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Fetal circulatory response to oxygen lack
Abstract
The knowledge on fetal and neonatal circulatory physiology accumulated by basic scientists and clinicians over the years has contributed considerably to the recent decline of perinatal morbidity and mortality. This review will summarize the peculiarities of the fetal circulation, the distribution of organ blood flow during normoxemia, and that during oxygen lack caused by various experimental perturbations. Furthermore, the relation between oxygen delivery and tissue metabolism during oxygen lack as well as evidence to support a new concept will be presented along with the principal cardiovascular mechanisms involved. Finally, blood flow and oxygen delivery to the principal fetal organs will be examined and discussed in relation to organ function. The fetal circulatory response to hypoxemia and asphyxia is a centralization of blood flow in favour of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This response is qualitatively similar but quantitatively different under various experimental conditions. However, at the nadir of severe acute asphyxia the circulatory centralization cannot be maintained. Then there is circulatory decentralization, and the fetus will experience severe brain damage if not expire unless immediate resuscitation occurs. Future work in this field will have to concentrate on the important questions, what factors determine this collapse of circulatory compensating mechanisms in the fetus, how does it relate to neuronal damage, and how can the fetal brain be pharmacologically protected against the adverse effects of asphyxia.
Supplementary resource (1)
... Impairment of the utero-placental circulation and perfusion during the active phase of the 2nd stage of labor (2STG), as a consequence of synergic action of uterine contractions and maternal expulsive efforts, hold the potential of determining fetal hypoxia and acidemia. However, the fetus is relatively able to cope with evolving hypoxic insults by compensation mechanisms [3,4]. ...
... In this phase, there is an increase in the intensity of contractions and greater pressure due to maternal pushing [8]. Moreover, with advancing labor, the fetus employs part of its base's reserves achieving progressively a lower tolerance to hypoxic insults [3,4,9]. Normal fetal capillary-blood pH ranges from 7.25 to 7.45 during labor. ...
Purpose
The aim of the study was to estimate by a survival analysis model the hazard function (HF) for neonatal metabolic acidemia (MA) throughout the 2nd stage of labor (2STG) at the time of occurrence of a terminal bradycardia ≥ 10 min requiring expedited delivery, and the cumulative incidence function (CIF) for MA according with the duration of bradycardia stratified in 10–12 min and > 12 min.
Methods
Singleton pregnancies experiencing terminal fetal bradycardia requiring expedited delivery in the 2STG at 38 + 0–41 + 3 weeks and delivering in the year 2019, were identified. The presence of MA (pH < 7 and/or BE ≤ − 12 mmol/L) was determined based on the acid–base status in the umbilical artery cord blood. Survival analysis was used to assess the hazard function (HF) and the cumulative incidence function (CIF) for MA occurring after terminal fetal bradycardia, at the 2STG.
Results
Out of a non-consecutive population of 12,331 pregnancies, there were 52 cases that fit the inclusion criteria. Twenty-four (46.2%) of those develop MA. Abnormal quantitative pH values and the HF for MA correlated with the duration of 2STG at the time of bradycardia onset, but not with bradycardia duration. After 60 min of duration of 2STG, the HF (or instantaneous rate of failure) increased dramatically (from 1.2 to 20 about at 120 min). At paired duration of 2STG, a higher CIF was observed for the terminal bradycardia > 12 min.
Conclusion
Forty-six percent of term fetuses with terminal bradycardia had MA at birth. Despite the low sensitivity and a non-significant association with quantitative pH values, the duration of terminal bradycardia in the 2STG is associated with a higher CIF for MA.
... During this time, the fetus will utilise compensatory mechanisms to maintain cerebral blood flow to minimise brain injury (as reviewed by Ref. [27]). In response to hypoxaemia, the near-term fetus initiates chemo-reflex mediated responses followed by slower endocrine and endothelial responses characterised by bradycardia and intense peripheral vasoconstriction to redistribute ventricular output to central organs [100,101]. While the preterm fetus can tolerate a longer period of asphyxia without injury than their term counterparts due to greater anaerobic tolerance, this paradoxically increases the risk of severe brain injury [27]. ...
... The sheep fetus responds to acute hypoxia by prioritizing blood flow to the brain, heart and adrenal glands, consonant with the notion of protective mechanisms that prioritize the brain 188,225,226 . In hyperinsulinaemia, however, the heart, but not the brain, receives an increased share of cardiac output 227,228 . ...
Despite improvements in clinical management, pregnancies complicated by pre-existing diabetes mellitus, gestational diabetes mellitus or obesity carry substantial risks for parent and offspring. Some of the endocrine and metabolic changes in parent and fetus in diabetes mellitus and obesity lead to fetal oxygen deficit, mostly due to insulin-induced accelerated fetal metabolism. The human fetus deals with reduced oxygenation through a wide range of adaptive responses that act at various levels in the placenta as well as the fetus. These responses ensure adequate oxygen delivery to the fetus, increase the oxygen transport capacity of fetal blood and redistribute oxygen-rich blood to vital organs such as the brain and heart. The liver has a central role in adapting to reduced oxygenation by increasing its oxygen extraction and stimulating erythropoietin synthesis to increase haematocrit. The type of adaptive response depends on the onset and duration of hypoxia and the severity of the metabolic disturbance. In pregnancies characterized by diabetes mellitus or obesity, these adaptive systems come under additional strain owing to the increased maternal supply of glucose and resultant fetal hyperinsulinaemia, both of which stimulate oxidative metabolism. In the rare situation that the adaptive responses are overwhelmed, stillbirth can ensue.
... These shunts, shown in Figure 1, include the ductus arteriosus (DA) that connects the main pulmonary artery (MPA) to the proximal descending aorta (DAo), and the foramen ovale (FO), which allows oxygen rich blood from the placenta to stream from the umbilical vein (UV) through the ductus venosus (DV) and then across the atrial septum to the left side of the heart. 1 In combination with physiologic changes in the vasculature, these shunts allow for redistribution of blood to the brain either from the left heart, through the ascending aorta (AAo), or from the right heart as retrograde aortic arch flow, in conditions where flow is obstructed or the blood is hypoxic. 2,16 Blood returns to the heart from the brain and upper body by the superior vena cava (SVC). ...
Fetal cardiac magnetic resonance imaging (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.
... These shunts help deliver oxygenated blood from the placenta to the fetal brain and myocardium, with flows partially bypassing the fetal lungs and liver [1]. Fetal pathologies, such as fetal growth restriction and congenital heart disease, disrupt this distribution, causing injury to critical fetal organs and increasing risk of fetal mortality [2], [3]. Accurate measurement of this flow distribution is important because it may identify impairment of organs and thereby help to guide appropriate therapy and monitor efficacy. ...
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 (
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.
... The depolarised neuronal membrane releases high concentrations of glutamate, which are typically cleared via the glia reuptake pumps during aerobic respiration, establishing an excito-oxidative cascade (Rocha-Ferreira and Hristova, 2016) causing neurotoxicity (Sanders et al., 2010) and mostly necrotic cell death (Rocha-Ferreira and Hristova, 2016). After successful re-oxygenation, a latent recovery phase takes place, where respiration switches back to aerobic and homoeostasis is recovered (Vannucci, 1990;Jensen and Berger, 1991;Gunn et al., 1992;Jensen et al., 1999). Depending on the severity of the HI insult, primary energy failure might not be compensated and would lead to secondary energy failure (Rocha-Ferreira and Hristova, 2016). ...
Neonatal hypoxic–ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic–ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic–ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic–ischaemic brain injury. Models of neonatal hypoxia–ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18–22 months, is approximately 6–7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.
... These shunts help deliver oxygenated blood from the placenta to the fetal brain and myocardium, with flows partially bypassing the fetal lungs and liver [1]. Fetal pathologies, such as fetal growth restriction and congenital heart disease, disrupt this distribution, causing injury to critical fetal organs and increasing risk of fetal mortality [2], [3]. Accurate measurement of this flow distribution is important because it may identify impairment of organs and thereby help to guide appropriate therapy and monitor efficacy. ...
Fetal development relies on a complex circulatory network and accurately assessing the flow distribution is important for understanding pathologies and potential therapies. In this paper, we demonstrate a method for volumetric multidimensional imaging of fetal flow with magnetic resonance imaging (MRI). Fetal application of MRI faces several challenges such as small vascular structures, unpredictable motion, and lack of traditional cardiac gating methods. Here, orthogonal multislice stacks are acquired with accelerated multidimensional radial phase contrast (PC) MRI. Each slice is reconstructed into flow sensitive time-series images (CINEs) with retrospective intraslice motion correction and image-based fetal cardiac gating. CINEs are then combined into a dynamic 3D volume using slice-to-volume reconstruction (SVR) while accounting for interslice spatiotemporal coregistration. Validation of the technique is demonstrated in adult volunteers by comparing mean flows from SVR with 4D radial PCMRI with bias and limits of agreement being -1.1 ml/s and [-12.5 10.2] ml/s. Feasibility is demonstrated in late gestation fetuses by comparing SVR with 2D Cartesian PCMRI with bias and limits of agreement being -0.9 ml/min/kg and [-39.7 37.8] ml/min/kg for mean flows. With SVR, we also 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 side of the heart, and blood returning 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.
... These shunts help deliver oxygenated blood from the placenta to the fetal brain and myocardium, with flows partially bypassing the fetal lungs and liver [1]. Fetal pathologies, such as fetal growth restriction and congenital heart disease, disrupt this distribution, causing injury to critical fetal organs and increasing risk of fetal mortality [2], [3]. Accurate measurement of this flow distribution is important because it may identify impairment of organs and thereby help to guide appropriate therapy and monitor efficacy. ...
Fetal development relies on a complex circulatory network and accurately assessing the flow distribution is important for understanding pathologies and potential therapies. In this paper, we demonstrate a method for volumetric multidimensional imaging of fetal flow with magnetic resonance imaging (MRI). Fetal application of MRI faces several challenges such as small vascular structures, unpredictable motion, and lack of traditional cardiac gating methods. Here, orthogonal multislice stacks are acquired with accelerated multidimensional radial phase contrast (PC) MRI. Each slice is reconstructed into flow sensitive time-series images (CINEs) with retrospective intraslice motion correction and image-based fetal cardiac gating. CINEs are then combined into a dynamic 3D volume using slice-to-volume reconstruction (SVR) while accounting for interslice spatiotemporal coregistration. Validation of the technique is demonstrated in adult volunteers by comparing mean flows from SVR with 4D radial PCMRI with bias and limits of agreement being -1.1 ml/s and [-12.5 10.2] ml/s. Feasibility is demonstrated in late gestation fetuses by comparing SVR with 2D Cartesian PCMRI with bias and limits of agreement being -0.9 ml/min/kg and [-39.7 37.8] ml/min/kg for mean flows. With SVR, we also 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 side of the heart, and blood returning 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.
... However, ensuing and larger falls in AoT blood flow and RV output were associated with a decline of arterial blood pressures and a pronounced bradycardia, and thus were more likely to be related to a deterioration of cardiac function accompanying a rapid arterial blood de-oxygenation that reached asphyxial levels by 45−60 s after cord clamping (Smolich et al. 2015(Smolich et al. , 2017(Smolich et al. , 2020. Furthermore, this asphyxial state was associated with surges in circulating concentrations of the catecholamines noradrenaline and adrenaline that were exponentially related to falling levels of aortic oxygenation (Smolich et al. 2017), reflecting a marked degree of sympathoadrenal activation (Cohen et al. 1982;Jensen & Berger, 1991). As catecholamines exert potent inotropic and vasoconstrictor effects (Jones & Ritchie, 1978;Padbury et al. 1987;Seri, 2001), it is likely that these surges contributed to rebound rises evident in ventricular contractility and arterial blood pressure (Smolich et al. 2017), with possible associated effects on ventricular outputs. ...
Key points
Controversy exists about the physiological mechanism(s) underlying decreases in cardiac output after immediate clamping of the umbilical cord at birth.
To define these mechanisms, the four major determinants of ventricular output (afterload, preload, heart rate and contractility) were measured concurrently in fetal lambs at 15 s intervals over a 2 min period after cord clamping and before ventilation following delivery.
After cord clamping, right (but not left) ventricular output fell by 20% in the initial 30 s, due to increased afterload associated with higher arterial blood pressures, but both outputs then halved over 45 s, due to a falling heart rate and deteriorating ventricular contractility accompanying rapid declines in arterial oxygenation to asphyxial levels.
Ventricular outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in ventricular contractility accompanying asphyxia‐induced surges in circulating catecholamines.
These findings provide a physiological basis for the clinical recommendation that effective ventilation should occur within 60 s after immediate cord clamping.
Abstract
Controversy exists about the physiological mechanism(s) underlying large decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, anaesthetized preterm fetal lambs (127(1)d, n = 12) were instrumented with flow probes and catheters in major central arteries, and a left ventricular (LV) micromanometer‐conductance catheter. Following immediate cord clamping at delivery, haemodynamics, LV and right ventricular (RV) outputs, and LV contractility were measured at 15 s intervals during a 2 min non‐ventilatory period, with aortic blood gases and circulating catecholamine (noradrenaline and adrenaline) concentrations measured at 30 s intervals. After cord clamping, (1) RV (but not LV) output fell by 20% in the initial 30 s, due to a reduced stroke volume associated with increased arterial blood pressures, (2) both outputs then halved over the next 45 s, associated with falls in heart rate, arterial blood pressures and ventricular contractility accompanying a rapid decline in arterial oxygenation to asphyxial levels, (3) reduced outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in blood pressures and ventricular contractility accompanying exponential surges in circulating catecholamines. These findings are consistent with a time‐dependent decline of ventricular outputs after immediate cord clamping, which comprised (1) an initial, minor fall in RV output related to altered loading conditions, (2) ensuing large decreases in both LV and RV outputs related to the combination of bradycardia and ventricular dysfunction during emergence of an asphyxial state, and (3) subsequent stabilization of reduced LV and RV outputs during ongoing asphyxia, supported by cardiovascular stimulatory effects of marked sympathoadrenal activation.
The antioxidant defense system is involved in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). To analyze the relationship between first serum blood glucose levels and outcomes in neonatal HIE, seventy-four patients were divided, based on the first glucose level, into group 1 (>0 mg/dL and <60 mg/dL, n =11), group 2 (≥60 mg/dL and <150 mg/dL, n = 49), and group 3 (≥150 mg/dL, n = 14). Abnormal glucose levels had poor outcomes among three groups in terms of the clinical stage (p = 0.001), brain parenchymal lesion (p = 0.004), and neurodevelopmental outcomes (p = 0.029). Hearing impairment was more common in group 3 than in group 1 (p = 0.062) and group 2 (p = 0.010). The MRI findings of group 3 exhibited more thalamus and basal ganglion lesions than those of group 1 (p = 0.012). The glucose level was significantly correlated with clinical staging (p< 0.001), parenchymal brain lesions (p = 0.044), hearing impairment (p = 0.003), and neurodevelopmental outcomes (p = 0.005) by Pearson’s test. The first blood glucose level in neonatal HIE is an important biomarker for clinical staging, MRI findings, as well as hearing and neurodevelopment outcomes. Hyperglycemic patients had a higher odds ratio for thalamus, basal ganglia, and brain stem lesions than hypoglycemic patients with white matter and focal ischemic injury. Hyperglycemia can be due to prolonged or intermittent hypoxia and can be associated with poor outcomes.
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