Norman Beischer Medical Research Foundation research grants for 2023

A number of Researcher and Honoraries from the Department of Obstetrics & Gynaecology were successful in being awarded Norman Beischer Medical Research Foundation research grants for 2023.

Congratulations to  Dr Natalie Binder, Prof Natalie Hannan, Dr Natasha de Alwis, Dr Samantha Mooney, Dr Emma Readman (Hon), A/Prof Kirsten Palmer (Hon), Dr Stefan Kane (Hon), A/Prof Joanne Said, Dr Melvin Barrientos Marzan, A/Prof Lisa Hui, Dr Natasha Pritchard, Dr Kirsten R Palmer (Hon), Prof Susan P. Walker Dr Wan Tinn The (Hon), Dr Alex Polyakov (PhD), Prof Peter Rogers, Dr Ellen Menkhorst, Prof Evdokia Dimitriadis, Dr Wei Zhou, Dr Clare Whitehead & Dr Louie Ye (Hon).

The Norman Beischer Medical Research Foundation supports and promotes improvements in the reproductive health of women and in the health of their babies and infants.

It actively supports research into obstetrics and the prevention, control and treatment of gynaecological diseases and related problems. It funds clinical and scientific research by leading and emerging researchers and uses this research to educate and inform medical practice in Australia and elsewhere.

The Foundation’s Research Committee meets annually to review grant applications. Submissions are assessed by the Committee members, and recommendations for grants are approved by the Board of Directors.

The projects awarded:

A linkage study to investigate the potential impact of different frozen embryo transfer protocols on health outcomes of offspring

Dr Wan Tinn The (Hon), Dr Alex Polyakov (PhD), Dr Franca Agresta, Dr Michael Chan, Prof Peter Rogers

The University of Melbourne (Sum provided $34,350)

Pregnancies from IVF constitute almost 5% of Victorian live births. In the recent years, there is also a trend towards increased use of frozen embryos (1). There is mounting evidence that pregnancies resulting from frozen embryo transfer (FET) have an increased risk of certain pregnancy complications. In particular, studies have shown that the use of hormone replacement therapy (HRT) for endometrial preparation prior to FET is associated with the highest risk. Of these pregnancy complications, increased risk of hypertensive disorders of pregnancy (HDP) including pre-eclampsia (PE) is most significant, with up to 2-fold increased risk reported in FET with HRT protocols compared to non-HRT natural cycles. Pre-eclampsia is a progressive condition where maternal organ function deteriorates with time. There is no effective treatment to slow disease progression and the only option to stop the disease is to deliver the fetus and placenta. This often results in delivery of a premature fetus. (2) Preterm birth can have significant implication on subsequent health outcomes of the offspring. However, the actual magnitude of the impact is currently unknown.

We plan to investigate the effects of different FET protocols on the health and developmental outcomes of offspring across their childhood, by performing linkage of different health databases in Victoria with assistant from The Centre for Victorian Data Linkage (CVDL). The overall aim for this research project is to investigate whether pregnancies resulted from HRT FET are associated with adverse health outcomes in offspring, when compared to non-HRT natural FET pregnancies.

The magnitude of emerging evidence regarding increased risk of pregnancy complications, especially HDP in HRT FET cycles is sufficient to warrant clinical concern and potential changes in practice. Despite evidence surrounding increased pregnancy complications in HRT FET compared to other FET protocols, the medium to long term health outcomes of these offspring have yet to be investigated. This study will provide evidence on health outcomes of offspring from different FET protocols, to guide clinical practice in IVF treatment.

Selective endothelin-1 inhibition: novel strategies to treat preeclampsia

Dr Natalie Binder, Professor Natalie Hannan, Dr Natasha de Alwis

The University of Melbourne (Sum provided $63,958)

Preeclampsia is an insidious disease of pregnancy responsible for an estimated 70,000 maternal deaths and more than 500,000 stillbirths and neonatal deaths around the world each year. During a preeclamptic pregnancy, the placenta releases toxic factors into the maternal circulation. In otherwise healthy blood vessels, these toxic factors induce excessive release of vasoconstrictive peptide, endothelin-1. When endothelin-1 is in excess, it causes drastic constriction of the blood vessels, resulting in damage to maternal organs, severe hypertension, and compromised blood flow to the developing baby. There is no treatment for preeclampsia, except delivery, which comes with its own problems if occurring before the baby is ready to be born. The management of preeclampsia has seen little change since the 1960’s, and discovery of a therapeutic that can stabilise the preeclamptic state or reduce disease severity would save many lives.

Previously, through support of the Norman Beischer Medical Research Foundation, we identified endothelin-1 to be significantly in excess in the maternal circulation during preeclampsia. In this project, we will investigate endothelin-1 as a therapeutic target for preeclampsia using two innovative drugs that selectively inhibit the endothelin-1 receptors. These drugs block the action of endothelin-1 and thus prevent maternal vessel and organ injury. We will assess these agents in several sophisticated models of preeclampsia that we have developed in our laboratory to pre-clinically test candidate therapeutics before taking them to clinical trial. Our pipeline for drug testing examines both maternal and placental vessels; we can assess drug candidates for their ability to reduce vasoconstriction and endothelial dysfunction and enhance vasorelaxation in a ‘preeclampsia-like’ environment. These discoveries will offer the potential to enhance the management of preeclampsia, improving outcomes for both mothers and babies.

Fetal exome sequencing in Victoria: Are we achieving ‘better care, better health, and better access’ in perinatal genomics?

Dr. Willem Gheysen FRANZCOG, Dr Willem Gheysen, Ms Melissa Graetz, Prof David Amor, Prof Michael Fahey, Dr Calder Hamill Monash, Ms Yael Prawer, A/Prof Kirsten Palmer (Hon), Ms Nikki Gelfand, Ms Susan Fawcett, Dr Anand Vasudevan, Ms Tenielle Davis, Dr Stefan Kane (Hon), A/Prof Joanne Said, Ms Kate Riley, Ms Samantha Dayman

Mercy Hospital for Women (Sum provided $39,686)

Over the last decade, we have seen genomic medicine advance at a breath-taking rate. No field has been more affected by changes in genomic knowledge and technology than in reproductive medicine. The use of new genetic technologies now provides answers to many families affected by rare diseases and facilitates new options for future family planning.

Exome sequencing is a powerful genomic test that analyses many thousands of genes at once. It has been instrumental in improving our understanding the genetic causes of ill health and providing rapid diagnosis of rare childhood diseases. In recognition of the growing importance of this technology, the Victorian Government recently invested $25 million to build genome sequencing capability in Victoria. While exome sequencing is quickly becoming part of routine clinical care in pediatrics, it has only recently been applied during pregnancy to diagnose conditions in a baby before birth.

In two landmark papers published in The Lancet in 20191,2 independent research groups found that exome sequencing of fetuses with major structural abnormalities could identify a genetic cause in about 10% of cases. While this is an exciting development, the high cost of exome sequencing makes this an extremely limited resource.

In Victoria, the state government made genomic sequencing publicly available through established genetics services though the Victorian Clinical Genomic Sequencing Initiative. This scheme commenced in 2018 for adult and paediatric patients, and was expanded in 2019 to include perinatal exome sequencing in 2019 for fetuses with congenital anomalies. There are unique practical, clinical and ethical considerations with offering exome sequencing in the perinatal setting. To date, there has been no formal assessment of the clinical implementation of fetal exome sequencing in Australia. Furthermore, there is no population-based data on how the results of fetal exome sequencing impacts clinical management of Australian couples and how it contributes to future decision making.

We have assembled a state-wide multidisciplinary group of experts in perinatal genetics to analyze the first five years of publicly funded fetal exomes in Victoria so that we can assess the impact of fetal exome sequencing on Australian families and genetics services. We aim to see if this scheme achieves to Victorian Government’s overall mission to provide “better health, better access, better care”.

Pain with outpatient hysteroscopic procedures: A case control study

Dr Pinar Cingiloglu, Dr Samantha Mooney, Dr Lenore Ellett, Dr Emma Readman (Hon), Dr Helen McNamara, Dr Lauren Hicks, Dr Avelyn Wong, Dr Kate McIlwaine, Dr Caroline Hoggenmuller

Mercy Hospital for Women (Sum provided $8,000)

Hysteroscopy is the gold standard investigation to work up abnormal uterine bleeding. It is a way to look inside the uterus through a thin, telescope-like device that is inserted into the uterus through the vagina and cervix. It allows clinicians to diagnose or treat a uterine problem.

Endometrial polyps are focal outgrowths of the uterine lining and are detected in 20-40% of women with abnormal uterine bleeding. Advances in technology have increased the capacity for gynaecologists remove endometrial polyps under hysteroscopic guidance in an outpatient clinic setting. This has the benefit of avoiding a general anaesthetic and hospital admission. Devices used to achieve this include the Myosure® tissue removal device. Studies have shown that outpatient hysteroscopy it is well tolerated and accepted by patients and is offered widely in Australia and United Kingdom.

The Mercy Hospital for Women runs an outpatient hysteroscopy clinic which offers investigation and management of abnormal uterine bleeding in the outpatient clinic setting. All women undergoing such a procedure are asked to complete a pre- and post-procedure questionnaire that includes providing a pain score for any pre-existing pain, anticipated pain with procedure, and actual pain experienced. Data is collected at the time of procedure and entered into a secure database. This study will analyse this data, specifically comparing pain scores with a simple hysteroscopy and a polypectomy (removal of polyp). We will assess these pain scores to see if both diagnostic and management of abnormal uterine bleeding in the outpatient setting is acceptable for patients, and look at what factors influence overall satisfaction and willingness to attend again.

Enhancing the value of the Collaborative Maternity and Newborn Dashboard for the COVID-19 pandemic: epidemiological and geospatial analyses of perinatal datasets

Dr Melvin Barrientos Marzan, A/Prof Lisa Hui, Dr Daniel L. Rolnik, Dr Stephanie Potenza, Dr Natasha Pritchard, A/Prof Joanne M. Said, A/Prof Kirsten R Palmer (Hon), Dr Clare L. Whitehead, Dr Penelope M. Sheehan, Prof Jolyon Ford, Prof Ben W. Mol, Prof Susan P. Walker

The University of Melbourne (Sum provided $65,000)

The Collaborative Maternity and Newborn Dashboard (CoMaND) project was created by maternity health professionals at the onset of the COVID-19 pandemic in 2020, out of concerns about the negative impacts of disruptions to maternity care on maternal and newborn outcomes. With the Foundation’s generous support, the CoMaND project has grown into a Melbourne-wide collaboration involving all 12 metropolitan public maternity hospitals. Over the past 2 years, CoMaND has provided regular reports on key outcomes such as weekly births, stillbirths, preterm births, neonatal intensive care admissions to health services, the Consultative Council on Obstetrics and Paediatric Mortality and Morbidity (CCOPMM) and Safer Care, Victoria. We have now accumulated a large and valuable dataset that enables us to examine specific questions as they emerge, thus providing an agile and granular surveillance system to “take the pulse” of our maternity sector through each stage of the COVID-19 pandemic.

Two years on, the pandemic has underscored the crucial influence of social and economic status on health outcomes [1]. In this application, we propose to maximize the value of the 230,000 birth records in CoMaND by performing sophisticated geospatial and epidemiological modelling studies to study the influence of social determinants of health on maternal and newborn outcomes before and during the pandemic. There is a notable increase in the prevalence of large for gestational age babies. This increase is alongside the rise in the prevalence of GDM and maternal obesity.

We will explore the impacts of social determinants of health on outcomes such as maternal and fetal overweight and gestational diabetes. These analyses will help us unpack the impacts of non-modifiable risk factors (such as age, ethnicity, and pre-existing disease), modifiable risk factors (such as the built environment, pollution, food environment, alcohol, and cigarette smoking), and socioeconomic position on key maternal and perinatal outcomes such as maternal obesity, gestational diabetes, and large for gestational age babies.

Alongside geospatial and epidemiological analyses, we will continue to expand our maternal and perinatal surveillance works in CoMaND. Our collaboration enabled surveillance of the impacts and safety of COVID-19 vaccination, which we analysed in 2022.

The huge public interest in this work is demonstrated by the exceptional Altmetrix score of 717 received by our preprint paper on pregnancy outcomes in vaccinated and unvaccinated women, with over 1000 tweets by the general public.

As case numbers and deaths accumulate in Melbourne, the CoMAND project will continue a vital role as the only Australian system with a robust capacity to rapidly monitor the perinatal impacts of COVID-19 lockdowns, COVID-19 infections, and COVID-19 vaccinations.

Discovering new therapies to treat preeclampsia

Dr Ellen Menkhorst, Prof Evdokia Dimitriadis, Dr Wei Zhou, Dr Clare Whitehead, Dr Louie Ye (Hon), Dr Sarah Marshall

The University of Melbourne (Sum provided $64,887)

Preeclampsia is a life-threatening, pregnancy-induced disorder unique to humans. If left unmanaged, preeclampsia can lead to maternal organ failure and death.

Preeclampsia is caused by a damaged placenta releasing toxins into the maternal blood stream which damage the maternal blood vessels, causing the clinical symptoms of preeclampsia. Currently, the only treatment for preeclampsia is delivery of the placenta, often resulting in preterm birth. A new therapeutic option to improve placental health and prolong pregnancy until the baby can be safely delivered is desperately needed.

In this study we will test whether blocking an inflammatory cytokine that causes much of the placental damage in preeclampsia, can prevent placental secretion of toxins that damage maternal blood vessels. We have identified three medications currently used clinically that block action of this cytokine (interleukin 1β): canakinumab, anakinra and rilonacept. Here we will determine whether these medications can improve placental and maternal blood vessel health in preeclamptic pregnancies. We will test whether these medications can prevent secretion of toxins by the preeclamptic placenta and whether these medications can stop the damage to maternal blood vessels that cause the maternal symptoms of preeclampsia. We expect that these medications would ameliorate the maternal symptoms of preeclampsia, allowing the pregnancy to continue until it is safe to deliver the baby. If successful and advanced to the clinic, this would be a breakthrough in the treatment of preeclampsia and improve health outcomes for mothers and babies worldwide.