Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Comparison of dried blood spot and plasma sampling for untargeted metabolomics.

INTRODUCTION: Untargeted metabolomics holds significant promise for biomarker detection and development. In resource-limited settings, a dried blood spot (DBS)-based platform would offer significant advantages over plasma-based approaches that require a cold supply chain. OBJECTIVES: The primary goal of this study was to compare the ability of DBS- and plasma-based assays to characterize maternal metabolites. Utility of the two assays was also assessed in the context of a case-control predictive model in pregnant women living with HIV. METHODS: Untargeted metabolomics was performed on archived paired maternal plasma and DBS from n = 79 women enrolled in a large clinical trial. RESULTS: A total of 984 named biochemicals were detected across both plasma and DBS samples, of which 627 (63.7%), 260 (26.4%), and 97 (9.9%) were detected in both plasma and DBS, plasma alone, and DBS alone, respectively. Variation attributable to study individual (R2 = 0.54, p < 0.001) exceeded that of the sample type (R2 = 0.21, p < 0.001), suggesting that both plasma and DBS were capable of differentiating individual metabolomic profiles. Log-transformed metabolite abundances were strongly correlated (mean Spearman rho = 0.51) but showed low agreement (mean intraclass correlation of 0.15). However, following standardization, DBS and plasma metabolite profiles were strongly concordant (mean intraclass correlation of 0.52). Random forests classification models for cases versus controls identified distinct feature sets with comparable performance in plasma and DBS (86.5% versus 91.2% mean accuracy, respectively). CONCLUSION: Maternal plasma and DBS samples yield distinct metabolite profiles highly predictive of the individual subject. In our case study, classification models showed similar performance albeit with distinct feature sets. Appropriate normalization and standardization methods are critical to leverage data from both sample types. Ultimately, the choice of sample type will likely depend on the compounds of interest as well as logistical demands.

Early pregnancy metabolites predict gestational diabetes mellitus: implications for fetal programming.

BACKGROUND: Aberrant fetal programming in gestational diabetes mellitus seems to increase the risk of obesity, type 2 diabetes, and cardiovascular disease. The inability to accurately identify gestational diabetes mellitus in the first trimester of pregnancy has thwarted ascertaining whether early therapeutic interventions reduce the predisposition to these prevalent medical disorders. OBJECTIVE: A metabolomics study was conducted to determine whether advanced analytical methods could identify accurate predictors of gestational diabetes mellitus in early pregnancy. STUDY DESIGN: This nested observational case-control study was composed of 92 gravidas (46 in the gestational diabetes mellitus group and 46 in the control group) in early pregnancy, who were matched by maternal age, body mass index, and gestational age at urine collection. Gestational diabetes mellitus was diagnosed according to community standards. A comprehensive metabolomics platform measured 626 endogenous metabolites in randomly collected urine. Consensus multivariate criteria or the most important by 1 method identified low-molecular weight metabolites independently associated with gestational diabetes mellitus, and a classification tree selected a subset most predictive of gestational diabetes mellitus. RESULTS: Urine for both groups was collected at a mean gestational age of 12 weeks (range, 6-19 weeks' gestation). Consensus multivariate analysis identified 11 metabolites independently linked to gestational diabetes mellitus. Classification tree analysis selected a 7-metabolite subset that predicted gestational diabetes mellitus with an accuracy of 96.7%, independent of maternal age, body mass index, and time of urine collection. CONCLUSION: Validation of this high-accuracy model by a larger study is now needed to support future studies to determine whether therapeutic interventions in the first trimester of pregnancy for gestational diabetes mellitus reduce short- and long-term morbidity.

Management of Pregnancy in Patients With Complex Congenital Heart Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Today, most female children born with congenital heart disease will reach childbearing age. For many women with complex congenital heart disease, carrying a pregnancy carries a moderate to high risk for both the mother and her fetus. Many such women, however, do not have access to adult congenital heart disease tertiary centers with experienced reproductive programs. Therefore, it is important that all practitioners who will be managing these women have current information not only on preconception counseling and diagnostic evaluation to determine maternal and fetal risk but also on how to manage them once they are pregnant and when to refer them to a regional center with expertise in pregnancy management.

Thalamic mediation of hypoxic respiratory depression in lambs.

Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development.

Fetal breathing movements and changes at birth.

The fetus, which develops within a fluid-filled amniotic sac, relies on the placenta for respiratory gas exchange rather than the lungs. While not involved in fetal oxygenation, fetal breathing movements (FBM) nevertheless have an important role in lung growth and in development of respiratory muscles and neural regulation. FBM are regulated differently in many respects than postnatal respiration, which results from the unique intrauterine environment. Prominent distinctions of FBM include its episodic nature and apnea-sensitivity to hypoxia. The latter characteristic is the basis for using FBM in the assessment of fetuses at risk for hypoxic injury. At birth, the transition to continuous postnatal respiration involves a fall in temperature, gaseous distention of the lungs, activation of the Hering-Breuer reflexes, and functional connectivity of afferent O2 chemoreceptor activity with respiratory motoneurons and arousal centers. Importantly, exposure to drugs or adverse conditions in utero not only can change patterns of FBM but also can lead to epigenetic dysregulation in postnatal respiration. Such changes, can blunt respiratory and arousal defenses against hypoxic challenges in sleep. Thus, fetal hypoxia and/or drug exposure may in later life dispose sleeping infants, children, and adults to hypertension, diabetes mellitus, brain injury, and sudden death.

Approaches to Preventing Intrapartum Fetal Injury.

Electronic fetal monitoring (EFM) was introduced into obstetric practice in 1970 as a test to identify early deterioration of fetal acid-base balance in the expectation that prompt intervention ("rescue") would reduce neonatal morbidity and mortality. Clinical trials using a variety of visual or computer-based classifications and algorithms for intervention have failed repeatedly to demonstrate improved immediate or long-term outcomes with this technique, which has, however, contributed to an increased rate of operative deliveries (deemed "unnecessary"). In this review, we discuss the limitations of current classifications of FHR patterns and management guidelines based on them. We argue that these clinical and computer-based formulations pay too much attention to the detection of systemic fetal acidosis/hypoxia and too little attention not only to the pathophysiology of FHR patterns but to the provenance of fetal neurological injury and to the relationship of intrapartum injury to the condition of the newborn. Although they do not reliably predict fetal acidosis, FHR patterns, properly interpreted in the context of the clinical circumstances, do reliably identify fetal neurological integrity (behavior) and are a biomarker of fetal neurological injury (separate from asphyxia). They provide insight into the mechanisms and trajectory (evolution) of any hypoxic or ischemic threat to the fetus and have particular promise in signaling preventive measures (1) to enhance the outcome, (2) to reduce the frequency of "abnormal" FHR patterns that require urgent intervention, and (3) to inform the decision to provide neuroprotection to the newborn.

Adenosine A2a receptors and O2 sensing in development.

Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O2 sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5'-nucleotidase and the resulting activation of adenosine A(2A) receptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A(2A) receptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A(2A) receptors mediate hypoxic inhibition of breathing and rapid eye movements. A(2A) receptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A(2A) receptors play virtually no role in O2 sensing by the carotid bodies, but brain A(2A) receptors remain critically involved in the roll-off ventilatory response to hypoxia. In adult mammals, A(2A) receptors have been implicated in O2 sensing by carotid glomus cells, while central A(2A) receptors likely blunt hypoxic hyperventilation. In conclusion, A(2A) receptors are crucially involved in the transduction mechanisms of O2 sensing in fetal carotid bodies and brains. Postnatally, central A(2A) receptors remain key mediators of hypoxic respiratory depression, but they are less critical for O2 sensing in carotid chemoreceptors, particularly in developing lambs.

Central hemodynamics are associated with fetal outcomes in pregnancies of advanced maternal age.

OBJECTIVES: Age is a known risk factor for both maternal cardiovascular disease and adverse outcomes in pregnancy. We aimed to characterize the hemodynamic profiles in pregnancies of advanced maternal age (AMA) and correlate these with fetal outcomes. STUDY DESIGN: This was a prospective observational study of pregnancies undergoing antenatal testing. Maternal hemodynamics were measured non-invasively using an imaging probe at the descending aorta and the Uscom BP + arm cuff utilizing pulse pressure wave analysis. The Wilcoxon rank-sum test, Fisher's exact test, and Spearman rank correlation test were used for statistical analysis in R. MAIN OUTCOME MEASURES: Hemodynamic measurements, neonatal birthweight. RESULTS: Twenty-one AMA and twenty-four control patients were enrolled. Mean age ± SD was 39 ± 3.22 in the AMA cohort and 28 ± 4.32 in the control cohort (p < 0.001). AMA patients were evaluated at a later gestational age (36 4/7 weeks) compared to control (34 1/7 weeks, p = 0.02). Between groups, there was no difference in BMI, race, hypertensive disease, diabetes, asthma, drug use, or indication for antenatal testing. 38% (AMA) and 37% (control) had hypertensive disorders of pregnancy. In AMA patients but not control patients, cardiac output (r = 0.52, p = 0.01), systemic vascular resistance (r = -0.53, p = 0.01), and systemic vascular resistance index (r = -0.62, p = 0.002) were significantly correlated with neonatal birthweight percentile. CONCLUSIONS: Hemodynamic alterations consistent with a low output, high resistance cardiovascular circuit were associated with lower birthweight in AMA, but not in control pregnancies.

Maternal Central Blood Pressure Is Associated with Fetal Middle Cerebral Artery Dopplers.

Cardiovascular adaptations to pregnancy involve physiological mechanisms that increase cardiac output, decrease total vascular resistance, and decrease both systolic and diastolic blood pressure (BP). These maternal hemodynamic changes modulate uteroplacental blood flow and fetal-placental Doppler indices. Our objective was to create maternal cardiac profiles of pregnant women using non-invasive measurements of central BP to identify changes in maternal-fetal hemodynamics as a surrogate to fetal status. This was a prospective cohort study of all singleton pregnancies in a perinatal referral center between January and April 2018. Central BP was measured non-invasively using the BP+ device. The BP+ device is a supra-systolic oscillometric central BP device, which measures BP waveforms peripherally and calculates central BP. We compared various BP+ values for peripheral BP with central BP and stratified by gestational age. We investigated the correlations between peripheral BP, central BP, estimated fetal weight (EFW), and the pulsatility indices (PI) of Doppler velocimetry and demonstrate that both central systolic and diastolic BP correlated to peripheral systolic and diastolic BP. Linear regression analysis confirmed that central BP predicts the middle cerebral artery (MCA) PI. The MCA PI correlated with EFW, specifically higher central systolic BP is associated with a lower MCA PI, implying a possible etiology of fetal brain shunting with poor placental perfusion. Future studies using predictors and markers of fetal outcomes from maternal cardiac parameters should consider maternal cardiovascular measurements to peripheral arterial BP.

Maternal Fontan procedure is a predictor of a small-for-gestational-age neonate: a 10-year retrospective study.

BACKGROUND: Women with single ventricle cardiac physiologic condition who have undergone Fontan procedures are surviving well into reproductive age and historically have been discouraged from pregnancy, despite the paucity of data regarding maternal and neonatal outcomes. OBJECTIVE: Our primary objective was to investigate, in a large cohort, the maternal and neonatal outcomes of pregnant women who have undergone the Fontan procedure and to understand maternal and neonatal sequelae of their pregnancies. STUDY DESIGN: This single-center retrospective cohort study involves pregnant women with a Fontan palliation who delivered at UCLA Medical Center over a 10-year period (2007-2017). All pregnancies were evaluated for differences in maternal and neonatal characteristics. RESULTS: We identified 37 distinct pregnancies in 24 women with a Fontan procedure. The physiologic pregnancy-related increase in cardiac output is blunted substantially in Fontan circulation. Third-trimester cardiac index positively correlated to birthweight z-score (R2=0.48; P=.038) but not to small for gestational age (R2=0.13; P=.339). The most common cardiac complications in pregnancies of >24 weeks gestation were sustained arrhythmia (37.5%) and decompensated heart failure (21%). The 37 pregnancies comprised 25 live births (67.6%), 1 fetal death (2.7%), 9 spontaneous abortions (24%), and 2 pregnancy terminations (5.4%). Of the live births, 60% were preterm at an average gestational age of 34.9±3.7 weeks. Newborn infants were delivered via cesarean in 53%, operative vaginal delivery in 28%, and spontaneous vaginal delivery in 20%. Forty percent of neonates were born small (<10th percentile) for gestational age; 44.0% of all neonates were admitted to the neonatal intensive care unit. CONCLUSION: Women with a single ventricle and Fontan circulation can have a successful pregnancy, although they are at increased risk for arrhythmias and heart failure. The decreased cardiac reserve in these pregnancies blunts the normal increase in maternal cardiac output, which is associated with preterm delivery and small-for-gestational-age neonates. Further studies are needed to determine to what extent the impaired rise in maternal cardiac output reduces uteroplacental perfusion, placental exchange, fetal growth, and onset of parturition.

Increased senescence and reduced functional ability of fetal endothelial progenitor cells in pregnancies complicated by preeclampsia without intrauterine growth restriction.

OBJECTIVE: The aim of this study was to investigate the number and functional ability of fetal endothelial progenitor cells in pregnancies complicated by preeclampsia without intrauterine growth restriction. STUDY DESIGN: Fetal endothelial progenitor cells were isolated, and counted from 17 women with preeclampsia without intrauterine growth restricion and 30 normal women. Colony-forming assay and differentiation time assay were performed to detect functional activity of the cells. To assess cellular senescence, senescence-associated beta-galactosidase staining was performed for endothelial progenitor cells. RESULTS: Compared with normal pregnancy, the number of endothelial progenitor cells was significantly lower, differentiation time from endothelial progenitor cell into outgrowing cell was longer, and the number of colonies after differentiation was smaller in preeclampsia (P< .001), respectively. The intensity of senescence-associated beta-galactosidase staining was higher in preeclamptic pregnancy (P < .001). CONCLUSION: The number and functional ability of fetal endothelial progenitor cells from preeclampsia without intrauterine growth restriction are significantly decreased and they are more senescent compared with those of normal pregnancy.

Litigation related to intrapartum fetal surveillance.

The role of intrapartum care including cardiotocography (CTG) monitoring in cases of perinatal neurological injury receives considerable debate in both clinical and medicolegal settings. The debate, however, has distracted attention from fundamental questions about the timing, mechanism, and preventability of perinatal injury. CTG tracings are used as a surrogate for asphyxia with the timing of intervention ("rescue") predicated on the presumed severity of asphyxia. Using CTG in this way has prevented intrapartum stillbirth, but it has not reduced the long-term injury in part, because, contrary to popular belief, the majority of intrapartum fetal injuries are unassociated with severe hypoxia or severe neonatal depression. This article describes the timing and mechanisms, including mechanical factors, of intrapartum perinatal injury and the benefit of using the CTG, not for the purpose of "rescue", but for identifying risk factors for fetal injury and keeping the fetus out of harm's way.

Urinary Excretion of Myo-Inositol and D-Chiro-Inositol in Early Pregnancy Is Enhanced in Gravidas With Gestational Diabetes Mellitus.

The effects of gestational diabetes mellitus (GDM) were determined on urinary excretion of putative components of insulin signaling. Random urine samples were collected from 375 gravidas at 6 to 14 weeks' gestation, 22 to 32 weeks' gestation, and ∼6 weeks' postpartum. Gestational diabetes mellitus developed in 35 women who were matched with 59 normal gravidas. Urinary concentrations of myo-inositol (MI) and D-chiro-inositol (DCI) were measured by gas chromatography/mass spectrometry and normalized to creatinine levels. Compared to postpartum values, urinary excretion of MI and DCI was increased 2.9-fold and 2-fold, respectively, in early pregnancy, and 5.5-fold and 4.5-fold, respectively, in later gestation. Gravidas with GDM had significantly greater MI and DCI excretion than controls in the first trimester but not subsequently. The results suggest that gravidas destined to develop GDM have altered synthesis, metabolism, and/or renal excretion of MI and DCI in early pregnancy.

Cardiovascular and Neonatal Outcomes in Pregnant Women With High-Risk Congenital Heart Disease.

Congenital heart disease (CHD) increases the risk of adverse maternal and neonatal outcomes. However, previous studies have included mainly women with low-risk features. A single-center, retrospective analysis of pregnant women with CHD was performed. Inclusion criteria were the following high-risk congenital lesions and co-morbidities: maternal cyanosis; New York Heart Association (NHYA) functional class >II; severe ventricular dysfunction; maternal arrhythmia, single ventricle (SV) physiology, severe left-sided heart obstruction and severe pulmonary arterial hypertension. Multivariate analyses for predictors of adverse maternal cardiovascular and neonatal outcomes were performed. Forty-three women reported 61 pregnancies. There were no maternal or neonatal deaths. Maternal cardiac (31%) and neonatal (54%) complications were frequent. The most frequent cardiac events were pulmonary edema, arrhythmia, and reduced NYHA class. Previous arrhythmia conferred a 12-fold increase in the odds of experiencing at least one major cardiac complication. Maternal SV physiology was an independent risk factor for low birth weight, risk of neonatal intensive care unit admission and lower gestational age. Maternal cyanosis and severe pulmonary arterial hypertension also predicted adverse neonatal outcomes. In conclusion, mothers without antepartum arrhythmia or functional incapacity are unlikely to experience arrhythmias or a decrease in NYHA class during pregnancy. In addition, SV physiology is a robust predictor of neonatal complications. Antepartum counseling and assessment of maternal fitness are crucial for the woman with CHD.

Electrical stimulation of the posteromedial thalamus modulates breathing in unanesthetized fetal sheep.

Having previously shown that lesions in the posteromedial group of thalamic nuclei abolish hypoxic inhibition of fetal breathing, we devised this study to identify thalamic loci that depress breathing by focal stimulation of specific sectors of the caudal thalamus and adjacent structures. Multipolar electrode arrays consisting of a series of eight stimulation contacts at 1.25-mm intervals were implanted vertically through guide cannulae into the caudal diencephalon of 12 chronically catheterized fetal sheep (>0.8 term), and central neural tissue was stimulated between adjacent contacts. Each site was stimulated repeatedly with increasing current searching for spatial and stimulus strength parameters for a reliable alteration in respiratory rate. Respiratory period increased when stimulation involved areas of the parafascicular nuclear complex (Pf), which more than doubled the mean period compared with the baseline of 0.90 +/- 0.19 s. The change in respiratory period was due to an increase in expiratory time, whereas inspiratory time and breath amplitude were not significantly affected. Breathing period and expiratory time were also increased when the stimulations involved the intralaminar wing surrounding the mediodorsal nucleus, the rostral central gray, zona incerta, and ventral tegmental area. Reductions in respiratory frequency occurred less consistently, with stimulation involving surrounding zones including the sub-Pf, ventromedial nucleus, and ventrobasal nuclear complex. These findings support the hypothesis that a restricted area of the posteromedial thalamus (principally Pf) constitutes part of a neuronal circuitry that modulates respiratory motoneurons.

Induced fetal depressor or pressor responses associated with c-fos by intravenous or intracerebroventricular losartan.

Previous fetal studies have indicated depressor responses of intravenous (i.v.) administration of angiotensin antagonists. However, little is known of central effects of angiotensin blockers on fetal cardiovascular controlling. The cardiovascular effects of central administration of the angiotensin-1 (AT(1)) and angiotensin-2 (AT(2)) receptor antagonists, losartan and PD123319, were investigated in the chronically catheterized near-term ovine fetuses. Intravenous losartan produced within 1.5 min a significant and persistent depressor response [maximum Delta mean arterial pressure (MAP)=9 mm Hg] without altering fetal heart rate. Intracerebroventricular (i.c.v.) administration of losartan (1-5 mg/kg) increased fetal arterial pressures (Delta MAP=9-14 mm Hg). Central application of losartan (1 mg/kg) also increased fetal heart rate (maximum Delta heart rate=33 beat per minute). Losartan increased c-fos expression in the median preoptic nucleus and paraventricular nuclei in the forebrain, and the tractus solitarius nuclei, the lateral parabrachial nuclei, and the ventrolateral medullabrain. These brain sectors are with abundant AT(1) receptors and have been demonstrated in the involvement in cardiovascular regulation. In contrast, intracerebroventricular injection of the AT(2) receptor antagonist PD123319 had no effect on fetal arterial pressure and heart rate. The results demonstrate strikingly functional differences of losartan on the fetal cardiovascular regulation in central and peripheral sides.

Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep.

Adenosine A(1) and A(2A) receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (>0.8 term). In normoxic fetuses (Pa(O(2)) approximately 24 Torr), systemic blockade of A(1) receptors with DPCPX (n = 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A(2A) receptors with ZM-241385 (n = 5) had no significant effects. Intravascular administration of adenosine (n = 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX (n = 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 (n = 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (Pa(O(2)) approximately 13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A(1) (n = 6) or A(2A) (n = 6) receptors. We conclude that 1) endogenous adenosine via A(1) receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A(2A) receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A(1) receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A(1) and A(2A) receptors. We predict that adenosine, via A(1) receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses.