Lay summaries are provided below of the Research Grants given in 2022
Dr Roshan Selvaratnam, Prof Euan Wallace, Dr Mary-Ann Davy
The Ritchie Centre
(Sum provided $26,852)
All too often choices that women are asked to make in pregnancy are informed by very short-term outcomes. But most parents want to know long-term implications for their child’s health, development, function, and quality of life. The problem is that this information is often not known. In this application, using whole-of-population Victorian data, we propose an exciting series of studies that will explore the effects of various pregnancy complications and perinatal interventions on the developmental and educational outcomes of children across their schooling life. In particular, we plan to explore the effect of elective medical interventions, early birth, method of birth, pre-eclampsia with medical comorbidities, fetal growth restriction, and hypertensive disorders during pregnancy, on childhood school outcomes. Multiple facets of child development, including physical health, social competence, and emotional maturity, and child education, including spelling, numeracy, and reading, will be explored. This information will provide robust information on whether perinatal interventions are beneficial or harmful to the future neurodevelopmental integrity of children. The purpose is to help guide clinical decisions during the perinatal period and to support women in making more informed decisions for themselves and their offspring.
A/Prof Lisa Hui, Melvin Barrientos Marzan, Daniel Rolnik, Stephanie Potenza, Natasha Pritchard,
Joanne Said, Kirsten Palmer, Clare Whitehead, Penelope Sheehan, Jolyon Ford, Ben Mol, Susan Walker
The University of Melbourne
(Sum provided $50,000)
Globally, the COVID-19 pandemic has worsened health outcomes for pregnant women and their babies . In 2020, Melbourne experienced the most restrictive lockdown measures in the country, resulting in widespread concerns about the impacts of disruptions to maternity care. Lisa Hui and the local maternal fetal medicine community conceived of the Collaborative Maternity and Newborn Dashboard (CoMaND) for the COVID-19 pandemic in April 2020 to monitor the impacts of lockdown on maternal and perinatal outcomes. With the generous support of the Foundation, the CoMaND project has grown into a collaboration involving all 12 metropolitan Melbourne public maternity services, capturing 75% of all births in the metropolitan area. We are now using de-identified maternity data to analyse key clinical quality indicators such as stillbirth and preterm birth rates. CoMaND has provided regular reports to participating health services and Safer Care Victoria through 2020-21. 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 during this public health emergency.
The Foundation supported the creation of the CoMaND project in an extraordinary out-of-cycle grant to principal investigator Lisa Hui in May 2020, providing $50,000 towards a part-time research assistant salary. In August 2021, Victoria continues to rely on lockdowns as a major component of the public health strategy for reducing transmission of COVID-19. There is an urgent need to continue the work of CoMAND for at least another 12 months as we grapple with a resurgence of COVID-19 due to the delta variant and anticipate ongoing effects on mothers and babies from repeated lockdowns through 2021.
In this application, we request a second year of funding to continue our clinical quality monitoring and to obtain the best research value out of the dataset that has been established through our multicentre collaboration.
Dr Wentao Li, Prof Ben Mol, Dr Rui Wang, A/Prof Ryan Hodges, Dr Matthew Page, Prof Zarko Alfirevic, Prof Arri Coomarasamy
(Sum provided $49,366)
Postpartum haemorrhage is heavy bleeding after the birth of a baby. It causes serious medical conditions, sometimes requires blood transfusion and can even lead to the death of the mother if bleeding is severe and uncontrollable. About half of the cases of severe maternal medical conditions and a quarter of maternal deaths are attributable to postpartum haemorrhage.
As treatment of postpartum haemorrhage is often too late for many women, prevention is important. Both uterotonics and tranexamic acid are inexpensive and widely available drugs, and therefore, have been used to prevent postpartum haemorrhage. However, existing evidence regarding their roles in preventing postpartum haemorrhage predominantly comes from many small trials.
Unfortunately, major concerns in many of these trials have been identified. These concerns are not limited to biases arising from methodological weaknesses, but also problems related to potential data manipulation and other forms of research misconduct, which greatly weaken the confidence in the existing evidence that guides practice. Therefore, there is an urgent need for innovation in future evidence synthesis, with tightened scrutiny and up-to-date methods, to provide more reliable evidence for women and practitioners.
In recent years, we have established an innovative framework to assess the trustworthiness of randomized trials and already successfully applied this framework to several important topics in women’s health. It offers an opportunity to assess the trustworthiness of trials on a case-by-case basis. Our framework consists of a screening checklist that identifies studies at risk for trustworthiness concerns. It is possible to filter out problematic trials from future evidence synthesis by using this framework. Subsequently, individual participant data meta-analysis, a novel method that combines participant-level data of reliable trials, can generate convincing evidence.
As rates of postpartum haemorrhage are rising, the Victorian government has prioritised implementation of new guidelines for prevention and treatment of postpartum haemorrhage. It is therefore of the utmost importance to have guidelines that are based on reliable evidence and provide personalized management guidance.
In this project, we will combine the assessment of trials’ trustworthiness and subsequently perform an individual participant data meta-analysis of trials that evaluate tranexamic acid for preventing postpartum haemorrhage. More than 30 trials with data of over 13,000 women will be scrutinised in terms of trustworthiness before being used to synthesize evidence.
We will not only be able to assess trustworthiness, but the availability of individual participant data also will allow the application of personalized medicine. This means that we can identify which women will benefit most from prophylactic tranexamic acid and provide personalized prevention.
This pilot project will be an important prior step for us to apply the same method to assess the evidence base for another high-priority topic – prophylactic use of uterotonics, which involves more than 200 trials including over 140,000 women.
A/Prof Piero Perucca, Prof Frank Vajda, Prof Sue Walker, Prof Torbjorn Tomson, Dr Dina Battino, Prof Emilio Rerucca
(Sum provided $56,104)
Every year 1 in 50 pregnancies are exposed to antiepileptic drugs (AEDs), which are the ‘backbone’ of the treatment of epilepsy and are also used to treat several other conditions, including psychiatric disorders, pain, and migraine. These medications typically need to be continued throughout pregnancy to reduce the health risks to the mother and baby, such as those resulting from uncontrolled seizures.
While taking AEDs during pregnancy has long been known to carry increased risks of having a baby with a birth defect, less is known about the other consequences of exposing pregnancies to these medications. Our work and that of other researchers have recently suggested that AEDs, as a group, increase the risk of having a baby that is ‘small-for-gestational age’ (SGA), which means that the baby is smaller in size than normal for the number of weeks of pregnancy. SGA babies are vulnerable to a wide range of health complications, including premature death.
Of concern, there is almost no other information on the relationship between AEDs and SGA. This explains why clinicians do not generally discuss the risks of AED-associated SGA with women who are taking AEDs and who may become pregnant one day. Clearly, this lack of information is a missed opportunity to improve clinical care, and thus urgent research in this area is needed.
In this project, we will address the ‘unknowns’ surrounding the relationship between AEDs and SGA. By combining for the first time two of the largest pregnancy registers of AEDs in the world, we will first compare the risk of SGA in pregnancies exposed to a single AED (monotherapy) and those exposed to two or more AEDs (polytherapy). We will then determine the risk of SGA associated with specific AED monotherapies as well as their doses. We expect that the results of this project will change the way clinicians manage and counsel women of childbearing age who are taking AED, ultimately leading to a reduction in the number of pregnancies exposed to AEDs which result in SGA babies.
A/Prof Joanne Said, Prof Susannah Ahern, Prof Susan Walker, A/Prof Lisa Hui, Dr Stefan Kane, Dr Clare Whitehead, Dr Kirsten Palmer, Prof Melissa Wake
Joan Kirner, Western Health
(Sum provided $55,000)
While Australian women and their babies experience some of the best maternity care in the world, around 10% of pregnancies are complicated by problems with the baby such as feta I abnormalities, feta I growth restriction (the baby not growing well inside the womb) or complications of twin pregnancies (for example unequal sharing of the twin placenta); or problems with the mother such as Type 1 diabetes or severe illness requiring admission to the Intensive Care Unit (ICU). Within Victoria, women diagnosed with these problems are usually managed in one of the four Maternal Feta I Medicine (MFM) Units (Monash Health, The Royal Women’s Hospital, Joan Kirner Women’s & Children’s at Sunshine Hospital, (Western Health) and Mercy Health). These women often receive more frequent antenatal care visits during their pregnancies compared to women without these complications and are also much more likely to have many more investigations such as blood tests or ultrasounds or receive treatments that may be uncommon or relatively new. Despite this intensive investment in the antenatal care, there is often little to no follow up of the women and the babies from these complex pregnancies.
The NONA (Newborn Obstetric Network Australasia) registry is a collaborative that benefits mothers of these high risk pregnancies, and their babies, for future decades. NONA collects data regarding five specific high risk maternal and fetal conditions, with the aim of identifying optimal strategies that improve outcomes, and providing regular site benchmarking and feedback. NONA was established in 2020 in conjunction with Monash Clinical Registries at Monash University and the four major Victorian MFM units.
The registry takes advantage of the statewide Generation Victoria (GenV) cohort study which aims to recruit all babies born in Victoria over a 2 year period from late 2021 (including those with complex pregnancies) and follow the children, and their families, into the future. This partnership with GenV provides a once in a lifetime opportunity to improve our understanding of some of the long term outcomes of these complicated pregnancies.
The NONA registry will provide a coordinated, collaborative approach to prospectively identifying high-risk newborns before birth. There is currently no similar registry specific for high-risk pregnancy care in Australia that allows granular data from fetal ultrasound and other obstetric care to be linked with newborn and childhood outcomes. A state-wide, clinician-led, collaborative approach provides significantly greater power to advance discovery. Once established, we would be well positioned to progress to an Australia-wide initiative, ensuring that future generations of all Australian children, and their families, will benefit.
Dr Samantha Mooney, Dr Vanessa Ross, Prof Kate Stern, Dr Keryn Harlow, Dr Uri Dior, Dr Anthea Lindquist, Dr Amber Kennedy, Prof Peter Rogers, A/Prof Martin Healey
Mercy Hospital for Women
(Sum provided $49,105)
Endometriosis is a condition where tissue similar to the lining of the uterus (endometrium) is found developing in other areas of the pelvis. Several authors have published reports indicating that there is an association between endometriosis and poor outcomes for pregnant mothers and their babies. The accuracy of this association has not been confirmed.
This feasibility study aims to assess the study protocol, and the ability to access and use data from a large pregnancy outcome database. Should the pilot be successful, a larger study incorporating interstate and international collaborators will hopefully follow.
This study aims to prospectively assess feasibility of a data collection and data linkage protocol to explore the association between surgery for moderate or severe endometriosis and risk of adverse maternal or perinatal outcomes.
The impact of surgical treatment of moderate to severe endometriosis on pregnancy outcomes for women conceiving spontaneously and through IVF is unknown. Due to this significant of evidence, gynaecologists are limited in their counselling of patients regarding pre-emptive surgical treatment of endometriosis to alter future obstetric outcomes for mother or baby.
In the Australian population at least 10% of women of reproductive age have endometriosis; approximately one third of these will have endometriomas or extensive deep endometriosis.
Clarifying the role of endometriosis surgery in potentially altering obstetric outcomes will assist to better manage patients with endometriosis.
Prof Della Forster, Dr Touran Shafiei, Dr Stefan Kane, Prof Sue Walker, Prof Helen McLachlan, A/Prof Lisa Hui, Prof Jeanie Cheong,
Prof Christine East, A/Prof Emily Callander, Ms Rebecca Hyde, Ms Robyn Matthews, Ms Andrea Dodd
Judith Lumley Centre
(Sum provided $59,927)
Most maternity providers in Victoria have been providing a proportion of pregnancy care as telephone or video health during the COVID-19 pandemic, with 52% planning to continue post-pandemic. Even within Victoria, there is great variation in what constitutes telehealth, and at what points in pregnancy women should have face-to-face visits.
Current evidence raises concerns about clinical outcomes when women receive combined telehealth and face-to-face care in pregnancy compared with the standard face-to-face schedule; but there is a lack of rigorous evidence of the benefit or any potential harm associated with the use of telehealth for pregnancy care. One large single site study in Melbourne found no evidence of harm when providing up to 50% of pregnancy care by telehealth, and the authors suggest this approach could be continued after the pandemic. Few other studies support those findings. Another local study including births from all 12 Melbourne public maternity services found evidence of more babies stillborn before 37 weeks compared with pre-pandemic. This is in keeping with other international evidence.
Women report high levels of stress and anxiety related to telehealth, and that care is of poorer quality, and they have concerns about the lack of some (normally) routine screening during telehealth visits. Doctors and midwives are similarly concerned about the quality of care, and the potential mental health impacts on women. They are also concerned telehealth is here to stay. There are many other unknowns too, e.g., providers’ ability to screen for family violence, whether women present less often with their concerns, and whether they express their concerns in a telehealth context. We also need to understand whether outcomes such as the increase in stillborn babies are related to changes in the delivery of pregnancy care.
These are unprecedented changes in the way we deliver care, and given the evidence of potential harm, it is a critical moment in pregnancy care in Victoria and elsewhere. There is no rigorous evidence of the safety or efficacy of a combined telehealth/face-to-face model of providing pregnancy care, but despite this, there is mounting pressure to incorporate telehealth into routine care.
A randomised controlled trial (RCT) is needed to test the effect of the combination of video-based telehealth and face-to-face care compared with standard face-to-face pregnancy care, but before an RCT can go ahead, a pilot study is needed.
We propose to undertake a pilot RCT at two tertiary Melbourne maternity services to assess the feasibility of undertaking a larger study with many more women. We will develop and implement a pregnancy care schedule that combines video-based telehealth care with face-to-face visits, and pilot test it against the standard schedule of face-to-face visits with 200 women. This will help refine the model and work out the best outcomes to measure, how many women we need for the larger study, the best costing model etc.
This is the crucial first step to developing a robust evidence base around wholesale changes to models of pregnancy care.
Dr Teresa MacDonald, Prof Sue Walker, Ms Allison Thomas
Mercy Hospital for Women
(Sum provided $42,100)
Babies that are small – those in the bottom 10% for the number of weeks of pregnancy – are at four times higher risk of stillbirth than babies that are normally grown. In particular, the smallest 3% of babies are at the greatest risk. If doctors and midwives managing pregnancies suspect that a baby is small, they can arrange close monitoring, and then deliver the baby slightly earlier, before it is too late. This approach has been proven to reduce stillbirth risk.
The main problem is that the majority of small babies remain undetected and unsuspected by doctors and midwives in the clinic, and for these babies, the risk of stillbirth is therefore much higher. It is particularly tragic that the majority of stillbirths occur late in pregnancy, around or after, the due date. This is a time where, if the small baby was detected and simply delivered, stillbirth could be safely avoided and a healthy newborn baby would be taken home with its parents. Most people are unaware that current clinical practice of measuring the mothers’ uterine size in the clinic, and arranging an ultrasound scan if it seems small, only picks up about 20% of babies destined to be born small. Better ways are needed.
We recently reported a new ultrasound test called the “cerebral-placental-uterine ratio” or CPUR. We found that if we measure, and then combine, the resistance to blood flow in the mother’s blood vessels supplying the uterus, in the umbilical cord, and in the baby’s brain, at 36 weeks, that this new test detected more small babies than any other test currently in clinical use. Even more importantly, this new ultrasound test picked up 89% of the babies in the lowest 3% for size – those at the highest risk of stillbirth. This is an exciting finding, as even if all pregnant women had an ultrasound to measure the baby’s size at 36 weeks, only 77% of babies in the lowest 3% would be detected. Potentially, the CPUR could detect more babies in the lowest 3% than any other test available, and could transform clinical care.
We now need to test the CPUR further to confirm its value in identifying small babies. If confirmed, the CPUR could be used in the clinic to enable doctors and midwives to identify small babies, allowing them to plan monitoring and well-timed delivery to prevent stillbirth.
We now plan to measure the CPUR in 1050 more women, at or after 34 weeks of pregnancy, who present to the Mercy Fetal Monitoring Unit, and who are increased risk of having a small baby. This includes women presenting with reduced movements, those with a small uterine height measurement, and those whose pregnancies have gone overdue. We will measure the CPUR among these three groups, and then see how big their babies are once born, to investigate if the CPUR does indeed detect the smallest, most at-risk, babies.
Dr Emily Camm, Dr Kirsten Palmer, Dr Carole-Anne Whigham, Prof Suzie Miller
The Ritchie Centre
(Sum provided $52,000)
As the bridge between mother and baby, the placenta provides oxygen, nutrients, and hormones essential for the baby’s growth and development. Both the formation of the placenta and then its ongoing role supporting the developing baby requires energy; energy which is primarily provided by mitochondria- the energy powerhouses of cells. Emerging data suggests that maternal obesity, or pregnancy complications including preeclampsia (high blood pressure) or fetal growth restriction (FGR), alter the shape and number of mitochondria within the placenta as well as their ability to provide energy to support normal fetal development. The purpose of this study is to better understand how mitochondria within the placenta are impaired in response to pregnancy complications or poor environmental conditions, and the extent to which these changes are related to the growth and health of the baby at birth. An improved understanding of placental mitochondria is critical as we work towards better predictive and/or diagnostic tests for at-risk pregnancies, as well as assisting with the development of new treatments.
We will collect blood samples during the last trimester of pregnancy, and the placenta at birth, from women who are obese or who have experienced pregnancy complications, such as preeclampsia or FGR, and from uncomplicated pregnancies. We will then compare mitochondrial function in placenta samples between these groups, in addition to measuring the expression and abundance of key genes, proteins, lipids, and metabolites that regulate mitochondrial structure and function. Data on mitochondrial function will also be linked with findings from ultrasound scans performed earlier in pregnancy, and the baby’s body weight and body composition at birth to understand their impact on the baby’s growth. Combined, these methodologies are expected to identify signatures of poor placental or mitochondrial function. This is a critical proof of principle study to demonstrate that placental mitochondrial dysfunction is common in a range of pregnancy disorders, and has important implications for maternal and fetal/neonatal health. Knowledge gained from work lays the foundation for the identification of key biomarkers associated with poor mitochondrial function in pregnancies that may better identify pregnancies ‘at risk’, or new treatments to minimise the risk of complications to the developing baby.
Dr Lauren Booker, Prof Timothy Skinner, Dr Jo Spong, Ms Melissa Deacon-Crouch, Dr Danielle Wilson
(Sum provided $50,000)
Research has shown that human breastmilk provides more than nutritional benefits to a baby. It has been shown that breastmilk contains melatonin and cortisol, hormones associated with regulating the sleep-wake cycle. The concentrations, in healthy non-shift working mothers, clearly exhibiting a 24-hour pattern, which varies throughout the morning and evening. Melatonin, which promotes sleep onset, can barely be detected in daytime milk, but rises in the evening and peaks around 3am. Cortisol, promotes alertness and can be more than double the concentration in morning breast milk compared to evening breast milk. It is thought that these hormones may help provide sleep timing information to infants, thereby supporting/enabling the development of their own circadian cycle.
Circadian timing is important because a person’s circadian rhythm regulates a range of bodily functions, not just sleep, including feeding patterns, core body temperature, hormone production, regulation of glucose and insulin levels, cell regeneration, and many other biological activities. Infant, however, are not born with an established circadian rhythm, it develops over time.
It is theorized that giving infants mis-timed breastmilk could disrupt the development of the infant’s circadian rhythm. Mis-timed breastmilk can occur for a few different reasons:1). When a mother expresses/pumps breastmilk at a certain time, then feds the infant this milk at a different time, or 2) from disturbances of the maternal circadian rhythm such as from shift work.
In the past, human breast milk could only be consumed directly from the breast, meaning that milk was always ingested when it was produced. Now, with the advent of breast pumps and refrigeration, that’s no longer the case. The problem with the convenience of expressing breast milk and storing it is that it is then potentially consumed at different times of the day to when it was expressed. Mothers who express/pump milk, tend to do so via breast pump and then frozen or refrigerated for later use. Infants are then given breast milk that has been expressed previously that day or night. This can result in infants receiving breastmilk that contain hormones that are promoting either sleep or alertness, potentially impacting on their circadian rhythm development.
In addition, mothers who undertake shift work, are working during times that conflict with their sleep/wake cycles. Due to the disruption between a mother’s natural circadian timing and their shift work schedules, it is feasible to suggest that mothers who are working shift work and breastfeeding might also have a change in the timing of melatonin and cortisol in their breastmilk.
The consequences of mis-timed breastmilk and the impact of an infant circadian development could potentially be substantial. Based on previous adult research that has explored circadian misalignment disorders in adults, there are possibly significant physical and mental health consequences including an increased risk of diabetes, hypertension, high cholesterol, cardiovascular disease, and obesity. It is not unreasonable to extrapolate these findings out to potentially impact on infants as well.
Therefore, it is important to explore the issue of mis-timed breastmilk. The objective of this project to investigate the impact of disturbances of maternal circadian rhythm on breastmilk by exploring whether breastmilk composition changes when mothers work shift work.
A/Prof Natalie Hannan, Prof Sue Walker, Dr Alina Roman
Mercy Hospital for Women
(Sum provided $59,948)
Preeclampsia is a condition that causes significant illness to both mothers and their babies. In preeclamptic pregnancies the placenta is in a state of stress caused by poor oxygenation, this
results in the release of pro-inflammatory and toxic damaging factors into the maternal circulation. These toxins spread throughout the body causing major damage to the mother’s blood vessels and her major organs, especially the cardiovascular system. Currently no effective treatment exists, apart from the removal of the placenta and as a consequence the baby is born prematurely to save the mother. A therapeutic approach is urgently needed. In this project, we aim to demonstrate that neutralizing the toxic factors in the mother’s blood stream offers a very promising therapeutic approach. Using an innovative biologic drug approach we will test two new drugs, etanercept and certolizumab, traditionally used to treat rheumatoid arthritis and inflammatory bowel disease. They work by directly neutralizing the toxic inflammatory factors tumour necrosis factor-alpha (TNF-a). They have been shown to effectively reduce the injury to tissue as well as preventing tissue stress. Here we will examine their benefit in the preeclamptic placenta and maternal blood vessels. We will demonstrate whether they can decrease injury to the placenta as well as maternal blood vessels, which would reduce the mother’s clinical symptoms allowing the pregnancy to continue to a safer time to deliver. If successful and advanced for use in the clinic, it would be a breakthrough in the management of preeclampsia, dramatically improving outcomes for both the mother and the baby.
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