Fetal Oxygen Delivery Research Articles

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

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. Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control (n = 12) and FGR (n = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state. Fetal oxygen delivery (DO2) was lower in FGR fetuses than controls during the normoxia state but cerebral DO2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO2. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased. Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO2. However, this upregulation is unable to maintain cerebral DO2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO2, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

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. 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 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC). 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. 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.

Abstract 17366: Effects of Acute Maternal Supplemental Oxygen on the Fetal Circulation in Transposition of the Great Arteries

Introduction: The presence of a restrictive atrial septum in the setting of transposition of the great arteries (TGA) is associated with a high risk of hypoxic ischemic injury upon transition to postnatal circulation. Fetal cardiovascular magnetic resonance (CMR) measures of vessel flow and oxygen saturation provide a unique opportunity to study fetal TGA hemodynamics at baseline and during acute maternal hyperoxygenation. Methods: Thirty-one pregnant mothers with fetuses diagnosed with TGA and an intact ventricular septum (n=23) or small ventricular septal defect (n=8) were recruited and underwent fetal CMR in room air and during administration of 10L/min of oxygen by face mask for up to 45 minutes. Blood flow and oxygen saturations were measured in the major fetal vessels using cine phase contrast MRI and MR relaxometry at baseline and during hyperoxygenation. Results: Two patients exhibited severe restriction at the atrial septum, one undergoing fetal atrial septostomy at 37 weeks and one requiring cannulation onto ECMO shortly after birth. Both revealed reversal of the usual relationship of oxygen saturation between the aorta and the main pulmonary artery at baseline and during hyperoxygenation, i.e. in TGA with restrictive atrial septum the saturations are higher in the aorta than pulmonary. Acute maternal supplemental oxygen was associated with increased pulmonary blood flow (p=0.008) and reduced foramen ovale (p=0.01) and ductus arteriosus shunting (p=0.01). There were no significant changes in umbilical vein, descending aorta and superior vena cava flow. Fetal oxygen saturations increased throughout fetal circulation (p<0.0001) with an associated increase in fetal oxygen delivery (p=0.007), but no increase in fetal cerebral oxygen delivery (p=0.58). Conclusions: This study characterized the effects of acute maternal supplemental oxygen on the fetal circulation in patients with TGA and confirmed the redistribution of flow toward the fetal pulmonary circulation. We observed higher oxygen saturations in the aorta than main pulmonary artery in fetuses with TGA with an intact or highly restrictive atrial septal communication. This finding could be helpful in selecting patients for prenatal or emergency neonatal balloon atrial septostomy.

PSXI-2 Preliminary Investigations into Developmental Origins of Pulmonary Arterial Pressure in Beef Cattle

Abstract High pulmonary arterial pressure (PAP) is a predisposing factor in the development of high mountain disease in cattle. Since PAP testing is often used to prevent disease, a better understanding of the genotype X environmental interactions that drive PAP may lead to the development of additional management and selection strategies. Hypoxia during gestation promotes adaptive fetal programming, a hallmark of which is altered cardiovascular development and disease. However, to our knowledge, no studies have investigated the link between maternal gestational environment and offspring cardiovascular performance as indicated by PAP score. Thus, the objective of this preliminary study was to evaluate the impact of temperature during gestation on yearling PAP in offspring from cattle residing at high altitudes. Yearling PAP data from Colorado State University’s Beef Improvement Center located near Saratoga, Wyoming (7,200 m elevation) was used in the analysis. Data were collected on individual Angus animals born from 1993 to 2021. There were 8,080 individuals with PAP phenotypes averaging 42.23 ± 9.59 mmHg. PAP testing was performed in individuals at an average age of 338.1 ± 46.4 d. Local historical temperature data from September to March, representing the time frame of middle to late gestation, were collected from the [National Oceanic and Atmospheric Administration (NOAA) database] and averaged. This historical average was compared with the yearly mid- to late gestational average temperatures to classify whether an individual animal went through gestation in an above or below-average temperature year. To determine the influence of temperature during gestation on PAP, a single trait linear regression model was used to regress PAP on age at PAP, sex, and temperature classification. The effects of age (P < 0.005), sex (P < 0.0005), and temperature classification (P < 0.05) all accounted for a significant amount of variation in PAP. The least-square means for temperature classification were 42.8 ± 0.51 and 42.3 ± 0.17 for above and below-average temperatures, respectively, which suggests that cows experiencing colder temperatures during gestation produce calves with lower yearling PAPs versus those from cows experiencing warmer temperatures. The internalization of maternal blood during cold temperatures may protect fetal oxygen and nutrient delivery, promoting normal heart development in a high-altitude environment.

The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study.

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34-38weeks' gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2 ), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P=0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P=0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. KEY POINTS: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies.

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

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

Using omics to breathe new life into our understanding of the ductus arteriosus oxygen response

The ductus arteriosus (DA) connects the aorta to the pulmonary artery (PA), directing placentally oxygenated blood away from the developing lungs. High pulmonary vascular resistance and low systemic vascular resistance facilitate shunting of blood in utero from the pulmonary to the systemic circulation through the widely patent DA, thereby optimizing fetal oxygen (O2) delivery. With the transition from fetal (hypoxia) to neonatal (normoxia) oxygen conditions, the DA constricts while the PA dilates. This process often fails in prematurity, promoting congenital heart disease. Impaired O2-responsivness in the DA promotes persistent ductus arteriosus (PDA), the most common form of congenital heart disease. Knowledge of DA oxygen sensing has greatly advanced in the past few decades, however we still lack a complete understanding of the sensing mechanism. The genomic revolution of the past two decades has facilitated unprecedented discovery in every biological system. This review will demonstrate how multiomic integration of data generated from the DA can breathe new life into our understanding of the DA's oxygen response.

Abstract 11766: Late Gestation Fetal Oxygenation is Associated With Birthweight and Head Circumference in Patients With Cyanotic Congenital Heart Disease

Introduction: Abnormal fetal growth and development are evident in patients with cyanotic congenital heart disease (cCHD). However, the relationship between growth and fetal oxygenation is unknown. We sought to investigate the relationship between fetal hemodynamics and fetal growth in cCHD using fetal cardiovascular Magnetic Resonance Imaging (MRI). Hypothesis: The impaired fetal oxygenation would be associated with diminished fetal brain and body growth in cCHD. Methods: We performed a prospective observational study in fetuses diagnosed with cCHD at our institution from June 2010 to January 2020. Late-gestational fetal cardiovascular MRI was performed in 152 fetuses with cCHD to assess fetal blood flow (phase-contrast MRI) and oxygen saturation (T2 oximetry) in the major fetal vessels to calculate oxygen delivery to the brain and body according to our previously published techniques. Results are provided as medians with IQR and compared with 30 gestational age-matched normal controls using Mann-Whitney U test. A Pearson’s correlation was used to examine the relationships between variables. Results: Compared with normal controls, fetuses with cCHD had significantly reduced birth weight Z-scores [-0.41 (-0.29, 0.84) vs. -0.19 (-0.46, 0.37), p = 0.03], and neonatal head circumference Z-scores [0.1 (-1.75, 0.95) vs. 0.69 (0.1, 1.79), p = 0.003]. As a combined cohort, birthweight Z-score was correlated with fetal oxygen delivery (r = 0.33, p = 0.003), umbilical vein flow (r = 0.2, p = 0.006) and oxygen saturation (r = 0.25, p = 0.02). Birth head circumference Z-score was correlated with fetal cerebral oxygen delivery (r = 0.33, p = 0.01) and ascending aorta oxygen saturation (r = 0.33, p = 0.009). We also found an inverse relationship between ascending aorta oxygen saturation and superior vena cava flow (r = -0.24, p = 0.036). Conclusions: In conclusion, we observed associations between placental function in late gestation and birthweight, as well as cerebral oxygen delivery in utero and head circumference at birth. Our findings are in keeping with the concept that cCHD impacts fetal development through abnormal circulatory physiology and placental function.

Impact of maternal late gestation undernutrition on surfactant maturation, pulmonary blood flow and oxygen delivery measured by magnetic resonance imaging in the sheep fetus.

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 ( ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140days' 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 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 to the fetal lung. There was a negative relationship between left pulmonary artery flow and 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 . 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.

Mechanisms linking hypoxia to phosphorylation of insulin-like growth factor binding protein-1 in baboon fetuses with intrauterine growth restriction and in cell culture.

Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling. Western blotting (n=6) and immunohistochemistry (n=3) using fetal liver indicated greater expression of HIF-1α, REDD-1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2 ) (n=3) induced REDD-1, inhibited mTOR complex-1 (mTORC1) activity and increased IGFBP-1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF-1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia-mediated inhibition of mTORC1 and induction of IGFBP-1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF-1α and also REDD-1 expression, inhibited mTORC1 and increased IGFBP-1 secretion/phosphorylation. Induction of HIF-1α (DMOG) and REDD-1 by Compound 3 inhibited mTORC1, increased IGFBP-1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF-1α induction, increased REDD-1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP-1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia-responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.

An MRI approach to assess placental function in healthy humans and sheep.

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 ( ) 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 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental by MRI was ∼4mlmin-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 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential. It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( ) 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 ( ) and in healthy humans and sheep. Women (n=20) and Merino sheep (n=10; 23sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36±2weeks and 128±9days, 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 and . Maternal (mlmin-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 (human=25±4, sheep=22 ± 5, P=0.049) was slightly lower in sheep. Uteroplacental and fetal (mlmin-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 ratio did not change with age (human, P=0.256; sheep, P=0.121). Human umbilical blood flow (mlmin-1 kg-1 fetus) decreased with advancing age (P=0.008), while fetal was preserved through an increase in oxygen extraction (P=0.046). By contrast, sheep fetal was preserved through stable umbilical flow (mlmin-1 kg-1 ; P=0.443) and oxygen extraction (P=0.582). MRI derived measurements of uteroplacental and fetal 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'.

Impact of resveratrol‐mediated increase in uterine artery blood flow on fetal haemodynamics, blood pressure and oxygenation in sheep

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. 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 113days 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.

Fetal Cerebral Oxygenation Is Impaired in Congenital Heart Disease and Shows Variable Response to Maternal Hyperoxia.

BackgroundImpairments in fetal oxygen delivery have been implicated in brain dysmaturation seen in congenital heart disease (CHD), suggesting a role for in utero transplacental oxygen therapy. We applied a novel imaging tool to quantify fetal cerebral oxygenation by measuring T2* decay. We compared T2* in fetuses with CHD with controls with a focus on cardiovascular physiologies (transposition or left‐sided obstruction) and described the effect of brief administration of maternal hyperoxia on T2* decay.Methods and ResultsThis is a prospective study performed on pregnant mothers with a prenatal diagnosis of CHD compared with controls in the third trimester. Participants underwent a fetal brain magnetic resonance imaging scan including a T2* sequence before and after maternal hyperoxia. Comparisons were made between control and CHD fetuses including subgroup analyses by cardiac physiology. Forty‐four mothers (CHD=24, control=20) participated. Fetuses with CHD had lower total brain volume (238.2 mm3, 95% CI, 224.6–251.9) compared with controls (262.4 mm3, 95% CI, 245.0–279.8, P=0.04). T2* decay time was faster in CHD compared with controls (beta=−14.4, 95% CI, −23.3 to −5.6, P=0.002). The magnitude of change in T2* with maternal hyperoxia was higher in fetuses with transposition compared with controls (increase of 8.4 ms, 95% CI, 0.5–14.3, P=0.01), though between‐subject variability was noted.ConclusionsCerebral tissue oxygenation is lower in fetuses with complex CHD. There was variability in the response to maternal hyperoxia by CHD subgroup that can be tested in future larger studies. Cardiovascular physiology is critical when designing neuroprotective clinical trials in the fetus with CHD.

Abstract 17390: Maternal and Fetal Cardiovascular Adaptations to Pregnancy and Outcomes in Mothers With Cardiac Disease - A Magnetic Resonance Imaging Study

Introduction: Insufficient maternal cardiac output (CO) has been implicated in poor pregnancy outcomes in mothers with heart disease (HD). Simultaneous delineation of vascular flows in the mother and her fetus have not been reported but could contribute to our understanding of the mechanisms of adverse events in this susceptible population. Methods: Pregnant women with moderate or severe HD (n=22; age 32±5 years) were studied using magnetic resonance imaging (MRI) and were compared with healthy controls (n=21; 34±3 years). Each MRI study included maternal and fetal components during the third trimester of pregnancy (corresponding to peak CO) and six months postpartum (surrogate for baseline hemodynamics). Phase contrast (PC) imaging was used to quantify maternal and fetal vascular flows. Fetal vessel T1 and T2 oximetry was used for derivation of fetal oxygen delivery and consumption. Maternal cardiac index (CI) was calculated using CO and pre-pregnancy body surface area. In the HD group, an “adapter” to pregnancy was defined as a woman with peak pregnancy CI measurement which met or exceeded the mean CI in the control population. Maternal and fetal outcomes were recorded. Results: There was no antepartum differences in absolute CO or CI in HD versus controls (CO 7.2±1.5 versus 7.3±1.6 L/min, p=0.79; CI 4.0±0.7 versus 4.3±0.7 L/min/m 2 , p=0.28). The percent increase in CO and CI (antepartum minus postpartum) was greater in women with HD versus controls (CO 46±24% versus 27±16%, p=0.02; CI 51±28% versus 28±17%, p<0.01). Fetal growth and oxygen delivery/consumption were similar between groups. Six adverse maternal cardiovascular events occurred in the HD group (heart failure n=2 and arrhythmia n=4) and there were none in the control group. There were no adverse fetal events in either group. There were 6 HD adapters (30%) and the adverse event rate was lower as compared with non-adapters (0% versus 38%, p=0.03). Conclusions: Maternal and fetal vascular flows can be characterized in pregnancy using MRI. Impaired adaptation to pregnancy in women with HD, as determined by magnitude of change in CO/CI, appears to be associated with adverse outcomes of pregnancy in the mother.

Interventions for Intrapartum Fetal Heart Rate Abnormalities.

Intrapartum fetal heart rate (FHR) decelerations may represent interrupted oxygen transfer to the fetus. In many cases, these interruptions are transient and do not result in progressive fetal acidemia with risk for asphyxia and neurological compromise. When significant FHR decelerations are present, reversible causes of reduced fetal oxygen delivery should be considered and corrective measures should be undertaken to optimize oxygenation. In this review, we describe potential intrapartum causes of reduced fetal oxygen delivery and the efficacy of common interventions for an abnormal FHR tracing.

Ex Utero Extracorporeal Support as a Model for Fetal Hypoxia and Brain Dysmaturity

Congenital heart disease (CHD) is associated with abnormal fetal brain development, a phenomenon that may be related to decreased cerebral oxygen delivery in utero. We used an artificial womb model to test the hypothesis that decreasing fetal oxygen delivery would reproduce physiologic changes identified in fetuses with CHD. Experimental (hypoxemic) fetal lambs (mean gestational age, 111 ± 3 days; n= 4) and control animals (112 days; n= 5) were maintained in the artificial womb for a mean of 22 ± 6 days. Oxygen delivery was reduced to 15.6 ± 1.0 mL/kg/min in the hypoxemia animals versus 21.6 ± 2.0 mL/kg/min in the control animals. Blood chemistry analysis and sonographic evaluation were performed daily. An additional control group (n= 7) was maintained in utero and harvested for analysis at gestational age 134 ± 4 days. Physiologic variables were monitored continuously, and no statistical differences between the groups were identified. Fetal oxygen delivery and arterial partial pressure of oxygen were remarkably lower in the experimental group longitudinally. Increased umbilical artery and decreased middle cerebral artery resistance resulted in a lower cerebral to umbilical resistance ratio, similar to the brain sparing effect observed in human fetuses with CHD. Experimental brains were smaller than control brains in relation to the calvarium on magnetic resonance. Sustained hypoxemia in fetal sheep leads to altered cerebrovascular resistances and loss of brain mass, similar to human fetuses with CHD. This unique model provides opportunities to investigate the pathologic process underlying CHD-associated brain dysmaturity and to evaluate potential fetal neuroprotective therapies.

Chronically Hypoxic Fetal Lambs Supported by an Extra-Uterine Device Exhibit Mitochondrial Dysfunction and Elevations of Hypoxia Inducible Factor 1-Alpha

Introduction: We have recently developed an extra-uterine environment for neonatal development (EXTEND) capable of supporting premature fetal lambs and have been able to replicate hypoxic in utero conditions by controlling fetal oxygen delivery. In this study, we investigated the fetal mitochondrial response to hypoxia. Methods: Eight premature fetal lambs were delivered via hysterotomy and transitioned to extra-uterine support for 3 weeks. The lambs were divided into 2 groups: normoxic fetuses which maintained physiologic oxygen delivery and hypoxic fetuses in which oxygen delivery was significantly reduced. Control fetuses were delivered via hysterotomy but not cannulated. Measurements of mitochondrial membrane potential (MMP) were performed in peripheral blood mononuclear cells. Results: There were no significant differences in MMP between normoxic EXTEND fetuses and controls. Hypoxic fetuses had significantly more depolarized mitochondria compared to normoxic fetuses overall, and these changes were specifically appreciated in weeks 1 and 2, but not by week 3. Hypoxic fetuses had significantly elevated levels of HIF-1α compared to normoxic fetuses in the first 2 weeks. Discussion: Normoxic fetal lambs supported by EXTEND demonstrate normal mitochondrial function as evidenced by equivalent membrane potentials compared to control fetuses. Hypoxic fetuses exhibit mitochondrial dysfunction, though they do show evidence of adaptation after 3 weeks of hypoxic exposure.

The hemodynamics of late-onset intrauterine growth restriction by MRI

Late-onset intrauterine growth restriction (IUGR) results from a failure of the placenta to supply adequate nutrients and oxygen to the rapidly growing late-gestation fetus. Limitations in current monitoring methods present the need for additional techniques for more accurate diagnosis of IUGR in utero. New magnetic resonance imaging (MRI) technology now provides a noninvasive technique for fetal hemodynamic assessment, which could provide additional information over conventional Doppler methods. The objective of the study was to use new MRI techniques to measure hemodynamic parameters and brain growth in late-onset IUGR fetuses. This was a prospective observational case control study to compare the flow and T2 of blood in the major fetal vessels and brain imaging findings using MRI. Indexed fetal oxygen delivery and consumption were calculated. Middle cerebral artery and umbilical artery pulsatility indexes and cerebroplacental ratio were acquired using ultrasound. A score of ≥ 2 of the 4 following parameters defined IUGR: (1) birthweight the third centile or less or 20% or greater drop in the centile in estimated fetal weight; (2) lowest cerebroplacental ratio after 30 weeks less than the fifth centile; (3) ponderal index < 2.2; and (4) placental histology meets predefined criteria for placental underperfusion. Measurements were compared between the 2 groups (Student t test) and correlations between parameters were analyzed (Pearson's correlation). MRI measurements were compared with Doppler parameters for identifying IUGR defined by postnatal criteria (birthweight, placental histology, ponderal index) using receiver-operating characteristic curves. We studied 14 IUGR and 26 non-IUGR fetuses at 35 weeks' gestation. IUGR fetuses had lower umbilical vein (P = .004) and pulmonary blood flow (P = .01) and higher superior vena caval flow (P < .0001) by MRI. IUGR fetuses had asymmetric growth but smaller brains than normal fetuses (P < .0001). Newborns with IUGR also had smaller brains with otherwise essentially normal findings on MRI. Vessel T2s, oxygen delivery, oxygen consumption, middle cerebral artery pulsatility index, and cerebroplacental ratio were all significantly lower in IUGR fetuses, whereas there was no significant difference in umbilical artery pulsatility index. IUGR score correlated positively with superior vena caval flow and inversely with oxygen delivery, oxygen consumption, umbilical vein T2, and cerebroplacental ratio. Receiver-operating characteristic curves revealed equivalent performance of MRI and Doppler techniques in identifying IUGR that was defined based on postnatal parameters with superior vena caval flow area under the curve of 0.94 (95% confidence interval, 0.87-1.00) vs a cerebroplacental ratio area under the curve of 0.80 (95% confidence interval, 0.64-0.97). MRI revealed the expected circulatory redistribution in response to hypoxia in IUGR fetuses. The reduced oxygen delivery in IUGR fetuses indicated impaired placental oxygen transport, whereas reduced oxygen consumption presumably reflected metabolic adaptation to diminished substrate delivery, resulting in slower fetal growth. Despite brain sparing, placental insufficiency limits fetal brain growth. Superior vena caval flow and umbilical vein T2 by MRI may be useful new markers of late-onset IUGR.

Circulation: Clinical Summaries.

Circulation: Clinical Summaries.

Hypoxic conditions alter developing branchial arch-derived structures in zebrafish

Background: Previous epidemiological findings have implicated hypoxia as a risk factor for craniofacial defects including cleft lip, microtia and branchial arch anomalies. This study tests the hypothesis that hypoxic exposure results in craniofacial shape variation in a zebrafish model. Methods: Three sets of zebrafish embryos were raised in uniform conditions with the exception of dissolved oxygen level. At 24 hours past fertilization (hpf) embryos were placed in hypoxic conditions (70% or 50% dissolved oxygen tank water) and compared to unexposed control embryos. After 24 hours of exposure to hypoxia, the embryos were incubated under normoxia. Larvae were collected at 5 days post fertilization (dpf) and stained for cartilage. Images were taken of each specimen and subsequently landmarked to capture viscerocranial morphology. A geometric morphometric analysis was performed to compare shape variation across groups. Results: The mean branchial arch shape of each exposure group was significantly different from controls (p&lt;0.001). Principal components analysis revealed a clear separation of the three groups, with controls at one end of the shape spectrum, the 50% hypoxia group at the other end, and the 70% hypoxia group spanning the variation in between. Conclusions: This experiment shows that hypoxia exposure at 24hpf is capable of affecting craniofacial shape in a dose-dependent manner. These results may have implications not only for high altitude fetal health, but other environments, behaviors and genes that affect fetal oxygen delivery.