Effect of maternal hyperketonemia in hyperglycemic pregnant ewes and their fetuses

The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses. These observations may in part help explain the increased perinatal mortality in the pregnant woman with uncontrolled diabetes.     

Changes in amniotic fluid glucose, beta-hydroxy-butyrate, glycerol, and lactate concentration in diabetic pregnancy

Amniotic fluid glucose, beta OH butyrate, glycerol, and lactate concentrations were measured in 75 samples collected in the third trimester of pregnancy from 50 diabetic patients, all but four of whom required insulin. Increases in maternal fasting plasma sugar were accompanied by corresponding increases in amniotic fluid glucose and on occasion increases in amniotic fluid beta OH butyrate. These data correspond to previous reports of placental glucose transfer and in addition, provide statistically significant evidence of placental betaOH butyrate transfer since the hyperglycemic, hyperinsulinemic fetus of a diabetic mother would be a poor primary source for ketogenesis. Relatively poor correlation of elevated fluid levels of these solutes to fetal outcome probably reflects a low incidence of maternal hyperglycemia, ketogenesis. Relatively poor correlation of elevated fluid levels of these solutes to fetal outcome probably reflects a low incidence of maternal hyperglycemia, ketoacidosis, and over-all reduced neonatal morbidity-mortality rates in this group of metabolically well-controlled, predominantly insulin-requiring diabetic patients managed in a regional high-risk perinatal center.     

Fetal reacting bradycardia.

Acute and abrupt fetal bradycardia are considered to be vagal in origin. In addition to head compression and funis compression bradycardias, we will report on those acute fetal bradycardias occurring during maternal seizures and maternal voiding, during aortocaval compression, during terminal labor, and during the immediate postpartum period. While certain mechanisms are known which can explain some or parts of these bradycardias, we conclude that in the clinical setting information is insufficient to determine their etiology with precision. Instead of labeling abrupt fetal heart rate pattern as resulting from either head or funis compression, it is suggested that the patterns be described according to their severity and duration. Such acute fetal bradycardias can be detrimental in terms of reduced umbilical flow. Administration of atropine may be indicated in the otherwise healthy fetus with acute bradycardia.     

Effect of maternal diabetes on human and rat fetal development

Diabetes is a genetically determined metabolic disease with fasting hyperglycemia due to relative or absolute absence of insulin. With the use of exogenous insulin, successful gestations are now possible. Nevertheless, there are still severe problems associated, such as spontaneous abortion, perinatal mortality and congenital malformations. Caudal regression syndrome, disclosure of the neural tube and cardiovascular alterations are the most common malformations. Gestational diabetes can induce increased fetal corporal fat and macrosomia with hyperinsulinemia, hypoglycemic, hypoxia, metabolic acidosis and perinatal death. During adult life, diabetic mothers' children can develop obesity, glucose intolerance and type 2 diabetes. In order to study fetuses' alterations during diabetic gestations we now have animal models of diabetes. Maternal diabetes in rats alters fetal development in a very similar manner to that of humans. Although we do not accurately know the pathogenic mechanism by which diabetes produces fetuses' abnormal development, hyperglycemia and hyperketonemia had been mentioned to have predominant roles. Hyperglycemia damages DNA and increases oxidative stress and hyperketonemia increases the rate of embryo malformations. The addition of antioxidants such as C and E vitamins can reduce this damage. During adult life, diabetic rats' cubs have alterations in glucose metabolism and in reproductive function. The understanding of mechanisms by which maternal diabetes affects fetuses development, can help us to prevent complications and improve mothers' and children's life quality.     

Maternal and fetal hemodynamic effects of diazoxide.

Effects of diazoxide on systemic and uterine hemodynamics as well as on fetal circulation and blood respiratory gases were investigated in chronically instrumented pregnant sheep. Diazoxide was administered intravenously either to the ewe or directly to the fetus in doses calculated on the basis of body weight. Transfer of drug across placenta was also investigated. Results showed that: a) when injected into the mother, there was consistent hypotensive effect with increased cardiac output and decreased systemic vascular resistance; uterine blood flow might not change or might decrease slightly with moderate hypotension; when maternal systemic arterial pressure fell to critical closing pressure level, uterine flow decreased significantly; but despite these maternal changes, the fetal circulatory functions were not significantly altered; b) when injected into the fetus in doses up to 15 mg/kg, diazoxide failed to alter fetal circulation appreciably; c) diazoxide crossed the placenta when injected intoeither mother or fetus according to a definite gradient; fetal levels were always lower than maternal levels because of rapid loss of the drug by the fetus; d) moderate maternal and fetal hyperglycemia occurred after drug administration.     

Effects of maternal anemia on uteroplacental and fetal oxidative metabolism in sheep

We studied the effects of acute isovolemic maternal anemia on several variables of uterine and fetal oxygenation to answer these two questions: (1) Does maternal anemia cause reductions in oxygen delivery to the uterus, placenta, and fetus? (2) If so, what is the impact of such reductions on fetal oxidative metabolism? In 15 chronically catheterized pregnant sheep and fetal lambs, we measured uterine and umbilical blood flows and uterine and fetal oxygen deliveries, oxygen extractions, and oxygen consumptions at various, randomly selected maternal hematocrits ranging from 30% to 8%. We altered maternal hematocrit by performing isovolemic exchange transfusions with plasma or packed red blood cells. Uterine and umbilical blood flows were measured with the radionuclide-labeled microsphere technique, and the variables of oxygenation were calculated with modifications of the Fick principle. Decreases in maternal hematocrit led to linear reductions in oxygen delivery to the uterus, placenta, and fetus. Despite reductions in oxygen delivery of up to 50%, fetal oxygen consumption was maintained, because of compensatory increases in oxygen extraction. When hematocrit (and thus fetal oxygen delivery) was reduced by more than 50%, fetal oxygen consumption and the arterial blood base excess both decreased, indicating that, at these hematocrit levels, the supply of oxygen to fetal tissues was inadequate for the demands for oxygen by these tissues.     

Neonatal polycythemia in infants of insulin-dependent diabetic mothers

The rate of neonatal polycythemia was determined prospectively in 34 infants of diabetic mothers pair-matched to 34 infants of nondiabetic mothers (control group) for site of sampling, time of sampling, time of cord clamping, gestational age, mode of delivery, and one- and five-minute Apgar scores. Polycythemia (venous hematocrit greater than or equal to 65%) was present in 29.4% of infants of diabetic mothers and 5.9% of control subjects (P less than .03). Mean nucleated red blood cell counts were significantly higher in infants of diabetic mothers than in controls. Polycythemia did not correlate with higher maternal hemoglobin A1 concentration or with increased infant weight percentile, but did correlate with neonatal hypoglycemia. The authors speculate that increased erythropoiesis exists in infants of diabetic mothers and might be subsequent to fetal hypoxemia due to fetal hyperglycemia, hyperinsulinism, and hyperketonemia.     

Relationship between maternal and fetal plasma glucose and insulin concentrations during graded maternal hyperglycemic states in primates

Our goal was to conduct a controlled study using an established timed-pregnant baboon model to describe the maternal and fetal plasma glucose and insulin concentrations during graded increases in maternal circulating glucose levels. Timed-pregnant baboons were operated on during the second half of pregnancy, and after recovery from surgery, maternal glucose infusions were started. To determine changes in plasma glucose and insulin concentrations, maternal and fetal blood samples were obtained before glucose infusion and at 30-minute intervals to include 30 minutes postinfusion. Maternal plasma glucose concentrations ranged from 97 to 392 mg/dL and fetal plasma glucose concentrations from 78 to 278 mg/dL. Maternal plasma insulin concentrations ranged from 123 to 1384 U/mL, and the fetal plasma insulin concentrations from 76 to 260 U/mL. Significant correlations were noted between maternal plasma glucose and insulin concentrations (N = 10; R(2), 80%; P < 0.001), as well as maternal and fetal plasma glucose concentrations (N = 10; R(2), 97%; P < 0.001). Maternal-to-fetal glucose gradient ranged from 16 to 34% (mean, 23%) and did not correlate with maternal plasma glucose concentration. No correlation was found between fetal plasma glucose and insulin concentration. Maternal-to-fetal insulin gradient ranged from 31 to 87% (mean, 70.7%) and was significantly different from the glucose gradient ( P < 0.0001). Results from this study suggests that (1) there is a relatively steady transplacental glucose transfer during the second half of pregnancy at maternal plasma glucose concentrations ranging from 97 to 392 mg/dL; and (2) there is also a relative incapacity of the fetal pancreas, compared with the maternal pancreas, to respond to graded increases of hyperglycemia. Studies aimed at determining whether particular thresholds of maternal hyperglycemia at different gestational ages can lead to transitory hyperosmolar and polyuric fetal states could provide further insights into the mechanisms leading to idiopathic polyhydramnios.     

Absence of physiological tolerance to cocaine in pregnant sheep.

OBJECTIVE: To determine whether repetitive administration of cocaine to sheep during pregnancy altered basal hemodynamic states in the mother and fetus, and to determine whether this cocaine exposure would alter subsequent hemodynamic responses to cocaine. METHODS: Cocaine or saline was administered to 16 pregnant sheep daily from day 75 to day 128 of gestation (term = 145 days). At 128 days' gestation, maternal and fetal basal physiological measurements, including organ-specific blood flow in the fetus, were determined. Each experimental and control ewe then received cocaine 2 mg/kg and these physiological parameters were again measured over the next 30 min to determine whether the experimental animals had developed tolerance to the effects of cocaine. RESULTS: No differences were seen in basal physiological parameters between treatment groups. Likewise, following an acute administration of cocaine, physiological parameters in both groups responded in a similar fashion. Fetal hypoxemia occurred in both groups after the ewe received cocaine. In response to hypoxemia, whether it was the animals' first or 53rd exposure to cocaine, fetal cerebral, myocardial and adrenal blood flow increased so that oxygen delivery was unimpaired. CONCLUSIONS: For the cardiovascular parameters measured in this study, we found no tolerance to cocaine in the ewe or fetus. The acute hemodynamic effects of maternal cocaine administration were as severe for animals having received it more than 50 times as for those that received it for the first time.     

Temperature gradient between fetus and mother as an index for assessing intrauterine fetal condition.

Temperature gradient between fetus and mother (deltaTF-M) was measured in 29 pregnant baboons. Thermocouples were implanted in the fetal esophagus and the maternal colon, and, in some instances, thermistor probes were also placed in the fetal esophagus, scalp, and shoulder muscle. Under steady-state conditions, the fetal temperature was found to be higher than that of the mother. Temperatures in the fetal esophagus, scalp, and shoulder were 0.47, 0.28, and 0.19 degrees C. respectively, higher than those in the maternal colon. There was an increase in deltaTF-M during acute fetal stress induced by asphyxia, secondary to occlusion of the umbilical cord, maternal aorta, or inferior vena cava, or to acutely increased uterine activity. This increase in deltaTF-M most likely reflects impairment of heat dissipation from the fetus to the maternal compartment. A decreased deltaTF-M was observed when the stress on the fetus was subacute and prolonged. This is probably the result of a diminution of heat production by the fetus as the metabolic rate is lowered during prolonged hypoxia. Ten to 30 minutes after the cessation of vital signs of the fetus, the deltaTF-M became zero.     

Glycemic control in the diabetic pregnancy: is tighter always better?

Glucose is the principal nutrient that the mother supplies to the fetus through the placenta by way of concentration-dependent mechanisms. In the presence of maternal hypoglycemia, with limited glucose supply, fetal hypoglycemia and hypoinsulinism ensue. This may be viewed as an adaptive mechanism to increase the chances of fetal survival in the face of limited maternal supply, albeit of a growth-restricted fetus. Fetal nutrient deprivation and the resulting hypoinsulinism may have both short- and long-term consequences. Intrauterine growth failure is associated with higher rates of gestational age-specific neonatal mortality and with long-term cognitive deficits. Furthermore, epidemiologic data suggest that diabetes, coronary artery disease, and hypertension are more common among adults who were small for gestational age at birth. Thus, pancreatic failure in adulthood may be either a response to excessive exposure to glucose as a result of maternal hyperglycemia, or as a result of hypoglycemia where nutrient deprivation leads to fetal growth restriction and reduced islet cell proliferation. Because low mean concentrations of maternal glucose in gestational diabetes are associated with an increased risk of fetal growth restriction, overzealous glycemic control during pregnancy may raise concerns regarding the possible effects on the infant. In the mother with Type 1 diabetes, strict glycemic control is often associated with an increased incidence of severe hypoglycemia. Up to 40% of women report at least one episode of severe hypoglycemia during pregnancy, requiring assistance by another person or professional intervention. It is quite possible that in some patients striving to optimize pregnancy outcome by maintaining the best possible glycemic control jeopardizes the well-being of the mother and the fetus. Thus, with respect to tight glycemic control of pregnant women with diabetes, the question arises: How tight is too tight? Is there a threshold below which the trade-off in terms of maternal morbidity as well as fetal growth restriction and its consequences outweighs the benefits of preventing the effects of maternal hyperglycemia?     

Circulatory changes in the fetal aorta after maternal smoking

The acute cardiovascular responses of the human fetus to maternal smoking of one cigarette were studied in 10 healthy pregnant women. Following maternal smoking, a significant increase was found in the nicotine concentration in maternal plasma accompanied by a significant increase in the fetal heart rate. The flow velocity was recorded in the fetal descending aorta by combining real-time ultrasonography and the 2 MHz pulsed Doppler technique and the waveform of the maximum blood velocity was analysed. The duration of the acceleration part of the pulse cycle (start-to-peak time) remained unchanged during the study period. The least diastolic blood velocity increased significantly after smoking. The pulsatility index fell significantly during the first 5 min after smoking, probably as the consequence of fetal tachycardia, but was normal again at 10 min. The rising slope rose significantly within the first 10 to 20 min after the onset of smoking. The results indicate, that, following maternal smoking of one cigarette, fetal central circulation increases but peripheral resistance is unchanged.     

Acute effects of maternal smoking on fetal blood flow

Thirty healthy pregnant women were studied to assess the immediate cardiovascular responses of the fetus to the smoking of one cigarette. The fetal blood flow was measured in the aorta and in the umbilical vein by combining real-time ultrasonography and the pulsed Doppler technique. Following maternal smoking, a significant increase was found in the maternal heart rate and also in the blood pressure. In the fetus, a significant transient increase in the aortic and the umbilical blood flow was measured, as characterized by the increase in the fetal heart rate, the mean and maximum blood velocity, and the vessel diameter. Thus, maternal smoking induced acute circulatory changes in the fetus similar to those found in adults. Furthermore, the study demonstrated the feasibility of the method to evaluate non-invasively the immediate effect of a given stress stimulus on the cardiovascular system of the human fetus.     

妊娠期糖尿病酮症酸中毒的处理

妊娠期糖尿病酮症酸中毒是一种少见的产科危重症,是以高血糖、高血酮、严重脱水和代谢性酸中毒为主要临床表现的一种综合征,若治疗不及时则母婴死亡率及病率明显升高。及时给予紧急补充血容量,同时辅以胰岛素补充治疗。病情多能快速缓解,母儿预后良好。     

Effect of maternal intravenous infusions on fetal extracellular fluid composition in pregnant ewes

Infusion of intravenous solutions to women in labor is common clinical practice. Since these infusions may change the volume and electrolyte balance between the mother and fetus, we investigated the influence of acute maternal volume expansion upon fetal and maternal fluid and electrolyte equilibrium in the chronically catheterized fetal lamb. Paired measurements of maternal and fetal plasma sodium and potassium concentrations, osmolality, and colloid osmotic pressure (COP), plus measurements in the fetal-placental plasma volume were obtained following rapid maternal infusions with saline, dextrose, and dextran solutions. Maternal infusions resulted in changes in fetal electrolyte concentrations as well as alterations in transplacental COP differences. Despite these changes, however, no changes in fetal plasma volume were noted.     

Vasoconstrictive effect of bile acids on isolated human placental chorionic veins.

Intrahepatic cholestasis of pregnancy (ICP) is a rare complication of late pregnancy associated with a high rate of premature delivery, antepartum fetal death and fetal hypoxia. Since the principal biochemical feature of ICP is a marked elevation of maternal serum bile acid levels, a role of these substances in the pathophysiology of fetal complications has been suggested. In this study, the effect of bile acids on isolated human placental chorionic veins is described. High concentrations of bile acids, especially cholic acid, have a dose-dependent vasoconstrictive effect, which suggests that these substances could exert a detrimental effect on the fetus by increasing the resistance in chorionic veins through a vasospasm of the placental chorionic surface. An abrupt reduction of the oxygenated blood flow at the level of the placental chorionic plate may cause an acute impairment of the fetal perfusion and oxygenation, leading to fetal asphyxia. This is the first report that provides experimental evidence of the possible role of bile acids in those mechanisms that trigger fetal asphyxia in pregnancies complicated by ICP.     

Does glucose administration affect the cerebral response to fetal asphyxia?

This study was designed to test whether the fetal brain has an increased resistance towards asphyxia at high levels of blood-glucose, compared with low levels. 35 fetal sheep were exteriorized and investigated under general anesthesia. Cerebral blood flow (CBF) was estimated with the 133Xenon-washout method. Cerebral uptake of oxygen, glucose, and lactate was measured. Somatosensory evoked potentials (SEP) were recorded. The fetuses were subjected to controlled asphyxia by ventilating the ewes with gas mixtures low in oxygen. The blood sugar levels of the fetuses were varied over a four-fold range. During normal oxygenation of the fetus variations in the blood glucose concentration induced considerable changes in the cerebral glucose uptake, whereas CBF and oxygen uptake were unaffected. During asphyxia, hyperglycemia was associated with rapid development of acidosis and reduction in cerebral oxygen consumption together with deterioration of the neurophysiological characteristics of the brain. Far from being beneficial during asphyxia, fetal hyperglycemia appeared to reduce the tolerance of the fetal brain towards asphyxia. This report together with other evidence provides support for the view that extra glucose might be disadvantageous for the asphyxiated fetus.     

Infusion of gonadotropin-releasing hormone agonist during pregnancy: maternal and fetal responses in primates

To determine whether a gonadotropin-releasing hormone agonist could cross the placenta to the fetus, each pregnant rhesus monkey (110 to 155 days' gestation, n = 10) and her in utero fetus had indwelling cannulas placed in the femoral veins. Gonadotropin-releasing hormone agonist (1000 micrograms intravenously) was injected into the mother (n = 8) or fetus (n = 2); serial blood samples were collected from mother and fetus for luteinizing hormone and follicle-stimulating hormone determination. None of the mothers responded to the gonadotropin-releasing hormone agonist bolus. In contrast, some of the fetal monkeys receiving gonadotropin-releasing hormone agonist via placental transfer and all fetal monkeys injected directly with the agonist responded as indicated by increased luteinizing hormone (2.8- to 12.3-fold) and follicle-stimulating hormone (1.5- to 8.9-fold) concentrations. In evaluating maternal and fetal effects, we found that continuous maternal infusion with either gonadotropin-releasing hormone agonist (n = 14) or saline solution (n = 11) throughout pregnancy did not alter maternal hormonal profiles. Histologically, gonads from their infants, removed within 3 days post partum, were normal. Although neonatal ovarian weights were unaffected by the in utero treatment, the testes weighed less (p less than 0.05) in male infants born of mothers treated with gonadotropin-releasing hormone agonist compared to controls. Thus gonadotropin-releasing hormone agonist can cross from maternal to fetal circulation, and the fetus can respond (at least during the third trimester).     

Neonatal lymphocytes dominate against lymphocytes of their own mother but not against allogenic maternal or adult lymphocytes in bidirectional mixed lymphocyte cultures

OBJECTIVE: Recent studies have shown a regular prenatal transfer of maternal immunocompetent cells into the fetal circulation. However, these cells engraft and proliferate only in a few exceptional cases if the fetus reaches an immunocompetent state. Thus the fetus has to have an immunologic defense mechanism against the engraftment of maternal cells. In the current study we investigated whether the fetus has such an immune defense and whether this defense mechanism specifically attacks cells of the mother. PATIENTS, MATERIAL AND METHODS: Blood samples were obtained from 15 mothers and 15 newborns directly after delivery. We compared individual vitality and spontaneous cytotoxicity between fetal and maternal lymphocytes in a cell ratio of 1:1 in nonstimulated bidirectional mixed lymphocyte cultures (MLC). The distribution of each cell population within the MLC was visualized by fluorescence in situ hybridization and X/Y-DNA probes. This was compared to MLCs between unrelated fetal and maternal as well as between unrelated adult lymphocytes. RESULTS: After 72 h, a significant cell shift was observed only in the MLC with neonatal lymphocytes mixed with cells of their own mother; there was a significantly higher number of neonatal cells (0.71 vs. 0.29) present. All other groups continued to have a cell distribution of 1:1. CONCLUSION: Our results show that neonatal lymphocytes specifically dominate against maternal but not allogenous maternal or adult lymphocytes in nonstimulated bidirectional MLCs.     

母血中胎儿有核红细胞数量与胎儿异常的关系

目的 :探讨母血中胎儿有核红细胞数量与胎儿异常的关系 ,为将它用于无创性产前诊断提供实验依据。方法 :对孕 6～ 40周的 86例妇女 (包括胎儿正常组 68例、胎儿异常组 1 8例 )的外周血进行单密度梯度离心、瑞氏染色和细胞计数 ,分析母血中胎儿有核红细胞数量与孕周、胎儿异常及胎儿性别的关系。结果 :胎儿正常组 ,母血中胎儿有核红细胞平均数量为 1 4.2 3±1 2 .0 1 /ml,与妊娠周数呈直线相关 (R >R0 .0 5)。胎儿异常组中 ,母血中胎儿有核红细胞平均数量较正常胎儿组显著增加 ,约为 3 8.73± 2 4.97/ml,且与妊娠周数无明显直线相关性。母体外周血中胎儿有核红细胞数量与胎儿性别无统计学相关性。结论 :胎儿发生异常时母血中胎儿有核红细胞数量较正常妊娠时增加。母血中胎儿有核红细胞数量在胎儿正常时随孕周而增加 ,且不受胎儿性别的影响。母血中胎儿有核红细胞计数可以辅助用于产前筛查胎儿异常的发生。