RESEARCH 2021

2021 Research Grants

Lay summaries are provided below of the Research Grants given in 2021.

Guaranteeing the health of mothers and babies at risk of haemolytic disease of the newborn

Professor Ian Wicks, Dr Behnaz Heydarchi, Professor David Irving,

Walter & Eliza Hall Institute of Medical Research

(Sum provided $60,000)

Antibodies are naturally occurring molecules produced by the B-lymphocytes in our immune
system to help protect against infection and disease. Rhesus D (RhD) is a type of blood group
which is found on human red blood cells. Approximately 85% of people are RhD positive (RhD+)
and 15% are RhD negative (RhD-). When an RhD- mother is carrying an RhD+ infant, foetal red
blood cells (RBCs) enter the maternal circulation, sensitizing the mother and provoking an
antibody response to the RhD molecule. This ‘anti-D response’ increases with each pregnancy
and can cause destruction of the baby’s red blood cells, known as hemolytic disease of the
newborn (HDN). HDN can lead to miscarriage or stillbirth. HDN has been a major cause of
infant mortality throughout history, and it is still so in many parts of the world.

In the 1960s, an Australian doctor (Dr John Gorman), suggested that anti-RhD serum (i.e.
serum containing anti-RhD antibodies) might be given to RhD- women in order to rapidly
remove the small population of RhD+ blood cells that enter the maternal circulation, and thereby
avoid sensitization of the mother’s immune system. This proved to be remarkably successful
and since then the standard of care clinically has been to treat RhD- women preventatively (at
28 and 34 weeks of pregnancy) with anti-RhD serum. As a result, HND is now rare in developed
countries and Gorman and colleagues were awarded the Lasker prize in 1980 for this major
clinical breakthrough in obstetric medicine.

Anti-RhD plasma is derived from a small pool of altruistic blood donors who have been screened
for the presence of anti-RhD antibodies by the Red Cross Blood Bank. These donors are then
periodically boosted with RhD+ RBCs to boost the immune system and maintain high levels of
anti-D antibodies. In Australia, some donors (often referred to as ‘super producers’) have
donated blood over 1,000 times for this purpose, but in many parts of the world, no such
service exists.

This study represents a major new collaboration between WEHI and the Australian Red Cross
Life Blood Service, which coordinates the national anti-RhD donor program and has a
longstanding research interest in HDN. The project will apply cutting edge technology to
understand the antibody response that causes HDN. WEHI will contribute its expertise in B cell
biology, proteomics, bioinformatics and monoclonal antibodies to analyse this ‘experiment of
nature’. Although WEHI has a long history in B cell immunology (including Macfarlane Burnet’s
Nobel Prize), this is the institute’s first attempt to characterise naturally occurring human
antibodies. Given the foundational nature of this work and the restrictions on anti-RhD donors
imposed by COVID, we request two years of funding to establish the project.

In collaboration with Red Cross and their donors in the Australian anti-RhD program, we
will explore the B cells and antibody repertoire of ‘super producers’, with the ultimate
aim of developing a standardised therapeutic antibody for use globally.

Particularly in low and middle-income countries, HDN still affects thousands of babies annually.
Worldwide estimates for 2010 were 141,000 foetal and neonatal deaths and 27,000 cases of
neonatal jaundice (with the risk of lifelong neurological dysfunction) from HDN. If problems
(such as viral pandemics) reduce supply of these therapeutic anti-RhD antibodies, HDN with its
attendant miseries for mothers and babies, could be commonplace again.

Assessing fetal growth to identify babies at increased risk of death and developmental disability

Dr Teresa MacDonald, Prof Sue Walker, Dr Richard Hiscock

Mercy Hospital for Women

(Sum provided $56,540)

Ultrasound is commonly used in pregnancy to assess babies’ size. This is often performed to try and detect placental insufficiency. In this condition, the placenta is unable to meet the oxygen and nutritional demands of the growing fetus, growth slows and this results in a small baby. Placental insufficiency is hugely important because it is associated with increased risks of death, of survival with long-term disability, and with adult diseases. 

Being a small baby due to placental insufficiency is the single biggest risk factor for stillbirth – the death of the baby before it is born. This is due to the baby being starved of oxygen. Likewise, where there is placental insufficiency, the low oxygen levels can also lead to brain injury. Small babies are more likely to show signs of low oxygen during labour – which is a stress test for them – and are known to be at increased risk of developmental disability from cerebral palsy compared to those with normal placental function.

While pregnancy and birth are times of high risk for a baby with placental insufficiency, the consequences of this condition also continue into adulthood. In the face of low oxygen levels, babies in the womb preferentially send blood flow and oxygen to their brain. This reduces blood flow to the kidneys, stunting their development and increasing the risks of kidney disease and high blood pressure in adulthood. Nutritional deficits from the poorly functioning placenta also mean that small fetuses are programmed for a life of starvation. Once born and fed in the outside world, this translates to a lifelong predisposition to obesity and diabetes. Babies that suffer placental insufficiency are affected for their whole lives with higher rates of major adult diseases and earlier death. 

If placental insufficiency is detected during pregnancy, intervention is possible that can vastly reduce the risk of death, and of survival with disability. However, current detection rates are poor. Only 20-30% of babies that are small at birth are detected during pregnancy. Furthermore, placental insufficiency can also affect babies considered to be a normal size – these are therefore babies at risk who are even more difficult to identify. Promisingly, our previous work has identified an important ‘missing piece of the puzzle’. The rate of a baby’s growth during pregnancy may be just as important as the size of the baby in predicting placental insufficiency. We will now confirm these findings to translate them to clinical care. We plan to build a calculator to enable clinicians to quickly and easily calculate babies’ growth rates as either normal or low. We will then use this to calculate growth rates from all of the babies who have had two ultrasound scans during the second half of their pregnancy at the Mercy over the last 15 years. We will analyse this historic information to confirm whether assessment of the babies’ growth rates would have been able to predict the most serious and devastating consequence of placental insufficiency – stillbirth.

Stillbirth is one of the most pressing challenges in obstetrics. It is globally responsible for 2.6 million losses annually, and stillbirth rates in Australia have remained static over recent decades. Promisingly, we have found that slowing fetal growth rates in late pregnancy are associated with placental insufficiency. Babies that demonstrate slowing growth likely represent a group exposed to low oxygen levels – which can cause disability and stillbirth – but they currently remain largely unrecognised.

We plan to confirm slowing growth trajectory as a new sign of placental insufficiency in this study. We will utilise our very large database of ultrasound scans to assess the relationship between fetal growth rates and the ultimate end-point of placental insufficiency and low oxygen – stillbirth.

World-first trial of sulforaphane to improve placental and vascular function in women with preeclampsia

Dr Sarah A. Marshall

The Ritchie Centre, Monash University

(Sum provided $59,830)

Unraveling the mechanisms by which chronic hepatitis B infection is associated with
an increased risk of gestational diabetes: a prospective cohort study

Assoc/Prof Michelle Giles, Professor Joanne Said, Dr Sushena Krishnaswamy, Dr Kirsten Palmer

Department of Obstetrics and Gynaecology, Monash University,

(Sum provided $45,952)

MEDICATIONS TO TREAT MENTAL ILLNESS; WHICH ARE SAFE
FOR USE DURING PREGNANCY?

Dr Roxanne HastieDr Anthea Lindquist, Professor Stephen Tong

Mercy Hospital for Women, 

(Sum provided $49,553)

An important gap in medical care that needs to be addressed: Mental illness is one of
the most common co-existing complications that affect pregnant women, with at least 1 in 5
experiencing some form of psychiatric illness. And yet, little is known about the safety of
medications that can alleviate their suffering. Tragically, suicide is the leading cause of
maternal death during pregnancy in many high resource countries, including Australia.

Very little is known about safety and offspring outcomes following the use of medications to
treat psychiatric illness during pregnancy. This lack of evidence has made treating mental
illness during pregnancy a significant challenge, as it is not possible for clinicians to weigh
the potential benefit for the mother against the risks to the developing fetus.

To address this, we are using Victorian state-wide data to see how safe these medications
are. We will link data from over a million births to the Pharmaceutical Benefit Scheme and
identify which mothers used medications of interest during pregnancy and what the outcomes
of their pregnancies were. We will also link this data to the Australian Early Developmental
Census (AEDC) and the National Assessment Program-numeracy and literacy (NAPLAN) to
determine the effect of these medications on childhood development and educational
attainment. Together, this will allow us to find out whether taking these medications during
pregnancy adversely affects neonatal health, longer term childhood development and
education.

We will create a detailed safety profile for each medication and identify those that are safe
and those that cause harm. This will allow women and clinicians to make informed
decisions about treating mental illness during pregnancy and ultimately, improve outcomes
for mothers and babies.

Mental illness in pregnancy is common and although there are effective medications to treat
these disorders none are approved for use during pregnancy. Currently, clinicians and
patients are forced to make decisions regarding treatment with little evidence or based on
the findings of small, poor quality and often conflicting studies. Due to this lack of evidence
and the potential for harm, many women stop the medications they need when they discover
they are pregnant. This leaves women unnecessarily suffering and at high risk of
adverse outcomes themselves and for their unborn child.

Many women who choose to continue medication during pregnancy often blame themselves
if adverse newborn or child outcomes arise, such as being born small or behavioural
disorders. Currently, we are unable to rule in or out these suspicions or offer women
medications which may be safe alternatives during pregnancy.

Our investigation will provide evidence of the safety of psychotropic fetal exposure, spanning
from pregnancy outcomes to educational attainment. Such a thorough investigation has not
been done before and will provide a clear picture of the risks related to each psychotropic
medication. Ultimately, this may have direct clinical impact by allowing patients and
clinicians to make informed decisions regarding medications selection during
pregnancy. This will improve the care of women with mental illnesses during
pregnancy, whilst minimising the risks to their offspring

Developing novel MRI techniques to measure oxygen levels
in the placenta in pregnancies at risk of fetal growth
restriction

Dr Clare Whitehead, Dr Andrew Dobrotwir, Dr Stefan Kane, Dr Jacqueline Keene, Dr Ekaterina Alibrahim

Pregnancy Research Centre, The Royal Women’s Hospital

(Sum provided $58,500)

The placenta is one of the most important human organs allowing the baby to safely
develop and grow within the mother. When these complex functions are disrupted,
oxygen and nutrient supply to the baby is impaired: the baby is unable to grow properly,
oxygen levels fall and the baby may ultimately suffer a stillbirth if not delivered in time.
Current tests to image (ultrasound) the placenta cannot measure the level of oxygen
reaching the placenta from the mother and going to the baby. They can only describe
how a baby may be adapting to low oxygen levels. In late pregnancy, ultrasound does
not identify these changes in oxygen levels well, and many babies at risk of adverse
outcomes may not be identified using current tests.

Magnetic resonance imaging (MRI) is safe in pregnancy and frequently used in the clinic
to tell us information about how the baby is developing and if the placenta is attached to
womb normally. New MRI techniques have recently been developed that may be able to
tell us about how much blood is flowing from the mother to the placenta and from the
placenta to the baby. They may also allow us to measure how much oxygen is in this
blood which may allow us to better identify babies at risk of adverse outcomes when the
placenta is not working properly.

In this study we will recruit pregnant women who have a baby that is thought to be small
for gestational age (SGA) and women with normally grown babies. These women will
have an additional ultrasound scan to study the placenta and measure blood flows in the
mother and baby. They will then have an MRI performed using new advanced techniques
to tell us about the function of the placenta and oxygen levels in it. We will compare which
test (ultrasound or MRI) is best at identifying a placenta that is not working well and
therefore which small babies are lacking in oxygen, and which babies are small but
healthy. 

Currently, ultrasound is the gold standard test to identify pregnancies where the placenta
is not working well, but it will only detect 50-60% of babies that are not growing properly
in the womb. These babies are at high risk of adverse brain development and even death
due to a lack of oxygen supply. MRI can sensitively detect oxygen levels in the placenta
and blood, and may therefore be ideally placed to identify babies at risk. These high risk
babies can then be delivered before brain or tissue damage occurs to give them to the best chance of a healthy life. In contrast, those babies that are a small but have good
oxygen levels can be allowed to remain in the womb until the end of pregnancy. This is
important because preterm birth in itself may effect long term development. Currently
many small babies are being delivered early “just in case” they have low oxygen levels.
If we know that it is safe for them to stay in the womb, we can also improve their outcomes
by preventing unnecessary preterm delviery. This study will be the first in Australia to use
this new technology and is an exciting approach which may revolutionise how we care
for small babies. 

Improving patient-focused research in endometriosis:
Development and validation of a tool to measure Most Bothersome Symptom for clinical trials in endometriosis

Dr Sarah Lensen, Prof Martha Hickey, Prof Martin Healey 

Royal Women’s Hospital 

(Sum provided $54,493)

Around one in nine Australian women have endometriosis. The condition is associated with a range of symptoms which are often severe and impact on quality of life, including infertility, fatigue, and pelvic pain such as painful periods, pain with intercourse and painful bowel movements. There is considerable variation between women in the nature and severity of symptoms; some women have debilitating pain while others have no symptoms at all.

Across a wide range of health areas there is growing recognition that Patient Reported Outcome Measures (PROMS) are the optimal approach to measuring patient symptoms. PROMS are defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else” (1). PROMS can tell us whether healthcare interventions actually make a difference to people’s lives. PROMS usually take the form of a questionnaire; common examples include quality of life questionnaires and patient satisfaction surveys.

Measurement of ‘Most Bothersome Symptom’ is a new PROM proposed for endometriosis research. Most Bothersome Symptom has been measured in other health areas before, but not endometriosis. This measure is particularly valuable for conditions where the nature and severity of symptoms differ between people, such as endometriosis. For example, some women with endometriosis are most troubled by pelvic pain and others by infertility. The approach to measuring Most Bothersome Symptom is to list several common symptoms, and ask patients to rate the severity of each symptom (e.g. on a scale from 1-5). The PROM also asks which of the symptoms causes them the most bother (i.e. cause distress, interference or disruption to daily life). Patients complete this PROM before the start of treatment (e.g. before a new drug or a type of surgery, in the case of endometriosis) then again at the end of treatment. Researchers measure how the severity score has changed for the specified Most Bothersome Symptom before and after the treatment. 

As there is no PROM available to measure Most Bothersome Symptom in endometriosis, the purpose of this project is to review and literature and engage with women affected by endometriosis to determine which symptoms should be included in the list, and then to develop and validate the Most Bothersome Symptom PROM. The final PROM will be a brief (one page) questionnaire. It will be recommended for use in all clinical trials of treatments for endometriosis and can also be used in clinical practice to monitor symptoms over time.  

Endo:Outcomes is an international consensus project which recently selected Most Bothersome Symptom as a core outcome for measurement in all future trials for endometriosis interventions (2). Development and validation of this new PROM will have two major impacts. First, it will provide a validated PROM for measuring an outcome prioritised by clinicians, researchers and women with endometriosis. This will be the first PROM in endometriosis to measure changes in symptoms that are most troublesome for women. Availability of this PROM will allow for future research to collect and measures this outcome, improving the standard of research and enabling better understanding of the impact of treatment options on symptoms that bother women.

Secondly, the delivery of this tool will enable realisation of the Endo:Outcomes Core Outcome Set which requires a tool to measure Most Bothersome Symptom before the outcome set can be implemented internationally. Implementation of Endo:Outcomes will help to ensure that clinical trials in endometriosis measure the same outcomes, which are prioritised by clinicians, researchers and women with endometriosis, thereby allowing the most patient-focused comparison of different treatments options.

Whilst the Most Bothersome Symptom PROM is intended primarily for use as an outcome measure in randomised clinical trials, it can also be used to determine inclusion criteria for clinical trials or to measure how symptoms change over time in other research or clinical settings. Therefore, the availability of this validated PROM will generate important new information about symptoms in women with endometriosis, which will inform further research and target new treatments towards symptoms that have the most impact on women. This is particularly important for endometriosis where disease staging is based on the surgical extent of disease and does not include a measure of patient symptoms (3).

Does serum AMH aid in the diagnosis of polycystic ovary syndrome?

Professor Susan Davis, Professor Robin Bell, Dr Rakibul Islam

Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University

(Sum provided $56,473)

Polycystic ovary syndrome, often called “PCOS”, is a health condition that is thought to affect as many
as 10% of premenopausal women. However, because the diagnosis of PCOS is not straightforward,
this figure remains uncertain.
Typical features of PCOS include irregular or absent menstrual cycles, clinical changes suggesting
hormonal imbalance (typically excessive hair facial/body hair) and high blood levels of androgens
(testosterone and hormones that have testosterone-like effects). Affected women may have a high
number of developing eggs in their ovaries which appear as little ‘cysts’ on ultrasound. PCOS is
associated with reduced fertility and metabolic changes that predispose women to diabetes.

The challenge is that what constitutes “excess hair growth” or “elevated blood testosterone” or even
the number of cysts in an ovary that is abnormal has not been defined. In addition, ultrasounds are
costly and requires specialist interpretation. Therefore, women who have one or two of these
characteristics, but in fact do not have PCOS, may still be labelled as having this condition. Not only
might this lead to inappropriate treatment but misdiagnosis adds the psychological burden of infertility
and ill health that may not be valid. There is an urgent need to improve the accuracy of the diagnosis
of PCOS to ensure women with PCOS are diagnosed and correctly treated, and that women with
some features that are just a variation of normal, or due to another underlying condition, are not
incorrectly labelled as having PCOS.

AMH (anti-mullerian hormone) is a protein made in the ovaries by developing eggs that can be
measured in blood. Research suggests AMH may help increase the accuracy of the diagnosis of
PCOS, but this remains highly controversial.

Our study involves a step-wise approach to determine if blood levels of AMH aid the diagnosis of
PCOS. We will compare different methods used to measure AMH in premenopausal women and
determine if women with higher blood AMH concentrations are more likely to have higher blood
androgen levels and/or ultrasound features of PCOS. The participants in this study are women who
have participated in the Australian Grollo-Ruzzene Foundation Younger Women’s Health Study which
recruited 6986 women, aged 18 to 39 years, from the community across Victoria, NSW and QLD.
Being community based this study reflects the way PCOS is manifest in the community. This research
will determine whether measurement of AMH levels aids the diagnosis of PCOS. It will determine
whether, as proposed, the measurement of AMH might replace ultrasounds for PCOS diagnosis.

Polycystic ovary syndrome (PCOS) is said to be a common condition in reproductive-aged women, but
the diagnosis is often uncertain. The symptoms and signs of PCOS 1) overlap with what is normal,
and 2) are seen in other health conditions. This highlights the lack of specificity of the accepted
clinical, biochemical and ovarian ultrasound features (polycystic ovary morphology; PCOM) used to
diagnose PCOS.
AMH, a glycoprotein made in ovarian follicles, has been nominated as an alternative to ultrasound
PCOM to diagnose PCOS. To date, studies of the use of AMH have provided provocative but
inconclusive findings. Although AMH has been shown to be higher in women with clinician-diagnosed
PCOS versus controls, whether AMH identifies women with PCOM/PCOS in an unselected population
is not known. Additionally, newly identified 11-ketoandrogens have been hailed as new indicators of
PCOS, but this has not been tested in the community.

There is an urgent need to determine whether AMH effectively identifies women with PCOM,
and possible PCOS, in an unselected sample, a critical step in evaluating the diagnostic utility
of AMH in the community, and whether 11-ketoandrogens offer any clinical value in PCOS diagnosis.
This study is the first of an unselected sample of women, with two separate AMH assays,
measurement of sex steroids by gold standard methods and high-resolution ultrasound for ovarian
assessment. We will establish whether AMH levels are associated with hyperandrogenism, and for the
first time, if the newly identified 11-ketoandrogens are associated with blood AMH levels and PCOM.

The protective effect of maternal immunisation on stillbirth and preterm birth:
does timing or number of vaccinations given together matter?

Associate Professor Michelle Giles, Professor Euan Wallace, Dr Mary-Ann Davey, Dr Miranda Davies-Tuck, Dr Kong Khai Lin

Department of Obstetrics and Gynaecology, Monash University,

(Sum provided $51,485)

This project focuses on reducing preterm birth (PTB) and stillbirth, two of the most important unresolved challenges in modern pregnancy care. About 10% of all births are preterm. With nearly one million children dying each year due to PTB, it is the most common cause of death among children under five years of age. The numbers for stillbirth are no less shocking. Worldwide, 2.6 million babies are stillborn each year, with six Australian babies stillborn every day. Worse, the overall rates of both PTB and stillbirth in Australia have barely changed in over 20 years. Reducing stillbirth has also been recognised by the Australian government as a national priority as reflected by the senate inquiry in 2018. But beyond current knowledge, there also is an urgent need to identify new and more effective strategies to prevent these pregnancy outcomes, particularly in reducing stillbirth in the preterm period. In this proposal we present a completely new approach to tackling both PTB and stillbirth. An approach that, we hope, will transform future outcomes. We have observed that maternal immunisation for whooping cough and for influenza is associated with profound reductions in both PTB and stillbirth. Stillbirth is reduced by 76% and PTB by 33% in women who are vaccinated during pregnancy. No other intervention in pregnancy comes even close to these outcomes. When we look at the lack of drop in stillbirth and PTB we see that stillbirth at term has fallen but it’s the early group which are extremely difficult to target. Maternal immunisation may hold the key to impacting on this group, which to date, have been challenging to prevent. Furthermore, this striking benefit was not due to reduced influenza or whooping cough infection but rather more likely related to changes in the immune system in response to the vaccination. In this proposal we seek to understand whether the gestation when the vaccine is given or the number of vaccines given together (whooping cough and influenza versus one alone) makes a difference to the protective effect on PTB or stillbirth.

Maternal immunisation has historically been recommended for its specific protection against diseases in the pregnant woman or her newborn baby. This project proposes to better understand the non specific benefits of maternal immunisation on pregnancy outcomes including PTB and stillbirth. Given that maternal immunisation may hold the key to prevention of up to 33% of premature births and 76% of stillbirths, defining the optimal time to achieve this is crucial. This would confirm the place of maternal immunisation as part of a “three for one” deal including disease-specific protection for the mother and newborn baby, and non-specific immunological benefits leading to protection for the fetus. PTB is the single biggest cause of newborn death in the world, therefore, the scope of impact that new insights into this devastating and costly outcome is enormous. Stillbirth not only leads to emotional and psychological devastation, but the cost to the healthcare system is estimated to be 10-70% more than a live birth. The total projected direct and indirect costs of stillbirth to the Australian economy are estimated to be $681.4 million for the five-year period from 2016 to 2020. The average cost of care for each preterm baby is $70,517. Therefore, with over 26,000 babies per year born preterm in Australia, significantly reducing this number by a low cost intervention such as maternal immunisation, has potential for significant healthcare cost savings. Furthermore, findings from our work are relevant to all settings given that influenza vaccine is yet to be introduced into many maternal immunisation programs in countries with some of the highest rates of PTB and stillbirth in the world. Our findings may provide further justification for acceleration of the maternal immunisation agenda in these settings including the addition of pertussis vaccine.

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