Brian J. Koos

Pregnancy outcomes after the Fontan repair

OBJECTIVES This study sought to determine risks and outcome of pregnancy and delivery after the modified Fontan operation. BACKGROUND Increasingly, female Fontan patients reaching child-bearing years are interested in having children. To date, the number of reported pregnancies is small, and pregnancy has therefore been discouraged. METHODS One hundred ten of 126 female patients from the Fontan registries of the Mayo Clinic and University of California Los Angeles Medical Center responded to a mailed questionnaire. An additional six patients with a reported pregnancy from other centers were identified and reviewed to assess pregnancy outcomes. RESULTS Among the participating centers, a total of 33 pregnancies after Fontan operation for various types of univentricular heart disease were reported. There were 15 (45%) live births from 14 mothers, with 13 spontaneous abortions and 5 elective terminations. In the 14 women with live births, the median number of years between operation and pregnancy was 4 (range 2 to 14). Reported prepregnancy problems in these gravidas included atrial flutter in one patient and ventricular dysfunction, aortic regurgitation and atrioventricular valve regurgitation in another. One patient developed supraventricular tachycardia during pregnancy and had conversion to sinus rhythm. No maternal cardiac complications were reported during labor, delivery or the immediate puerperium. There were six female and nine male infants (mean gestational age 36.5 weeks; median weight 2,344 g). One infant had an atrial septal defect. At follow-up, mothers and infants were alive and well. CONCLUSIONS Pregnancy after the Fontan operation appears to have been well tolerated in 13 to 14 gravidas. There does appear to be an increased risk of miscarriage. The tendency to routinely discourage pregnancy may need to be reconsidered.

Enhancing adenosine A1 receptor binding reduces hypoxic-ischemic brain injury in newborn rats.

Hypoxia increases brain adenosine concentrations, which provides neuroprotection through activation of central adenosine A1 receptors. This study was carried out to determine whether PD 81,273, which increases adenosines binding to A1 receptors, would reduce hypoxia-induced brain injury. PD 81,273 (3 mg/kg, i.p.) decreased by about 50% the weight loss of the left cerebral hemisphere caused by hypoxia-ischemia in neonatal rats. Thus, enhancing adenosines binding to the A1 receptor decreases hypoxic brain damage.

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.

Fetal cardiovascular and breathing responses to an adenosine A2a receptor agonist in sheep

CGS-21680 (CGS), a highly selective adenosine A2a receptor agonist, may excite the fetal carotid bodies. This study was designed to determine 1) whether CGS stimulates fetal breathing and 2) whether sinoaortic denervation abolishes CGS-induced tachycardia. In eight intact fetuses (>0.8 term), intra-arterial CGS infusion (6 μg ⋅ min-1 ⋅ kg estimated fetal wt-1) increased mean arterial [Formula: see text] by 3-7 Torr, reduced fetal arterial[Formula: see text] by 2-5 Torr, and produced a mild metabolic acidemia. Heart rate increased from 154 ± 7 (control) to 249 ± 12 beats/min, but mean arterial pressure was not significantly affected. CGS initially increased the frequency, amplitude, and incidence of fetal breathing, but this hyperpnea was followed by prolonged respiratory depression that was not reversed with blockade of adenosine A1 receptors. Denervation of both carotid bodies together with interruption of the vagi abolished the hyperpnea without altering the respiratory depression or the maximum rise in heart rate. We conclude that CGS induces 1) tachycardia by a mechanism independent of the peripheral arterial chemoreceptors, 2) hyperpnea by stimulating peripheral adenosine A2areceptors, and 3) respiratory depression by activating central A2a receptors.CGS-21680 (CGS), a highly selective adenosine A2a receptor agonist, may excite the fetal carotid bodies. This study was designed to determine 1) whether CGS stimulates fetal breathing and 2) whether sinoaortic denervation abolishes CGS-induced tachycardia. In eight intact fetuses (> 0.8 term), intra-arterial CGS infusion (6 micrograms.min-1.kg estimated fetal wt-1) increased mean arterial PCO2 by 3-7 Torr, reduced fetal arterial PO2 by 2-5 Torr, and produced a mild metabolic acidemia. Heart rate increased from 154 +/- 7 (control) to 249 +/- 12 beats/min, but mean arterial pressure was not significantly affected. CGS initially increased the frequency, amplitude, and incidence of fetal breathing, but this hyperpnea was followed by prolonged respiratory depression that was not reversed with blockade of adenosine A1 receptors. Denervation of both carotid bodies together with interruption of the vagi abolished the hyperpnea without altering the respiratory depression or the maximum rise in heart rate. We conclude that CGS induces 1) tachycardia by a mechanism independent of the peripheral arterial chemoreceptors, 2) hyperpnea by stimulating peripheral adenosine A2a receptors, and 3) respiratory depression by activating central A2a receptors.

Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

1. In seven unanaesthetized fetal sheep (> 80% term), isocapnic hypoxia (arterial partial pressure of O2, Pa,O2, approximately 15 mmHg) was induced for 1 h by lowering maternal inspired PO2. Fetal hypoxia was also produced during intra‐arterial administration of the adenosine receptor antagonist 8‐(p‐sulphophenyl)‐theophylline (8‐SPT). The fetal 8‐SPT infusion was begun just prior to hypoxia and was stopped when fetal Pa,O2 was returned to normal. 2. Hypoxia induced a progressive fetal acidosis, a rise in mean arterial pressure, a transient fall in heart rate and a decrease in breathing movements. 8‐SPT significantly reduced the metabolic acidosis and abolished the hypertension and bradycardia without altering hypoxic inhibition of fetal breathing. Administration of the vehicle for 8‐SPT during hypoxia did not significantly affect the normal fetal metabolic and cardiovascular responses to acute O2 deprivation. 3. It is concluded that adenosine mediates the fetal bradycardia and hypertension produced by hypoxia, indicating that adenosine modulates fetal autonomic responses to acute oxygen deficiency. Secondly, adenosine contributes to fetal metabolic acidaemia, suggesting that adenosine also modulates fetal glycolytic responses to hypoxia.

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.

Ultrasound and fetal diagnosis.

Purpose of review The purpose of this review is to highlight publications from the last year that have advanced the use of ultrasound in obstetrics. Recent findings Anatomic examination of the fetus in the first trimester has been emphasized because it allows for early diagnosis of many conditions. The prevalence of absent nasal bone, a marker for trisomy 21, in euploid fetuses depends on ethnicity. Nasal bone hypoplasia is another marker for Down syndrome. Studies on genetic screening in the first trimester have involved various serum analytes, adjustments in timing and calculations, use in multiple gestations, and the association of extreme measurements with adverse outcomes. A first-trimester integrated screening approach, which incorporates nuchal translucency, nasal bone, crown–rump length, pregnancy-associated plasma protein-A, and free β-human chorionic gonadotropin, has the potential to maximize detection rates of Down syndrome and trisomy 18 and minimizes the screen-positive rate. The value of combining first and second-trimester results in sequential, contingent, or integrated screening protocols has been assessed. Isolated mild ventriculomegaly (10–12 mm) may prove to be a normal variant, and the role of ‘soft’ ultrasound markers in genetic counseling continues to be debated. Anomaly or high-risk status detection in the second trimester has been enhanced by the use of Doppler, 3D/4D ultrasound, and magnetic resonance imaging. Summary Imaging techniques have been critical in the development of screening methods for Down syndrome or trisomy 18 and for euploid fetuses at high risk for adverse outcomes.

Adenosine modulates corticotropin and cortisol release during hypoxia in fetal sheep

OBJECTIVE This study was designed to determine the role of adenosine in the hypoxic release of corticotropin in fetal sheep. STUDY DESIGN The adenosine receptor antagonist 8-phenyltheophylline or the vehicle was infused intra-arterially to chronically catheterized fetal sheep (>0.8 term) during an hour of fetal hypoxemia (Pa O 2 congruent with 14 mm Hg). Control studies were also performed in which 8-phenyltheophylline or the vehicle was administered to normoxic fetuses. RESULTS 8-Phenyltheophylline abolished hypoxia-induced bradycardia and hypertension and produced a nearly 5-fold greater rise in fetal plasma concentrations of corticotropin and approximately a 3-fold greater increase in plasma cortisol levels. During normoxia 8-phenyltheophylline increased plasma cortisol concentrations by 2-fold without altering corticotropin levels, mean arterial blood pressure, or heart rate. CONCLUSION Adenosine blunts fetal corticotropin release during hypoxia, which in turn reduces cortisol secretion. At lower corticotropin concentrations, adenosine also appears to dampen the cortisol response through direct effects on the adrenals.

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.

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.