Cardiac output and blood flow redistribution in fetuses with D-loop transposition of the great arteries and intact ventricular septum: insights into pathophysiology.

OBJECTIVES: Although the postnatal physiology of D-loop transposition of the great arteries with intact ventricular septum (D-TGA/IVS) is well established, little is known about fetal D-TGA/IVS. In the normal fetus, the pulmonary valve (PV) is larger than the aortic valve (AoV), there is exclusive right-to-left flow at the foramen ovale (FO) and ductus arteriosus (DA), and the left ventricle (LV) ejects 40% of combined ventricular output (CVO) through the aorta, primarily to the brain. In D-TGA/IVS, the LV ejects oxygen-rich blood to the pulmonary artery, theoretically leading to pulmonary vasodilation, increased branch pulmonary artery flow and reduced DA flow. In this study, we tested the hypothesis that D-TGA/IVS anatomy results in altered cardiac valve sizes, ventricular contribution to CVO, and FO and DA flow direction. METHODS: Seventy-four fetuses with D-TGA/IVS that underwent fetal echocardiography at our institution between 2004 and 2015 were included in the study. AoV, PV, mitral valve and tricuspid valve sizes were measured and Z-scores indexed to gestational age were generated. Ventricular output was calculated using Doppler-derived velocity-time integral, and direction of flow at the FO and DA shunts was recorded in each fetus using both color Doppler and flap direction. Measurements in the D-TGA/IVS fetuses were compared with data of 222 controls, matched for gestational-age range, from our institutional normal fetal database. RESULTS: The LV component of CVO was higher in D-TGA/IVS fetuses than in controls (50.7% vs 40.2%; P < 0.0001), with no difference in the total CVO. Flow was bidirectional at the FO in 56 (75.7%) and at the DA in 24 (32.4%) D-TGA/IVS fetuses. Only 21.6% fetuses had normal right-to-left flow at both shunts. Bidirectional shunting was more common in third-trimester fetuses than in second-trimester ones (P < 0.03). AoV and PV diameters were nearly identical in D-TGA/IVS in contrast to control fetuses, hence AoV Z-score was higher than PV Z-score (1.13 vs -0.65, P < 0.0001) in D-TGA/IVS. CONCLUSIONS: In fetuses with D-TGA/IVS there is loss of the normal right-sided dominance, as each ventricle provides half of the CVO, with a relatively large AoV diameter and a small PV diameter, and high incidence of bidirectional FO and DA flow. This may support the theory that high pulmonary artery oxygen content reduces pulmonary vascular resistance, thereby increasing branch pulmonary artery flow and venous return, which results in increased LV preload and output. Pulmonary sensitivity to oxygen is thought to increase later in gestation, which may explain the higher incidence of bidirectional shunting. Consequences of these flow alterations include increased aortic and, most likely, brain flow, perhaps in an attempt to compensate for the substrate deficiency observed in D-TGA/IVS. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Cerebral glucose deficiency versus oxygen deficiency in neonatal encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) in newborn infants is generally considered to result from decreased arterial oxygen content or cerebral blood flow. Cerebral injury similar to that of HIE has been noted with hypoglycemia. Studies in fetal lambs have shown that ventilation with 3% oxygen did not change cerebral blood flow, but ventilation with 100% oxygen resulted in marked reduction in cerebral blood flow, glucose delivery and glucose consumption. Blood glucose concentration falls markedly after birth; this, associated with the fall in cerebral blood flow, greatly reduces glucose supply to the brain. In preterm infants, blood glucose levels tend to be very low. Also persistent patency of the ductus arteriosus may reduce cerebral flow in diastole, thus exaggerating the decrease in glucose supply. I propose that glycopenic-ischemic encephalopathy is a more appropriate term for the cerebral insult. We should consider more aggressive management of the low blood glucose concentrations in the neonate, and particularly in preterm infants. Administration of high levels of oxygen in inspired air should be avoided to reduce the enhancement of cerebral vasoconstriction and decreased flow that normally occurs after birth.

Hepatic oxygen and glucose metabolism in the fetal lamb. Response to hypoxia.

Although the fetal liver is an active metabolic organ, its oxygen and glucose requirements have not previously been described. We measured hepatic blood flows and the oxygen and glucose differences across the liver in 12 late gestation fetal lambs in utero. Four animals were studied at least 1 wk postsurgically and again 2-5 d later to assess daily variations in hepatic blood flow and metabolism (group I). A second group of eight animals was studied 3-5 d postsurgically during a control period and during acute fetal hypoxia (group II). Under control conditions total hepatic blood flow averaged 400 ml/min per 100 g in both groups, and 75-80% was of umbilical origin. Liver blood flow and oxygen consumption were usually similar during repeated measurements, but in one animal varied considerably. During periods of normoxia, oxygen consumption for both the right and left lobes of liver was 4 ml/min per 100 g. Oxygen consumption of the whole liver accounted for 20% of total fetal oxygen consumption. This was achieved with oxygen extraction of 10-15%, so that hepatic venous blood was well oxygenated and provided an important source of oxygen for other fetal tissues. Under control conditions we could demonstrate no net hepatic uptake or release of glucose suggesting that the liver ultimately utilizes another carbon source to support its oxidative metabolism. During acute hypoxia total liver blood flow and its umbilical venous contribution both fell by 20%. Blood flow to the right lobe of the liver fell twice as much as that to the left lobe. Hepatic oxygen consumption was linearly related to oxygen delivery during the control and hypoxic periods. Consequently, right hepatic oxygen uptake fell by 45% whereas left hepatic oxygen uptake was unchanged, suggesting a functional difference between the lobes. During hypoxia glucose was released from both liver lobes; 6 mg/min per 100 g for the right lobe and 9 mg/min per 100 g for the left lobe. Total hepatic release of glucose was estimated to nearly equal umbilical uptake, so that 45% of the glucose available to fetal tissues was of hepatic origin. We conclude that the fetal liver responds to acute hypoxia by reducing its own oxygen consumption and releasing glucose to facilitate anaerobic metabolism.

Role of thyroid hormone in postnatal circulatory and metabolic adjustments.

To assess the role of the early postnatal surge in plasma thyroid hormone concentrations on cardiovascular and metabolic adaptations, we measured cardiac output, total oxygen consumption, and plasma triiodothyronine (T3) concentrations in three groups of lambs in the first 6 h after delivery. 15 fetal lambs were prepared at gestational ages of 128-129 d by placing catheters in the brachiocephalic artery, descending aorta, distal inferior vena cava, left atrium, and pulmonary artery so that measurements could be made soon after delivery. They were divided into three groups: Group I comprised five control animals; Group II consisted of five fetuses in which thyroidectomy was performed at surgery at 129 d gestation; and Group III consisted of five animals in which thyroidectomy was performed at term gestation during delivery by caesarian section, prior to severing the umbilical cord. The lambs in Group I exhibited a rapid postnatal rise in T3 concentrations, similar to that described previously, reaching a peak value of about 5 ng/ml. Although the postnatal surge in T3 concentration was arrested in Group II and III animals, Group II had no detectable plasma T3, while the Group III animals had T3 concentrations of about 0.8 ng/ml, which were within the range previously reported for term lamb fetuses. The lambs in group II showed 40-50% lower left ventricular outputs (190 vs. 297 ml/kg per min), systemic blood flows (155 vs. 286 ml/kg per min), and oxygen consumptions (9.8 vs. 20.2 ml/kg per min) as compared with Group I animals over the entire 6-h period. The lambs in Group II also had significantly lower heart rates (131 vs. 192 beats/min) and mean systemic arterial pressures (56 vs. 72 torr). However, there were no significant differences for any of these measurements between the Group III and Group I lambs. The reduction in cardiac output in the Group II animals were reflected in a significantly lower blood flow to the peripheral circulation, but there were no significant differences in blood flow to other organs in the three groups. These studies indicate that plasma thyroid concentrations in the 2-3 wk prior to delivery and not the increase in thyroid hormone concentrations which occur after birth are important for postnatal cardiovascular and metabolic adjustments. We speculate that lack of circulating triiodothyronine in late gestation may affect postnatal cardiovascular adaptation by modifying normal beta adrenergic receptor development.

Developmental aspects of the pituitary-adrenal axis response to hemorrhagic stress in lamb fetuses in utero.

Plasma ACTH and corticosteroid concentrations were measured by radioimmunoassay in chronically catheterized fetuses of 32 pregnant sheep. Fetal plasma ACTH levels 38+/-5 pg/ml (means+/-SEM) were slightly (P < 0.05) lower than maternal 54+/-4 pg/ml levels. No general rise in fetal plasma ACTH concentration was noted before 140 days gestation; however, fetal plasma corticoid levels began to increase after about 125 days. This suggested that an increase in fetal adrenal responsiveness to endogenous ACTH occurred during gestation. Hemorrhage of 15% of estimated blood volume decreased mean arterial pressure from 54+/-3 to 36+/-3 torr and increased plasma ACTH from 30+/-5 to 130+/-30 pg/ml in fetuses older than 0.80 gestation. In fetuses younger than 0.67 gestation, 15% hemorrhage caused no change in plasma ACTH levels despite a significant fall in mean arterial pressure. This suggests that system(s) subserving the ACTH response to mild hemorrhage are either absent or nonfunctional in the younger fetuses. The hemorrhage-induced increase in plasma ACTH levels was associated with a small rise in plasma corticoids in fetuses younger than 0.94 gestation. In older fetuses, a similar increase in plasma ACTH was associated with a pronounced increase in plasma corticoid levels. This also suggests that an increase in adrenal responsiveness to endogenous ACTH occurs during gestation. No detectable changes in maternal plasma ACTH or corticoids were found in response to fetal hemorrhage, thus the fetal pituitary-adrenal axis can autonomously respond to stress.

Failure to detect an effect of prolactin on pulmonary surfactant and adrenal steroids in fetal sheep and rabbits.

Recent reports have indicated an association between low cord prolactin (PRL) and the occurrence of respiratory distress syndrome in premature infants, and it is reported that PRL administration increases the lecithin content of fetal rabbit lung. We administered 1 mg ovine PRL to 32 rabbit fetuses on day 24 of gestation and evaluated lung phospholipid synthesis and content on day 26. Compared with diluent-injected littermates, PRL had no effect on the rate of choline incorporation into lecithin, tissue content of phospholipid and disaturated lecithin, or plasma corticoids. However, both choline incorporation and corticoids were increased in all animals undergoing surgery compared with unoperated controls. We also infused PRL (1 mg/day, i.v.) into three fetal sheep continuously over five periods of 5-8 days. Although supraphysiologic concentrations of PRL were achieved in plasma and amniotic fluid, there was no effect of this treatment on the flux of tracheal fluid surfactant or on plasma concentrations of corticoids of dehydroepiandrosterone sulfate. Thus, in this study, we failed to detect either a stimulation of the surfactant system or an adreno-corticotropic effect by PRL as previously postulated. This suggests that the relationship between PRL and respiratory distress sundrome is an indirect association.

Effects of aspirin and acetaminophen in pregnancy and in the newborn.

Inhibitors of prostaglandin synthesis are increasingly recommended for delaying premature delivery. However, such inhibitors--eg, aspirin, indomethacin, or naproxen--may interfere with uterine contractility, with maternal, fetal, and neonatal platelet function, and especially with fetal circulation and postnatal adaptation. The instillation of aspirin (50 to 90 mg/kg of fetal body weight) into the rumina of fetal lambs resulted in significant increase of pulmonary arterial pressure, which was directly related to constriction of the ductus arteriosus. Such pressure elevation may act as a stimulus to increased muscular development in the small vessels of the lung, which, in turn, could interfere with the rapid reduction in pulmonary vascular resistance normally occurring after birth. The effects of acetaminophen in pregnancy and in the newborn have not been studied extensively; when ingested in usual therapeutic doses, the available data have shown no adverse effects.

Can maternal stress alter fetal adrenocorticotropin secretion?

The purpose of this study was to assess the role of increases in maternal plasma cortisol, within the range observed after stress, in the control of fetal ACTH responses to subsequent fetal stress. We infused cortisol or vehicle into the inferior venae cavae of pregnant ewes which, with their fetuses (120-130 days gestation), had been chronically catheterized. Five-hour maternal cortisol infusions produced increases in maternal plasma cortisol smaller in magnitude than those induced by hypoxia stress and resulted in physiological increases in fetal plasma cortisol. One hour after the end of the maternal cortisol infusion, fetal ACTH secretion was stimulated by infusion of sodium nitroprusside into the fetal inferior vena cava. After maternal cortisol infusion, the fetal ACTH and cortisol responses to fetal hypotension were inhibited. We conclude that increases in maternal cortisol alters the fetal ACTH response to stress.

Negative feedback regulation of adrenocorticotropin secretion by cortisol in ovine fetuses.

The purpose of this study was to test the hypothesis that physiological increases in the fetal plasma cortisol concentration inhibit fetal ACTH responses to stress. Fetal sheep, between 121 and 131 days gestation, were infused with cortisol (4 micrograms/min) or vehicle for 5 h. One hour after the end of the cortisol or vehicle infusion, fetuses were infused with sodium nitroprusside (100 micrograms/min) to stimulate fetal ACTH and adrenal corticosteroid secretion. Cortisol, but not vehicle, elevated fetal plasma cortisol and suppressed the fetal ACTH and cortisol responses to nitroprusside. Cortisol and 11-deoxycortisol concentrations were significantly correlated in fetal plasma samples drawn during experiments in which cortisol was not infused; however, the cortisol to 11-deoxycortisol ratio was significantly increased during the infusion of nitroprusside. Fetal heart rate increased during vehicle infusion and decreased during cortisol infusion. Fetal blood pressure was not altered by either cortisol or vehicle infusion. Cortisol infusion increased fetal blood hemoglobin concentration, decreased maternal blood hemoglobin concentration, and produced metabolic acidosis in both mother and fetus. Vehicle infusion did not alter either fetal or maternal hemoglobin or pH. The data do not suggest an obvious mechanism for the cortisol-induced changes in fetal and maternal pH and hemoglobin or in fetal heart rate. However, some of the changes might be attributable to changes in fetal sympathetic outflow or to fluid shifts. We conclude that physiological increases in fetal plasma cortisol concentration: 1) inhibit subsequent ACTH responses to stress and 2) alter fetal cardiovascular function.

Physiological inhibition of ovine fetal plasma renin activity by cortisol.

The purpose of this study was to test the hypothesis that physiological increases in the fetal plasma cortisol concentration after basal and stimulated levels of PRA and vasopressin. Seven fetal sheep, between 121 and 131 days gestation, were infused with cortisol (4 micrograms/min) or vehicle for 5 h. One hour after the end of cortisol or vehicle infusion, sodium nitroprusside was infused into the fetus (100 micrograms/min, iv) to stimulate fetal hormone secretion. Cortisol, but not vehicle, infusion increased the fetal plasma cortisol concentration and decreased fetal PRA, but did not alter the fetal plasma vasopressin concentration. Cortisol-infused fetuses responded to nitroprusside with slightly smaller PRA responses but with equal vasopressin responses compared to those of vehicle-infused controls. Fetal blood pressure was not affected by either cortisol or vehicle infusion. Nitroprusside caused a slightly greater reduction in pressure in fetuses receiving cortisol infusion compared to those receiving the vehicle. We conclude that physiological increases in fetal plasma cortisol decrease fetal PRA without altering the fetal plasma vasopressin concentration. The results suggest that repeated fetal stress might produce progressive reduction of fetal PRA activity and might, therefore, alter cardiovascular homeostasis.

alpha-Melanocyte-stimulating hormone and adrenocorticotropin in the regulation of glucocorticoid secretion during the perinatal period in sheep.

To determine the role of other ACTH-like peptides in the regulation of glucocorticoid secretion in fetal sheep, we examined the responses of the adrenal gland of fetal and newborn sheep to comparable single doses of alpha MSH (75 micrograms) or ACTH (50 micrograms) during the last third of gestation and the first month of postnatal life. alpha MSH first increased the plasma glucocorticoid concentration at 121--130 days of gestation [from 16 +/- 1.5 to 36.9 +/- 9 (SE) ng/ml]; the response to alpha MSH persisted on days 131--140 of gestation and during the first month after birth. ACTH first increased the plasma glucocorticoid concentration at 131--140 days of gestation and increased it further in the first month after birth (from 18.9 +/- 3.6 to 97.0 +/- 10 ng/ml). The observations that the adrenal glands of fetuses and newborn lambs responded to alpha MSH at a dose comparable to that of ACTH and that the response to alpha MSH in the fetus preceded the response to ACTH may indicate that adrenal receptors mature during fetal development. These data also suggest that the regulation of the adrenal during fetal life may involve more than one tropic hormone.

Ductus arteriosus dilatation by prostaglandin E1 in infants with pulmonary atresia.

Infants with pulmonary atresia depend on patency of the ductus arteriosus for survival in the immediate postnatal period. Despite continuing hypoxemia after birth the ductus arteriosus usually constricts, thus reducing pulmonary blood flow. This often occurs while awaiting surgical palliation or correction, leading either to marked deterioration in the infant's condition, or death. In ten infants with pulmonary atresia, we infused prostaglandin E1 (PGE1) at a rate of 0.1 mug/kg/min in six and 0.05 mug/kg/min in four into the descending aorta at the orifice of the ductus arteriosus. The ductus arteriosus was effectively dilated; at the narrowest point the diameter, measured in eight infants, almost doubled. In all ten infants arterial blood PO2 increased, averaging 24.6 mm Hg before and 43.7 mm Hg after the infusion was started. Infusion of PGE1 directly into the aorta adjacent to the ductus arteriosus avoided the complications of pyrexia, muscular twitching, and excitability which may be related to the effects of prostaglandins on the central nervous system.

Developmental alterations in hepatic UDP-glucuronosyltransferase. A comparison of the kinetic properties of enzymes from adult sheep and fetal lambs.

The kinetic properties of hepatic microsomal UDP-glucuronosyltransferase were studied in sheep in the perinatal period, using acetaminophen as the aglycone. Kinetic analyses indicated that activity at Vmax was significantly less in fetal microsomes (113, 135 or 141 days) as compared with the adult sheep. However, these differences between fetal and adult animals were not due simply to smaller amounts of UDP-glucuronosyltransferases catalyzing conjugation of acetaminophen in fetuses versus adults. Thus, the kinetic properties of UDP-glucuronosyltransferase(s) were different in fetus and adult. The "fetal" versus "adult" enzyme had a higher affinity for UDP-glucuronic acid, but a poorer affinity for acetaminophen. Furthermore, enzyme in fetal liver (113 days of gestation) was activated about 30% by the allosteric effector UDP-N-acetylglucosamine, whereas enzyme in adult liver was activated by 500%. These differences between fetal and adult enzymes diminished just prior to parturition (141-day fetus). Enzyme in microsomes from the 141-day fetus responded to UDP-N-acetylglucosamine-like enzyme in adult microsomes and had affinities for substrates that were similar to "adult" enzymes. These data indicate that maturation of the system that glucuronidates acetaminophen is a complex process. It may involve the expression in fetuses of a type of UDP-glucuronosyltransferase that is different from that expressed in the adult. An alternative but not mutually exclusive possibility is that maturation of the glucuronidation system involves modification of enzyme function by alteration of the phospholipids in the immediate environment of UDP-glucuronosyltransferase within the microsomal membrane.

Surgical management of severe aortic coarctation and interrupted aortic arch in neonates.

Forty-four infants, 2 to 90 days of age, with severe obstructive lesions of the aortic arch, underwent emergency surgical correction between Jan. 1, 1966, and April 1, 1975. The typical clinical presentation was severe congestive heart failure and acidemia. Resection of an aortic coarctation with end-to-end anastomosis was performed in 31 patients. Eight (26 per cent) died after the operation. Since 1969, the mortality rate has been reduced to 14 per cent (3 of 22 patients) even though the incidence of major associated cardiac lesions has remained essentially constant (56 per cent from 1966 through 1969, 64 per cent from 1970 through March, 1975). This suggests that the higher survival rate has resulted from improved surgical techniques and postoperative care. The mortality rate in the infants operated upon during the second and third months of life was twice as high as that in those operated upon before the age of 1 month. Eight patients with Type A interrupted aortic arch were operated upon and 5 survived. Five patients with Type B aortic arch were operated upon and 3 survived.

Stopping the biologic clock for globin gene switching.

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if expression of the adult (beta) globin genes is defective and produces little or no protein, as in the beta-thalassemias. Preventing or reversing the globin gene switch could provide a way of keeping the abnormal globin genes "silent" and maintaining expression of the fetal globin gene. We have identified a class of agents which, when present in elevated plasma concentrations during gestation, inhibits the gamma----beta-globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma-globin and decrease beta-globin expression in cultured erythroid cells of patients with beta-thalassemia. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited and even reversed in some fetal lambs. Histone hyperacetylation, which maintains active chromatin structure, and an effect on the gamma-globin promoter appear to be mechanisms of action involved. These data suggest that inhibiting expression of abnormal beta-globin genes by pharmacologic means may in the future be possible for treatment of individuals with beta-globin disorders.

The effects of nonsteroidal antiinflammatory compounds on fetal circulation and pulmonary function.

Nonsteroidal antiinflammatory compounds that act by inhibiting synthesis of prostaglandins from arachidonic acid have been shown to have various and sometimes profound effects on fetal and neonatal circulation. Agents such as acetylsalicylic acid, indomethacin, and naproxen pass readily across the placenta and have been shown to cause severe constriction and, in some cases, closure of the ductus arteriosus, resulting in an increase in pulmonary blood pressure and a significant pressure gradient between the pulmonary artery and the aorta of the fetus. Inhibitors of prostaglandin synthesis produce only a mild increase in systemic vascular resistance under normal conditions, but have been observed to potentiate vasoconstriction under conditions of hypoxia. Umbilical-placental and myocardial blood flow was increased by these agents. Although single doses of these agents do not appear to affect fetal pulmonary vessels, prolonged pulmonary arterial hypertension resulting from chronic administration may stimulate an increased development of medial smooth muscle in fetal precapillary vessels, resulting in persistent pulmonary hypertension in the newborn. Inhibitors of prostaglandin synthesis have also been shown to produce a marked increase in fetal respiration, resulting in an increased oxygen requirement.

Congenital obstructive lesions of the right aortic arch.

BACKGROUND: In the setting of normal cardiac situs, a right-sided aortic arch is uncommon. When a right arch does occur, it is typically in conjunction with other congenital cardiovascular anomalies, especially defects with abnormal right ventricular outflow. Congenital obstruction of a right arch, caused by coarctation, interruption, or cervical arch, is extremely rare. METHODS: We reviewed our experience and all reported cases of right aortic arch with coarctation of the aorta, interrupted arch, or obstruction of a cervical arch in the setting of normal cardiac situs and topology. RESULTS: Since 1992, 4 such patients have undergone repair at our institution, including 1 with interrupted arch, 1 with coarctation of a mirror image arch, and 2 with obstruction of a cervical arch. In addition to these 4 patients, 38 others have been described in the published reports: 15 with interrupted arch, 19 with coarctation, and 4 with obstruction of a cervical arch. Associated cardiac defects were uncommon, except for ventricular septal defect in patients with interrupted arch, but abnormalities of the brachiocephalic vessels were frequent. Except for most of the patients with interrupted right arch, the majority of patients described have undergone successful surgical repair. CONCLUSIONS: Although obstructive arch lesions are often grouped together, the etiologies of coarctation of the aorta, interrupted arch, and cervical arch with obstruction almost certainly differ. The rarity of such lesions among patients with right aortic arch may be explained in part by the fact that the fetal hemodynamic conditions associated with persistence of a right arch do not facilitate flow-related arch obstruction. In this review, we discuss these issues in detail, along with specific surgical considerations in the management of obstruction lesions of the right aortic arch.

Developmental biology of the heart: is there a role for the physiologist?

Support for physiological research has generally declined, as interest in cellular and molecular investigation has assumed ascendancy. However, there are many important issues relating to cardiovascular development that require a systems approach to study of the circulation. Examples are mechanisms of circulatory response to hypoxia during fetal life; changes in myocardial growth in response to loading before and after birth, and resultant cardiac function; and prenatal and postnatal development of the great vessels with altered circulatory patterns in congenital heart lesions. These issues are of great concern in considerations for potential fetal cardiovascular surgery.

Butyric acid modulates developmental globin gene switching in man and sheep.

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if the adult (beta) globin genes are defective. Preventing or reversing the globin gene switch would be beneficial for subjects with abnormal beta globin genes. We have now identified a class of agents which, when present in elevated plasma concentrations during gestation, appears to inhibit the gamma beta globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma globin and decrease beta globin expression in erythroid cells cultured from subjects with diseases of abnormal beta globin. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited in most and reversed in some fetal lambs. These data suggest that inhibiting expression of abnormal beta globin genes may be possible in future generations. Histone modification may be a mechanism of action involved. The developmental switch from production of gamma globin to beta globin results in significant morbidity when the beta globin genes are defective. The globin switch has therefore been extensively studied, appearing to be set on a biologic clock and proceeding despite the site of blood production and solely on the basis of gestational age. We previously found that this developmental gene switch is delayed in human fetuses developing in the presence of maternal diabetes. A number of metabolites present in abnormal concentrations in these infants were therefore tested for effects on globin expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular changes with in utero correction of diaphragmatic hernia.

In utero surgical correction of fetal diaphragmatic hernia is a new therapeutic alternative for selected prenatally diagnosed patients. With increasing experience, the authors have found that fetuses with herniation of the liver through the diaphragmatic defect have a high incidence of perioperative death. The hypothesis was that reduction of the liver during fetal diaphragmatic hernia repair caused distortion of fetal vascular anatomy resulting in fetal demise. To study this, the authors performed angiograms through the umbilical vein in fetal and neonatal cadavers, with and without diaphragmatic hernias, and simulated in utero repair. Large fetal congenital diaphragmatic hernias can be associated with dramatic changes in the vascular anatomy of the liver. The liver does not simply rotate up into the chest through a diaphragmatic defect; instead, the liver more likely develops in the chest, with its vascular anatomy situated accordingly. Attempts to reduce a herniated liver can result in significant distortion of the fetal vasculature, leading to fetal death. Techniques to prevent vascular compromise during hepatic manipulation may improve the outcome for fetuses during in utero repair of diaphragmatic hernias.