Testing the first treatment to protect babies of asthmatic women from lung disease – a pilot study

Chief Investigator: Dr Kathryn Gatford

Funding Amount: $85,000

Recipient: University of Adelaide

Overview:

Babies of mothers who have asthma are more likely to have problems breathing at birth, including respiratory distress syndrome. There are NO treatments available to protect babies of asthmatic women from neonatal lung problems. We have provided the first evidence that maternal asthma delays fetal lung maturation, and we will now use our pre-clinical model to test whether a clinically-used therapy to promote lung maturation protects babies of asthmatic mothers from neonatal lung disease. If this therapy is effective, it will reduce the numbers of Australian babies requiring admission to special care or neonatal intensive care units by 945-1075 /year.

Research Outcomes:

Researchers: Kathryn Gatford, Janna Morrison, Michael Stark, Andrew Tai, Beverly Muhlhausler, Robert Bischof, Vicki Clifton, Tim Moss, Megan Wallace

Research Completed: 2022

Research Findings: Babies of mothers who have asthma are more likely to have problems breathing at birth, including respiratory distress syndrome. In this study, we have tested the first treatment to prevent neonatal lung disease in infants of asthmatic mothers, with some benefits. We have also used this study to investigate whether pregnancy makes asthma worse, and to look at effects on progeny lungs that might explain long-term increased risk of asthma.

Key Outcomes:

Babies of mothers who have asthma are more likely to have problems breathing at birth, including respiratory distress syndrome. We have generated evidence in a preclinical model of asthma in pregnancy that suggests the lungs of the offspring appear immature. As there are NO current treatments available to protect babies of asthmatic women from neonatal lung problems, the aim of this project was to perform a pilot preclinical study to test the first treatment to prevent neonatal lung disease in infants of asthmatic mothers, including the first functional assessments of the impact of asthma on lung function in the neonate.

Experimental work for this project was conducted over 2020 and 2021 in order to generate sufficient pregnancies to test our hypothesis. In addition to the primary aim above, we have leveraged this project to answer two additional questions:

• Does pregnancy make asthma worse? (unclear from human studies)

• Does exposure to asthma before birth alter development of lung airways? (which might explain the increased risk of asthma in children whose mothers had asthma during pregnancy)

Aim 1 – does antenatal betamethasone improve neonatal lung function after maternal asthma?

We have studied lung function and structure in lambs born to control ewes (n=17), asthmatic ewes (n=14) and asthmatic ewes who had been treated with antenatal betamethasone (n=12), with the final in vivo experiments completed in November 2021. Analyses of lung structure and surfactant expression are in progress. To date, we have found that lung function was not impaired in lambs whose mothers had asthma, possibly reflecting a lack of mechanical changes in the lung. Antenatal betamethasone did improve outcomes in lambs of asthmatic ewes, even in these term-born animals. For example, dynamic compliance, inversely related to how much effort is required to breathe, was higher in betamethasone-exposed lambs than in lambs from untreated asthmatic ewes. This Aim formed the basis for an Honours project in 2020- 2021 (Joshua Robinson, supervised by Kathy Gatford, Michael Stark, Janna Morrison, Megan Wallace, recipient of a HDA and Channel 7 Children’s Research Foundation PhD Excellence Award 2022) and Josh is now continuing with his analysis of the neonatal outcomes for the first chapter of his PhD studies (2021- 2024, supervised by Michael Stark, Kathy Gatford, Janna Morrison and Vicki Clifton).

Aim 2 – does pregnancy make asthma worse?

Lung function was measured in ewes before mating, in early pregnancy and again in late pregnancy, before antenatal treatment. Our analyses of the functional data show worsening of dynamic compliance in asthmatic compared to control ewes, but that the impairment was similar regardless of whether ewes were nonpregnant, pregnant with singletons or pregnant with twins. We are currently completing analyses of lung structure, immune responses and inflammatory markers, in order to thoroughly compare phenotypes of pregnant and non-pregnant as well as control and asthmatic ewes. This Aim formed the basis for an Honours project in 2020 (Andrea Roff, supervised by Kathy Gatford, Janna Morrison, Rob Bischof) and Andrea is now continuing with her analysis of the maternal outcomes for the first chapter of her PhD studies, with the same supervisory team (2021-2023). This aspect of the project has also supported research training of four 3rd year Bachelor of Health & Medical Sciences program students undertaking research placements during 2020-2022.

Aim 3 – does exposure to asthma before birth alter development of lung airways? Airways were collected from the cohort of lambs described above in Aim 1 and are being analysed for size as well as assessment of structures that change during remodelling of active asthma (collagen and smooth muscle) and/or are predictors of later asthma development (reticular basement membrane thickness). This has been completed for the 2020 tissues, and we are seeing trends for smaller airways in lambs whose mothers had experimental asthma. Statistical analysis requires additional numbers, and sectioning, staining and imaging of airways from the 2021 cohort is underway. This Aim formed the basis for an Honours project in 2021 (Sarah Hammond, supervised by Kathy Gatford, Janna Morrison, Andrew Tai and Megan Wallace) and will be completed in 2021 in parallel with Sarah’s PhD work on a different project in fetal development and pregnancy complications. Our preliminary results suggest that antenatal betamethasone can improve neonatal lung function, but that asthma does not impair this outcome, in ventilated newborns. If our maternal results are supported by the additional outcomes, this will support advice to women that they can improve asthma and reduce associated risks to themselves and their baby by adhering to asthma management plans, and that pregnancy itself should not worsen asthma.

Research Papers:

Publications in preparation:

Analyses of 2021 samples and images will be completed in the first half of 2021 and will generate papers relating to each aim:

• Antenatal betamethasone and neonatal lung function after maternal asthma

• Effects of pregnancy on asthma progression

• The impact of maternal asthma on neonatal airway structure

Conference presentations – local

• Andrea J Roff, Joshua L Robinson, Sarah J Hammond, Andrew Davies, Vicki L Clifton, Megan J Wallace, Tim J M Moss, Jack R T Darby, Andrew Tai, Michael J Stark, PO Box 2438, REGENCY PARK SA 5942 T: +61 8 8243 8202 F: +61 8 8243 8218 E: crf@crf.org.au W: www.crf.org.au GRANT ACQUITTAL FORM Last updated MARCH 2020 PAGE 5 OF 6 Beverly S Muhlhausler, Robert J Bischof, Janna L Morrison and Kathryn L Gatford. Asthma progression during pregnancy. Australian Society for Medical Research SA Scientific Meeting, June 2021. Oral presentation A Roff.

• Sarah J. Hammond, Andrea J. Roff, Joshua L. Robinson, Jack R. T. Darby, Tim J. M. Moss, Ashley Meakin, Vicki L. Clifton, Andrew Davies, Beverly S. Muhlhausler, Robert J. Bischof, Michael J. Stark, Megan J. Wallace, Andrew Tai, Janna L. Morrison and Kathryn L. Gatford. Does in utero exposure to maternal asthma affect fetal airway development? University of Adelaide Undergraduate Research Conference, July 2021. Oral presentation S Hammond

• Sarah J. Hammond, Andrea J. Roff, Joshua L. Robinson, Jack R. T. Darby, Tim J. M. Moss, Ashley Meakin, Vicki L. Clifton, Andrew Davies, Beverly S. Muhlhausler, Robert J. Bischof, Michael J. Stark, Megan J. Wallace, Andrew Tai, Janna L. Morrison and Kathryn L. Gatford. The impact of maternal asthma during pregnancy on fetal airway development, Australian Society for Medical Research Annual Meeting, June 2021. Oral presentation S Hammond • Kathryn L Gatford. “Understanding and alleviating the impacts of maternal asthma”. HBI Symposium, University of South Australia. August 2021. Invited symposium KL Gatford

• Andrea J Roff, Joshua L Robinson, Sarah J Hammond, Andrew Davies, Vicki L Clifton, Megan J Wallace, Tim J M Moss, Jack R T Darby, Andrew Tai, Michael J Stark, Beverly S Muhlhausler, Robert J Bischof, Janna L Morrison and Kathryn L Gatford. Asthma progression during pregnancy. Florey Postgraduate Research Conference, September 2021. Poster presentation A Roff.

• Andrea J Roff, Joshua L Robinson, Sarah J Hammond, Andrew Davies, Vicki L Clifton, Megan J Wallace, Tim J M Moss, Jack R T Darby, Andrew Tai, Michael J Stark, Beverly S Muhlhausler, Robert J Bischof, Janna L Morrison and Kathryn L Gatford. Asthma progression during pregnancy. Nutrition, Diabetes and Gut Health 2021 Conference, December 2021. Oral presentation A Roff.

• Sarah J. Hammond, Andrea J. Roff, Joshua L. Robinson, Jack R. T. Darby, Tim J. M. Moss, Ashley Meakin, Vicki L. Clifton, Andrew Davies, Beverly S. Muhlhausler, Robert J. Bischof, Michael J. Stark, Megan J. Wallace, Andrew Tai, Janna L. Morrison and Kathryn L. Gatford. Does in utero exposure to maternal asthma affect fetal airway development? Nutrition, Diabetes and Gut Health Conference, December 2021. Oral presentation S Hammond. Conference presentations – national

• Kathryn L Gatford. “Asthma in pregnancy”. Placental Symposium, CRE for Stillbirth Prevention. December 2021. Invited symposium KL Gatford

• Kathryn L Gatford. “Teasing apart the yin and yang of asthma and pregnancy”, ANZ DOHaD monthly seminar series, February 2022. Invited symposium KL Gatford

Conference presentations – international

• Andrea J Roff, Joshua L Robinson, Sarah J Hammond, Andrew Davies, Vicki L Clifton, Megan J Wallace, Tim J M Moss, Jack R T Darby, Andrew Tai, Michael J Stark, Beverly S Muhlhausler, Robert J Bischof, Janna L Morrison and Kathryn L Gatford. Asthma progression during pregnancy. Fetal and Neonatal Physiological Society 47th Annual Meeting, October 2021. Oral Presentation A Roff.

• Joshua L Robinson, Andrea J Roff, Sarah J Hammond, Jack RT Darby, Andrew Tai, Timothy J Moss, Ashley Meakin, Vicki L Clifton, Andrew Davies, Beverley S Muhlhausler, Robert J Bischof, Janna L Morrison, Megan J Wallace, Michael J Stark, and Kathryn L Gatford. Efficacy of betamethasone to prevent poor pulmonary outcomes at birth in an experimental model of maternal asthma. Fetal and Neonatal Physiology Society Conference, October 2021. Oral presentation J Robinson. • Sarah J. Hammond, Andrea J. Roff, Joshua L. Robinson, Jack R. T. Darby, Tim J. M. Moss, Ashley Meakin, Vicki L. Clifton, Andrew Davies, Beverly S. Muhlhausler, Robert J. Bischof, Michael J. Stark, Megan J. Wallace, Andrew Tai, Janna L. Morrison and Kathryn L. Gatford. Does in utero exposure to maternal asthma affect fetal airway development? Fetal and Neonatal Physiological Society Annual Meeting, October 2021. Poster presentation and flash talk S Hammond.

Related Publications:

Future Outcomes:

Testing the first treatment to protect babies of asthmatic women from lung disease – a pilot study

Research Outcomes:

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