Maternal high fat-high energy diet alters metabolic factors in the non-human primate fetal heart.

The consumption of high fat-high energy diets (HF-HEDs) continues to rise worldwide and parallels the rise in maternal obesity (MO) that predisposes offspring to cardiometabolic disorders. Although the underlying mechanisms are unclear, thyroid hormones (TH) modulate cardiac maturation in utero. Therefore, we aimed to determine the impact of a high fat-high energy diet (HF-HED) on the hormonal, metabolic and contractility profile of the non-human primate (NHP) fetal heart. At ∼9 months preconception, female baboons (Papio hamadryas) were randomly assigned to either a control diet or HF-HED. At 165 days gestational age (term = 184 days), fetuses were delivered by Caesarean section under anaesthesia, humanely killed, and left ventricular cardiac tissue (Control (n = 6 female, 6 male); HF-HED (n = 6 F, 6 M)) was collected. Maternal HF-HED decreased the concentration of active cardiac TH (i.e. triiodothyronine (T3)), and type 1 iodothyronine deiodinase (DIO1) mRNA expression. Maternal HF-HED decreased the abundance of cardiac markers of insulin-mediated glucose uptake phosphorylated insulin receptor substrate 1 (Ser789) and glucose transporter 4, and increased protein abundance of key oxidative phosphorylation complexes (I, III, IV) and mitochondrial abundance in both sexes. Maternal HF-HED alters cardiac TH status, which may induce early signs of cardiac insulin resistance. This may increase the risk of cardiometabolic disorders in later life in offspring born to these pregnancies. KEY POINTS: Babies born to mothers who consume a high fat-high energy diet (HF-HED) prior to and during pregnancy are predisposed to an increased risk of cardiometabolic disorders across the life course. Maternal HF-HED prior to and during pregnancy decreased thyroid hormone triiodothyronine (T3) concentrations and type 1 iodothyronine deiodinase DIO1 mRNA expression in the non-human primate fetal heart. Maternal HF-HED decreased markers of insulin-dependent glucose uptake, phosphorylated insulin receptor substrate 1 and glucose transporter 4 in the fetal heart. Maternal HF-HED increased mitochondrial abundance and mitochondrial OXPHOS complex I, III and IV in the fetal heart. Fetuses from HF-HED pregnancies are predisposed to cardiometabolic disorders that may be mediated by changes in T3, placing them on a poor lifetime cardiovascular health trajectory.

Advanced magnetic resonance imaging in human placenta: insights into fetal growth restriction and congenital heart disease.

Placental function plays a crucial role in fetal development, as it serves as the primary interface for delivery of nutrients and oxygen from the mother to fetus. Magnetic resonance imaging (MRI) has significantly improved our ability to visualize and understand the placenta's complex structure and function. This review provides an up-to-date examination of the most common and novel placental MRI techniques. It will also discuss the clinical applications of MRI in diagnosing and monitoring placental insufficiency, as well as its implications for fetal growth restriction (FGR) and congenital heart disease (CHD). Ongoing research using multi-parametric MRI techniques aims to develop novel biomarkers and uncover the relationships between placental parameters and pre-onset diseased states, ultimately contributing to better maternal and fetal health outcomes, which is essential to better guide clinical judgement.

Maternal obesogenic diet during pregnancy and its impact on fetal hepatic function in baboons.

OBJECTIVE: Maternal obesity (MO) increases the risk of later-life liver disease in offspring, especially in males. This may be due to impaired cytochrome P450 (CYP) enzyme activity driven by an altered maternal-fetal hormonal milieu. MO increases fetal cortisol concentrations that may increase CYP activity; however, glucocorticoid receptor (GR)-mediated signaling can be modulated by alternative GR isoform expression. We hypothesized that MO induces sex-specific changes in GR isoform expression and localization that contribute to reduced hepatic CYP activity. METHODS: Nonpregnant, nulliparous female baboons were assigned to either an ad libitum control diet or a high-fat, high-energy diet (HF-HED) at 9 months pre pregnancy. At 165 days' gestation (term = 180 days), fetal liver samples were collected (n = 6/sex/group). CYP activity was quantified using functional assays, and GR was measured using quantitative RT-PCR and Western blot. RESULTS: CYP3A activity was reduced in the HF-HED group, whereas CYP2B6 activity was reduced in HF-HED males only. Total GR expression was increased in the HF-HED group. Relative nuclear expression of the antagonistic GR isoform GRß was increased in HF-HED males only. CONCLUSIONS: Reduced CYP activity in HF-HED males may be driven in part by dampened hepatic-specific glucocorticoid signaling via altered GR isoform expression. These findings highlight targetable mechanisms that may reduce later-life sex-specific disease risk.

Maternal asthma during pregnancy and risks of allergy and asthma in progeny: A systematic review and meta-analysis.

BACKGROUND: Clinical and preclinical evidence indicate that in utero maternal asthma exposure increases progeny asthma risk. Whether maternal asthma also increases the risks of progeny allergy is unclear. OBJECTIVES: To synthesise the available evidence on the relationship between in utero exposure to maternal asthma and postnatal asthma, wheezing and allergic diseases (Prospero: CRD42020201538). SEARCH STRATEGY: We systematically searched MEDLINE [PubMed], Embase [Ovid], Web of Science, Informit Health, the Cochrane Library, CINAHL [EBSCOhost], MedNar [Deep Web Technologies], ProQuest Theses and Dissertations, Scopus [Elsevier] and Trove, to the end of 2023. SELECTION CRITERIA: Studies reporting asthma, wheeze and/or allergic disease in progeny of women with and without asthma or with asthma classified by control, exacerbation or severity. DATA COLLECTION AND ANALYSIS: Double screening, selection, data extraction and quality assessment were performed, using Joanna Briggs Institute (JBI) scoring. MAIN RESULTS: Of 134 non-overlapping studies, 127 were included in ≥1 meta-analysis. Maternal asthma ever was associated with greater risks of asthma (65 studies, risk ratio [95% confidence interval] 1.76 [1.57-1.96]), wheeze (35 studies, 1.59 [1.52-1.66]), food allergy (5 studies, 1.32 [1.23-1.40]), allergic rhinitis (7 studies, 1.18 [1.06-1.31]) and allergic dermatitis (14 studies, 1.17 [1.11-1.23]) ever in progeny. Asthma during the pregnancy, more severe, and uncontrolled maternal asthma were each associated with greater risks of progeny asthma. CONCLUSIONS: Children of mothers with asthma are at increased risk for the development of allergic diseases. Whether improved maternal asthma control reduces risks of child allergy as well as asthma requires further investigation.

Cardiac programming in the placentally restricted sheep fetus in early gestation.

Fetal growth restriction (FGR) occurs in 8% of human pregnancies, and the growth restricted newborn is at a greater risk of developing heart disease in later adult life. In sheep, experimental restriction of placental growth (PR) from conception results in FGR, a decrease in cardiomyocyte endowment and an upregulation of pathological hypertrophic signalling in the fetal heart in late gestation. However, there is no change in the expression of markers of cellular proliferation nor in the level of cardiomyocyte apoptosis in the heart of the PR fetus in late gestation. This suggests that FGR arises early in gestation and programs a decrease in cardiomyocyte endowment in early, rather than late, gestation. Here, control and PR fetal sheep were humanely killed at 55 days' gestation (term, 150 days). Fetal body and heart weight were lower in PR compared with control fetuses and there was evidence of sparing of fetal brain growth. While there was no change in the proportion of cardiomyocytes that were proliferating in the early gestation PR heart, there was an increase in measures of apoptosis, and markers of autophagy and pathological hypertrophy in the PR fetal heart. These changes in early gestation highlight that FGR is associated with evidence of early cell death and compensatory hypertrophic responses of cardiomyocytes in the fetal heart. The data suggest that early placental restriction results in a decrease in the pool of proliferative cardiomyocytes in early gestation, which would limit cardiomyocyte endowment in the heart of the PR fetus in late gestation. KEY POINTS: Placental restriction leading to fetal growth restriction (FGR) and chronic fetal hypoxaemia in sheep results in a decrease in cardiomyocyte endowment in late gestation. FGR did not change cardiomyocyte proliferation during early gestation but did result in increased apoptosis and markers of autophagy in the fetal heart, which may result in the decreased endowment of cardiomyocytes observed in late gestation. FGR in early gestation also results in increased hypoxia inducible factor signalling in the fetal heart, which in turn may result in the altered expression of epigenetic regulators, increased expression of insulin-like growth factor 2 and cardiomyocyte hypertrophy during late gestation and after birth.

Post-Myocardial Infarction Remodeling and Hyperkinetic Remote Myocardium in Sheep Measured by Cardiac MRI Feature Tracking.

BACKGROUND: Cardiac MRI feature tracking (FT) allows objective assessment of segmental left ventricular (LV) function following a myocardial infarction (MI), but its utilization in sheep, where interventions can be tested, is lacking. PURPOSE: To apply and validate FT in a sheep model of MI and describe post-MI LV remodeling. STUDY TYPE: Animal model, longitudinal. ANIMAL MODEL: Eighteen lambs (6 months, male, n = 14; female, n = 4; 25.2 ± 4.5 kg). FIELD STRENGTH/SEQUENCE: Two-dimensional balanced steady-state free precession (bSSFP) and 3D inversion recovery fast low angle shot (IR-FLASH) sequences at 3 T. ASSESSMENT: Seven lambs underwent test-retest imaging to assess FT interstudy reproducibility. MI was induced in the remaining 11 by coronary ligation with MRI being undertaken before and 15 days post-MI. Injury size was measured by late gadolinium enhancement (LGE) and LV volumes, LV mass, ejection fraction (LVEF), and wall thickness (LVWT) were measured, with FT measures of global and segmental radial, circumferential, and longitudinal strain. STATISTICAL TESTS: Sampling variability, inter-study, intra and interobserver reproducibility were assessed using Pearson's correlation, Bland-Altman analyses, and intra-class correlation coefficients (ICC). Diagnostic performance of segmental strain to predict LGE was assessed using receiver operating characteristic curve analysis. Significant differences were considered P < 0.05. RESULTS: Inter-study reproducibility of FT was overall good to excellent, with global strain being more reproducible than segmental strain (ICC = 0.89-0.98 vs. 0.77-0.96). MI (4.0 ± 3.7% LV mass) led to LV remodeling, as evident by significantly increased LV volumes and LV mass, and significantly decreased LVWT in injured regions, while LVEF was preserved (54.9 ± 6.9% vs. 55.6 ± 5.7%; P = 0.778). Segmental circumferential strain (CS) correlated most strongly with LGE. Basal and mid- CS increased significantly, while apical CS significantly decreased post-MI. DATA CONCLUSION: FT is reproducible and compensation by hyperkinetic remote myocardium may manifest as overall preserved global LV function. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 2.

Characterisation of ciclesonide metabolism in human placentae across gestation.

INTRODUCTION: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. METHODS: Differential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. RESULTS: ACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. DISCUSSION: Conversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.

Acute-on-chronic: using magnetic resonance imaging to disentangle the haemodynamic responses to acute and chronic fetal hypoxaemia.

Introduction: The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia. Methods: Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control (n = 12) and FGR (n = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state. Results: Fetal oxygen delivery (DO2) was lower in FGR fetuses than controls during the normoxia state but cerebral DO2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO2. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased. Conclusion: Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO2. However, this upregulation is unable to maintain cerebral DO2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO2, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.

Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe.

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .

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.

Pulmonary Vascular Regulation in the Fetal and Transitional Lung.

Fetal lungs have fewer and smaller arteries with higher pulmonary vascular resistance (PVR) than a newborn. As gestation advances, the pulmonary circulation becomes more sensitive to changes in pulmonary arterial oxygen tension, which prepares them for the dramatic drop in PVR and increase in pulmonary blood flow (PBF) that occur when the baby takes its first few breaths of air, thus driving the transition from fetal to postnatal circulation. Dynamic and intricate regulatory mechanisms control PBF throughout development and are essential in supporting gas exchange after birth. Understanding these concepts is crucial given the role the pulmonary vasculature plays in the development of complications with transition, such as in the setting of persistent pulmonary hypertension of the newborn and congenital heart disease. An improved understanding of pulmonary vascular regulation may reveal opportunities for better clinical management.

Placenta-Specific Transcripts Containing Androgen Response Elements Are Altered In Silico by Male Growth Outcomes.

A birthweight centile (BWC) below the 25th is associated with an elevated risk of adverse perinatal outcomes, particularly among males. This male vulnerability may stem from alterations in placenta-specific androgen signalling, a signalling axis that involves the androgen receptor (AR)-mediated regulation of target genes containing androgen response elements (AREs). In this study, we examined global and ARE-specific transcriptomic signatures in term male placentae (≥37 weeks of gestation) across BWC subcategories (<10th, 10th-30th, >30th) using RNA-seq and gene set enrichment analysis. ARE-containing transcripts in placentae with BWCs below the 10th percentile were upregulated compared to those in the 10th-30th and >30th percentiles, which coincided with the enrichment of gene sets related to hypoxia and the suppression of gene sets associated with mitochondrial function. In the absence of ARE-containing transcripts in silico, <10th and 10th-30th BWC subcategory placentae upregulated gene sets involved in vasculature development, immune function, and cell adhesion when compared to those in the >30th BWC subcategory. Collectively, our in silico findings suggest that changes in the expression of ARE-containing transcripts in male placentae may contribute to impaired placental vasculature and therefore result in reduced fetal growth outcomes.

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.

Maternal obesity impacts fetal liver androgen signalling in a sex-specific manner.

BACKGROUND: Maternal obesity (MO) increases fetal androgen concentrations, the prevalence of macrosomia, and predisposes offspring to metabolic dysfunction in later life, especially males. These risks may be, in part, the result of increased liver-specific androgen signalling pathway activity in utero. Androgen signalling activity can be suppressed by androgen metabolism via cytochrome P450 (CYP) isoenzymes (CYP2B6, CYP3A) or through inhibition of the full-length androgen receptor (AR-FL) via the antagonistic isoform, AR-45. We hypothesised MO impairs CYP enzyme activity and AR-45 expression in male fetal livers, thereby enhancing activity of androgen signalling pathways. METHODS: Nine months prior to pregnancy, nulliparous female baboons were assigned to either ad libitum control or high fat diet. At 165 day (d) gestation (term, 180 d) fetal liver was collected (n = 6/sex/group). CYP activity was quantified using functional assays; subcellular AR expression was measured using Western blot. RESULTS: CYP2B6 and CYP3A activity, and nuclear expression of AR-45, was reduced in MO males only. Nuclear AR-45 expression was inversely related with fetal body weight of MO males only. CONCLUSIONS: Reduced CYP2B6 and CYP3A activity in conjunction with decreased nuclear AR-45 expression may enhance liver androgen signalling in males from MO pregnancies, thereby increasing the risk of macrosomia, as well as metabolic dysfunction in later life.

Reduced in utero substrate supply decreases mitochondrial abundance and alters the expression of metabolic signalling molecules in the fetal sheep heart.

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life.

Feasibility of MRI assessment of maternal-fetal oxygen transport and consumption relative to maternal position in healthy late gestational pregnancies.

Late gestational supine positioning reduces maternal cardiac output due to inferior vena caval (IVC) compression, despite increased collateral venous return. However, little is known about the impact of maternal position on oxygen (O2 ) delivery and consumption of the gravid uterus, fetus, placenta and lower limbs. We studied the effects of maternal positioning on these parameters in 20 healthy pregnant subjects at 36 ± 2 weeks using magnetic resonance imaging (MRI); a follow-up MRI was performed 6-months postpartum (n = 16/20). MRI techniques included phase-contrast and T1/T2 relaxometry for blood flow and oximetry imaging, respectively. O2 transport was measured in the following vessels (bilateral where appropriate): maternal abdominal descending aorta (DAoabdo ), IVC, ovarian, paraspinal veins (PSV), uterine artery (UtA) and external iliacs, and umbilical. Maternal cardiac output was measured by summing DAothoracic and superior vena cava flows. Supine mothers (n = 6) had lower cardiac output and O2 delivery in the DAoabdo , UtA and external iliac arteries, and higher PSV flow than those in either the left (n = 8) or right (n = 6) lateral positions during MRI. However, O2 consumption in the gravid uterus, fetus, placenta and lower limbs was unaffected by maternal positioning. The ratio of IVC/PSV flow decreased in supine mothers while ovarian venous flow and O2 saturation were unaltered, suggesting a major route of pelvic venous return unaffected by maternal position. Placental-fetal O2 transport and consumption were similar between left and right lateral maternal positions. In comparison to non-pregnant findings, DAoabdo and UtA O2 delivery and pelvic O2 consumption increased, while lower-limb consumption remained constant , despite reduced external iliac artery O2 delivery in late gestation. KEY POINTS: Though sleeping supine during the third trimester is associated with an increased risk of antepartum stillbirth, the underlying biological mechanisms are not fully understood. Maternal cardiac output and uteroplacental flow are reduced in supine mothers due to inferior vena caval compression from the weight of the gravid uterus. This MRI study provides a comprehensive circulatory assessment, demonstrating reduced maternal cardiac output and O2 delivery (uteroplacental, lower body) in supine compared to lateral positioning; however, O2 consumption (gravid uterus, fetus, placenta, lower limbs) was preserved. Unlike other mammalian species, the ovarian veins conduct substantial venous return from the human pregnant uterus that is unaffected by maternal positioning. Lumbar paraspinal venous flow increased in supine mothers. These observations may have important considerations during major pelvic surgery in pregnancy (i.e. placenta percreta). Future studies should address the importance of maternal positioning as a potential tool to deliver improved perinatal outcomes in pregnancies with compromised uteroplacental O2 delivery.

Cardiac growth and metabolism of the fetal sheep are not vulnerable to a 10 day increase in fetal glucose and insulin concentrations during late gestation.

Aims: To evaluate the effects of fetal glucose infusion in late gestation on the mRNA expression and protein abundance of molecules involved in the regulation of cardiac growth and metabolism. Main methods: Either saline or glucose was infused into fetal sheep from 130 to 140 days (d) gestation (term, 150 d). At 140 d gestation, left ventricle tissue samples were collected. Quantitative real-time RT-PCR and Western blot were used to determine the mRNA expression and protein abundance of key signalling molecules within the left ventricle of the fetal heart. Key findings: Although intra-fetal glucose infusion increased fetal plasma glucose and insulin concentrations, there was no change in the expression of molecules within the signalling pathways that regulate proliferation, hypertrophy, apoptosis or fibrosis in the fetal heart. Cardiac Solute carrier family 2 member 1 (SLC2A1) mRNA expression was decreased by glucose infusion. Glucose infusion increased cardiac mRNA expression of both Peroxisome proliferator activated receptor alpha (PPARA) and peroxisome proliferator activated receptor gamma (PPARG). However, there was no change in the mRNA expression of PPAR cofactors or molecules with PPAR response elements. Furthermore, glucose infusion did not impact the protein abundance of the 5 oxidative phosphorylation complexes of the electron transport chain. Significance: Despite a 10-day doubling of fetal plasma glucose and insulin concentrations, the present study suggests that within the fetal left ventricle, the mRNA and protein expression of the signalling molecules involved in cardiac growth, development and metabolism are relatively unaffected.

MitoQ as an antenatal antioxidant treatment improves markers of lung maturation in healthy and hypoxic pregnancy.

Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. However, whether antenatal antioxidant therapy confers any benefit on lung development in complicated pregnancies has not yet been investigated. Here, we tested the hypothesis that maternal antenatal treatment with MitoQ will protect the developing lung in hypoxic pregnancy in sheep, a species with similar fetal lung developmental milestones as humans. Maternal treatment with MitoQ during late gestation promoted fetal pulmonary surfactant maturation and an increase in the expression of lung mitochondrial complexes III and V independent of oxygenation. Maternal treatment with MitoQ in hypoxic pregnancy also increased the expression of genes regulating liquid reabsorption in the fetal lung. These data support the hypothesis tested and suggest that MitoQ as an antenatal targeted antioxidant treatment may improve lung maturation in the late gestation fetus. KEY POINTS: Chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. MitoQ is a targeted antioxidant that uses the cell and the mitochondrial membrane potential to accumulate within the mitochondria. Treatment of healthy or hypoxic pregnancy with MitoQ, increases the expression of key molecules involved in surfactant maturation, lung liquid reabsorption and in mitochondrial proteins driving ATP synthesis in the fetal sheep lung. There were no detrimental effects of MitoQ treatment alone on the molecular components measured in the present study, suggesting that maternal antioxidant treatment has no effect on other components of normal maturation of the surfactant system.

Acute resveratrol exposure does not impact hemodynamics of the fetal sheep.

Babies born growth restricted are at an increased risk of both poor short-and long-term outcomes. Current interventions to improve fetal growth are ineffective and do not lower the lifetime risk of poor health status. Maternal resveratrol (RSV) treatment increases uterine artery blood flow, fetal oxygenation, and fetal weight. However, studies suggest that diets high in polyphenols such as RSV may impair fetal hemodynamics. We aimed to characterize the effect of RSV on fetal hemodynamics to further assess its safety as an intervention strategy. Pregnant ewes underwent magnetic resonance imaging (MRI) scans to measure blood flow and oxygenation within the fetal circulation using phase contrast-MRI and T2 oximetry. Blood flow and oxygenation measures were performed in a basal state and then repeated while the fetus was exposed to RSV. Fetal blood pressure and heart rate were not different between states. RSV did not impact fetal oxygen delivery (DO2 ) or consumption (VO2 ). Blood flow and oxygen delivery throughout the major vessels of the fetal circulation were not different between basal and RSV states. As such, acute exposure of the fetus to RSV does not directly impact fetal hemodynamics. This strengthens the rationale for the use of RSV as an intervention strategy against fetal growth restriction.