Lay summaries are provided below of the Research Grants given in 2023
Miss Yvette Raymond, Dr Daniel Lorber Rolnk, Prof Ben Willem Mol, Dr Shavi Fernando, Dr Melody Menezes
(Sum provided $65,000)
We are seeking a grant for our research project titled ‘Prenatal cell-free DNA screening for rare chromosome abnormalities and adverse pregnancy outcomes’, which is being conducted as part of a PhD candidature at Monash University. This research project involves two arms; a prospective cohort study, and a data-linkage study.
Cell-free DNA (cfDNA) is a method of testing for fetal genetic problems, in which DNA released by the placenta is analysed. As this genetic material originates from the placenta and not the fetus, the performance of the test relies on the placenta and the fetus having the same genetic make-up. False-positive results, when the cfDNA test indicates an abnormal fetus but confirmatory testing (with, for example, amniocentesis) shows that the fetus is actually normal, may arise when there are genetic anomalies in the placenta but not the fetus.1, 2
Unfortunately, there is very little information available regarding the consequences of genetic anomalies in the placenta, with the exception of Trisomy 16 (an extra copy of chromosome 16) which is strongly associated with complications such as impaired growth of the fetus, premature birth and stillbirth.3
For the prospective cohort study arm of our research project, we are aspiring to follow a population of women who have received a false-positive cfDNA screening result and conduct genetic testing on their placentas after birth. It is our aim to determine what proportion of false-positive results are attributable to anomalies in the placenta, and what consequences this may have on pregnancy outcomes. We believe the results of this research project may provide valuable information in counselling women who receive false-positive results, and also guiding whether closer monitoring is indicated for the management of these pregnancies.
In the second arm of this research, our focus is on fetal fraction, which describes the proportion of cfDNA within a sample of the mother’s blood that originates from the placenta, versus her own tissues. Previous studies have attempted to investigate for any association between fetal fraction values and complications of pregnancy, including impaired fetal growth, preterm birth, diabetes in pregnancy or disorders involving high blood pressure in pregnancy, including pre-eclampsia. Unfortunately, the information that is currently available in the literature is conflicting across studies, and any evidence of associations are weak.4 This is largely because many of these studies have investigated small populations which may not accurately capture any actual associations.
It is thereby our aim to conduct a data-linkage study with a large number of participants to investigate for any association between pregnancy outcomes and fetal fraction values, which could provide valuable information to guide pregnancy care.
We are seeking a grant to fund the placental genetic testing required for this study, as well as to fund the cost of data matching by the Victorian Centre for Data Linkage for our data linkage project. We are also seeking funds to support the PhD candidate with the appointment of a research assistant, and provision of a Monash University encrypted computer for secure data storage.
Wan Tinn The, Alex Polyakov, Franca Agresta, Michael Chan, 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.
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.
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, Ms Nikki Gelfand, Ms Susan Fawcett, Dr Anand Vasudevan, Ms Tenielle Davis, Dr Stefan Kane, 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”.
Dr Pinar Cingiloglu, Dr Samantha Mooney, Dr Lenore Ellett, Dr Emma Readman, 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.
Helen McNamara, Emma Readman, Lenore Ellett, Martin Healey , Lauren Hicks, Claudia Cheng, Avelyn Wong
Royal Women’s Hospital
(Sum provided $10,800)
This project is exploring outcomes following a procedure involving injection of botulinum toxin type A (Botox) into the pelvic floor muscles for the treatment of pain and pelvic floor tension. Botulinum toxin type A blocks signals from nerves to muscles, so that the muscles relax. It is used for the treatment of many conditions including conditions causing muscle spasms (spasticity) and in cosmetic procedures.
In people with persistent pelvic pain and pelvic floor tension, there is some evidence that Botox injection into the pelvic floor muscles can reduce pelvic pain, pain with sex, and pelvic floor pressure and tenderness.
In this study, we are trying to determine if injection of Botox to the pelvic floor muscles is associated with post-procedural pain flare. A pain flare, in people with persistent pelvic pain, is defined as an episode of pain that is more intense than usual, that lasts from hours to a week, that is difficult to tolerate, and that generally impacts usual activities and/or emotions.
Dr Lore Schierlitz, Prof. Peter Dwyer, Dr Alison De Souza,Dr Yik Um, Dr Kris Cvach, Dr Linli Ow, Assoc Prof Anna Rosamilia
Mercy Hospital for Women
(Sum provided $47,098)
When conservative options fail for the management of utero-vaginal prolapse, the vaginal surgical route has long been the preferred method of treatment. Low complication rates, high patient satisfaction and favourable cost benefit ratios remain high for vaginal surgery when compared to other surgical routes including open, laparoscopic and robotic procedures.
Vaginal surgical techniques incorporating mesh grafts were developed over the last 20 years to improve long term surgical outcomes for prolapse. The risks of mesh complications in vaginal prolapse surgery has resulted in the TGA withdrawal of all prolapse mesh products in Australia. As a result, older more conventional surgeries are being revisited to give women options for prolapse repair.
Current data regarding the efficacy and longevity of these older surgical procedures is limited and insufficient to counsel women on their surgical options. There is an urgent need to reevaluate these traditional operations in light of the limited surgical options available for women in Australia. Prospective long-term data inclusive of patient reported outcomes is required.
The study objective is to compare the Manchester-Fothergill procedure (MP) with uterine conservation to the vaginal hysterectomy (VH), including vaginal repair and vault suspension for the treatment of utero-vaginal prolapse.
Women between the ages of 35-80 years with symptoms of prolapse who request surgical treatment in our outpatient clinic are invited to participate in the study. Our hypothesis is that the MP is non-inferior compared to the VH for objective and subjective cure rates of prolapse, quality of life outcomes and patient acceptance. The trial is a prospective cohort study based on patient preference due to the fact that one procedure is uterine preserving whilst the other will result in removal of the uterus as part of the prolapse correction. This is often a personal choice for women undergoing prolapse surgery and it is currently unclear which operation provides the best long term outcomes.
In addition to standardised history and examination findings, validated quality of life questionnaires will be administered to assess bladder-, bowel- and sexual function before and after surgery.
Melvin Barrientos Marzan, Lisa Hui, Daniel L. Rolnik, Stephanie Potenza, Natasha Pritchard, Joanne M. Said, Kirsten R Palmer, Clare L. Whitehead, Penelope M. Sheehan, Jolyon Ford,Ben W. Mol, 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 . 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.
Dr Ellen Menkhorst, Dr Wei Zhou, Dr Clare Whitehead, Dr Louie Ye, 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.
Paris Papagianis, Prof Claudia Nold, A/Prof Jane Bourke, Ms Briana Peterson, A/Prof Ram Nataraja, Prof Marcel Nold
(Sum provided $62,232)
Premature birth is the leading cause of mortality and morbidity in newborns worldwide. Complications in babies born too early or too small make up the greatest health burden in children under 5. Complications sometimes stretch into early life and adulthood and include lung disease, asthma, learning difficulties, brain injury and motor deficits. Necrotising Enterocolitis (NEC) is an inflammatory intestinal complication of premature birth (90% of all NEC cases) or abnormal pregnancy. Currently there is no treatment for NEC. Many newborns with NEC will require surgery, after which death rates can be as high as 65%. The transfer of immunity from mother to child via breastfeeding is well known, but we are becoming increasingly aware of other specialised cell types in breast milk. Specifically, breast milk contains stem cells with potential anti-inflammatory and reparative properties. We suggest that harnessing these stem cells from breast milk can reduce inflammation and injury in premature babies with NEC. We will collect breast milk from mothers at different lactation stages (early, middle and mature). Using genomic screening and functional assays, we will characterise the different types of stem cells in breast milk. In this way, we will identify stem cell candidates for therapeutic use in NEC. Breast milk stem cells which are anti-inflammatory and promote repair of the intestine will be applied to surgically resected intestinal tissue from premature babies with inflammatory bowel disease. This is a critical proof of concept study to demonstrate the therapeutic potential of easily-accessed breast milk cells for NEC. Successful application of isolated breast milk-derived cells to premature babies will quickly accelerate into clinical trial, as expression of milk and the consumption of breastmilk is routine and avoids some major ethical and safety hurdles of other drug discovery trials. This work also provides the opportunity to reduce rates of surgical intervention and long-term complications of NEC in a population of babies already vulnerable to other organ failures.
Mr Ritesh Warty, A/Prof Anna Rosamilia, Prof Caroline Gargett, Dr Gita Pendharkar
(Sum provided $63,555)
Pelvic organ prolapse (POP) is the downward displacement of one or more pelvic organs into the vagina. Occurring in up to 50% of women above the age of 50 years, POP often results from vaginal birth injury. Symptoms include pelvic heaviness, difficulty urinating or defecating, recurring urinary tract infections, sexual dysfunction, and urinary or faecal incontinence. In the most severe cases, the complete presentation of the uterus outside the vagina is possible. As such, this is a condition which can have a significant impact on the quality of life for the women of our society as well as those around the world.
Current clinical approaches have had limited success and either have a passive management focus (eg. lifestyle changes, physiotherapy, and devices called pessaries which physically hold the organs in place) or require surgical intervention which has a number of risks and contraindications. Approximately 10-20% of POP patients will undergo surgery, however roughly 30% of this population will experience an anatomical or subjective failure in the long-term. Attempts to improve these results with mesh placement has resulted in greater harm than benefit in some recipients and a subsequent class action and regulatory ban. As a result, many women wish to avoid surgery and there is a demand for novel non-surgical treatments which can provide further options for treatment.
To address this unmet clinical need, we are developing a novel intravaginal smart prosthetic device which will facilitate the rehabilitation of POP sufferers by helping to strengthen the pelvic floor muscles – important for maintaining support alongside ligamentous and fascial structures. This will be achieved using stimulation and smart technologies embedded in a structure that can provide a better tissue-device interface than existing stimulators (which are primarily used in incontinence), enabling a more effective strengthening program. In doing so, we will improve the quality-of-life of POP sufferers and limit worsening due to aging.
To date, we have developed early proof-of-concept prototypes and are preparing to perform an observational first-in-human study to demonstrate feasibility of concept for one of these prototype versions. Using the findings of this study, we will then develop advanced prototypes that can hopefully be translated into patient care to empower the lives of women.
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