Placental restriction and models of maternal hypoxia result in fetal growth restriction (FGR) with fetal circulatory redistribution, including increased ductus venosus shunting and brain sparing. In contrast, there are limited reports on the effects of fetal nutrient restriction on circulatory redistribution, with data on acute hypoglycaemic challenges or end-organ weights following chronic nutrient restriction. Fetal cardiovascular magnetic resonance (CMR) was employed to define fetal haemodynamics in utero following 25 days of maternal late gestation undernutrition (LGUN). Control ewes received 100% metabolizable energy requirements (MER), whereas LGUN and LGUN + intrafetal glucose supplementation (LGUN + G) ewes received 50% of MER. Fetal CMR was conducted after the dietary regime, and fetal liver was collected the following day. All fetuses were normoxaemic, whereas mean gestational fetal plasma glucose concentrations were lower in both LGUN and LGUN + G fetuses compared to control. There was a negative relationship between relative brain weight and fetal plasma glucose concentration. Biventricular ejection fraction and ductus venosus shunting were increased in LGUN compared to control but were normalized in LGUN + G. Relative left liver lobe weight demonstrated a negative linear relationship with fetal glucose, whereas right-lobe weight revealed a positive relationship. Cerebral oxygen delivery was lower in LGUN compared to control, whereas cerebral oxygen consumption (VO2) was diminished in both LGUN and LGUN + G compared to control. Cerebral VO2 correlated positively with fetal glucose. Although intrafetal glucose infusion did not normalize fetal glucose, cardiovascular changes were normalized, providing support for the role of glucose in mediating aspects of FGR physiology in normoxaemic but hypoglycaemic fetuses of LGUN ewes. KEY POINTS: Maternal late gestation undernutrition (LGUN) can lead to fetal growth restriction (FGR) independent of fetal hypoxaemia, but detailed characterization of fetal haemodynamics in utero is lacking. There was a negative relationship between relative brain weight and fetal plasma glucose concentration. LGUN increased fetal ventricular ejection fraction and ductus venosus shunting, both of which were normalized in LGUN fetuses that received intrafetal glucose infusion (LGUN + G). Relationships between left liver lobe sparing and cerebral oxygen consumption (VO2) and fetal glucose concentrations were observed. Cerebral VO2 was diminished in both LGUN and LGUN + G compared to control. This study is the first to comprehensively characterize fetal haemodynamics and oxygen consumption in the setting of LGUN and fetal normoxaemia, suggesting the role of fetal plasma glucose concentration in mediating aspects of FGR physiology.

Late-onset fetal growth restriction (FGR) from placental insufficiency results in progressive fetal hypoxia and is often associated with poor neurodevelopmental outcomes. In response to hypoxia, fetal brain sparing physiology is activated to protect the developing brain from injury via enhancing oxygen delivery. However, this protection may not be robust, and some brain regions remain susceptible to hypoxic injury. In addition, not all injury is manifested during fetal life, and may present in infant development. Using a mouse model of late-onset FGR where gestation is extended for 24 h, equivalent to approximately 2 weeks in humans, we deployed longitudinal in vivo magnetic resonance imaging to assess structural brain development from birth to adulthood. Postterm fetuses showed significantly smaller volumes of the perirhinal and ectorhinal cortex regions compared to controls, with no differences observed between sexes. These brain regions, essential for recognition memory, exhibited progressively greater volume reductions with increasing postnatal age. Our findings add to the growing body of literature demonstrating that an adverse fetal environment during critical periods of development can have effects on the brain that persist into adulthood.

There is an association between fetal growth restriction (FGR) and a poor lifetime cardiac health trajectory. Defining the underlying mechanisms will aid in developing interventions to decrease the contribution of FGR-born offspring to the global burden of cardiovascular disease. One cause of FGR is maternal undernutrition. In late-gestation undernutrition (LGUN) fetal glucose supply, a main energy source for the fetal heart, is reduced. This may be a key contributor to altered fetal cardiac development; thus restoration of fetal glucose availability in the LGUN setting may be a viable target for intervention. To investigate the role of glucose availability in fetal heart development, we utilized an established pregnant sheep model of LGUN (50% global nutrient restriction) with or without a continuous intrafetal glucose infusion. LGUN reduced fetal plasma glucose concentrations, resulting in brain sparing that was normalized by intrafetal glucose infusion. LGUN decreased the protein abundance of oxidative phosphorylation complexes 1 and 3; however glucose infusion returned complex 3 abundance to that of controls. LGUN increased the phosphorylation of contractility and hypertrophy marker CAMKII, which was associated with increased left ventricular cardiac output; however intrafetal glucose infusion normalized CAMKII. Our findings demonstrate that glucose plays a specific role in regulating cardiac development in utero, highlighting the importance of adequate maternal nutrition in late gestation. KEY POINTS: Maternal late-gestation undernutrition (LGUN) reduces fetal plasma glucose concentrations. To investigate the role of glucose availability in fetal left ventricle (LV) development, we assessed whether LGUN-induced alterations in the contractility, metabolic and hormonal profiles can be ameliorated in LGUN fetuses receiving glucose infusion (LGUN+G). Relative brain weight was increased in LGUN compared to controls and restored in LGUN+G despite fetal glucose infusion only partially normalizing fetal plasma glucose concentrations to that of controls. LGUN decreased cardiac oxidative phosphorylation (OXPHOS)complex 1 and 3 abundance, and LGUN+G restored complex 3 to that of controls. LGUN increased the activation of the contractility marker, Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), but restored in LGUN+G. The magnetic resonance imaging measure of the LV cardiac output was positively correlated with p-CAMKII expression in LGUN. This study highlights the role of in utero glucose availability in regulating the abundance of fetal LV OXPHOS complex 3 and CAMKII activation in utero.

Background: Dynamic fetal cardiovascular MRI (CMR) enables visualization of moving structures to assess congenital heart disease and plan treatment. Low field MRI systems can provide more comfortable platforms for fetal CMR. Here, we demonstrate the feasibility and utility of motion corrected fetal cardiac cine CMR and compare it with real-time CMR at multiple spatial resolutions at 0.55 T. Methods: Ten human pregnancies were scanned at 0.55T on a derated MAGNETOM Aera (Siemens Healthineers, Erlangen, Germany) with spiral steady-state free precession imaging. Real-time images were reconstructed and used for motion correction and fetal cardiac gating followed by cine reconstructions. The signal-to-noise ratio (SNR), image quality, blood-to-myocardium contrast, and contrast-to-noise ratio (CNR) from real-time and cine reconstructions were compared. The effect of acceleration on cine accuracy was assessed by retrospectively undersampling the data and measuring the reconstruction error with the normalized root-mean-squared difference (NRMSD) in five fetuses. Reproducibility of the measurements was assessed by reconstructing cines from two independent windows of data and computing the NRMSD relative to the reference image in five fetuses. Results: The SNR, CNR, and image quality were better for cines than their corresponding real-time reconstructions. The blood-to-myocardium contrast had no significant difference between real-time and cine reconstructions. With finer spatial resolution, real-time images degraded, and cardiac structures were less conspicuous. NRMSD in cines decreased with increasing scan times across all resolutions (NRMSD = 10 +/- 2% for 7 s scan duration). Good consistency (NRMSD = 11 +/- 3%) was achieved between independent reconstruction windows. Conclusion: While this study was performed on an experimental scanner (derated; not commercially available), we have shown that fetal cine CMR is feasible at 0.55T and provides high-quality fetal cardiac images at high spatiotemporal resolutions.

Importance:Fetal growth restriction (FGR) is associated with adverse neurodevelopmental outcomes. However, the delineation of neurodevelopmental sequela in late-onset FGR has been hampered by challenges in diagnosing late-onset FGR and the confounding influence of prematurity. Objective:To characterize neurodevelopmental outcomes in full-term infants exposed to late-onset FGR and to examine the association of FGR with fetal hemodynamics, perinatal brain development, and somatic growth. Design, Setting, and Participants:In this single-center cohort study, pregnant persons with fetuses small for gestational age were enrolled between April 1, 2010, and August 31, 2016, and followed up until the infant was 36 months of age. Follow-up was completed November 2019. Data analysis was performed from June to August 2024. Exposures:Late-onset FGR diagnosed based on a composite scoring system. Main Outcomes and Measures:The primary outcomes were neurodevelopmental outcomes at 4, 8, and 12 months of age assessed by the Alberta Infant Motor Scale (AIMS) and at 18 and 36 months of age assessed by the Bayley Scales of Infant and Toddler Development, Third Edition. Secondary outcomes included fetal hemodynamics and perinatal brain development assessed by magnetic resonance imaging findings and serial somatic growth. Results:Among 97 singleton pregnancies (mean [SD] maternal age, 33.5 [3.8] years; 50 [52%] male neonates), 41 neonates (42%) were exposed to late-onset FGR. At 12-month follow-up, motor development was significantly delayed among full-term infants exposed to late-onset FGR compared with neonates appropriate for gestational age (AIMS mean difference, -4.5; 95% CI, -8.6 to -0.3). At all other time points, neurodevelopmental outcomes were similar between the groups. In models adjusted for covariates, gestational age at birth was associated with 18-month cognitive outcomes (coefficient, 4.13 [95% CI, 0.54-7.72]), while the diagnosis of late-onset FGR was not. Preterm infants exposed to FGR exhibited higher fetal combined ventricular output, higher ratio of cerebral to pulmonary blood flow, and lower oxygen saturation compared with full-term infants exposed to FGR and infants with no FGR exposure. In general, neonatal brain maturation and somatic growth by 12 months of age were similar between full-term infants exposed to FGR and those with no exposure. However, head circumference was smaller from birth until the 36-month follow-up in infants exposed to FGR. Conclusions:In this cohort study, full-term infants exposed to late-onset FGR exhibited normal neurodevelopmental outcomes by 18 and 36 months of age, and longer gestation was associated with improved outcomes. These findings suggest that early delivery is unlikely to offer neurodevelopmental benefit, and any adverse impact on neurodevelopmental outcomes of late-onset FGR among full-term infants is likely to be modest.

Conventional four-dimensional (4D) flow magnetic resonance imaging (MRI) is limited by long scan times, particularly in pediatric congenital heart disease (CHD) patients. This study evaluates accelerated 4D flow MRI incorporating respiratory compensation and cardiac view sharing in healthy adults and pediatric CHD patients. Subjects underwent 5-min free-breathing protocol with a three-dimensional (3D) radial trajectory and compressed sensing reconstruction. The 4D flow MRI reconstruction pipeline was improved by respiratory soft-gating and cardiac view sharing. Flow in major thoracic vessels was compared with two-dimensional (2D) phase contrast MRI, the reference standard. Fourteen pediatric CHD patients (median age: 13 years (interquartile range (IQR): 5)) and four healthy adult volunteers (median age: 26 years (IQR: 3)) were recruited. Soft-gating improved diaphragm sharpness and reduced respiratory-induced blur (image quality scores: healthy: 46.1 soft-gated vs. 47.2 non-gated; CHD: 47.8 soft-gated vs. 48.2 non-gated). View sharing reduced undersampling artifacts and enhanced the signal-to-noise ratio (SNR, healthy: +9.9

Dynamic fetal cardiovascular MRI (CMR) enables visualization of moving structures to assess congenital heart disease and plan treatment. Low field MRI systems can provide more comfortable platforms for fetal CMR. To demonstrate the feasibility and utility of motion corrected fetal cardiac cine CMR and compare it with real-time CMR at multiple spatial resolutions at 0.55T. 10 human pregnancies were scanned at 0.55T (derated Siemens Aera) with spiral steady-state free precession imaging. Real-time images were reconstructed and used for motion correction and fetal cardiac gating followed by cine reconstructions. The signal-to-noise ratio (SNR), image quality, blood-to-myocardium contrast, and contrast-to-noise ratio (CNR) from real-time and cine reconstructions were compared. The effect of acceleration on cine accuracy was assessed by retrospectively undersampling the data and measuring the reconstruction error with the normalized root-mean-squared difference (NRMSD) in 5 fetuses. Reproducibility of the measurements was assessed by reconstructing cines from 2 independent windows of data and computing the NRMSD relative to the reference image in 5 fetuses. The SNR, CNR, and image quality were better for cines than their corresponding real-time reconstructions. The blood-to-myocardium contrast had no significant difference between real-time and cine reconstructions. With finer spatial resolution, real-time images degraded, and cardiac structures were less conspicuous. NRMSD in cines decreased with increasing scan times across all resolutions (NRMSD = 10 ± 2% for 7s scan duration). Good consistency (NRMSD = 11 ± 3%) was achieved between independent reconstruction windows. While this study was performed on an experimental scanner (derated; not commercially available), we have shown that fetal cine CMR is feasible at 0.55T and provide high quality fetal cardiac images at high spatiotemporal resolutions.

BACKGROUND:Cardiovascular magnetic resonance (CMR) allows cardiac hemodynamic assessment in patients with congenital heart disease (CHD). However, conventional techniques are time-consuming and may require blood contrast agents. Slice-to-volume reconstruction (SVR) four-dimensional (4D) flow is an innovative imaging technique that may overcome these limitations. This study aimed to assess the feasibility of SVR 4D flow in pediatric CHD. METHODS:Patients with CHD (n=7, age=12.9±2.8years) underwent CMR with conventional two-dimensional (2D) phase-contrast magnetic resonance imaging (2D PCMRI) and SVR 4D flow. SVR 4D flow datasets were reconstructed from multi-slice 2D spiral PCMRI acquisitions, which were combined via slice-to-volume reconstruction. Mean flows in major thoracic vessels were measured and compared between the two techniques. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated for each participant and compared between imaging techniques. RESULTS:Linear regression for SVR 4D flow against 2D PCMRI showed good agreement for mean flows (slope=1.03, intercept=-5.31 mL/s, r2=0.95). The SNR and CNR did not differ significantly between 2D PCMRI and SVR 4D flow data (SNR: p=0.85, CNR: p=0.90). CONCLUSION:Our results suggest that SVR 4D flow CMR is a feasible 5-minute scan (relative to multiple 2D PCMRI prescriptions and scans) in pediatric patients with CHD. SVR 4D flow showed good agreement with 2D PCMRI for mean flow measurements. The advantages of SVR 4D flow support further research such as its comparison with conventional 4D flow.

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 (Mtrd), random additional angles (Mrnd), and optimized additional angles (Mopt). 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 Mtrd, Mrnd, and Mopt was analyzed using the structural similarity index measure (SSIM). Mtrd and Mopt were compared in three adults at high, low, and no HR variability. RESULTS:STADs from Mtrd were significantly different (p < 0.05) from Mopt and Mrnd. STAD (IQR × 10-2 rad) showed that Mopt (0.5) and Mrnd (0.5) reduced clustering relative to Mtrd (1.9) at constant HR. For variable HR, Mopt (0.5) and Mrnd (0.5) outperformed Mtrd (0.9). The SSIM (IQR) showed that Mopt (0.011) produced the best image quality, followed by Mrnd (0.014), and Mtrd (0.030). Mopt outperformed Mtrd 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.

Spiral SSFP of the fetal heart at low-field has the advantage of low artifact and high sampling efficiency, compared to conventional systems. This work demonstrates the feasibility of spiral SSFP on a high-performance 0.55 T scanner to produce high spatiotemporal resolution real-time 2D and motion-corrected slice-to-volume super-resolution reconstructed 3D cine images of the heart and great vessels of the human fetus in utero. Patient comfort is improved with the use of a low-field scanner, while motion-robust slice-to-volume reconstruction allows for free-breathing acquisitions that do not require precise scan plane prescriptions during acquisition.

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: 106 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.

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 ${D_{{{\mathrm{O}}_2}}}$ .

ObjectiveFetuses 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.MethodsThis 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 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC).ResultsAmong 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.ConclusionsThis 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. (c) 2024 International Society of Ultrasound in Obstetrics and Gynecology.