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Objective: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation, with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth, but current evidence on dosing, candidacy and outcomes is limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP., Methods: This single-center, open-label, pilot phase-1 safety and feasibility clinical trial included 25 pregnant individuals with a diagnosis of fetal SVP. Participants self-administered continuous MSO using medical-grade oxygen concentrators for up to 24 h per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation using echocardiography and late-gestation cardiovascular magnetic resonance imaging. Early outcomes were assessed, including perinatal growth and preoperative brain injury, and neurodevelopmental outcomes were assessed at 18 months using the Bayley Scales of Infant and Toddler Development 3 rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC)., Results: Among the 25 participants, the median maternal age at conception was 35 years, and fetal SVP diagnoses included 16 with right ventricle dominant, eight with left ventricle dominant and one with indeterminate ventricular morphology. Participants started the trial at approximately 29 + 2 weeks' gestation and self-administered MSO for a median of 16.1 h per day for 63 days, accumulating a median of 1029 h of oxygen intake from enrolment until delivery. The only treatment-associated adverse events were nasal complications that were resolved typically by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio or head-circumference-to-abdominal-circumference ratio Z-scores over gestation compared with SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over the study period compared with SOC (P = 0.02), this was probably due to initial baseline differences in placental resistance. At late-gestation cardiovascular magnetic resonance imaging, MSO was not associated with an increase in fetal cerebral oxygen delivery. Similarly, no differences were observed in neonatal outcomes, including preoperative brain weight Z-score and brain injury, mortality by 18 months of age and neurodevelopmental outcomes at 18 months of age., Conclusions: This pilot phase-1 clinical trial indicates that low-dose MSO therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with an increase in fetal cerebral oxygen delivery or improvements in early neurological or neurodevelopmental outcomes. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Sadiku, Sun, Macgowan, Seed and Morrison.)

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., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

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 T 2 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 (DO 2 ) was lower in FGR fetuses than controls during the normoxia state but cerebral DO 2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO 2 . 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 DO 2 . However, this upregulation is unable to maintain cerebral DO 2 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 DO 2 , may have lasting consequences on hepatic function and pulmonary vascular regulation after birth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Darby, Saini, Holman, Hammond, Perumal, Macgowan, Seed and Morrison.)

Background: Non-Cartesian magnetic resonance imaging trajectories at golden angle increments have the advantage of allowing motion correction and gating using intermediate real-time reconstructions. However, when the acquired data are cardiac binned for cine imaging, trajectories can cluster together at certain heart rates (HR) causing image artifacts. Here, we demonstrate an approach to reduce clustering by inserting additional angular increments within the trajectory, and optimizing them while still allowing for intermediate reconstructions., Methods: Three acquisition models were simulated under constant and variable HR: golden angle (M trd ), random additional angles (M rnd ), and optimized additional angles (M opt ). The standard deviations of trajectory angular differences (STAD) were compared through their interquartile ranges (IQR) and the Kolmogorov-Smirnov test (significance level: p = 0.05). Agreement between an image reconstructed with uniform sampling and images from M trd , M rnd , and M opt was analyzed using the structural similarity index measure (SSIM). M trd and M opt were compared in three adults at high, low, and no HR variability., Results: STADs from M trd were significantly different (p < 0.05) from M opt and M rnd . STAD (IQR × 10 -2 rad) showed that M opt (0.5) and M rnd (0.5) reduced clustering relative to M trd (1.9) at constant HR. For variable HR, M opt (0.5) and M rnd (0.5) outperformed M trd (0.9). The SSIM (IQR) showed that M opt (0.011) produced the best image quality, followed by M rnd (0.014), and M trd (0.030). M opt outperformed M trd at reduced HR variability in in-vivo studies. At high HR variability, both models performed well., Conclusion: This approach reduces clustering in k-space and improves image quality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes., Objectives: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD., Methods: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment., Results: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05)., Conclusions: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes., Competing Interests: Funding Support and Author Disclosures This work was supported by Canadian Institutes of Health Research Operating Grant MOP: 142204. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD), even after controlling for traditional cardiovascular risk factors. The increased risk of CVD in BD may be subserved by microvascular dysfunction. We examined coronary microvascular function in relation to youth BD., Methods: Participants were 86 youth, ages 13-20 years ( n = 39 BD, n = 47 controls). Coronary microvascular reactivity (CMVR) was assessed using quantitative T 2 magnetic resonance imaging during a validated breathing-paradigm. Quantitative T 2 maps were acquired at baseline, following 60-s of hyperventilation, and every 10-s thereafter during a 40-s breath-hold. Left ventricular structure and function were evaluated based on 12-15 short- and long-axis cardiac-gated cine images. A linear mixed-effects model that controlled for age, sex, and body mass index assessed for between-group differences in CMVR (time-by-group interaction)., Results: The breathing-paradigm induced a significant time-related increase in T 2 relaxation time for all participants (i.e. CMVR; β = 0.36, p < 0.001). CMVR was significantly lower in BD v. controls ( β = -0.11, p = 0.002). Post-hoc analyses found lower T 2 relaxation time in BD youth after 20-, 30-, and 40 s of breath-holding ( d = 0.48, d = 0.72, d = 0.91, respectively; all p FDR < 0.01). Gross left ventricular structure and function (e.g. mass, ejection fraction) were within normal ranges and did not differ between groups., Conclusion: Youth with BD showed evidence of subclinically impaired coronary microvascular function, despite normal gross cardiac structure and function. These results converge with prior findings in adults with major depressive disorder and post-traumatic stress disorder. Future studies integrating larger samples, prospective follow-up, and blood-based biomarkers are warranted.

Maternal exposure to microplastics and nanoplastics has been shown to result in fetal growth restriction in mice. In this study, we investigated the placental and fetal hemodynamic responses to plastics exposure in mice using high-frequency ultrasound. Healthy, pregnant CD-1 dams were given either 106 ng/L of 5 μm polystyrene microplastics or 106 ng/L of 50 nm polystyrene nanoplastics in drinking water throughout gestation and were compared with controls. Maternal exposure to both microplastics and nanoplastics resulted in evidence of placental dysfunction that was highly dependent on the particle size. The umbilical artery blood flow increased by 48% in the microplastic-exposed group and decreased by 25% in the nanoplastic-exposed group compared to controls (p < 0.05). The microplastic- and nanoplastic-exposed fetuses showed a significant decrease in the middle cerebral artery pulsatility index of 10% and 13%, respectively, compared to controls (p < 0.05), indicating vasodilation of the cerebral circulation, a fetal adaptation that is part of the brain sparing response to preserve oxygen delivery. Hemodynamic markers of placental dysfunction and fetal hypoxia were more pronounced in the group exposed to polystyrene nanoplastics, suggesting nanoplastic exposure during human pregnancy has the potential to disrupt fetal brain development, which in turn may cause suboptimal neurodevelopmental outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 10 6  ng/L of 740-4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p < 0.01). These results suggest polyethylene has the potential to cause adverse pregnancy outcomes through abnormal placental function., (© 2024. The Author(s).)

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 (O 2 ) 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. O 2 transport was measured in the following vessels (bilateral where appropriate): maternal abdominal descending aorta (DAo abdo ), IVC, ovarian, paraspinal veins (PSV), uterine artery (UtA) and external iliacs, and umbilical. Maternal cardiac output was measured by summing DAo thoracic and superior vena cava flows. Supine mothers (n = 6) had lower cardiac output and O 2 delivery in the DAo abdo , 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, O 2 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 O 2 saturation were unaltered, suggesting a major route of pelvic venous return unaffected by maternal position. Placental-fetal O 2 transport and consumption were similar between left and right lateral maternal positions. In comparison to non-pregnant findings, DAo abdo and UtA O 2 delivery and pelvic O 2 consumption increased, while lower-limb consumption remained constant , despite reduced external iliac artery O 2 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 O 2 delivery (uteroplacental, lower body) in supine compared to lateral positioning; however, O 2 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 O 2 delivery., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

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., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Introduction: Plastics used in everyday materials accumulate as waste in the environment and degrade over time. The impacts of the resulting particulate micro- and nanoplastics on human health remain largely unknown. In pregnant mice, we recently demonstrated that exposure to nanoplastics throughout gestation and during lactation resulted in changes in brain structure detected on MRI. One possible explanation for this abnormal postnatal brain development is altered fetal brain metabolism., Objectives: To determine the effect of maternal exposure to nanoplastics on fetal brain metabolism., Methods: Healthy pregnant CD-1 mice were exposed to 50 nm polystyrene nanoplastics at a concentration of 10 6 ng/L through drinking water during gestation. Fetal brain samples were collected at embryonic day 17.5 (n = 18-21 per group per sex) and snap-frozen in liquid nitrogen. Magic angle spinning nuclear magnetic resonance was used to determine metabolite profiles and their relative concentrations in the fetal brain., Results: The relative concentrations of gamma-aminobutyric acid (GABA), creatine and glucose were found to decrease by 40%, 21% and 30% respectively following maternal nanoplastic exposure when compared to the controls (p < 0.05). The change in relative concentration of asparagine with nanoplastic exposure was dependent on fetal sex (p < 0.005)., Conclusion: Maternal exposure to polystyrene nanoplastics caused abnormal fetal brain metabolism in mice. The present study demonstrates the potential impacts of nanoplastic exposure during fetal development and motivates further studies to evaluate the risk to human pregnancies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To examine the relationship between umbilical cord insertion site, placental pathology and adverse pregnancy outcome in a cohort of normal and complicated pregnancies., Methods: Sonographic measurement of the cord insertion and detailed placental pathology were performed in 309 participants. Associations between cord insertion site, placental pathology and adverse pregnancy outcome (pre-eclampsia, preterm birth, small-for-gestational age) were examined., Results: A total of 93 (30%) participants were identified by pathological examination to have a peripheral cord insertion site. Only 41 of the 93 (44%) peripheral cords were detected by prenatal ultrasound. Peripherally inserted cords were associated significantly (P < 0.0001) with diagnostic placental pathology (most commonly with maternal vascular malperfusion (MVM)); of which 85% had an adverse pregnancy outcome. In cases of isolated peripheral cords, without placental pathology, the incidence of adverse outcome was not statistically different when compared to those with central cord insertion and no placental pathology (31% vs 18%; P = 0.3). A peripheral cord with an abnormal umbilical artery (UA) pulsatility index (PI) corresponded to an adverse outcome in 96% of cases compared to 29% when the UA-PI was normal., Conclusions: This study demonstrates that peripheral cord insertion is often part of the spectrum of findings of MVM disease and is associated with adverse pregnancy outcome. However, adverse outcome was uncommon when there was an isolated peripheral cord insertion and no placental pathology. Therefore, additional sonographic and biochemical features of MVM should be sought when a peripheral cord is observed. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Fetal cardiac MRI is challenging due to fetal and maternal movements as well as the need for a reliable cardiac gating signal and high spatiotemporal resolution. Ongoing research and recent technical developments to address these challenges show the potential of MRI as an adjunct to ultrasound for the assessment of the fetal heart and great vessels. MRI measurements of blood flow have enabled the assessment of normal fetal circulation as well as conditions with disrupted circulations, such as congenital heart disease, along with associated organ underdevelopment and hemodynamic instability. This review provides details of the techniques used in fetal cardiovascular blood flow MRI, including single slice and volumetric imaging sequences, post-processing and analysis, along with a summary of applications in human studies and animal models.

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 T 2 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 (DO 2 ) or consumption (VO 2 ). 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., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Introduction: The rapid growth in the worldwide use of plastics has resulted in a vast accumulation of microplastics in the air, soil and water. The impact of these microplastics on pregnancy and fetal development remains largely unknown. In pregnant mice, we recently demonstrated that exposure to micro- and nanoplastics throughout gestation resulted in significant fetal growth restriction. One possible explanation for reduced fetal growth is abnormal placental metabolism., Objectives: To evaluate the effect of maternal exposure to microplastics on placental metabolism., Methods: In the present study, CD-1 pregnant mice were exposed to 5 μm polystyrene microplastics in filtered drinking water at one of four concentrations (0 ng/L (controls), 10 2 ng/L, 10 4 ng/L, 10 6 ng/L) throughout gestation (n = 7-11/group). At embryonic day 17.5, placental tissue samples were collected (n = 28-44/group). Metabolite profiles were determined using 1  H high-resolution magic angle spinning magnetic resonance spectroscopy., Results: The relative concentration of lysine (p = 0.003) and glucose (p < 0.0001) in the placenta were found to decrease with increasing microplastic concentrations, with a significant reduction at the highest exposure concentration. Multivariate analysis identified shifts in the metabolic profile with MP exposure and pathway analysis identified perturbations in the biotin metabolism, lysine degradation, and glycolysis/gluconeogenesis pathways., Conclusion: Maternal exposure to microplastics resulted in significant alterations in placental metabolism. This study highlights the potential impact of microplastic exposure on pregnancy outcomes and that efforts should be made to minimize exposure to plastics, particularly during pregnancy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To evaluate the impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in severe Ebstein anomaly and tricuspid valve dysplasia., Methods: Thirty-four fetuses with Ebstein anomaly/tricuspid valve dysplasia were referred from 2013 to 2019 for fetal echocardiography and clinical management. Nineteen fetuses with Ebstein anomaly/tricuspid valve dysplasia and 30 controls underwent cardiovascular magnetic resonance to quantify the fetal blood flow and to calculate cerebral oxygen delivery (cDO2) and consumption (cVO2). The 3D steady-state free precession acquisition was used to measure fetal brain volume. Surgical outcome, brain MRI, and neurodevelopmental follow-up were reviewed., Results: Twenty-six fetuses were live born (76%) and survival (65%) at a mean follow-up of 4 years. Nine fetuses had a brain MRI before discharge, and all had clinically silent injuries and volume loss. At 18 months, five single-ventricle patients had a neurodevelopmental delay in cognition and language (mean percentile: 11th), with gross-motor skills more affected than fine-motor skills (mean percentiles: 4th and 34th). Fetuses with Ebstein anomaly/tricuspid valve dysplasia had smaller brains, lower combined ventricular output, ascending aorta, superior caval vien and umbilical vein flows, lower oxygen saturation in ascending aorta and superior caval vien, lower cDO2 and cVO2 (p < 0.05). Superior caval vien/combined ventricular output and descending aorta/combined ventricular output ratios were lower in fetuses with circular shunt (p < 0.05). Fetuses requiring the Starnes procedure tended to have smaller brains, lower combined ventricular output, superior caval vien, descending aorta, and umbilical vein flows., Conclusions: All patients with Ebstein anomaly/tricuspid valve dysplasia are at high risk of neurodevelopmental delay and warrant follow-up. Fetal cardiovascular magnetic resonance revealed impaired brain growth with diminished cerebral blood flow and cDO2, the extenting dependent on the severity of the haemodynamic compromise.

Magnetic resonance imaging (MRI) assessment of fetal blood oxygen saturation (SO 2 ) can transform the clinical management of high-risk pregnancies affected by fetal growth restriction (FGR). Here, a novel MRI method assesses the feasibility of identifying normally grown and FGR fetuses in sheep and is then applied to humans. MRI scans are performed in pregnant ewes at 110 and 140 days (term = 150d) gestation and in pregnant women at 28 +3  ± 2 +5 weeks to measure feto-placental SO 2 . Birth weight is collected and, in sheep, fetal blood SO 2 is measured with a blood gas analyzer (BGA). Fetal arterial SO 2 measured by BGA predicts fetal birth weight in sheep and distinguishes between fetuses that are normally grown, small for gestational age, and FGR. MRI feto-placental SO 2 in late gestation is related to fetal blood SO 2 measured by BGA and body weight. In sheep, MRI feto-placental SO 2 in mid-gestation is related to fetal SO 2 later in gestation. MRI feto-placental SO 2 distinguishes between normally grown and FGR fetuses, as well as distinguishing FGR fetuses with and without normal Doppler in humans. Thus, a multi-compartment placental MRI model detects low placental SO 2 and distinguishes between small hypoxemic fetuses and normally grown fetuses., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Fetal development relies on a complex circulatory network. Accurate assessment of flow distribution is important for understanding pathologies and potential therapies. In this paper, we demonstrate a method for volumetric imaging of fetal flow with magnetic resonance imaging (MRI). Fetal MRI faces challenges: small vascular structures, unpredictable motion, and inadequate traditional cardiac gating methods. Here, orthogonal multislice stacks are acquired with accelerated multidimensional radial phase contrast (PC) MRI. Slices are reconstructed into flow sensitive time-series images with motion correction and image-based cardiac gating. They are then combined into a dynamic volume using slice-to-volume reconstruction (SVR) while resolving interslice spatiotemporal coregistration. Compared to prior methods, this approach achieves higher spatiotemporal resolution ( 1×1×1 mm 3 , ~30 ms) with reduced scan time - important features for the quantification of flow through small fetal structures. Validation is demonstrated in adults by comparing SVR with 4D radial PCMRI (flow bias and limits of agreement: -1.1 ml/s and [-11.8 9.6] ml/s). Feasibility is demonstrated in late gestation fetuses by comparing SVR with 2D Cartesian PCMRI (flow bias and limits of agreement: -0.9 ml/min/kg and [-39.7 37.8] ml/min/kg). With SVR, we demonstrate complex flow pathways (such as parallel flow streams in the proximal inferior vena cava, preferential shunting of blood from the ductus venosus into the left atrium, and blood from the brain leaving the heart through the main pulmonary artery) for the first time in human fetal circulation. This method allows for comprehensive evaluation of the fetal circulation and enables future studies of fetal physiology.

Background: Evaluation of structural lung abnormalities with magnetic resonance imaging (MRI) has previously been shown to be predictive of clinical neonatal outcomes in preterm birth. MRI during free-breathing with phase-resolved functional lung (PREFUL) may allow for complimentary functional information without exogenous contrast., Purpose: To investigate the feasibility of structural and functional pulmonary MRI in a cohort of neonates and infants with no cardiorespiratory disease. Macrovascular pulmonary blood flows were also evaluated., Study Type: Prospective., Population: Ten term infants with no clinically defined cardiorespiratory disease were imaged. Infants recruited from the general population and neonatal intensive care unit (NICU) were studied., Field Strength/sequence: T 1 -weighted VIBE, T 2 -weighted BLADE uncorrected for motion. Ultrashort echo time (UTE) and 3D-flow data were acquired during free-breathing with self-navigation and retrospective reconstruction. Single slice 2D-gradient echo (GRE) images were acquired during free-breathing for PREFUL analysis. Imaging was performed at 3 T., Assessment: T 1 , T 2 , and UTE images were scored according to the modified Ochiai scheme by three pediatric body radiologists. Ventilation/perfusion-weighted maps were extracted from free-breathing GRE images using PREFUL analysis. Ventilation and perfusion defect percent (VDP, QDP) were calculated from the segmented ventilation and perfusion-weighted maps. Time-averaged cardiac blood velocities from three-dimensional-flow were evaluated in major pulmonary arteries and veins., Statistical Test: Intraclass correlation coefficient (ICC)., Results: The ICC of replicate structural scores was 0.81 (95% CI: 0.45-0.95) across three observers. Elevated Ochiai scores, VDP, and QDP were observed in two NICU participants. Excluding these participants, mean ± standard deviation structural scores were 1.2 ± 0.8, while VDP and QDP were 1.0% ± 1.1% and 0.4% ± 0.5%, respectively. Main pulmonary arterial blood flows normalized to body surface area were 3.15 ± 0.78 L/min/m 2 ., Data Conclusion: Structural and functional pulmonary imaging is feasible using standard clinical MRI hardware (commercial whole-body 3 T scanner, table spine array, and flexible thoracic array) in free-breathing infants., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2022 International Society for Magnetic Resonance in Medicine.)

Objectives: To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs)., Methods: Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI., Results: Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P = .008), and with the UA with the lower PI (P = .008)., Conclusions: The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found., (© 2021 American Institute of Ultrasound in Medicine.)

Introduction: Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth., Methods: At 116-117 days gestational age (term, 150 days), pregnant Merino ewes (n = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T2 oximetry., Results: Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery., Conclusion: SC induces alterations to pulmonary haemodynamics in utero; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil's direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long-term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two-photon microscopy and phase-contrast MRI (PC-MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two-photon imaging revealed that the left ventricle of IUGR fetuses (at 140-141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC-MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood., (© 2021 Wiley-VCH GmbH.)

Objectives: To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis., Methods: Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO 2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls., Results: Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO 2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO 2 were reduced in nearly all CHD subtypes., Conclusions: Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes., Methods: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139-140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS)., Results: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods., Conclusions: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero. The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( D O 2 ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140 days' gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial P O 2 compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins (SFTP) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and D O 2 to the fetal lung. There was a negative relationship between left pulmonary artery flow and D O 2 to the left lung with SFTP-B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. KEY POINTS: Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial P O 2 . Surfactant maturation was not affected; however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White-Landrace-Duroc piglets (n = 34) spanning four age groups: term-9 days, term-3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow-term-9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter-term-9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R 2  = 0.32, p = 0.004), and left (R 2  = 0.33, p = 0.003) and right (R 2  = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p < 0.05). Expanded use of these techniques in preterm animal models will aid in providing new understandings of normal versus abnormal DA transition, as well as to test the effectiveness of related clinical interventions., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Key Points: Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( V O 2 ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and V O 2 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental V O 2 by MRI was ∼4 ml min -1  kg -1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental V O 2 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and V O 2 , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential., Abstract: It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( V O 2 ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( D O 2 ) and V O 2 in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal D O 2 and V O 2 . Maternal D O 2 (ml min -1  kg -1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal D O 2 (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal V O 2 (ml min -1  kg -1 fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal V O 2 ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min -1  kg -1 fetus) decreased with advancing age (P = 0.008), while fetal V O 2 was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal V O 2 was preserved through stable umbilical flow (ml min -1  kg -1 ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal V O 2 between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Background: The umbilical artery (UA) Doppler pulsatility index is used clinically to detect elevated feto-placental vascular resistance. However, this metric is confounded by variation in fetal cardiac function and is only moderately predictive of placental pathology. Our group developed a novel ultrasound methodology that measures wave reflections in the UA, thereby isolating a component of the Doppler signal that is specific to the placenta. The present study examined whether wave reflections in the UA are predictive of placental vascular pathology., Methods: Standard clinical Doppler ultrasound of the UAs was performed in 241 pregnant women. Of these, 40 women met narrowly defined preset criteria for the control group, 36 had maternal vascular malperfusion (MVM) and 16 had fetal vascular malperfusion (FVM). Using a computational procedure, the Doppler waveforms were decomposed into a pair of forward and backward propagating waves., Findings: Compared to controls, wave reflections were significantly elevated in women with either MVM (p<0.0001) or FVM pathology (p = 0.02). In contrast, the umbilical and uterine artery pulsatility indices were only elevated in the MVM group (p<0.0001) and there were no differences between women with FVM and the controls., Interpretation: The measurement of wave reflections in the UA, combined with standard clinical ultrasound parameters, has the potential to improve the diagnostic performance of UA Doppler to detect placental vascular pathology. Identifying women with FVM pathology is particularly challenging prenatally and future investigations will determine if women at risk of this specific placental disease could benefit from this novel diagnostic technique., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised., Abstract: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123-124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.

Background: Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy., Methods: A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex., Results: While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively)., Conclusions: Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

Background: There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies., Methods: A prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope., Results: While the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation., Conclusions: The uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

Background: Phase contrast MRI in the great vessels is a potential clinical tool for managing fetal pathologies. One challenge is the uncontrollable fetal motion, potentially corrupting flow quantifications., Purpose: To demonstrate improvements in fetal blood flow quantification in great vessels using retrospectively motion-corrected golden-angle radial phase contrast MRI relative to Cartesian phase contrast MRI., Study Type: Method comparison., Phantom/subjects: Computer simulation. Seventeen pregnant volunteers., Field Strength/sequence: 1.5T and 3T. Cartesian and golden-angle radial phase contrast MRI., Assessment: Through computer simulations, radial (with and without retrospective motion correction) and Cartesian phase contrast MRI were compared using flow deviations. in vivo Cartesian and radial phase contrast MRI measurements and reconstruction qualities were compared in pregnancies. Cartesian data were reconstructed into gated reconstructions (CINEs) after cardiac gating with metric optimized gating (MOG). For radial data, real-time reconstructions were performed for motion correction and MOG followed by CINE reconstructions., Statistical Tests: Wilcoxon signed-rank test. Linear regression. Bland-Altman plots. Student's t-test., Results: Simulations showed significant improvements (P < 0.05) in flow accuracy and reconstruction quality with motion correction ([mean/peak] flow errors with ±5 mm motion corruption: Cartesian [35 ± 1/115 ± 7] mL/s, motion uncorrected radial [25 ± 1/75 ± 2] mL/s and motion-corrected radial [1.0 ± 0.5/-5 ± 1] mL/s). in vivo Cartesian reconstructions without motion correction had lower quality than the motion-corrected radial reconstructions (P < 0.05). Across all fetal mean flow measurements, the bias [limits of agreement] between the two measurements were -0.2 [-76, 75] mL/min/kg, while the linear regression coefficients were (M radial = 0.81 × M Cartesian + 29.8 [mL/min/kg], r 2 = 0.67). The corresponding measures for the peak fetal flows were -23 [-214, 167] mL/min/kg and (P radial = 0.95 × P Cartesian -1.2 [mL/min/kg], r 2 = 0.80). Cartesian reconstructions of low quality showed significantly higher estimated mean and peak (P < 0.05) flows than the corresponding radial reconstructions., Data Conclusion: Simulations showed that radial phase contrast MRI with motion compensation improved flow accuracy. For fetal measurements, motion-corrected radial reconstructions showed better image quality than, and different flow values from, Cartesian reconstructions. Level of Evidence 1. Technical Efficacy Stage 1. J. MAGN. RESON. IMAGING 2021;53:540-551., (© 2020 International Society for Magnetic Resonance in Medicine.)

Magnetic resonance imaging (MRI) is an important tool for the clinical assessment of cardiovascular morphology and heart function. It is also the recognized standard-of-care for blood flow quantification based on phase contrast MRI. While such measurement of blood flow has been possible in adults for decades, methods to extend this capability to fetal blood flow have only recently been developed. Fetal blood flow quantification in major vessels is important for monitoring fetal pathologies such as congenital heart disease (CHD) and fetal growth restriction (FGR). CHD causes alterations in the cardiac structure and vasculature that change the course of blood in the fetus. In FGR, the path of blood flow is altered through the dilation of shunts such that the oxygenated blood supply to the brain is increased. Blood flow quantification enables assessment of the severity of the fetal pathology, which in turn allows for suitable in utero patient management and planning for postnatal care. The primary challenges of applying phase contrast MRI to the human fetus include small blood vessel size, high fetal heart rate, potential MRI data corruption due to maternal respiration, unpredictable fetal movements, and lack of conventional cardiac gating methods to synchronize data acquisition. Here, we describe recent technical developments from our lab that have enabled the quantification of fetal blood flow using phase contrast MRI, including advances in accelerated imaging, motion compensation, and cardiac gating.

Objective: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation., Methods: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using offline processing software. FHR STV was calculated using average R-R intervals extracted from the waveforms and baseline corrected for FHR., Results: Baseline-corrected FHR STV increased significantly with gestational age (conditional R 2  = 0.37; P < 0.0001) and was correlated inversely with FHR (conditional R 2  = 0.54; P < 0.0001). The STV ranged (median (interquartile range)) from 3.5 (2.9-4.1) ms at 14-20 weeks' gestation to 6.3 (4.8-7.7) ms at 34-40 weeks' gestation. The change in heart rate STV did not differ between study sites or individual sonographers., Conclusions: UA Doppler waveforms offer a robust and feasible method to derive STV of the FHR. It should be emphasized that the UA Doppler-derived STV is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations are needed to validate associations with outcome, in order to determine the value of concurrent fetal cardiovascular and heart rate evaluations that are possible with the technique described here. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls., Objective: This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses., Study Design: Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O 2 , n=24) or hypoxic environment (11% O 2 , n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration., Results: In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth., Conclusion: Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Key Points: The ductus venosus (DV) is a dynamic fetal shunt that allows substrate-rich blood from the umbilical vein to bypass the hepatic circulation. In vitro studies suggest a direct role of prostaglandin I 2 (PGI 2 ) in the regulation of DV tone; however, the extent of this regulation has not been determined in utero. 4D flow and T 2 oximetry magnetic resonance imaging can be combined to determine blood flow and oxygen delivery within the fetal circulation. PGI 2 increases DV shunting of substrate-rich blood but this does not increase cerebral oxygen delivery., Abstract: During fetal development, the maintenance of adequate oxygen and nutrient supply to vital organs is regulated through specialized fetal shunts. One of these shunts, the ductus venosus (DV), allows oxygen-rich blood to preferentially stream from the placenta toward the heart and brain. Herein, we combine magnetic resonance imaging (MRI) techniques that measure blood flow (4D flow) and oxygen saturation (T 2 oximetry) in the fetal circuit to determine whether umbilical vein infusion of prostaglandin I 2 (PGI 2 , regulator of DV tone ex utero) directly dilates the DV and thus increases the preferential streaming of oxygen-rich blood toward the brain. At 114-115 days gestational age (dGA; term = 150 days), fetal sheep (n = 6) underwent surgery to implant vascular catheters in the fetal femoral artery, femoral vein, amniotic cavity and umbilical vein. Fetal MRI scans were performed at 119-124 dGA. 4D flow and T 2 oximetry were performed to measure blood flow and oxygen saturation across the fetal circulation in both a basal state and whilst the fetus was receiving a continuous infusion of PGI 2 . The proportion of oxygenated blood that passed through the DV from the umbilical vein was increased by PGI 2 . Cerebral oxygen delivery was unchanged in the PGI 2 state. This may be a result of decreased flow from the right to left side of the heart as blood flow through the foramen ovale was decreased by PGI 2 . We have shown that although PGI 2 acts on the DV to increase the proportion of oxygen-rich blood that bypasses the liver, this does not increase cerebral oxygen delivery in the fetal sheep., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Elevated umbilical artery pulsatility is a widely used biomarker for placental pathology leading to intra-uterine growth restriction and, in severe cases, still-birth. It has been hypothesized that placental pathology modifies umbilical artery pulsatility by altering the degree to which the pulse pressure wave, which originates from the fetal heart, is reflected from the placental vasculature to interfere with the incident wave. Here we present a method for estimating the reflected pulse wave in the umbilical artery of human fetuses using asynchronously acquired Doppler ultrasound measurements from the two ends of the umbilical cord. This approach assumes non-dispersive and loss-less propagation of the waves along the artery and models the reflection process as a linear system with a parameterized impulse response. Model parameters are determined from the measured Doppler waveforms by constrained optimization. Velocity waveforms were obtained from 142 pregnant volunteers where 123 met data quality criteria in at least one umbilical artery. The reflection model was consistent with the measured waveforms in 183 of 212 arteries that were analyzed. The analysis method was validated by applying it to simulated datasets and comparing solutions to ground-truth. With measurement noise levels typical of clinical ultrasound, parameters describing the reflected wave were accurately determined.

Traumatic brain injury (TBI) can induce changes in vascular architecture. Although ultrasound metrics such as pulsatility index (PI) are sensitive to changes in hemodynamic resistance downstream from major arteries, these metrics depend on features unrelated to vessel architecture, such as blood pressure and heart rate. In contrast, input impedance and reflection coefficient that are derived from wave reflection theory seek to minimize the effects of altered cardiac output or heart rate. In this article, we investigate the use of ultrasound to assess changes in vascular impedance and wave reflection in the common carotid arteries of mice exposed to a controlled cortical impact. Focusing on the first harmonics of the reflected waves, the impedance phase was increased ipsilaterally in impacted mice compared with shams, whereas the magnitude of the impedance was unchanged. In contrast, PI was reduced bilaterally. Interestingly, PI and the first harmonic magnitude of input impedance in the carotid artery were correlated on the contralateral but not ipsilateral side. We investigated the use of these metrics to classify mice as sham or TBI, finding an area under the receiver operating characteristic curve ipsilaterally of 0.792 (confidence interval [CI]: 0.648-0.936) for correct classification with first harmonic impedance magnitude and phase as predictors and 0.716 (CI: 0.553-0.879) using carotid artery PI and diameter as predictors. Overall, the findings support the use of wave reflection analysis as a more specific measure of vascular changes following TBI and motivate the translation of this approach for monitoring vascular changes in humans affected by TBI.

Key Points: The comprehensive visualization and quantification of in vivo fetal hepatic haemodynamics, particularly the shunting of ductus venosus blood, has been elusive and is not yet fully understood. We introduce the combination of chronically instrumented fetal sheep and 4D flow MRI of the whole fetal liver, which allows retrospective blood flow measurement in all visible vessels as well as qualitative assessment. The applicability and usefulness of this technique is exhibited in normally grown fetal Merino sheep in mid- and late-gestation with detailed dynamic distribution of hepatic blood flow presented. The feasibility of this approach in clinical pathology is demonstrated in two growth-restricted fetuses at mid-gestation. Further exemplification of blood flow quantification is performed over major hepatic vessels., Abstract: Although the fetal vasculature has been demarcated and well understood for several decades, the corresponding haemodynamics permitting oxygen- and nutrient-rich blood delivery to the fetal organs has been comparatively difficult to study. We married two well-established methods: 4D flow MRI, a volumetric and dynamic blood-flow measurement technique, and chronically instrumented sheep to broadly assess fetal hepatic circulation. We performed this technique in mid- and late-gestation fetal Merino sheep under normoxemic conditions and major hepatic vasculature was segmented to quantify blood flow and related parameters. Dynamic blood flow was visualized, exhibiting an acceleration of umbilical vein blood through the ductus venosus as well as spiralling into the inferior vena cava where its stream remained separate from that of the hepatic veins and lower body. Ductus venosus changes from mid- to late-gestation included larger diameter (mid: 5.8 ± 0.9 vs. late: 7.1 ± 1.1 mm; P = 0.003) and cross-sectional area (mid: 27.1 ± 8.6 vs. late: 40.4 ± 11.8 mm 2 ; P = 0.003), and lower velocity averaged over the cardiac cycle (mid: 15.7 ± 5.4 vs. late: 9.8 ± 7.0 cm s -1 ; P = 0.020). This resulted in higher magnitude blood flow (indexed to umbilical vein input) at mid-gestation in the ductus venosus (mid: 0.73 ± 0.21; late: 0.46 ± 0.21; P = 0.008). The visualization and quantification results support the further use of this technique to better understand regional blood flow changes during normal or abnormal fetal growth, as well as to observe acute haemodynamic responses to physiological challenges or drug interventions., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Human fetal Doppler ultrasound and invasive blood gas measurements obtained by cordocentesis or at the time of delivery reveal similarities with sheep (an extensively used model for human fetal cardiovascular physiology). Oxygen saturation (SO 2 ) measurements in human fetuses have been limited to the umbilical and scalp vessels, providing little information about normal regional SO 2 differences in the fetus. Blood T2 MRI relaxometry presents a non-invasive measure of SO 2 in the major fetal vessels. This study presents the first in vivo validation of fetal vessel T2 oximetry against the in vitro T2-SO 2 relationship using catheterized sheep fetuses and compares the normal SO 2 in the major vessels between the human and sheep fetal circulations. Human fetal vessel SO 2 by T2 MRI confirms many similarities with the sheep fetal circulation and is able to demonstrate regional differences in SO 2 ; in particular the significantly higher SO 2 in the left versus right heart., Abstract: Blood T2 magnetic resonance imaging (MRI) relaxometry non-invasively measures oxygen saturation (SO 2 ) in major vessels but has not been validated in fetuses in vivo. We compared the blood T2-SO 2 relationship in vitro (tubes) and in vivo (vessels) in sheep, and measured SO 2 across the normal human and sheep fetal circulations by T2. Singleton pregnant ewes underwent surgery to implant vascular catheters. In vitro and in vivo sheep blood T2 measurements were related to corresponding SO 2 measured using a blood gas analyser, as well as relating T2 and SO 2 of human fetal blood in vitro. MRI oximetry was performed in the major vessels of 30 human fetuses at 36 weeks (term, 40 weeks) and 10 fetal sheep (125 days; term, 150 days). The fidelity of in vivo fetal T2 oximetry was confirmed through comparison of in vitro and in vivo sheep blood T2-SO 2 relationships (P = 0.1). SO 2 was similar between human and sheep fetuses, as was the fetal oxygen extraction fraction (human, 33 ± 11%; sheep, 34 ± 7%; P = 0.798). The presence of streaming in the human fetal circulation was demonstrated by the SO 2 gradient between the ascending aorta (68 ± 10%) and the main pulmonary artery (49 ± 9%; P < 0.001). Human and sheep fetal vessel MRI oximetry based on T2 is a validated approach that confirms the presence of streaming of umbilical venous blood towards the heart and brain. Streaming is important in ensuring oxygen delivery to these organs and its disruption may have important implications for organ development, especially in conditions such as congenital heart disease and fetal growth restriction., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)