research Council of Australia Dec 2007, Adelaide.
2005 - ASSHP: Andrew Phippard Award - best presentation.
         - ANZSN: Best Clinical presentation.
2004 - ISSHP: Young Investigator Award.

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PhD Candidate

Gabriele Bobek
"Placental Abnormalities and Hypertension in Pregnancy."

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