The Regulation of the Innate Immune System in Preterm Neonates

Preterm delivery is the leading contributor to neonatal death globally, with half of these deaths being associated with inflammatory conditions. An immature ability to regulate the innate immune response may contribute to the higher rate of morbidity and mortality among preterm neonates. Neonates rely on their innate immune response to protect them from infection. Toll-like receptors (TLRs) are ubiquitously expressed innate immune receptors that signal for pro-inflammatory cytokine transcription. This process requires strict regulation at different levels of its intracellular signalling cascade to avoid pathological inflammation. MicroRNAs (miRs) are post-transcriptional regulators that have been identified as critical regulators of inflammatory gene expression. Currently, miR expression is sparsely characterised in the context of neonatal TLR signalling. This thesis therefore aimed to examine immune regulation by term and preterm neonates through characterising the expression of miRs that regulate TLR signalling in placenta and cord blood. Cord blood and placenta were collected following term (≥ 37 weeks gestation), late preterm (32-36 weeks) and early preterm delivery (≤ 32 weeks), and assessed for baseline gene expression (Chapters 3 and 4). Cord blood was cultured and stimulated with TLR2, TLR3 and TLR4 agonists, and collected over a 24 hour period (Chapters 5 and 6). RNA was extracted and the relative expression of genes associated with TLR signalling (including select miRs) was quantified using qPCR. Bioinformatics analyses were used to determine network-level alterations in inflammatory signalling using publicly available microarray data on peripheral blood from neonates with infection (Chapter 7). There was no difference in the expression of miRs or genes associated with TLR signalling in the placenta or cord blood between term and late preterm deliveries. Early preterm cord blood showed decreased miR-155 and let-7e expression at birth, and demonstrated no change in miR expression following TLR stimulation despite increasing the expression of IL6, IL10 and NF-κB1. Term and late preterm cord blood also increased IL6 expression, but this occurred alongside increased anti-inflammatory let-7e expression. Further, term cord blood increased TNFα and IL6 protein production until 6 hours in vitro, while preterm cord blood continued to increase IL6 between 6 and 24 hours post-stimulation. Bioinformatics analysis confirmed an upregulation of innate immune pathways (including JAK-STAT and Nod-like Receptor signalling) in peripheral blood from preterm neonates with infection compared to term neonates with infection. In summary, our findings demonstrate preterm cord blood is able to mount a robust response to TLR stimulation through increasing pro-inflammatory gene expression. As this response occurs in the absence of any change in the miRs we measured, we postulate that the inflammatory response is dysregulated in preterm neonates. These results are the first to suggest differential miR expression alters the neonatal innate immune response. As such, in addition to an increased risk of contracting infection, preterm neonates may be unable to regulate inflammation effectively. Inappropriate inflammatory signalling may therefore underlie preterm neonates’ susceptibility to developing chronic and acute inflammatory morbidities.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

The effects of exercise during pregnancy on placental composition : A systematic review and meta-analysis

Introduction Morphological changes to the placenta occur as the demands of the foetus increase throughout gestation. Physical activity during pregnancy is known to benefit both the mother and infant, however the impact of antenatal exercise training on placental development is less known. The aim of this systematic review and meta-analysis was to investigate the effects of exercise training during pregnancy on measures of placental composition. Methods Six electronic databases were searched from inception to June 2021 for studies comparing regular antenatal exercise with either usual maternal care or no exercise for its effect on measures of placental morphological composition. Meta-analyses were performed for placental weight and the placental weight to birthweight (PWBW) ratio. Results Seven randomised controlled trials and two cohort studies were included in the systematic review and meta-analysis (n = 9). There was no significant difference in placental weight (mean difference (MD) = -9.07g, p = 0.42) or the PWBW ratio (MD = 0.00, p = 0.32) between exercise and control groups. Parenchymal tissue volume was higher, represented by an increase in villous tissue, and non-parenchymal volume was lower in women who exercised regularly compared to those that were not exercising during pregnancy. Discussion Exercise training during pregnancy may not alter placental weight or the PWBW ratio. However, findings from this review indicate that antenatal exercise training can promote advantageous morphological changes to placental tissues

Strategies towards improving pharmacological management of asthma during pregnancy

Maternal asthma represents a significant burden to individuals and the healthcare system, affecting 1 in 10 pregnancies worldwide. Approximately 50% of asthmatic women experience a deterioration of asthma control at some stage during pregnancy, with a number requiring use of oral corticosteroids for the management of acute exacerbations. The presence of maternal asthma and exacerbations during pregnancy is a noted risk factor for a range of adverse perinatal outcomes including preterm birth, small-for-gestational age, pre-eclampsia, and gestational diabetes. These negative impacts highlight the need for evidence-based approaches for improving asthma management during pregnancy and subsequent perinatal outcomes. Despite this, relatively small progress has been made in enhancing the management of maternal asthma in the clinical setting. A major challenge in improving outcomes of asthmatic pregnancies is that there is no single simplified approach for improving outcomes, but rather the requirement to consider the dynamic relationship between a myriad of interrelated factors that ultimately determine an individual's ability to maintain adequate asthma control. Understanding how these factors are impacted by pregnancy and how they can be addressed through various interventions is therefore important in optimising health outcomes. This review summarises key factors involved in influencing outcomes associated with maternal asthma. This includes an overview of the use of asthma medications in pregnancy, while also considering the impacts of interrelated aspects such as medication adherence, health-seeking behaviours, biological and lifestyle factors, co-morbidities, and asthma self-management strategies on asthma control. Addressing such factors through multidisciplinary approaches towards treatment have potential to improve the health of mothers and their offspring. Optimising asthma control should be a high priority within the antenatal setting, with women advised about the importance of good asthma control, managing asthma actively throughout pregnancy by utilising their asthma medications, and managing exacerbations in a timely and effective manner

Longitudinal association of physical activity during pregnancy with maternal and infant outcomes: Findings from the Australian longitudinal study of women’s health

Background: Physical activity has known benefits during pregnancy; however, the optimum volume of physical activity through the different stages of pregnancy is not well known. Objectives: The aims of this study were to investigate the associations of physical activity volume in pregnant women in each trimester of pregnancy with maternal and infant outcomes. Design: The study involved 1657 pregnant women from the Australian Longitudinal Study on Women’s Health, who completed surveys from 2006 to 2012 (aged 28–39 years). Methods: Women reported being in either the first, second or third trimester of pregnancy. Women were grouped into four groups according to their self-reported physical activity during pregnancy: (1) Nil (0–<33.3 MET.min/week), (2) Low (33.3–<500 MET.min/week), (3) Moderate (500–<1000 MET.min/week) and (4) High (⩾1000 MET.min/week). Women who reported their physical activity during pregnancy completed a survey within three years after the birth, relating to outcomes associated with pregnancy and childbirth (gestational diabetes, hypertension, and antenatal depression and anxiety) and infant outcomes (birthweight and prematurity). Results: There was no association of physical activity in any trimester with infant birthweight, prematurity, gestational diabetes, hypertension or antenatal depression. Antenatal anxiety was less prevalent in women who reported low (1.7%) or moderate (1.1%) physical activity than in those who reported no activity (4.7%; p = 0.01). Conclusion: Different amounts of physical activity during pregnancy were not associated with the measured adverse health outcomes. However, low and moderate amounts of physical activity were associated with reduced incidence of antenatal anxiety

Videomicroscopy as a tool for investigation of the microcirculation in the newborn

The perinatal period remains a time of significant risk of death or disability. Increasing evidence suggests that this depends on microcirculatory behavior. Sidestream dark-field orthogonal polarized light videomicroscopy (OPS) has emerged as a useful assessment of adult microcirculation but the values derived are not delineated for the newborn. We aimed to define these parameters in well term newborn infants. Demographic details were collected prospectively on 42 healthy term neonates (n = 20 females, n = 22 males). OPS videomicroscopy (Microscan) was used to view ear conch skin microcirculation at 6, 24, and 72 h of age. Stored video was analyzed by a masked observer using proprietary software. There were no significant differences between the sexes for any structural parameters at any time point. There was a significant increase over time in small vessel perfusion in female infants only (P = 0.009). A number of 6- and 72-h measurements were significantly correlated, but differed from the 24-h values. These observations confirm the utility of the ear conch for neonatal microvascular videomicroscopy. They provide a baseline for studies into the use of OPS videomicroscopy in infants. The changes observed are comparable with previous studies of term infants using these and other microvascular techniques. It is recommended that studies for examining the mature neonatal microvascular structure be delayed until 72 h of life, but studies of the physiology of cardiovascular transition should include the 24-h time point after delivery

Early microvascular changes in the preterm neonate: a comparative study of the human and guinea pig

Dysfunction of the transition from fetal to neonatal circulatory systems may be a major contributor to poor outcome following preterm birth. Evidence exists in the human for both a period of low flow between 5 and 11 h and a later period of increased flow, suggesting a hypoperfusion-reperfusion cycle over the first 24 h following birth. Little is known about the regulation of peripheral blood flow during this time. The aim of this study was to conduct a comparative study between the human and guinea pig to characterize peripheral microvascular behavior during circulatory transition. Very preterm (≤28 weeks GA), preterm (29-36 weeks GA), and term (≥37 weeks GA) human neonates underwent laser Doppler analysis of skin microvascular blood flow at 6 and 24 h from birth. Guinea pig neonates were delivered prematurely (62 day GA) or at term (68-71 day GA) and laser Doppler analysis of skin microvascular blood flow was assessed every 2 h from birth. In human preterm neonates, there is a period of high microvascular flow at 24 h after birth. No period of low flow was observed at 6 h. In preterm animals, microvascular flow increased after birth, reaching a peak at 10 h postnatal age. Blood flow then steadily decreased, returning to delivery levels by 24 h. Preterm birth was associated with higher baseline microvascular flow throughout the study period in both human and guinea pig neonates. The findings do not support a hypoperfusion-reperfusion cycle in the microcirculation during circulatory transition. The guinea pig model of preterm birth will allow further investigation of the mechanisms underlying microvascular function and dysfunction during the initial extrauterine period

The Health-e Babies App for antenatal education: Feasibility for socially disadvantaged women

BackgroundThe use of mobile technology such as phone applications (apps) has been proposed as an efficient means of providing health and clinical information in a variety of healthcare settings. We developed the Health-e Babies app as an Android smart phone application for pregnant women attending a tertiary hospital in a low socio-economic community, with the objective of providing health information about early pregnancy that would increase maternal confidence and reduce anxiety. Based on our earlier research, this form of health communication was viewed as a preferred source of information for women of reproductive age. However, the pilot study had a poor participation rate with 76% (n = 94) not completing the study requirements. These initial findings raised some very important issues in relation to the difficulties of engaging women with a pregnancy app. This paper analyses the characteristics of the participants who did not complete the study requirements in an attempt to identify potential barriers associated with the implementation of a pregnancy app.MethodsThis retrospective review of quantitative and qualitative data collected at the commencement of the Health-e Babies App trial, related to the participant's communication technology use, confidence in knowing where to seek help and mental health status, maternal-fetal attachment and parenting confidence. Engagement and use of the Health-e Babies App&#13; was measured by the completion of a questionnaire about the app and downloaded data from participant's phones. Mental health status, confidence and self-efficacy were measured by questionnaires.ResultsAll women were similar in terms of age, race, marital status and level of education. Of the 94 women (76%) who did not complete the trial, they were significantly more anxious as indicated by State Trait Anxiety Inventory (p = 0.001 Student T-test) and more likely to be unemployed (50% vs 31%, p = 0.012 Student T-Test).ConclusionThis study provides important information about the challenges associated with the implementation of a pregnancy app in a socially disadvantaged community. The data suggests that factors including social and mental health issues, financial constraints and technological ability can affect women’s engagement with a mobile phone app

The Effects of COVID-19 on the Placenta During Pregnancy.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission

Improving asthma during pregnancy with dietary antioxidants: the current evidence

The complication of asthma during pregnancy is associated with a number of poor outcomes for the mother and fetus. This may be partially driven by increased oxidative stress induced by the combination of asthma and pregnancy. Asthma is a chronic inflammatory disease of the airways associated with systemic inflammation and oxidative stress, which contributes to worsening asthma symptoms. Pregnancy alone also intensifies oxidative stress through the systemic generation of excess reactive oxidative species (ROS). Antioxidants combat the damaging effects of ROS; yet antioxidant defenses are reduced in asthma. Diet and nutrition have been postulated as potential factors to combat the damaging effects of asthma. In particular, dietary antioxidants may play a role in alleviating the heightened oxidative stress in asthma. Although there are some observational and interventional studies that have shown protective effects of antioxidants in asthma, assessment of antioxidants in pregnancy are limited and there are no antioxidant intervention studies in asthmatic pregnancies on asthma outcomes. The aims of this paper are to (i) review the relationships between oxidative stress and dietary antioxidants in adults with asthma and asthma during pregnancy, and (ii) provide the rationale for which dietary management strategies, specifically increased dietary antioxidants, might positively impact maternal asthma outcomes. Improving asthma control through a holistic antioxidant dietary approach might be valuable in reducing asthma exacerbations and improving asthma management during pregnancy, subsequently impacting perinatal health.Jessica A. Grieger, Lisa G. Wood and Vicki L. Clifto

The impact of iodine supplementation and bread fortification on urinary iodine concentrations in a mildly iodine deficient population of pregnant women in South Australia

Abstract Mild iodine deficiency during pregnancy can have significant effects on fetal development and future cognitive function. The purpose of this study was to characterise the iodine status of South Australian women during pregnancy and relate it to the use of iodine-containing multivitamins. The impact of fortification of bread with iodized salt was also assessed. Women (n = 196) were recruited prospectively at the beginning of pregnancy and urine collected at 12, 18, 30, 36 weeks gestation and 6 months postpartum. The use of a multivitamin supplement was recorded at each visit. Spot urinary iodine concentrations (UIC) were assessed. Median UICs were within the mildly deficient range in women not taking supplements (&lt;90 μg/L). Among the women taking iodine-containing multivitamins UICs were within WHO recommendations (150-249 μg/L) for sufficiency and showed an increasing trend through gestation. The fortification of bread with iodized salt increased the median UIC from 68 μg/L to 84 μg/L (p = .011) which was still in the deficient range. Pregnant women in this region of Australia were unlikely to reach recommended iodine levels without an iodine supplement, even after the mandatory iodine supplementation of bread was instituted in October 2009