Fetal Hypoxemia Research Articles

Comparison of weight-adjusted dose versus fixed dose ondansetron in preventing shivering following spinal anaesthesia for caesarean deliveries.

Spinal anaesthesia is an effective regional anaesthesia technique, which is preferred in almost 86% of caesarean sections in the United States and United Kingdom. Eighty percent of caesarean sections done at the Aga Khan University hospital are under spinal anaesthesia. Shivering is a common complication of spinal anaesthesia, it occurs in 40%-64% of patients after neuraxial anaesthesia. Shivering may cause maternal and fetal hypoxemia, maternal discomfort and a problem to the anaesthesiologists when it comes to monitoring the patient during caesarean sections. Ondansetron a 5-HT3 receptor antagonist is effective in treatment and prevention of post-spinal anesthesia shivering. In published studies, use of a fixed dose in patients with different weights, masked the dose effect ondansetron in preventing shivering, such that not adjusting the dose according to the weight of patients' resulted in a higher occurrence of shivering. No study has compared different doses of ondansetron in preventing shivering in parturient women who have had spinal anaesthesia for caesarean section. To determine if a weight-adjusted dose is better than a fixed dose of ondansetron in preventing shivering following spinal anesthesia for caesarean delivery. This was a randomized, double-blinded controlled trial of 124 women scheduled for elective caesarean surgery. The women were randomized into two equal groups. The intervention group received intravenous ondansetron weight adjusted dosing at 0.1mg/kg and the control group received a fixed dose of 4mg before spinal anesthesia. The occurrence and severity of shivering and other outcomes, such as headache, pruritus were assessed and recorded during the surgery and post-operative period. A total of 124 patients were included in the study. Social demographic data and baseline vital signs did not differ significantly between the groups. Shivering was observed in 14 patients (22.6%) in the control group that received 4mg ondansetron and 7 patients (11.3%) in the intervention group that had 0.1mg/kg of ondansetron, but there was no statistical difference between the groups (p- value 0.090). The severity of shivering was greater in the control group compared to intervention group where patients who developed grade two shivering were 8.1% to 0% respectively. (P value 0.047). There was no difference in the occurrence of pruritus between the two groups. No patient required treatment for very severe shivering. This study, found that ondansetron weight adjusted dose at 0.1mg/kg, reduced the severity of shivering when compared to a fixed dose ondansetron at 4mg.

Coagulation Profile in neonates with perinatal asphyxia

Background: Perinatal Asphyxia refers to a condition during the first and second stage of labour in which impaired gas exchange leads to fetal acidosis, hypoxemia and hypercarbia. It accounts for about 23 per cent of the four million newborn deaths worldwide.Methods: To estimate the magnitude of coagulation derangement in babies who suffered birth asphyxia and compare it with non-asphyxiated controls.Results: There were 61.9% and 64 % males in both the groups outnumbering females suggesting that the health care seeking behavior for male children is more than for their female counterparts. Birth weight and mode of delivery are comparable in both the groups. PT and APTT were significantly higher in the asphyxiated babies than in their respective control group. It may be noted , however, that PT and APTT values were higher in the control group also, when compared with the reference values. This may indicate that the hemostatic mechanisms are already compromised in the newborns and perinatal asphyxia further augment the situation tilting it in favour of bleeding. Thrombocytopenia is observed in the asphyxiated group which may be due to placental insufficiency. Severe bleeding is significant in asphyxiated group as compared to the control.Conclusion: Dyscoagulation should be considered in all asphyxiated babies, and they may present with clinically significant bleeding, which may require fresh frozen plasma to restore and maintain their coagulation status.

Sustained hypoxemia in late gestation potentiates hepatic gluconeogenic gene expression but does not activate glucose production in the ovine fetus.

Fetal hypoxemia is associated with pregnancy conditions that cause an early activation of fetal glucose production. However, the independent role of hypoxemia to activate this pathway is not well understood. We hypothesized that fetal hypoxemia would activate fetal glucose production by decreasing umbilical glucose uptake and increasing counter-regulatory hormone concentrations. We induced hypoxemia for 9 days with maternal tracheal N2 gas insufflation to reduce maternal and fetal arterial Po2 by ~20% (HOX) compared with fetuses from ewes receiving intratracheal compressed air (CON). At 0.9 of gestation, fetal metabolic studies were performed (n = 7 CON, 11 HOX). Umbilical blood flow rates, net fetal oxygen and glucose uptake rates, and fetal arterial plasma glucose concentrations were not different between the two groups. Fetal glucose utilization rates were lower in HOX versus CON fetuses but not different from umbilical glucose uptake rates, demonstrating the absence of endogenous glucose production. In liver tissue, mRNA expression of gluconeogenic genes G6PC (P < 0.01) and PCK1 (P = 0.06) were six- and threefold greater in HOX fetuses versus CON fetuses. Increased fetal norepinephrine and cortisol concentrations and hepatic G6PC and PCK1 expression were inversely related to fetal arterial Po2. These findings support a role for fetal hypoxemia to act with counter-regulatory hormones to potentiate fetal hepatic gluconeogenic gene expression. However, in the absence of decreased net fetal glucose uptake rates and plasma glucose concentrations, hypoxemia-induced gluconeogenic gene activation is not sufficient to activate fetal glucose production.

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia.

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

Neural and cardiac injury markers in fetal growth restriction and their relation to perinatal outcomes.

Objective:To compare the levels of umbilical cord blood Neuron-Specific Enolase (NSE) and troponin T and venous blood gas samples between healthy newborns and growth-retarded fetuses with impaired Doppler velocity or low APGAR scores.Materials and Methods:This study was a prospective cohort study. The study group comprised 26 patients with intrauterine growth restriction and pathologic Doppler symptoms, and the control group included 24 healthy fetuses. Umbilical cord blood and blood gas samples were taken from all patients. The blood samples were centrifuged and sent to a laboratory to study NSE and troponin T Perinatal outcomes were evaluated from the medical records of the newborns.Results:Both groups were similar in terms of demographic characteristics. Fetuses with fetal growth restriction (FGR) were born earlier and had lower APGAR scores than the study group. Chronic hypoxemic fetuses in the study group had lower cord pH and HCO3 levels. Further, troponin T levels were higher in the study group than in the control group. There were no major differences in Doppler velocity measurements.Conclusion:It has been understood that cardiac and neuronal injury detection on fetuses with FGR, troponin T, and NSE are indicators that can be used. In the literature there are studies with heterogeneous paradigms using different indicators to find neuronal injury. As a result of this study, it is clear that to assess neonatal prognosis, wider-scoped and comparative studies will provide more information about the subject.

Шляхи оптимізації моніторингу хронічної та гострої гіпоксемії плода

Шляхи оптимізації моніторингу хронічної та гострої гіпоксемії плода

Fetal hypoxemia causes abnormal myocardial development in a preterm ex utero fetal ovine model.

In utero hypoxia is a major cause of neonatal morbidity and mortality and predisposes to adult cardiovascular disease. No therapies exist to correct fetal hypoxia. In a new ex utero fetal support system, we tested the hypothesis that hypoxemic support of the fetus impairs myocardial development, whereas normoxic support allows normal myocardial development. Preterm fetal lambs were connected via umbilical vessels to a low-resistance oxygenator and placed in a sterile-fluid environment. Control normoxic fetuses received normal fetal oxygenation, and hypoxemic fetuses received subphysiologic oxygenation. Fetuses with normal in utero development served as normal controls. Hypoxemic fetuses exhibited decreased maximum cardiac output in both ventricles, diastolic function, myocyte and myocyte nuclear size, and increased myocardial capillary density versus control normoxic fetuses. There were no differences between control normoxic fetuses in the fetal support system and normal in utero controls. Chronic fetal hypoxemia resulted in significant abnormalities in myocyte architecture and myocardial capillary density as well as systolic and diastolic cardiac function, whereas control fetuses showed no differences. This ex utero fetal support system has potential to become a significant research tool and novel therapy to correct fetal hypoxia.

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates

ObjectiveNon-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure. MethodsWe utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester. ResultsFetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers. ConclusionsOur data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple “first hits” occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring.

Peculiarities of glucose intake in fetal tissues in chronic hypoxemia

Objective — to investigate fetal blood distribution and glucose metabolism of heart, liver and brain during chronic hypoxaemia. Establishment of a model of real time measurement of the metabolic changes during chronic fetal hypoxaemia using PET-CT measurement in pregnant sheep after iatrogenic induction of chronic fetal hypoxaemia. Laser coagulation of placental vessels was performed in pregnant sheep in order to cause fetal hypoxaemia 14 days before the PET-procedure. The following PET-Scans were performed after 18F-FDG was injected into the jugular vein of the sheep. Fetal glucose uptake was scanned in fetal brain, liver, heart and kidneys during a period of 60 min after injection of the FDG tracer. Glucose uptake of these organs was measured in comparison with placental glucose uptake during the above-called 60 minutes course. Here we present the analysis of the metabolic changes in fetal hypoxaemia in a small series of 8 fetal sheep. It was found that FDG Uptake in the placenta, brain, liver and heart of the fetus was measured at normal oxygenation and in chronic hypoxia in 8 sheep fetuses, between 112 and 135 days of pregnancy (gestational age) 125±4 days (mean±SD). Umbilical cord artery resistance was significantly higher in hypoxemic fetuses compared to normoxemic. Venous duct reactions as a respond to hypoxia was observed. Index of pulsation in the umbilical artery was not significantly increased during hypoxia (1,06±0,18 та 1,67±0,12, р=0,018). PI in venous duct during chronic hypoxia (0,62±0,25) was increased in compare with normoxemic (0,41±0,2), but not significantly. Relative FDG uptake was about 3.8 times higher in brain of hypoxemic fetuses (0.019±0.005) compared to normoxemic (0.005±0.002), (р=0,02). In contrast, hypoxic fetal heart showed no significant difference in absorption of FDG compared to normoxemic fetal brain (p=0.11). Relative FDG uptake in the liver did not differ substantially between the two groups (p=0.97). Thus, it was shown that chronic maternal hypoxemia led to decreased placental and increased brain blood flow, although, glucose metabolism was not decreased in the fetal liver and heart.

Effect of Oxygen vs Room Air on Intrauterine Fetal Resuscitation

Two-thirds of women in labor receive supplemental oxygen to reverse perceived fetal hypoxemia and prevent acidemia. Oxygen is routinely administered for category II fetal heart tracings, a class of fetal tracing used to designate intermediate risk for acidemia. This liberal use of oxygen may not be beneficial, particularly because neonatal hyperoxygenation is harmful. To test the hypothesis that room air is noninferior to oxygen in improving fetal metabolic status among patients with category II fetal heart tracings. This was a randomized, unblinded noninferiority clinical trial conducted between June 2016 and July 2017 in the labor and delivery ward of a single tertiary care center. Women with singleton pregnancies at 37 weeks' gestational age or more who were admitted for delivery were eligible. Of those who met inclusion criteria, the patients who developed category II tracings in labor that necessitated intrauterine resuscitation were randomized in a 1:1 ratio to room air or oxygen. Analyses were intention-to-treat. The oxygen group received 10 L of oxygen per minute by nonrebreather facemask until delivery. The room air group was exposed to room air only without a facemask. The primary outcome was umbilical artery lactate, a marker of metabolic acidosis and neonatal morbidity. Noninferiority was defined as a mean difference between groups of less than 9.0 mg/dL (1.0 mmol/L). Secondary outcomes were other umbilical artery gases, cesarean delivery for nonreassuring fetal status, and operative vaginal delivery. Of the 705 patients who met inclusion criteria, 277 (39.3%) were enrolled on admission. During labor, 114 patients (41.2% of the enrolled patients) developed category II tracings and were randomized to room air (57 patients; 50.0% of the randomized patients) or oxygen (57 patients; 50.0% of the randomized patients). A total of 99 patients (86.8% of the randomized patients) with paired cord gases were included in the modified intention-to-treat analysis. The 99 patients included 76 African American women (77%); mean (SD) age was 27.3 (6.3) years in the oxygen group and 27.8 (5.3) years in the room air group. There was no difference in umbilical artery lactate between the group on oxygen and the group on room air (mean, 30.6 mg/dL [95% CI, 27.0 to 34.2 mg/dL] vs 31.5 mg/dL [95% CI, 27.9 to 36.0 mg/dL]); P = .69). The mean difference in lactate was 0.9 mg/dL (95% CI, -4.5 to 6.3 mg/dL), which was within the noninferiority margin. There was no difference in other umbilical artery gas components or mode of delivery between groups. Among patients with category II fetal heart tracings, intrauterine resuscitation with room air is noninferior to oxygen in improving umbilical artery lactate. The results of this trial challenge the efficacy of a ubiquitous obstetric practice and suggest that room air may be an acceptable alternative. ClinicalTrials.gov Identifier: NCT02741284.

ST waveform analysis for monitoring hypoxic distress in fetal sheep after prolonged umbilical cord occlusion.

IntroductionThe inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO).MethodsEight fetal lambs were exposed to 25 minutes of UCO. ECG recordings were analyzed during a baseline period and during UCO. STAN-event rates and timing of episodic T/QRS rise, baseline T/QRS rise and the occurrence of biphasic ST-waveforms, as well as signal loss, were assessed.ResultsDuring baseline conditions of normoxemia, a median of 40 (IQR, 25–70) STAN-events per minute were detected, compared to 10 (IQR, 2–22) during UCO. During UCO STAN-events were detected in five subjects within 10 minutes and in six subjects after 18 minutes, respectively. Two subjects did not generate any STAN-event during UCO. Biphasic ST event rate was reduced during UCO (median 0, IQR 0–5), compared to baseline (median 32, IQR, 6–55). ST-waveforms could not be assessed in 62% of the recording time during UCO, despite a good quality of the ECG signal.ConclusionsThe STAN device showed limitations in detecting hypoxemia in fetal sheep after prolonged UCO. The STAN device produced high false positive event rates during baseline and did not detect T/QRS changes adequately after prolonged fetal hypoxemia. During 14% of baseline and 62% of the UCO period, the STAN-device could not process the ECG signal, despite its good quality. Resolving these issues may improve the clinical performance of the STAN device.

Reduced fetal movements and cerebroplacental ratio: evidence for worsening fetal hypoxemia.

To investigate the fetal cerebroplacental ratio (CPR) in women presenting with reduced fetal movements (RFM). This was a retrospective cohort study of data collected over an 8-year period at a fetal medicine unit at a tertiary referral center. The cohort comprised 4500 singleton pregnancies presenting with RFM at or after 36 weeks' gestation and 1527 control pregnancies at a similar gestational age without RFM. Fetal biometry and Doppler parameters were recorded and converted into centiles and multiples of the median (MoM). CPR was defined as the ratio between the fetal middle cerebral artery (MCA) pulsatility index (PI) and the umbilical artery (UA) PI. Subgroup analysis for fetal size and for single vs multiple episodes of RFM was performed. Compared with controls, pregnancies with RFM had lower MCA-PI MoM (median, 0.95 vs 0.97; P< 0.001) and CPR MoM (median, 0.97 vs 0.99; P= 0.018). Compared with women presenting with single episodes of RFM, pregnancies with multiple episodes (≥ 2 episodes) had lower CPR MoM (median, 0.94 vs 0.98; P= 0.003). On subgroup analysis for fetal size, compared with controls, appropriate-for-gestational-age fetuses in the RFM group had lower MCA-PI MoM (median, 0.96 vs 0.97; P= 0.003) and higher rate of CPR below the 5th centile (5.3% vs 3.6%; P= 0.015). Logistic regression analysis demonstrated an association of risk of recurrent RFM with maternal age (OR, 0.96; 95% CI, 0.93-0.99), non-Caucasian ethnicity (OR, 0.72; 95% CI, 0.53-0.97), estimated fetal weight centile (OR, 1.01; 95% CI, 1.00-1.02) and CPR MoM (OR, 0.24; 95% CI, 0.12-0.47). Pregnancies complicated by multiple episodes of RFM show significantly lower CPR MoM and MCA-PI MoM compared with those with single episodes and controls. This is likely to be due to worsening fetal hypoxemia in women presenting with recurrent RFM. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Impact of thermal stress on placental function and fetal physiology.

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternal- fetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period.

Obstetrics at Decisive Crossroads Regarding Pattern-Recognition of Fetal Heart Rate Decelerations: Scientific Principles and Lessons From Memetics.

The survival of cardiotocography (CTG) as a tool for intrapartum fetal monitoring seems threatened somewhat unjustifiably and unwittingly despite the absence of better alternatives. Fetal heart rate (FHR) decelerations are center-stage (most important) in the interpretation of CTG with maximum impact on three-tier classification. The pattern-discrimination of FHR decelerations is inexorably linked to their nomenclature. Unscientific or flawed nomenclature of decelerations can explain the dysfunctional CTG interpretation leading to errors in detection of acidemic fetuses. There are three contrasting concepts about categorization of FHR decelerations: 1) all rapid decelerations (the vast majority) should be grouped as “variable” because they are predominantly due to cord-compression, 2) all decelerations are due to chemoreflex from fetal hypoxemia hence their timing is not important, and 3) FHR decelerations should be categorized into “early/late/variable” based primarily on their time relationship to contractions. These theoretical concepts are like memes (ideas/beliefs). Lessons from “memetics” are that the most popular, attractive or established beliefs may not necessarily be true, scientific, beneficial or even without harm. Decelerations coincident with contractions with trough corresponding to the peak of contractions cannot be explained by cord-compression or increasing hypoxia (from compromised uteroplacental perfusion, cord-compression or even cerebral hypoperfusion/anoxia purportedly conceivable from head-compression). Decelerations due to hypoxemia would be associated with delayed recovery of decelerations (lag phase). It is a scientific imperative to cast away disproven/falsified theories. Practices based on unscientific theories lead to patient harm. Clinicians should urgently adopt the categorization of FHR decelerations based primarily of the time relationship to contractions as originally proposed by Hon and Caldeyro-Barcia. This analytical review shows it to be underpinned by most robust physiological and scientific hypotheses unlike the other categorizations associated with untruthful hypotheses, irreconcilable fallacies and contradictions. Without truthful framework and meaningful pattern-recognition of FHR decelerations, the CTG will not fulfil its true potential.

8: Oxygen for category ii intrauterine fetal resuscitation: a randomized, noninferiority trial

Approximately 2/3 of laboring women receive supplemental oxygen (O2) in an attempt to reverse perceived fetal hypoxemia and prevent acidosis. O2 supplementation is routinely used in patients with Category II fetal heart tracings (FHT). However, this liberal use of intrapartum O2 may not be beneficial, particularly since hyperoxygenation in neonates is harmful. We tested the hypothesis that room air (RA) for Category II FHT is not worse than O2 in reducing umbilical artery (UA) lactate, a marker of metabolic acidosis and neonatal morbidity. This was a randomized controlled noninferiority trial conducted from June 2016 to June 2017. Singleton pregnancies ≥ 37 weeks with Category II FHT necessitating intrauterine resuscitation in active labor (≥6cm) were randomized to RA or 10L/min O2 by face mask until delivery. The primary outcome was UA lactate measured by cord gases collected at delivery. Secondary outcomes were other UA gas components, cesarean delivery for nonreassuring fetal status (NRFS), and operative vaginal delivery. Assuming a mean UA lactate of 3.5 ± 1.6 mmol/L in patients with Category II FHT, 98 patients were needed for 90% power to detect non-inferiority with a margin of 30% and 1-sided alpha of 0.025. We increased the sample size to 114 patients to accommodate 15% loss to unattainable cord gases. Noninferiority was declared if the mean difference in lactate between RA and O2 was <1.0 mmol/L. Analysis was by intention-to-treat. Of the 114 patients randomized, 99 with paired cord gases were included in the intention-to-treat analysis; 48 O2 and 51 RA. There was no difference in mean UA lactate between patients randomized to O2 and RA (mean [95%CI], 3.4 [3.0, 3.8] vs 3.5 [3.1, 4.0]), P=0.69). The mean difference in UA lactate was 0.1 mmol/L (95% CI -0.5, 0.7), which is within the non-inferiority margin (Figure). There were no differences in other UA gas components, operative vaginal delivery or cesarean delivery for NRFS between groups (Table). Among patients with Category II FHT in active labor, intrauterine resuscitation with RA is not inferior to O2 in improving UA lactate. (ClinicalTrials.gov number NCT02741284).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity.

Preterm infants are at risk for a broad spectrum of neurobehavioral disabilities associated with diffuse disturbances in cortical growth and development. During brain development, subplate neurons (SPNs) are a largely transient population that serves a critical role to establish functional cortical circuits. By dynamically integrating into developing cortical circuits, they assist in consolidation of intracortical and extracortical circuits. Although SPNs reside in close proximity to cerebral white matter, which is particularly vulnerable to oxidative stress, the susceptibility of SPNs remains controversial. We determined SPN responses to two common insults to the preterm brain: hypoxia-ischemia and hypoxia. We used a preterm fetal sheep model using both sexes that reproduces the spectrum of human cerebral injury and abnormal cortical growth. Unlike oligodendrocyte progenitors, SPNs displayed pronounced resistance to early or delayed cell death from hypoxia or hypoxia-ischemia. We thus explored an alternative hypothesis that these insults alter the maturational trajectory of SPNs. We used DiOlistic labeling to visualize the dendrites of SPNs selectively labeled for complexin-3. SPNs displayed reduced basal dendritic arbor complexity that was accompanied by chronic disturbances in SPN excitability and synaptic activity. SPN dysmaturation was significantly associated with the level of fetal hypoxemia and metabolic stress. Hence, despite the resistance of SPNs to insults that trigger white matter injury, transient hypoxemia disrupted SPN arborization and functional maturation during a critical window in cortical development. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in cerebral growth and maturation related to SPN dysmaturation.SIGNIFICANCE STATEMENT The human preterm brain commonly sustains blood flow and oxygenation disturbances that impair cerebral cortex growth and cause life-long cognitive and learning disabilities. We investigated the fate of subplate neurons (SPNs), which are a master regulator of brain development that plays critical roles in establishing cortical connections to other brain regions. We used a preterm fetal sheep model that reproduces key features of brain injury in human preterm survivors. We analyzed the responses of fetal SPNs to transient disturbances in fetal oxygenation. We discovered that SPNs are surprisingly resistant to cell death from low oxygen states but acquire chronic structural and functional changes that suggest new strategies to prevent learning problems in children and adults that survive preterm birth.

OP18.02: Cerebroplacental ratio in recurrent reduced fetal movements: evidence for worsening fetal hypoxemia

OP18.02: Cerebroplacental ratio in recurrent reduced fetal movements: evidence for worsening fetal hypoxemia

Maternal body mass index impacts fetal-placental size at birth and umbilical cord oxygen values with implications for regulatory mechanisms

BackgroundMaternal under- and over-nutrition are known to effect fetal growth with altered placental development and nutrient transport, but whether fetal oxygenation is also altered remains unknown. AimsTo examine linkages between maternal BMI and birth weights, placental weights, and umbilical vein and artery PO2, with implications for signaling mechanisms. Study designPopulation-based cohort study. SubjectsAnalysis of hospital database information on all patients with pre-pregnant BMI values delivering viable, singleton infants between Jan 1, 1999 and Dec 31, 2010 (N=29,212). BMI was categorized into underweight, normal weight, overweight, and obese, with birth weights categorized into small (SGA), appropriate (AGA), and large for gestational age (LGA). Outcome measuresMaternal BMI, birth and placental weights, umbilical vein and artery PO2. ResultsUnderweight mothers with smaller infants and overweight/obese mothers with larger infants had disproportionately large placentas, suggesting compensatory and/or enhanced placental growth in these pregnancies. All SGA infants had lower umbilical vein and artery PO2, consistent with aberrant placental development leading to diffusional impairment of oxygen. Both maternal overweight/obese BMI and LGA resulted in lower artery PO2, likely due to increased growth rates with the larger size in these infants. ConclusionsThese findings support fetal hypoxemia as a common determinant of growth restriction, whether in underweight mothers and due to under-nutrition or in overweight/obese mothers and due to placental insufficiency. However, oxygen is unlikely to be the primary promotor for fetal growth in overweight/obese mothers and LGA infants, with other substrates of more importance as nutritional cues in these pregnancies.

Hypoxia-ischemia is not an antecedent of most preterm brain damage: the illusion of validity.

Brain injury in preterm newborn infants is often attributed to hypoxia–ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that – despite all the work done in human fetal neuropathology and developmental models in animals – the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally‐based title we think appropriate is ‘encephalopathy of prematurity’. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors.What this paper adds Fetal hypoxemia is rarely documented in brain injury studies.Animal studies fail to consider human–animal fetal anatomical differences.Putative treatments from animal models have not found clinical use.Observational studies constitute the only approach to etiological understanding.No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder.Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder.

Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation.

Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero. Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O2 ) or hypoxia (10% O2 ) from 105 to 138days of gestation (term ∼145days). At 138days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106±2.9vs. 47±2.8mmHg) and fetal body weight (4.0±0.4vs. 3.2±0.9kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.