Preclinical models of maternal asthma and progeny outcomes: a scoping review.

There is an increased risk of adverse perinatal outcomes in the ∼17% of women with asthma during pregnancy. The mechanisms linking maternal asthma and adverse outcomes are largely unknown, but reflect joint effects of genetics and prenatal exposure to maternal asthma. Animal models are essential to understand the underlying mechanisms independent of genetics and comorbidities, and enable safe testing of interventions. This scoping review aimed to explore the methodology, phenotype, characteristics, outcomes and quality of published studies using preclinical maternal asthma models. MEDLINE (PubMed), Embase (Elsevier) and Web of Science were systematically searched using previously validated search strings for maternal asthma and for animal models. Two reviewers independently screened titles and abstracts, full texts, and then extracted and assessed the quality of each study using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) 2.0 guidelines. Out of 3618 studies identified, 39 were eligible for extraction. Most studies were in rodents (86%) and all were models of allergic asthma. Maternal and progeny outcomes included airway hyperresponsiveness, airway resistance, inflammation, lung immune cells, lung structure and serum immunoglobulins and cytokines. Experimental design (100%), procedural details (97%) and rationale (100%) were most often reported. Conversely, data exclusion (21%), blinding (18%) and adverse events (8%) were reported in a minority of studies. Species differences in physiology and timing of development, the use of allergens not relevant to humans and a lack of comparable outcome measures may impede clinical translation. Future studies exploring models of maternal asthma should adhere to the minimum core outcomes set presented in this review.

Child development education in the Neonatal Unit: Understanding parent developmental literacy needs, priorities and preferences.

OBJECTIVE: To describe child development knowledge needs, priorities, and preferences for education to enhance developmental literacy among parents with children admitted to the neonatal unit (NNU). METHODS: Two separate cohorts completed a survey; 1) Parents with children graduated from Australian NNUs (n = 316); 2) Parents with infants' inpatient at two South Australian NNUs (n = 209). RESULTS: Parents considered it extremely important to understand child development (Graduates: 80%; Inpatients: 71%). Inpatient parents reported lower child development knowledge. Almost half (42%) of graduate parents described the child development education provided by neonatal staff as poor or inadequate. There was consistency in preferences for developmental literacy education provision. Parents desired education to commence during NNU and continue post discharge. Priorities included content specific to preterm birth and how to support child development over the first two years of life. Individualised education by a Neonatal Nurse/Midwife was most preferred. CONCLUSION: Mothers and fathers value guidance to support their child's development during NNU admission and early childhood. Our study highlights the importance of improved early developmental literacy education for parents with children admitted to the neonatal unit. PRACTICE IMPLICATIONS: Our findings can be used to inform the creation of future educational resources targeting improved parent developmental literacy.

Thresholds for Red Blood Cell Transfusion in Preterm Infants: Evidence to Practice.

Rapid blood loss with circulatory shock is dangerous for the preterm infant as cardiac output and oxygen-carrying capacity are simultaneously imperilled. This requires prompt restoration of circulating blood volume with emergency transfusion. It is recommended that clinicians use both clinical and laboratory responses to guide transfusion requirements in this situation. For preterm infants with anemia of prematurity, it is recommended that clinicians use a restrictive algorithm from one of two recently published clinical trials. Transfusion outside these algorithms in very preterm infants is not evidence-based and is actively discouraged.

Study protocol of the WashT Trial: transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks' gestation - a multicentre, blinded, parallel group, randomised controlled trial.

INTRODUCTION: Many extremely preterm newborns develop anaemia requiring a transfusion, with most receiving three to five transfusions during their admission. While transfusions save lives, the potential for transfusion-related adverse outcomes is an area of growing concern. Transfusion is an independent predictor of death and is associated with increased morbidity, length of hospital stay, risk of infection and immune modulation. The underlying mechanisms include adverse pro-inflammatory and immunosuppressive responses. Evidence supports an association between transfusion of washed red cells and fewer post-transfusion complications potentially through removal of chemokines, lipids, microaggregates and other biological response modifiers. However, the clinical and cost-effectiveness of washed cells have not been determined. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blinded trial of washed versus unwashed red cells. Infants <28 weeks' gestation requiring a transfusion will be enrolled. Transfusion approaches will be standardised within each study centre and will occur as soon as possible with a recommended fixed transfusion volume of 15 mL/kg whenever the haemoglobin is equal to or falls below a predefined restrictive threshold, or when clinically indicated. The primary outcome is a composite of mortality and/or major morbidity to first discharge home, defined as one or more of the following: physiologically defined bronchopulmonary dysplasia; unilateral or bilateral retinopathy of prematurity grade >2, and; necrotising enterocolitis stage ≥2. To detect a 10% absolute reduction in the composite outcome from 69% with unwashed red blood cell (RBCs) to 59% with washed RBCs with 90% power, requires a sample size of 1124 infants (562 per group). Analyses will be performed on an intention-to-treat basis with a prespecified statistical analysis plan. A cost-effectiveness analysis will also be undertaken. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Women's and Children's Health Network Human Research Ethics Committee (HREC/12/WCHN/55). The study findings will be disseminated through peer-reviewed articles and conferences. TRIAL REGISTRATION NUMBER: ACTRN12613000237785 Australian New Zealand Clinical Trials Registry.

PKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN-γ propensity.

A significant number of babies present transiently with low protein kinase C zeta (PKCζ) levels in cord blood T cells (CBTC), associated with reduced ability to transition from a neonatal Th2 to a mature Th1 cytokine bias, leading to a higher risk of developing allergic sensitisation, compared to neonates whose T cells have 'normal' PKCζ levels. However, the importance of PKCζ signalling in regulating their differentiation from a Th2 to a Th1 cytokine phenotype propensity remains undefined. To define the role of PKCζ signalling in the regulation of CBTC differentiation from a Th2 to a Th1cytokine phenotype we have developed a neonatal T cell maturation model which enables the cells to develop to CD45RA- /CD45RO+ T cells while maintaining the Th2 immature cytokine bias, despite having normal levels of PKCζ. The immature cells were treated with phytohaemagglutinin, but in addition with phorbol 12-myristate 13-acetate (PMA), an agonist which does not activate PKCζ. This was compared to development in CBTC in which the cells were transfected to express constitutively active PKCζ. The lack of PKCζ activation by PMA was monitored by western blot for phospho-PKCζ and translocation from cell cytosol to the membrane by confocal microscopy. The findings demonstrate that PMA fails to activate PKCζ in CBTC. The data show that CBTC matured under the influence of the PKC stimulator, PMA, maintain a Th2 cytokine bias, characterised by robust IL-4 and minimal interferon gamma production (IFN-γ), and lack of expression of transcriptional factor, T-bet. This was also reflected in the production of a range of other Th2/Th1 cytokines. Interestingly, introduction of a constitutively active PKCζ mutant into CBTC promoted development towards a Th1 profile with high IFN-γ production. The findings demonstrate that PKCζ signalling is essential for the immature neonatal T cells to transition from a Th2 to a Th1 cytokine production bias.

Preclinical models of maternal asthma and progeny outcomes: a scoping review protocol.

OBJECTIVE: This scoping review will describe the methodology, phenotype, and characteristics of maternal asthma models used in preclinical studies and the outcomes that have been measured in the mother and progeny. The review This will identify gaps in knowledge of maternal and progeny outcomes following maternal asthma in pregnancy. INTRODUCTION: Maternal asthma affects up to 17% of pregnancies worldwide and is associated with adverse perinatal outcomes in mothers and babies, including pre-eclampsia, gestational diabetes, cesarean section, preterm birth, small for gestational age, nursery admission, and neonatal death. While the associations are well established, the mechanisms linking maternal asthma and adverse perinatal outcomes are largely unknown due to the difficulties of human mechanistic studies. The appropriate selection of animal models is vital to understanding the mechanisms underlying associations between human maternal asthma and adverse perinatal outcomes. INCLUSION CRITERIA: This review will include primary studies published in English where outcomes have been studied in vivo in non-human mammalian species. METHODS: This review will follow the JBI methodology for scoping reviews. We will search MEDLINE (PubMed), Embase, and Web of Science to identify papers published before the end of 2022. Initial keywords will include pregnancy, gestation, asthma , and wheeze , as well as validated search strings to identify papers that describe animal models. Extracted data will include information on methods used to induce maternal asthma; asthmatic phenotypes and characteristics; and maternal, pregnancy, placental, and progeny outcomes. The characteristics of each study will be presented in summary tables and a core outcome list to assist researchers in developing, reporting, and comparing future animal studies of maternal asthma. REVIEW REGISTRATION: Open Science Framework osf.io/trwk5.

Red cell infusion but not saline is effective for volume expansion in preterm piglets.

BACKGROUND: A common first-line treatment for supporting cardiovascular function in preterm infants is volume expansion using saline, but this does not improve outcomes. This study aimed to determine if volume expansion with saline increases blood volume, blood pressure and cerebral oxygenation; and if volume expansion with packed red blood cells (RBC) is more effective. We hypothesized that RBC infusion is more effective than saline for increasing blood volume and maintaining cardiovascular function and cerebral oxygenation. METHODS: Five groups of preterm piglets (98/115d gestation) were infused with saline (10 or 20 mL/kg) or RBC (10 or 20 mL/kg) or no treatment. Blood volume, blood pressure, central venous pressure, heart rate, carotid flow, cerebral oxygenation, arterial pH, base excess, and lactate levels were assessed for 6 h after treatment started. RESULTS: Both RBC groups had significant increases in blood volume, and improved measures of cardiovascular function, cerebral oxygenation and metabolic acidosis. Saline infusion did not increase blood volume or measures of cardiovascular function, cerebral oxygenation or metabolic acidosis. CONCLUSIONS: The results suggest that the deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in premature babies, may be reversed or halted by more effective support of blood volume. IMPACT: Blood volume decreases after birth in preterm piglets and this decrease is associated with deteriorating cardiovascular function and cerebral oxygenation. Infusion of saline does not increase blood volume nor prevent deterioration in cardiovascular function. Infusion of packed red blood cells results in an increase in blood volume and improvements in cardiovascular function and cerebral oxygenation. Deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in human preterm neonates, may be reversed or halted by more effective support of blood volume.

The impact of maternal asthma on the fetal lung: Outcomes, mechanisms and interventions.

Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers.

Red Blood Cell Donor Sex Associated Effects on Morbidity and Mortality in the Extremely Preterm Newborn.

Transfusion exposure increases the risk of death in critically ill patients of all ages. This was thought to relate to co-morbidities in the transfusion recipient. However, donor characteristics are increasingly recognised as critical to transfusion recipient outcome with systematic reviews suggesting blood donor sex influences transfusion recipient health. Originally focusing on plasma and platelet transfusions, retrospective studies report greater risks of adverse outcomes such as transfusion related acute lung injury in those receiving products from female donors. There is increasing awareness that exposure to red blood cells (RBCs) poses a similar risk. Recent studies focusing on transfusion related outcomes in extremely preterm newborns report conflicting data on the association between blood donor sex and outcomes. Despite a renewed focus on lower versus higher transfusion thresholds in neonatal clinical practice, this group remain a heavily transfused population, receiving on average 3-5 RBC transfusions during their primary hospital admission. Therefore, evidence supporting a role for better donor selection could have a significant impact on clinical outcomes in this high-risk population. Here, we review the emerging evidence for an association between blood donor sex and clinical outcomes in extremely preterm newborns receiving one or more transfusions.

Differential effects of ibuprofen and indomethacin on cerebral oxygen kinetics in the very preterm baby.

Background: Ibuprofen is preferred to indomethacin for treatment of a significant patent ductus arteriosus (PDA) in preterm babies despite indomethacin being associated with a lower risk of intraventricular haemorrhage. This difference is thought to relate to the discrepant effects of each medication on cerebral oxygen kinetics yet the effect of ibuprofen on cerebral perfusion is uncertain. Methods: Forty-eight babies < 30 weeks with a significant PDA, defined by echocardiography, were randomly assigned to either indomethacin or ibuprofen (n = 24 per group) and stratified by gestation and chronologic age. Cerebral blood flow [total internal carotid blood flow (TICF)] and oxygen physiology [oxygen delivery (modCerbDO2) and consumption (modCerbVO2)] were measured using cranial Doppler ultrasound and near-infrared spectroscopy, and cerebral oxygen extraction (cFTOE) calculated, immediately before and following administration. Temporal and treatment related changes were analysed. Results: A fixed effect of time was seen for TICF (p = 0.03) and therefore modCerbDO2 (p = 0.046) and cFTOE (p = 0.04) for indomethacin alone. In the indomethacin group, TICF and modCerbDO2 fell from baseline to 5 and 30 min respectively (TICF p < 0.01, cDO2 p = 0.01) before increasing from 5 min to 24 h (p < 0.01) and 30 min and 24 h (p < 0.01) timepoints. cFTOE peaked at 30 min (p = 0.02) returning to baseline at 24 h. There was a parallel increase in arterial lactate. Conclusion: Indomethacin significantly reduces cerebral blood flow soon after administration, resulting in a parallel increase in oxygen extraction and arterial lactate. This implies that the balance of oxygen kinetics at the time of treatment may be critical in very preterm babies with significant PDA.

Parent concerns for child development following admission to neonatal intensive or special care: From birth to adolescence.

AIM: To describe the presence and nature of parent concerns regarding the development of their children admitted to Australian neonatal units (NNUs), comprising neonatal intensive care or special care. METHODS: In a cross-sectional survey, mothers and fathers provided information regarding concerns for their child's development. The self-administered survey was completed by two separate cohorts; (i) parents of child graduates from Australian NNUs (n = 381); (ii) parents of infant's inpatient in two South Australian NNUs (n = 209). Data were analysed using thematic analysis and descriptive statistics. RESULTS: Information was provided for 730 children. Developmental concern was reported for 39% of NNU graduates and 35% of inpatients. Children born very preterm (< 32 weeks' gestation) elicited greater parent concern than those born more mature (Cohort 1: 41% vs 36%; Cohort 2: 49% vs 22%), including in multiple developmental domains (Cohort 1: 17% vs 15%; Cohort 2: 28% vs 4%). Parents with inpatient infants were predominantly concerned about general development-milestones (19.1%) and the potential impact of medical or CNS issues (13.7%). Graduate parents commonly focused on specific domains, such as their child's speech-language (13.7%) and motor (12.9%) development. CONCLUSION: Neurodevelopment is a substantial source of concern for mothers and fathers during NNU admission and childhood, particularly for children born very preterm. However, in the first year of life, developmental concerns are poorly defined. This highlights the need for clinical education resources detailing infant developmental expectations and supportive strategies for parents of these high-risk infants.

Effect of washed versus unwashed red blood cells on transfusion-related immune responses in preterm newborns.

Objectives: Transfusion with washed packed red blood cells (PRBCs) may be associated with reduced transfusion-related pro-inflammatory cytokine production. This may be because of alterations in recipient immune responses. Methods: This randomised trial evaluated the effect of transfusion with washed compared with unwashed PRBCs on pro-inflammatory cytokines and endothelial activation in 154 preterm newborns born before 29 weeks' gestation. Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. Results: By the third transfusion, infants receiving unwashed blood had an increase in IL-17A (P = 0.04) and TNF (P = 0.007), whereas infants receiving washed blood had reductions in IL-17A (P = 0.013), TNF (P = 0.048), IL-6 (P = 0.001), IL-8 (P = 0.037), IL-12 (P = 0.001) and IFN-γ (P = 0.001). The magnitude of the post-transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL-12 (P = 0.001), IL-17A (P = 0.01) and TNF (P = 0.03), with the difference between the groups reaching significance by the third transfusion (P < 0.001 for each cytokine). Conclusion: The pro-inflammatory immune response to transfusion in preterm infants can be modified when PRBCs are washed prior to transfusion. Further studies are required to determine whether the use of washed PRBCs for neonatal transfusion translates into reduced morbidity and mortality.

Non-invasively Measured Venous Oxygen Saturation as Early Marker of Impaired Oxygen Delivery in Preterm Neonates.

INTRODUCTION: Adequate oxygen supply for preterm neonates may be defined through non-invasive measurement of venous oxygen saturation (SvO2) and fractional oxygen extraction using near-infrared spectroscopy (NIRS). We investigated whether there was a difference in peripheral muscle SvO2 (pSvO2) and peripheral fractional oxygen extraction (pFOE) in preterm neonates with early inflammation/infection compared to healthy subjects during the first 72 h after birth. MATERIALS AND METHODS: We retrospectively analyzed secondary outcome parameters of prospective observational studies, including preterm neonates at risk of infection in whom peripheral NIRS measurements were performed in combination with venous occlusions. Early neonatal inflammation/infection was diagnosed by clinical signs and laboratory parameters. Peripheral muscle tissue oxygenation index (pTOI) was measured using either NIRO 300 or NIRO 200-NX (both Hamamatsu Photonics, Japan) on the patients' lower legs. Using 20-s venous occlusions, pSvO2 and pFOE were calculated incorporating simultaneous measurements of arterial oxygen saturation (SpO2). RESULTS: We analyzed measurements from 226 preterm neonates (median gestational age 33.9 weeks), 64 (28.3%) of whom were diagnosed with early neonatal inflammation/infection. During the first 24 h after birth, pSvO2 (66.9% [62.6-69.2] vs. 69.4% [64.6-72.0]; p = 0.04) and pTOI (68.6% [65.3-71.9] vs. 71.7% [67.3-75.1]; p = 0.02) were lower in those neonates with inflammation/infection, while there was no such difference for measurements between 24-48 and 48-72 h. DISCUSSION: NIRS measurement of pSvO2 and pFOE is feasible and may be utilized for early detection of impaired peripheral oxygen delivery. As pTOI was also significantly lower, this parameter may serve as substitute for diminished regional oxygen supply.

Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells.

Cord blood T cells (CBTC) from a proportion of newborns express low/deficient levels of some protein kinase C (PKC) isozymes, with low levels of PKCζ correlating with increased risk of developing allergy and associated decrease in interferon-gamma (IFN-γ) producing T cells. Interestingly, these lower levels of PKCζ were increased/normalized by supplementing women during pregnancy with n-3 polyunsaturated fatty acids. However, at present, we have little understanding of the transient nature of the deficiency in the neonate and how PKCζ relates to other PKC isozymes and whether their levels influence maturation into IFN-γ producing T cells. There is also no information on PKCζ isozyme levels in the T cell subpopulations, CD4+ and CD8+ cells. These issues were addressed in the present study using a classical culture model of neonatal T cell maturation, initiated with phytohaemagglutinin (PHA) and recombinant human interleukin-2 (rhIL-2). Of the isozymes evaluated, PKCζ, ß2, δ, µ, ε, θ and λ/ι were low in CBTCs. The PKC isozyme deficiencies were also found in the CD4+ and CD8+ T cell subset levels of the PKC isozymes correlated between the two subpopulations. Examination of changes in the PKC isozymes in these deficient cells following addition of maturation signals showed a significant increase in expression within the first few hours for PKCζ, ß2 and µ, and 1-2 days for PKCδ, ε, θ and λ/ι. Only CBTC PKCζ isozyme levels correlated with cytokine production, with a positive correlation with IFN-γ, interleukin (IL)-2 and tumour necrosis factor-alpha (TNF), and a negative association with IL-9 and IL-10. The findings reinforce the specificity in using CBTC PKCζ levels as a biomarker for risk of allergy development and identify a period in which this can be potentially 'corrected' after birth.

Effect of repeat transfusion exposure on plasma cytokine and markers of endothelial activation in the extremely preterm neonate.

BACKGROUND: Very preterm newborns receive up to three to five red blood cell (RBC) transfusions, often early, after birth. Despite awareness of the association of transfusion with increases in cytokines and markers of endothelial activation, research has focused on single transfusions weeks after birth. With pathophysiologic processes contributing to the development of morbidities starting soon after delivery, we investigated the response to early, repeated transfusion exposure. STUDY DESIGN AND METHODS: Three consecutive transfusion exposures were studied in transfusion-naive infants less than 30 weeks' gestation (n = 46). Plasma cytokines and markers of endothelial activation were measured before and 2 to 4 hours after transfusion by multiplex enzyme-linked immunosorbent assay. RESULTS: The median (IQR) age was 3 (1-9) days at first transfusion, 7 (3-20) days at the second, and 18 (7-28) days at the third. Baseline concentrations did not differ between the three transfusions. Interleukin (IL)-17A and tumor necrosis factor (TNF)-α did not change after the first transfusion but increased after the second (P < .05) and third transfusions (P < .01). While IL-1ß, IL-6, and IL-8 concentrations did not differ after the first and second transfusions, all increased after the third (IL-1ß, P < .01; IL-6, P < .01; IL-8, P < .05). The magnitude of posttransfusion increase in IL-1ß, IL-17A, and TNF-α increased between the first and third transfusion exposure. CONCLUSION: Early, repeated transfusion results in alterations in proinflammatory cytokines and markers of endothelial activation in the very preterm newborn and suggests that the potential for transfusion-related immunomodulation is present in the initial days after birth rather than confined to later in the postnatal period.

High binding site occupancy of corticosteroid-binding globulin by progesterone increases fetal free cortisol concentrations.

OBJECTIVE: Corticosteroid-binding globulin (CBG) binds and transports cortisol in the circulation in high cortisol-binding affinity (haCBG) and low affinity (laCBG) forms, the latter resulting from enzyme cleavage to target cortisol delivery at sites of inflammation. CBG also has substantial progesterone binding affinity, 3-fold less than cortisol. Progesterone and cortisol are important in the maintenance of pregnancy and in fetal development, respectively. The interactions of cortisol, progesterone and CBG affinity forms have not been studied together. We examined the interaction between progesterone and cortisol with CBG during fetal development. STUDY DESIGN: A retrospective cohort analysis of 351 neonates born between January and December 2012 at the Women's and Children's Hospital, Adelaide, South Australia. Cord blood serum samples were collected immediately following delivery. Clinical data was provided by hospital records. Total cortisol, free cortisol, total progesterone, total CBG and haCBG were measured by immunoassay. RESULTS: Cord blood total and free cortisol, and progesterone concentrations increased with gestational age. Cord blood progesterone concentrations were 100-fold luteal and 10-fold those in late pregnancy maternal circulation. The proportion of haCBG to total CBG was similar to that in healthy non-pregnant adults. However, free cortisol comprised approximately 15% of total cortisol, 3-fold higher than that in adults. CONCLUSION: In a manner unique to fetal life, very high progesterone concentrations are capable of elevating free cortisol concentrations through competition with cortisol at CBG's hormone binding site, without altered binding affinity through CBG cleavage or altered CBG hormone-binding affinity. High circulating fetal progesterone concentrations compete for CBG binding with cortisol, leading to a 3-fold increase in the free cortisol fraction in cord blood. Higher free-to-bound cortisol may alter fetal cortisol distribution facilitating cortisol's roles such as neurodevelopment in concert with dehydroepiandrosterone (sulfate) and lung maturation, or support cortisol action at times of low ambient cortisol. This mechanism may underlie the known association between cortisol, progesterone and CBG, and be relevant principally in the fetal circulation due to the high progesterone concentrations encountered.

Targeting Toll-like receptor-4 to tackle preterm birth and fetal inflammatory injury.

Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long-term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and pro-inflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro-inflammatory mediators is emerging as a major factor in the 'fetal inflammatory response syndrome' that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll-like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel small-molecule inhibitors of TLR4 signalling, specifically the non-opioid receptor antagonists (+)-naloxone and (+)-naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat-killed Escherichia coli, or the TLR4-dependent pro-inflammatory lipid, platelet-activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.

The impact of maternal asthma during pregnancy on offspring retinal microvascular structure and its relationship to placental growth factor production in utero.

Asthma is a common chronic disease in pregnancy that affects placental function and fetal growth and associated with cardio-metabolic disorders in the offspring but the mechanisms are unknown. This study explored whether maternal asthma in pregnancy is associated with the development of offspring microvascular structure and whether it was related to biomarkers of angiogenesis in utero. Children aged 4 to 6 years, born to either asthmatic mothers (n = 38) or healthy controls (n = 25), had their retinal microvascular structure examined. Maternal plasma PlGF concentrations at 18 and 36 weeks' gestation were measured. There was a significant global difference in all retinal microvascular measures between children of asthmatic mothers relative to controls and increased retinal venular tortuosity in children born to asthmatic mothers (7.1 (95% CI 0.7-13.5); P = .031). A rise in plasma PlGF from 18 to 36 weeks' gestation was observed in the control population which was significantly lower in the asthma group by 190.9 pg/mL. PlGF concentrations were correlated with microvascular structure including arteriolar branching and venular tortuosity. These exploratory findings indicate that exposure to maternal asthma during pregnancy is associated with persistent changes in microvascular structure in childhood that may be driven by alterations to angiogenic mechanisms in utero.

Regional cluster of vanishing gastroschisis: A comparative study of antenatal and post-natal outcomes.

AIM: Vanishing gastroschisis describes the in utero spontaneous closure of the periumbilical defect. It is usually associated with intestinal loss due to ischaemia, necrosis and atresia. This comparative study aims to investigate the spectrum of pathology, antenatal ultrasound characteristics and post-natal outcomes. METHODS: Our tertiary centre provides antenatal and post-natal care of major congenital anomalies for a population of 1.6 million. Medical records were retrospectively evaluated for all cases of vanishing gastroschisis from May 2014 to May 2015. Cases of normal variant gastroschisis born during the same period were used for comparison. Maximum antenatael bowel diameter measurements were compared using the Mann-Whitney U-test. RESULTS: Six infants with vanishing gastroschisis were born during the study period, representing 50% of all live-born gastroschisis. Antenatal ultrasound showed progressively increasing intra-abdominal bowel dilatation, with antenatal intra-abdominal bowel diameter significantly greater in vanishing, than normal, variant gastroschisis (23.2 vs. 4.1 mm, P < 0.01). The classification of vanishing gastroschisis severity comprised two type I, three type II and one type III cases. Complete midgut atresia affected three infants, leading to overall mortality of 50% for the vanishing gastroschisis group versus 0% in the normal variant group (P = 0.05). CONCLUSION: Vanishing gastroschisis is a severe, often catastrophic variant of gastroschisis. Aetiological factors contributing to the recent high incidence of this rare complication in our population of newborns remain unknown, prompting secondary prevention strategies to salvage the midgut. We propose closer antenatal surveillance for fetuses with intra-abdominal bowel dilatation >10 mm to prompt consideration of earlier delivery to improve morbidity and mortality.