Relationships between intrauterine fetal growth trajectories and markers of adiposity and inflammation in young adults

Background There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. Methods Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1–Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. Results Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (β = −1.45 kg/m2, 95% CI: −2.43 to −0.46, P = 0.004) and (β = −1.01 kg/m2, 95% CI: −1.96 to −0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9–73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5–33%, P = 0.011). Conclusion This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease

The relationship between fetal growth and retinal nerve fiber layer thickness in a cohort of young adults

Purpose: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. Methods: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). Results: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. Conclusions: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. Translational Relevance: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Treatment with antenatal steroids (ANS) is standard practice for reducing the risk of respiratory distress in the preterm infant. Despite clear overall benefits when appropriately administered, many fetuses fail to derive benefit from ANS therapies. In standardized experiments using a pregnant sheep model, we have demonstrated that around 40% of ANS-exposed lambs did not have functional lung maturation significantly different from that of saline-treated controls. Surfactant protein A is known to play an important role in lung function. In this genotyping study, we investigated the potential correlation between polymorphisms in SFTPA1, messenger RNA and protein levels, and ventilation outcomes in animals treated with ANS. 45 preterm lambs were delivered 48 h after initial ANS therapy and 44 lambs were delivered 8 days after initial ANS therapy. The lambs were ventilated for 30 min after delivery. SFTPA1 mRNA expression in lung tissue was not correlated with arterial blood PaCO2 values at 30 min of ventilation in lambs delivered 48 h after treatment. SFTPA1 protein in lung tissue was significantly correlated with PaCO2 at 30 min of ventilation in lambs ventilated both 48 h and 8 days after ANS treatment. Six different single nucleotide polymorphisms (SNPs) in the Ovis aries SFTPA1 sequence were detected by Sanger Sequencing. No individual SNPs or SNP haplotypes correlated with alterations in PaCO2 at 30 min of ventilation or SFTPA1 protein levels in the lung. For the subset of animals analyzed in the present study, variable lung maturation responses to ANS therapy were not associated with mutations in SFTPA1

Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate

Background Antenatal corticosteroid (ACS) therapy is standard of care for women at imminent risk of preterm labour. Despite this, much remains to be understood regarding an optimal (maximum benefit, minimal risk of side effects) ACS dosing strategy. Although conveying overall benefit when given to the right patient at the right time, ACS treatment efficacy is highly variable, and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high materno-fetal betamethasone concentrations it generates are redundant for fetal lung maturation. Objective Using an established sheep model of prematurity and post-natal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of a low-dose treatment with betamethasone acetate only against a standard dose of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynaecologists for women at risk of imminent preterm delivery between 24 and 35+6 weeks’ gestation. Methods Ewes carrying a single fetus at 122±1 d gestational age (term=150d) were randomized to receive either: i) maternal intramuscular injections of sterile saline (the Saline Negative Control Group, n=12), ii) two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + acetate spaced by 24h (the Beta-P+Ac Group, n=12); or iii) two maternal intramuscular injections of 0.125 mg/kg betamethasone acetate spaced by 24h (the Beta-Ac Group, n=11). Fetuses were surgically delivered 48h after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. Fetuses were euthanized after ventilation and lung were collected for analysis using quantitative polymerase chain reaction and western blot assays. Fetal plasma ACTH levels were measured in the cord blood samples taken at delivery. Results Preterm lambs were defined as either ACS treatment responders or non-responders using an arbitrary cut-off, being a PaCO2 level at 30 minutes of ventilation being more extreme than two standard deviations from the mean value of the normally-distributed Saline Control Group values. Relative to Saline Control Group animals, both ACS treatment group animals showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (mRNA and surfactant protein assays) consistent with functional maturation. However, the Beta-Ac Group had a significantly higher treatment response rate than the Beta-P+Ac Group. These physiological results were strongly correlated to the amount of surfactant protein A. Birth weight was lower in Beta-P+Ac Group and the fetal HPA axis was supressed to a greater extent in the Beta-P+Ac Group. Conclusion Low dose ACS therapy solely employing Beta-Ac was sufficient for fetal lung maturation. The elevated materno-fetal betamethasone concentrations associated with the co-administration of betamethasone phosphate did not additionally improve lung maturation, but were associated with greater HPA axis suppression, a lower ACS treatment response rate, and lower birth weight – outcomes not desirable in a clinical setting. These data warrant a clinical investigation of sustained, low-dose ACS treatments that avoid high materno-fetal betamethasone exposures

Electronic structure and ferroelectricity in SrBi2Ta2O9

The electronic structure of SrBi2Ta2O9 is investigated from first-principles, within the local density approximation, using the full-potential linearized augmented plane wave (LAPW) method. The results show that, besides the large Ta(5d)-O(2p) hybridization which is a common feature of the ferroelectric perovskites, there is an important hybridization between bismuth and oxygen states. The underlying static potential for the ferroelectric distortion and the primary source for ferroelectricity is investigated by a lattice-dynamics study using the Frozen Phonon approach.Comment: 17 pages, 7 figures. Phys. Rev. B, in pres

Carbon stable isotopes as a palaeoclimate proxy in vascular plant dominated peatlands

Carbon stable isotope (δ¹³C) records from vascular plant dominated peatlands have been used as a palaeoclimate proxy, but a better empirical understanding of fractionation processes in these ecosystems is required. Here, we test the potential of δ¹³C analysis of ombrotrophic restiad peatlands in New Zealand, dominated by the wire rush (Empodisma spp.), to provide a methodology for developing palaeoclimatic records. We took surface plant samples alongside measurements of water table depth and (micro)climate over spatial (six sites spanning > 10 latitude) and temporal (monthly measurements over 1 year) gradients and analysed the relationships between cellulose δ¹³C values and environmental parameters. We found strong, significant negative correlations between δ¹³C and temperature, photosynthetically active radiation and growing degree days above 0 C. No significant relationships were observed between δ¹³C and precipitation, relative humidity, soil moisture or water table depth, suggesting no growing season water limitation and a decoupling of the expected link between δ¹³C in vascular plants and hydrological variables. δ¹³C of Empodisma spp. roots may therefore provide a valuable temperature proxy in a climatically sensitive region, but further physiological and sub-fossil calibration studies are required to fully understand the observed signal

Fat mass and obesity-associated obesity-risk genotype is associated with lower foetal growth: An effect that is reversed in the offspring of smoking mothers

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention. Copyrigh

Variability in the efficacy of a standardized antenatal steroid treatment is not due to maternal or fetal plasma drug levels. Evidence from a sheep model of pregnancy.

Background Antenatal steroids (ANS) are standard of care for women judged to be at imminent risk of preterm delivery. Worldwide, there is significant variation in ANS dosing strategy, selection for treatment criteria, and agent choice. This, combined with very limited optimization of ANS use per se means that treatment efficacy is highly variable and the rate of respiratory distress syndrome is decreased perhaps as little as 40%. In some cases, ANS use is associated with limited benefit and potential harm. Objective We hypothesized that individual differences in maternal and fetal steroid exposure would contribute to observed variability in ANS treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between materno-fetal steroid exposure and ANS treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. Methods Ewes carrying a single fetus had surgery to catheterize a fetal and maternal jugular vein at 119 days’ gestation. Animals recovered for 24h before being randomized to either: i) a single maternal intramuscular injection (IM) of 2ml saline (Negative Control Group, n=10); or ii) a single maternal IM of 0.25mg/kg betamethasone phosphate + acetate (ANS Group, n=20). Serial maternal and fetal plasma samples were collected from each animal over 48h before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. Results One animal of the Control Group and one animal from the ANS Group had did not complete their treatment protocol and were removed from analyses. Animals in the ANS Group were divided into a Responder (n=12/19) Sub-Group and a Non-Responder Sub-Group (n=7/19) using a cut-off of a PaCO2 at 30 minutes ventilation within 2SD of the mean value from saline-treated Negative Control Group animals. While ANS improved fetal lung maturation in the undivided ANS group, and in the Responder Sub-Group both physiologically (blood gas and ventilation related data) and biochemically (mRNA expression related to fetal lung maturation), these values were not improved relative to saline-treated Control Group animals in the ANS Non-Responder Sub-Group. Interestingly, no differences in betamethasone distribution, clearance, or protein binding were identified between the ANS Responder and Non-Responder Sub-Groups. Conclusion This study correlated individual materno-fetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation not significantly different to saline-treated Control Group animals. These non-responsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of ANS therapy is not solely determined by materno-fetal drug levels, and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid-driven signaling

Ex-Vivo Uterine Environment (EVE) Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model

Introduction Ex-vivo uterine environment (EVE) therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume. Methods Ewes underwent surgical delivery at 115 days of gestation (term is 150 days), and fetuses were transferred to EVE therapy (EVE group; n = 5). Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6) were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups. Results Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD) hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p0.05) in surfactant protein mRNA expression level between the two groups. Conclusion In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of futur

Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis

Background Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks’ gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues. Methods Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. Results LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery samples, the expression of IL-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group. Conclusion A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines/chemokines in fetal tissues undergoing an active inflammatory response