The effect of nicotine on fetal breathing movements in conscious pregnant ewes.

Nicotine (0.14--0.25 mg/kg), injected intravenously or intraarterially into conscious pregnant ewes, caused a decrease in fetal PaO2 within 5 minutes, persisting for up to 30 minutes. There was a significant fall in the incidence of fetal breathing movements. These changes did not occur if the ewe was treated with an alpha-blocking agent (phentolamine) or if the nicotine was infused for 30 minutes at 0.27 to 0.85 mg/minute. Nicotine crossed the placenta; fetal concentrations equaled those in the ewe 5 minutes after the injection and remained at or above maternal levels for 1 hour. Nicotine given directly to the fetus (0.005--0.03 mg/kg estimated fetal weight) stimulated fetal breathing movements in a dose-related manner. We suggest that the maternal injection of nicotine results in a fall of uterine blood flow by a sympathomimetic action, leading to transient fetal hypoxemia and a reduction of fetal breathing movements and that a similar phenomenon may occur when a pregnant woman smokes cigarettes.     

Review of fetal cardiovascular and metabolic responses to diabetic insults in the pregnant ewe

Studies with pregnant sheep are reviewed, which were designed to investigate whether short-term episodes of maternal hyperglycemia or hyperketonemia were detrimental to the fetus, whether ketones can cross the ovine placenta, and whether the combination of maternal hyperglycemia and hyperketonemia would contribute to an increased risk of fetal morbidity. It is concluded that acute increases in maternal ketones appear to be more detrimental to the fetus than acute increases in maternal glucose, as assessed by fetal cardiovascular, metabolic, and blood gas changes.     

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.     

Effect of long-term bromocriptine infusion on plasma prolactin and ovine chorionic somatomammotropin in the pregnant ewe and fetal sheep.

It has been shown in previous studies that the continuous infusion of bromocriptine (CB 154) into either the sheep fetus or pregnant ewe was followed by pronounced ultrastructural changes in the binucleate (BN) cells of the ovine chorionic epithelium, which are a likely source of ovine chorionic somatomammotropin (oCS). We have examined ovine fetal and maternal plasma prolactin (PRL) and oCS concentrations following intravascular CB 154 infusion separately into either the fetus (0.03 mg/hour) or ewe (0.2 mg/hour). The CB 154 infusions significantly depressed fetal and maternal plasma radioimmunoassayable PRL concentrations within 24 hours of the commencement of infusion. Maternal plasma radioimmunoassayable oCS concentration was significantly depressed during infusion of CB 154 to the ewe, but the infusion of CB 154 to the fetus did not lower fetal plasma radioimmunoassayable oCS concentration or affect the duration of gestation.     

Decreased fetal movements with sustained maternal hyperglycemia using the glucose clamp technique

The purpose of this study was to evaluate the effect of sustained maternal hyperglycemia (120 mg/dl) on fetal activity. The glucose infusion study group was comprised of nine healthy gravidas between 36 and 40 weeks' gestation, and six patients served as controls. The protocol design included an overnight fast for all patients. Fetal movements were evaluated by external fetal monitoring. A 2-hour preinfusion evaluation of fetal activity served as the baseline control for each patient studied. Study patients then received a glucose infusion by a glucose clamp technique to maintain a sustained hyperglycemia of 120 mg/dl for 3 hours. After the glucose infusion, fetal movements were observed for 1 hour. Control patients received a saline infusion for 2 hours after a 2-hour baseline evaluation. Maternal hyperglycemia was associated with a significant decrease of fetal movements greater than 1 second duration during the first hour of glucose infusion. Fetal movements returned to baseline during the second and third hours of glucose infusion. Saline infusion was not associated with a decrease in fetal activity. We conclude that sustained maternal hyperglycemia is associated with a transient decrease in fetal movement during the first hour of glucose infusion followed by a return to the control (preinfusion) level of fetal activity. These data may have implications in the study of fetal behavior in diabetes mellitus.     

Hemodynamic effects of intravenous cocaine on the pregnant ewe and fetus

Cocaine is a potent vasoconstrictive agent that is currently the subject of widespread drug abuse. Because little is known of the physiologic responses to cocaine in pregnancy, the effects of intravenous cocaine on uterine blood flow and other maternal and fetal cardiovascular parameters were studied. Eight ewes in late pregnancy were equipped with electromagnetic flow probes around both uterine arteries and catheters were placed in the maternal and fetal inferior vena cavae and aortas. Bolus intravenous infusion of 0.5 and 1.0 mg/kg of maternal body weight achieved peak plasma cocaine levels similar to those observed in human subjects after abuse of the drug (mean level = 229 to 400 ng/ml, n = 8). After bolus infusion of 0.5 or 1.0 mg/kg of cocaine, mean maternal arterial pressure increased 32% and 37%, respectively (p less than 0.005). Fetal blood pressure rose 12.6% after a dosage of 0.5 mg/kg of cocaine. These cocaine infusions significantly decreased uterine blood flow by 36% and 42% for a duration of 15 minutes (p less than 0.005). Analysis of maternal catecholamine responses demonstrated a significant (210%) rise in plasma norepinephrine levels after cocaine infusion. These studies demonstrate that cocaine, when administered in doses that produce plasma levels observed in humans, significantly decreases uterine blood flow for a duration of greater than or equal to 15 minutes while inducing a hypertensive response in the pregnant ewe and fetus.     

Relationship of fetal bradycardia to maternal administration of lidocaine in sheep.

The casual relationship between the use of lidocaine and fetal bradycardia and the effect of the drug on maternal and fetal hemodynamics were studied on 13 chronically instrumented pregnant sheep. Lidocaine was infused intravenously to the mother for 60 minutes during arterial lidocaine concentrations were maintained at 2 to 5 microgram per milliliter in the mother and at less than 2 microgram per milliliter in the fetus. A decrease in uterine blood flow and an increase in uterine vascular resistance and uterine activity occurred immediately following the administration of lidocaine to the ewe. These changes were followed by a transient fetal bradycardia in 12 out of 17 experiments, accompanied by a decrease in fetal PaO2 values. These phenomena were seen in the absence of such predisposing conditions as maternal hypotension and fetal acidosis. It would appear that the mechanism responsible for a transient fetal bradycardia following regional obstetric anesthesia, particularly paracervical block anesthesia, in the initially nonasphyxiated fetus may in part be related to a brief decrease in perfusion of intervillous spaces. The bradycardia can occur at low lidocaine concentrations in both the maternal and fetal blood in a range similar to that observed in clinical practice.     

Placental transfer of the thromboxane synthetase inhibitor ridogrel in the late-pregnant ewe.

OBJECTIVES: To assess the occurrence of placental transfer of the thromboxane synthetase inhibitor ridogrel in the pregnant ewe and to determine its effect on prostanoid levels in the ewe and fetal lamb, on uterine contractility and on maternal and fetal hemodynamics. STUDY DESIGN: Five chronically instrumented pregnant ewes at 122 days of gestation received intravenous infusions of 5 mg/kg/3 h ridogrel and solvent. Maternal and fetal arterial samples were obtained at predetermined intervals to determine concentrations of ridogrel and prostaglandin metabolites TXB2, 6-keto-PGF1alpha, PGF2alpha, and PGE2. Maternal and fetal responses of blood flow and pressures were determined. RESULTS: Fetal ridogrel levels were 25% of maternal concentrations. Ridogrel showed rapid and marked thromboxane synthetase inhibition and augmentation of levels of prostaglandin metabolites. There was no evidence of change in amniotic pressure, uterine blood flow, maternal and fetal blood pressure and heart rate. CONCLUSION: Ridogrel is a potent thromboxane synthetase inhibitor which passes the sheep placenta, does not influence maternal and fetal hemodynamics and uterine contractility, and shows similar antiplatelet activity in the ewe and the fetal lamb.     

Appraisal of "rigid" blood glucose control during pregnancy in the overtly diabetic woman

The degree of maternal glucose control achieved during the third trimester of pregnancy was evaluated for 120 overtly diabetic women hospitalized on a high-risk pregnancy ward. "Rigid" blood glucose control, defined as a mean preprandial plasma glucose concentration less than 115 mg/dl was achieved in only 14% of these women. Although mean preprandial plasmal glucose concentrations ranged between 115 and 172 mg/dl in 66% of women and exceeded 172 mg/dl in 20%, the perinatal salvage rate was greater than 95%. Pregnancies of those women whose mean plasma glucose levels exceeded 172 mg/dl required earlier intervention for signs of fetal jeopardy, but the degree of glucose control was not significantly related to either perinatal death or neonatal morbidity. These results suggest that maternal hyperglycemia exceeding a mean preprandial glucose concentration of 172 mg/dl is to be avoided, whereas, at the other extreme, mean glucose levels less than 115 mg/dl or "rigid" control is unnecessary for a successful perinatal outcome.     

Ovine fetal cardiorespiratory response to nicardipine

Nicardipine, a calcium antagonist associated with decreased uterine blood flow in near-term pregnant rabbits and fetal asphyxia after maternal administration in the rhesus monkey and sheep, was infused directly to the fetus in six chronically prepared pregnant ewes at 128 days' gestation. Changes in fetal mean arterial and diastolic blood pressure levels at 2 and 30 minutes after bolus injection of 50 micrograms were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 micrograms of nicardipine. Fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables did not change at either dose. Fetal plasma concentrations of nicardipine were 78 +/- 28 ng/ml and 114 +/- 48 ng/ml at 30 minutes after infusion of 50 micrograms and 100 micrograms, respectively, well within the range previously reported to be associated with fetal asphyxia. These data suggest that the previously reported fetal acidosis from maternal infusion of nicardipine may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug.     

Transplacental arteriovenous gradients for glucose, insulin, glucagon and placental lactogen during normoglycaemia in human pregnancy at term

The potential contributions of placental extraction and degradation to glucoregulatory hormone turnover in late pregnancy were assessed by measuring arteriovenous differences for glucose, insulin, glucagon and human placental lactogen (hPL) across the uterine and fetal circulation in ten pregnant women at the time of elective caesarean section. The observations were made during stable conditions of euglycaemia; values for maternal arterial glucose, insulin, glucagon and hPL were 78.8 +/- 5.0 mg/dl, 10.1 +/- 2.1 microU/ml, 72.0 +/- 8.5 pg/ml and 5.18 +/- 0.59 micrograms/ml, respectively. The glucose decrements observed consistently across the uterus and fetus indicated uptake by the placenta and fetus, and in the maternal circulation the arterial-uterine vein increment for hPL was 2.10 +/- 0.44 micrograms/ml. However, within the limits of analytical accuracy, no significant gradient could be demonstrated for insulin across the uterine (maternal) or umbilical (fetal) circulations. A small (8.5 per cent) but significant arteriovenous difference for glucagon was observed across the uterus but none was found on the fetal side of the placenta. The findings indicate that detectable gradients for insulin cannot be demonstrated under basal conditions of metabolism and at normal rates of placental blood flow. The results do not exclude the possibility of more significant extraction ratios under other physiological conditions or at higher concentrations of glucoregulatory hormones.     

Effects of maternal diabetes on embryogenesis

Through the use of the in vitro technique of mammalian whole embryo culture, the factors and mechanisms responsible for the increased incidence of congenital malformations among infants of diabetic mothers have been investigated. During early stages of embryogenesis, serum from streptozotocin-induced diabetic rats, hyperglycemia, hypoglycemia, hyperketonemia (beta-hydroxybutyrate), and low molecular weight somatomedin inhibitors are teratogenic or growth inhibitory, or both. Furthermore, combinations of these factors interact to increase the risk of a malformation occurring. In contrast, other factors, such as hyperinsulinemia and excess leucine, palmitic acid, and acetoacetate, have little or no teratogenic potential. Mechanisms of action of the factors are varied and may include alterations of arachidonic acid metabolism (hyperglycemia), glycolysis (hypoglycemia), DNA synthesis (beta-hydroxybutyrate), and embryonic nutrition (somatomedin inhibitors). The results demonstrate that the origin of the diabetic embryopathy is multifactorial, that many of the congenital defects are induced early in gestation before the diabetic woman may realize she is pregnant, and that insulin therapy reduces the risk.     

Perinatal outcome of pregnancies complicated by diabetes and by maternal daily hyperglycemia not related to diabetes. A retrospective 10-year analysis

We analyzed the perinatal outcome of 1,086 pregnancies classified according to the response to the 3-hour 100-gram glucose tolerance test and the diurnal glycemic profile into the Rudge groups corresponding to control pregnant women, class A gestational diabetic women, class A/B to FRH pregnant women and women with daily hyperglycemia. Despite treatment, the diabetic pregnant women and those with daily hyperglycemia presented higher mean blood glucose levels compared to controls (76.6+/-10.2 mg/dl). The pregnancies complicated by diabetes and by daily hyperglycemia were characterized by a high incidence of prematurity, macrosomia, large for gestational age newborn infants, malformation and fetal and neonatal death, with consequent perinatal mortality. The perinatal mortality of women with daily hyperglycemia was 10 times higher than that of the controls and was similar to that of the diabetic patients. These adverse perinatal results emphasize the need for the diagnosis and control of intrauterine hyperglycemia both in diabetic pregnant women and in women with an altered diurnal glycemic profile.     

Diagnosis and treatment of gestational diabetes according to amniotic fluid insulin levels

In spite of dietary treatment, the infants of pregnant patients with abnormal glucose tolerance have hyperinsulinism and diabetogenic fetopathy in 10 to 36% of cases. Those patients, who require insulin to prevent from fetopathy cannot be reliably selected by maternal parameters such as blood glucose and glycosylated hemoglobin values. We recommend the measurement of amniotic fluid insulin between the 28 and 32 weeks of pregnancy to differentiate whether the fetus is compromised or not. Subjects with values above the 97th centile require insulin therapy. Inadequate insulin dosage or delayed fetal hyperinsulinism can be discovered by checking the amniotic fluid insulin level at 33 to 36 weeks. In a total of 88 gestational diabetic patients 19 had raised amniotic fluid insulin levels indicating the onset of diabetic fetopathy at an early stage. Diabetic patients with raised amniotic fluid insulin levels needed large doses of insulin, namely 64.6 +/- 29.5 (Mean +/- SD) U/24 h. This treatment reduced mean blood glucose levels from 98 +/- 9 (Mean +/- SD) mg/dl to 82 +/- 10 mg/dl and was sufficient to prevent from diabetic fetopathy.     

Effects of maternal hyperglycemia on fetal growing mechanism

The aim of this study was to clarify the effects of maternal hyperglycemia on fetal growth in rats. In streptozotocin (STZ)-induced diabetic rats, maternal serum glucose levels during pregnancy were controlled by daily injection of NPH insulin or saline from day 3 to 21 of pregnancy. The body weight, hepatic glycogen content and serum concentrations of insulin and Insulin-like Growth Factor-I (IGF-I) in fetuses from these rats were measured on Day 21 of pregnancy. Fetal body weight positively correlated with maternal mean blood glucose (MBG) during pregnancy in the groups of diabetic mothers whose MBG was less than 220 mg/dl, whereas a negative correlation was observed in the groups whose MBG was more than 220 mg/dl. In addition, a similar correlation between hepatic glycogen content, serum concentrations of insulin or IGF-I and maternal MBG was observed. On the other hand, in the culture of fetal rat hepatocytes, glycogen content indicated a dose-related increase according to the increase in glucose concentration in the medium. These results suggest that the growth retardation observed in rats whose maternal mean glucose level is higher than 220 mg/dl is not caused by abnormalities in the metabolic function of the fetal metabolic organ (liver), but it is caused by a decrease in the production and/or secretion of growth-promoting factors (for example insulin and IGF-I) in the fetuses.     

The effects of xylazine on uterine activity, fetal and maternal oxygenation, cardiovascular function, and fetal breathing

Various pharmacologic agents used in the experimental study of physiologic processes may have pronounced effects on the systems under study. We have studied the effects of xylazine (Rompun) on myometrial activity, fetal and maternal pH, blood gases, heart rate, and fetal breathing movements in chronically catheterized fetal sheep. Xylazine is widely used as a premedication for various forms of animal operations, including the instrumentation of the chronically catheterized fetal sheep preparation. Animals were studied on postoperative day 5. Xylazine had pronounced effects on maternal PaO2 and heart rate that lasted for at least 3 hours. Fetal heart rate and PaO2 returned to preinjection levels within 60 minutes. Myometrial activity doubled in the first 60 minutes after administration of xylazine and did not return to preinjection levels for 3 hours. Fetal diaphragmatic electromyographic activity was almost completely absent in the first and second hours, with a return to normal within 4 hours. These changes were absent in the saline solution-injected control animals. The observed changes in uterine activity and fetal breathing may have been direct effects of xylazine itself or the result of increased uterine activity. The different duration of changes in the ewe and fetus suggests a compensatory mechanism at the uteroplacental level or in the fetoplacental unit.     

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.     

Maternal and fetal cardiovascular indices during fetal hypoxia due to cord compression in chronically cannulated sheep. I. Responses to timolol

Timolol, one of the newer beta-adrenergic antagonists, has less depressive effects on the heart than propranolol, so that it has the potential for use by pregnant women. In chronically cannulated ewes, timolol at 0.01 and 0.1 mg/kg of body weight induced maternal and fetal bradycardia; the higher dose also depressed uterine blood flow and fetal PaO2. When this higher dose preceded brief compression of the umbilical cord, uterine flow was further depressed and the usual posthypoxia rebound tachycardia did not develop. Both the blocking of fetal responses to hypoxia (precluding detection of fetal distress) and the reduction in uterine flow led us to conclude that timolol taken by a mother could pose particular hazards for her fetus in hypoxic conditions, such as during cord compression at parturition.     

Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels?

Intensive treatment of insulin-dependent diabetes mellitus during pregnancy often normalizes plasma glucose levels. However, it is unclear whether this adversely affects other metabolic fuels that are essential to normal fetal growth and development. Metabolic studies were conducted after the subjects ingested a standardized mixed meal during each trimester in 7 normal and 15 insulin-dependent diabetic pregnant women. The latter were treated with continuous subcutaneous insulin infusion or multiple injections, which were adjusted to achieve strict glucose control throughout pregnancy. Insulin, alanine, branched-chain amino acids, triglycerides, free fatty acids, and ketones were measured every 15 to 30 minutes before a standardized breakfast and for 150 minutes after the breakfast. Patients with insulin-dependent diabetes mellitus were studied while they received their unusual insulin dosages. Fasting glucose levels (87 +/- 7 mg/dl) and glucose levels 150 minutes after the meal (112 +/- 11 mg/dl) were near normal. However, normoglycemia was achieved at the expense of increased plasma insulin levels (area under insulin response curves, p less than 0.01, vs nondiabetic curves). Nevertheless, fasting and post-prandial plasma branched-chain amino acids, alanine, and free fatty acids were similar in both groups. Fasting cholesterol, triglyceride, and ketone levels were also normalized. We conclude that normalization of circulating amino acids and lipids in conjunction with correction of hyperglycemia may contribute to favorable outcomes in infants of intensively treated diabetic mothers.     

Hepatic and peripheral responsiveness to a glucose infusion in pregnancy

To enhance glucose transfer to the fetus, the pregnant woman may evidence hyperglycemia after feeding. In order to evaluate whether hepatic responsiveness, in contrast to peripheral uptake, contributes to this response, the glucose production rate was measured in 15 pregnant nondiabetic patients, in 12 pregnant insulin-dependent diabetic patients, and in 12 nonpregnant nondiabetic patients (controls). Seventeen of the women were infused with 3.2 mg X kg-1 min-1 of glucose. All glucose-infused groups had an elevated plasma glucose concentration compared to their saline solution-infused counterparts. The glucose production rate was suppressed in the nondiabetic glucose-infused groups. The glucose production rate of the pregnant nondiabetic patients was similar to that of the pregnant insulin-dependent diabetic patients, but the glucose production rate of the latter group was more variable than that of nonpregnant nondiabetic controls (p less than 0.05). We conclude that in third trimester, pregnant nondiabetic and insulin-dependent diabetic subjects have parallel hepatic and peripheral responsiveness to glucose and insulin compared to their nonpregnant counterparts. Although the pregnant patient may exhibit relative insulin insensitivity, hepatic or peripheral responsiveness to insulin would not explain the persistence of the relative hyperglycemia noted clinically.