RESEARCH 2020

2020 Research Grants

Lay summaries are provided below of the Research Grants given in 2020.

Short chain faty acids as novel therapeutics to prevent the development of gestational diabetes mellitus

A/Prof Martha Lappas

Mercy Hospital for Women

(Sum provided $60,000)

Gestational diabetes mellitus (GDM) currently affects 13% of all pregnancies in Australia, and the rates among Indigenous populations are even higher. Moreover, women are embarking on pregnancy at a later age, and with a higher BMI, than ever before. Age and obesity are both leading risk factors for GDM, and so the health burden of GDM is set to inexorably increase.

The lifelong and severe health complications directly resulting from GDM for both mother and child cannot be ignored. GDM not only contributes heavily to obstetric and perinatal morbidity, but leaves a legacy of future long-term health risks that places an extraordinary economic burden our healthcare system.

To date, interventions aimed at either treating or preventing GDM have failed to significantly reduce the burden of disease and have had no impact on the long term health risks of children born to mothers with GDM. Because GDM rates are steadily increasing, we must act swiftly if we are to solve this multigenerational problem. We urgently need a safe and effective intervention that can prevent GDM and thereby reduce its burden.

There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. They may reduce the risk of type 2 diabetes, obesity, heart disease and other conditions.

SCFAs are molecules produced by ‘friendly’ bacteria when they ferment fibre inside the gut. Epidemiological studies have shown that increased dietary fibre consumption is associated with many beneficial health effects including reduced risk of developing GDM. The relative contribution, however, of SCFAs to these beneficial effects is not known.

We seek to test our recent exciting discovery implying that SCFAs can disrupt pathways vital to the pathogenesis of GDM. If this were found to be effective, translation is highly feasible. This would significantly reduce public health costs and improve the lives of women and babies for generations to come.

Validation of a blood test to predict macrosomia

Associate Professor Tu’uhevaha Kaitu’u-Lino, Dr Teresa MacDonald, Dr Jessica Jellins, Profossor Jon Hyett, Profossor Stephen Tong, Profossor Sue Walker, Dr Richard Hiscock

Mercy Hospital for Women

(Sum provided $59,832)

Fetal macrosomia refers to a baby that is significantly larger than average.  Rates of macrosomia are rising in parallel with the increasing rates of obesity in pregnant women. This means that macrosomia is a significant challenge in contemporary obstetrics.   

Fetal macrosomia is one of the strongest risk factors for birth complications including the need for assistance during vaginal birth (eg. with instruments such as forceps), and emergency caesarean section because the infant is too large to safely deliver normally. The most serious sequelae of macrosomia is shoulder dystocia – a life threatening complication that occurs when the baby’s head is born, but the shoulders are too big to pass through the pelvis.  This exposes the baby to nerve damage that can result in upper limb paralysis, fractures and- most devastatingly- a lack of oxygen to the brain during this difficult birth, leaving the baby at risk of lifelong neurological injury, such as cerebral palsy.

Moreover, a large baby is also dangerous to the mother during vaginal birth, increasing her likelihood of serious trauma, haemorrhage, and pelvic floor damage which can result in lifelong bladder/bowel incontinence. Importantly, the risk of these complications is reduced among women where the baby is known to be large if labour is brought on a few weeks early. This is because the baby gains approximately 200-250g/ week in late pregnancy, thus bringing on labour a few weeks early ensures an easier birth. Given the serious complications of macrosomia can be partly averted with earlier induction of labour, identification of the large baby is a clinical imperative.  

Currently, doctors and midwives rely on clinical examination of the abdomen during routine pregnancy check-ups to detect fetal macrosomia, yet this is known to perform poorly.  Women at increased risk of macrosomia may be offered an ultrasound; but the test does not perform well, only identifying 40% of macrosomic cases.  A more accurate diagnostic tool is desperately needed. 

We recently identified 5 novel proteins that are significantly changed in the blood of women who are destined to birth a large baby. We measured these molecules in the blood of 1000 women before they had their babies, and our mathematical modelling indicates we are able to identify approximately 64% of large babies. This suggests that our blood test may be able to almost double the detection rate of ultrasound. In this study,we propose measuring these 5 proteins in the blood of women from an independent cohort (another 1200 women) to validate whether these circulating biomarkers could produce a new clinical blood test. 

The potential clinical significance of this project is huge. Currently, most women begin labour with their large baby unsuspected and undetected, putting both mother and baby at risk of serious complications.  Labour induction at 38 weeks has been shown to reduce the risk of shoulder dystocia, and the related adverse consequences for mum and baby. Given a safe and successful intervention is available, a simple blood test in late pregnancy that could reliably detect macrosomia would transform clinical care. 

Pregnancy and childhood outcomes associated with unregulated, adjunct medication use in IVF pregnancy

Mercy Hospital for Woman

Dr Anthea Lindquist, Dr Roxanne Hastie, Dr Amber Kennedy, Prof Sue Walker

(Sum provided $55,579)

The use of IVF in Australia is steadily increasing, with 5% of Australian livebirths resulting from IVF-assisted conception. Since the first successful IVF pregnancy in 1978, early technological advances dramatically improved rates of pregnancy. However, as the increments of improvement have diminished over recent decades, many IVF practitioners have turned to medications that have been poorly tested in clinical trials to improve success rates. This is concerning because we do not know whether these medications are safe.

Furthermore, they are being prescribed – often at high doses – during the first trimester of pregnancy. This is a vulnerable time when the fetus is most sensitive to the risk of structural malformations caused by harmful drugs.

There has been a proliferation of unregulated medications, now widely used as part of the IVF practitioner’s armamentarium. They may be safe, they may be improving outcomes, or they could be causing irreversible harm that has remained invisible to us all. The safety of these medications needs to be urgently determined, Furthermore, there is growing concern globally about the short and long-term effects of IVF interventions on the offspring and yet there are very few robust, published studies that look at childhood outcomes following IVFassisted conception.

An Assessment of the Prevalence and Severity of Sleep Apnea in Multiple PreGNANCY

Dr Megan Rees, Dr Steve Cole, Dr Tom Cade

Royal Melbourne Hospital and Royal Women’s Hospital

(Sum provided $24,000)

Obstructive sleep apnea occurs when there are frequent pauses in breathing during sleep. The back of the mouth and throat contain soft muscles, and when we sleep these muscles relax.  Sometimes these muscles and nearby soft tissues can come close together and vibrate causing snoring but when fully closed this can block the flow of air to the lungs. Then oxygen levels in the body drop which causes distress to the brain which wakes the body to breathe again. These frequent awakenings cause a rise in blood pressure and heart rate as well as fragmented unrefreshing sleep which results in daytime tiredness and low mood. 

Sleep apnea in pregnancy has been associated with adverse outcomes for both mother and fetus. These include high blood pressure, pre-eclamspia, diabetes, low birth weight and preterm delivery. Several methods to identify sleep apnea have been tested in women pregnancy with one baby, however there are no dedicated studies demonstrating their application to twin or multiple pregnancy. The greatest risk factors for sleep apnea in pregnancy are advanced maternal age and elevated BMI, both risk factors are increasing in the Australian pregnant population, particularly in twin or multiple pregnancies. In addition, the greater physical and hormonal strain of a multiple pregnancy are likely to contribute to the presence of sleep apnea.  Sleep apnea is a common, serious but treatable condition in pregnancy and women pregnant with twins or triplets may be at greater risk however this has not yet been studied.

We aim to determine how commonly sleep apnea occurs in multiple pregnancy. In addition, this study will be able to determine the usefulness of several established screening tests in pregnant women. Participants will be assessed for risk of sleep apnea with a screening questionnaire and non-invasive monitoring of sleep on a single night of sleep in their own home using a smart phone app and a monitoring device attached to the hand. We plan to assess risk of sleep apnea in women carrying twins and triplets and compare these to women with singleton pregnancy.  If sleep apnea is suggested by screening tests individual participants will be referred for specialist assessment and care of sleep apnea. 

Single Cell RNA sequencing of amniotic fluid: a novel approach to understanding fetal development

Associate Professor Lisa Hui, A/Prof Natalie Hannan, Dr Bhupinder Pal, Associate Professor Alicia Oshlack

Mercy Hospital for Women, Olivia Newton-John Cancer Research Institute and Murdoch Children’s Research Institute

(Sum provided $56,489)

Approximately 3-5% of pregnant women are given the unexpected news of a suspected abnormality in their unborn baby due to the results of routine screening test. Currently, we have only a few medical tools to observe how babies develop in the womb and to predict their childhood health, such as ultrasound for structural abnormalities, maternal blood tests for substances released from the placenta, and direct needle sampling of the placenta or amniotic fluid for the baby’s DNA.

There are many situations in which our questions about a baby’s health before birth cannot be answered by these methods. A/Prof Lisa Hui aims to discover more about human development by studying the amniotic fluid that surrounds the baby in the womb. This fluid is produced by the fetal kidneys, lungs, gut and other organs. Amniotic fluid can be sampled via a needle (amniocentesis) to test the DNA of the baby if a genetic condition is suspected. However, there are also other genetic molecules called “RNA” that are currently not analysed during diagnostic testing. Unlike DNA, RNA tells us which genes are actually switched “on” and “off” at particular time point, which gives us dynamic information about real-time biology rather than static information about the inherited genome.

Usually RNA must be extracted from solid tissue or a direct blood sample, which cannot be sampled from a baby before birth. However, if we could study RNA in amniotic fluid – which is safely obtainable during pregnancy – this would have the potential to transform the way in which we can understand how a baby develops in the womb. A/Prof Hui has previously pioneered research on amniotic fluid cell-free RNA and has demonstrated that multiple fetal organs release genetic information into the amniotic cavity. Technological advances now give us the ability to analyse RNA in even more detail with “single-cell RNA sequencing” (scRNAseq). This is a perfect solution for studying amniotic fluid because it contains many different types of cells, including cells from the baby’s skin, lungs, bladder, kidneys, and intestines, as well as stem cells, immune cells, and immature brain cells. The amazing diversity of the cell population in amniotic fluid can be preserved with scRNAseq, so we can find out what each type of cell is doing at a particular moment in time. This was not previously possible with prior cell-free RNA analysis, in which all the RNA molecules are pooled and analysed together.

Our project aims to apply scRNA sequencing to amniotic fluid that has been donated by women who are already undergoing amniocentesis for their clinical care, or who are having a Cesarean birth. We are collaborating with leaders in the field of scRNA sequencing from the Murdoch Children’s Research Institute and the Olivia Newton John Cancer Research Institute for this exciting project. We plan to create the world’s first single cell RNA “atlas” of amniotic fluid, an open up an entirely new field of studying the development of a baby before birth.

A trial of a position modification device for the prevention of supine sleep during pregnancy

Dr Danielle Wilson, Prof Sue Walker, A/Prof Mark Howard, Dr Maree Barnes

Austin Hospital (Institute for Breathing and Sleep)

(Sum provided $55,536)

Late stillbirth, which is the loss of a pregnancy after 28 weeks gestation, remains a common and devastating human tragedy, even in high income countries such as Australia.  Many of these tragic deaths remain unexplained. A recent analysis of five studies has shown that the risk of stillbirth is increased by more than 2.5 times in pregnant women who report going to sleep on their back.  In this sleep position, it is believed that the pregnant uterus compresses major blood vessels and thus reduces blood flow to the fetus.  This vital finding suggests that some stillbirths could be prevented by simply changing sleeping position.  As a result, the Centre of Research Excellence in Stillbirth has recently promoted recommendations to improve awareness of maternal safe sleeping position, yet ensuring this position is maintained during sleep can be difficult.

More than 80% of pregnant women spend time sleeping on their back, with the overall proportion of sleep time on the back ranging from 9 – 26%.  Only one device for pregnant women has been designed to avoid ‘back-sleeping’, with the aim of reducing the risk of stillbirth.  The belt-like device has had limited success at modifying sleep position, with one long-term trial showing that it had no benefit for the health of the baby.

The aim of this study is to test the effectiveness of a position modification device (PMD),worn around the lower back, designed to decrease the amount of time pregnant women spend sleeping supine (on their back).  This randomised study will involve two ‘study epochs’ for each woman: one week using the PMD and one week without the device, each ending with a night of comprehensive overnight sleep monitoring.The sleep monitoring will (i) measure body position throughout the night to establish whether the device is preventing back sleeping, and (ii) to determine if the device is disruptive to sleep quality.  Importantly, we will (iii) perform continuous fetal heart monitoring during the night to compare whether there are measurable differences in the baby’s heart rate between these two settings. This would provide a crucial evidentiary link between sleep position and stillbirth risk.  

The results of this pilot study will be used to inform the feasibility and design of a definitive randomised clinical trial evaluating this positional device to modify sleep position during late pregnancy.  This all-important pilot data will position us to apply for major funding for such a trial, where we will be able to definitively determine the impact of back sleeping on maternal and fetal health. 

A novel device to continuously monitor the fetal heart rate to reduce stillbirth

Dr Fiona Brownfoot, Prof Marimuthu Palaniswami, Emerson Keenan

Mercy and Melb Uni

(Sum provided $49,454)

We are developing a device that continuously monitors the fetal heart rate during pregnancy to detect fetal distress and prevent stillbirth. Our device is as thin as glad-wrap and comfortably adheres to the maternal abdomen to monitor fetal heart activity. In this application we will validate and refine our algorithms to automatically extract the fetal heart rate.

Stillbirth is a devastating complication affecting 1 in 130 pregnancies. Disappointingly the staggering rates of stillbirth in Australia have remained unchanged for decades. Perhaps the lack of progress results from the heterogenous causes of stillbirth. There is however a common final pathway that all face prior to stillbirth, fetal distress.

Fetal distress can be identified by characteristic changes in the fetal heart rate. Currently, the only available technology to monitor the fetal heart rate during pregnancy is using fetal cardiotocography (CTG). The major limitation of this tool is that it requires a bulky ultrasound machine, must be directed by a clinician and constantly needs repositioning depending on the fetal position. Therefore, it can only be used intermittently and we often miss the critical moment when a life-saving delivery could be performed to avoid stillbirth.  

The optimal way to detect fetal distress in pregnancy would be to use small, comfortable sensors placed on the mother’s abdomen. These sensors would wirelessly transmit data to a smartphone and alert the mother of fetal distress so she can attend hospital. Excitingly such a device is now within reach. We are developing technology that can reliably measure fetal electrical activity and wirelessly transmit the fetal heart rate to provide a continuous measure of fetal distress.    

This new technology has the potential to revolutionise fetal monitoring and reduce the risk of stillbirth for millions worldwide every year. 

Placental-released early pregnancy serum biomarkers of preeclampsia

Dr Ellen Menkhorst, Dr Wei Zhou, Prof Evdokia Dimitriadis

Royal Women’s Hospital

(Sum provided $45,896)

Preeclampsia is a life-threatening, pregnancy-induced disorder unique to humans. Preeclampsia’s classic symptoms are the sudden onset of maternal hypertension and protein in urine after 20 weeks gestation. If left unmanaged, preeclampsia can lead to maternal seizures (eclampsia) and death. Preeclampsia affects between 2- 7% of all pregnancies: world-wide >4 million women develop preeclampsia each year, leading to the deaths of 100,000 women and 500,000 babies. 

Preeclampsia is caused by a damaged placenta which releases toxins into the maternal blood stream causing the clinical symptoms of preeclampsia. There are no effective ways to prevent or treat preeclampsia except for delivery of the placenta, which often occurs pre-term. 

The inability to prevent or treat preeclampsia is due in part to the limited understanding of the underlying cause of preeclampsia. Much of our knowledge of preeclampsia is from samples collected late in pregnancy, after the diagnosis of preeclampsia. However, there is substantial evidence suggesting that abnormal placentation during the 1st trimester is the underlying cause of preeclampsia. A better understanding of the abnormal placental changes which underlie preeclampsia will enable the development of new biomarkers to help better predict women at risk of preeclampsia and also identify new therapeutic targets to improve placental development and function and hopefully prevent or treat preeclampsia. 

This project will utilize early pregnancy placental clinical biopsies to identify new biomarkers of placental damage in women who go on to develop preeclampsia. We will perform a comprehensive, unbiased screens of RNA and proteins produced by placentas from pregnancies that went on to be preeclamptic and compare these factors to healthy control placentas. These samples will provide us with a unique snapshot of the damaged placenta at the end of the 1st trimester. This snapshot will allow us to understand how the placenta is damaged prior to the onset of the clinical symptoms of preeclampsia. We will also identify whether there is a correlation of placental factors and serum factors in women who go on to develop preeclampsia and define those factors which can be used as biomarkers of placental damage to diagnose preeclampsia. The aim of his study is to develop a predictive tool that would allow doctors to select and monitor women at risk of developing preeclampsia. This study will also identify potential treatment targets to improve placental development, which to date is lacking, largely because of the inability to identify the factors that contribute to the damage to the placenta. 

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