Fetal Blood Glucose Concentration Research Articles

Prevention of hypotension during elective cesarean section with a combination of colloid co-load and a continuous infusion of a vasoconstrictive agent: A comparative randomized study

Background: Spinal anesthesia is considered the anesthetic technique of choice in cesarean section but it can be frequently complicated by hypotension, with occasionally serious consequences for both the mother and fetus. One of the standard techniques used in the prevention of maternal hypotension is the administration of a continuous phenylephrine infusion. However, phenylephrine can lead to baroreceptor-mediated reflex bradycardia with untoward consequences for the maternal cardiac output. Nowadays, noradrenaline has been proposed as an alternative agent in this context, since due to its additional weak dose-dependent β-action, it can be associated with an inferior incidence of maternal bradycardia and thus of propensity to decrease the cardiac output. Colloid co-hydration has also been proven to be an effective technique in the prevention of maternal hypotension. This double-blinded, prospective randomized study aimed to investigate whether the addition of a fixed rate phenylephrine infusion or noradrenaline infusion to a colloid co-hydration regimen results in better maternal hemodynamic status or in a more favorable metabolic profile in the newborn as compared to the administration of colloids alone without any vasoconstrictor during elective cesarean section under combined spinal-epidural anesthesia. Materials and methods: One hundred-twenty parturients were randomized to either phenylephrine 50 μg/min (group P) or noradrenaline 4 μg/min (group N) or placebo (group C). All infusions had been prepared in identical syringes and the infusion rate was 30 mL/h in order to ensure the “blindness” of the study. As soon as the spinal injection started, all groups were administered 10 mL/kg of hydroxyethyl starch (HES) solution simultaneously with the onset of vasoconstrictor infusion. The primary end-point of the study was the incidence of maternal hypotension (SAP <80% of baseline). Additionally, maternal hemodynamics at specific time-points were recorded using non-invasive technology (Edwards Lifesciences ClearSight System) as well as the incidence of reactive hypertension, bradycardia, the requirement for bolus vasoconstrictor administration and the fetal acid-base status, the umbilical venous and arterial blood gases and the newborn Apgar score. Results: The incidence of maternal hypotension was higher in group C than in group P and also higher in group C than in group N (p = 0.024 and 0.073, respectively). The need of bolus administration of vasoconstrictor was higher in group C than in group P and also higher in group C than in group N (p = 0.001 and 0.003, respectively). The incidence of bradycardia was higher in group P than in group N (p = 0.018). The incidence of reactive hypertension was higher in group P than in group N and also higher in group P than in group C (p = 0.029 and 0.005, respectively). The need of modification of the infusion rate was higher in group P than in group N and also higher in group P than in group C (p < 0.001 και p = 0.002, respectively). The fetal pH of the umbilical vein was higher in groups N and P than in group C (p < 0.001), the fetal pO2 of the umbilical vein was higher in group N than in group C (p = 0.023) and fetal blood glucose concentration was higher in group N than in group C (p = 0.025) as well as in group N than group P with no statistical significance. Higher systematic vascular resistance index (SVRI) and higher SAP were observed at specific time-points in group P versus the other two groups. Finally, post-delivery Apgar scores were similar in all groups. Conclusions: The combination of a fixed-rate infusion of noradrenaline with the co-administration of colloid seems to be the most effective in the obstetric management of the parturient during cesarean section under regional anesthesia since it ensures maternal hemodynamic stability and a favorable metabolic profile in the newborn. This regimen seems to be superior to either a combination of colloid co-administration with a fixed rate of phenylephrine or to the administration of colloid alone without any vasoconstrictor agent. The higher concentration of fetal blood glucose in group N might be due to a catecholamine-induced glucose metabolism activation and due to a β-receptor-mediated decrease of insulin release.

Prolonged prepregnant maternal high-fat feeding reduces fetal and neonatal blood glucose concentrations by enhancing fetal β-cell development in C57BL/6 mice

To read the full abstract: Diabetes. 2019 Aug;68(8):1604–1613. doi: 10.2337/db18-1308. Epub 2019 May 24. PMID: 31127056

Prevention of hypotension during elective cesarean section with a fixed-rate norepinephrine infusion versus a fixed-rate phenylephrine infusion. Α double-blinded randomized controlled trial

BackgroundSpinal anesthesia for cesarean section can be complicated by hypotension, with untoward effects for both the mother and fetus. Frequently used phenylephrine can lead to baroreceptor-mediated reflex bradycardia. The aim of the present study was to compare a fixed-rate prophylactic norepinephrine infusion to a fixed-rate prophylactic phenylephrine infusion during elective cesarean section under combined spinal-epidural anesthesia. Materials and methodsEighty-two parturients were randomized to either norepinephrine 4 μg/min or phenylephrine 50 μg/min fixed-rate infusions, starting simultaneously with the administration of the subarachnoid solution. The primary endpoint was the incidence of maternal bradycardia. Maternal hemodynamics at specific timepoints, the incidence of hypotension or hypertension, the requirement for ephedrine or atropine bolus administration as well as the acid-base status and Apgar score of the neonate were recorded. ResultsThe incidence of bradycardia as well as the requirement for atropine administration was lower in the norepinephrine group (4.8% vs. 31.7%, p = 0.004 and 2.4% vs. 24.3%, p = 0.01, respectively). Fetal pH, and fetal blood glucose concentration were higher in the norepinephrine group (p = 0.027 and 0.019, respectively). No difference in the occurrence of hypotension, hypertension, in the requirement for bolus vasoconstrictive medication or in Apgar scores was demonstrated. ConclusionsA fixed-rate infusion of norepinephrine is as effective in the management of hypotension during regional anesthesia for cesarean section as a fixed-rate infusion of phenylephrine, with the avoidance of phenylephrine-induced bradycardia. The more favourable neonatal acid-base profile of noradrenaline might be due to better maintenance of placental blood flow in the noradrenaline group due to its beta action, while the higher fetal glucose concentration in the same group might result from a catecholamine-stimulated glucose metabolism increase and a β-receptor mediated insulin decrease.

Consumption of the Artificial Sweetener Acesulfame Potassium throughout Pregnancy Induces Glucose Intolerance and Adipose Tissue Dysfunction in Mice

Sugar-sweetened beverage consumption is associated with metabolic dysfunction. Artificially sweetened beverages (ASBs) are often promoted as an alternative. However, evidence for the safety of ASB consumption during pregnancy is lacking. The effects of sugar-sweetened beverage and ASB consumption during pregnancy in mice were examined, and we hypothesized that both sugar-sweetened beverages and ASBs would impair maternal metabolic function. Pregnant female C57BL/6J mice received control drinking water (CD), high-fructose corn syrup (Fr; 20% kcal intake; 335 mM), or the artificial sweetener acesulfame potassium (AS; 12.5 mM) in their drinking water, from gestational day (GD) 0.5 (n=8/group). Body weights and food and water intakes were assessed every second day, an oral-glucose-tolerance test (OGTT) was performed at GD 16.5, and mice were culled at GD 18.5. RT-PCR was carried out on adipose tissue, liver, and gut. Adipose tissue morphology was assessed using histological methods. In a separate cohort of animals, pregnancy length was assessed. Repeated-measures ANOVA was performed for the OGTT and weight gain data. All other data were analyzed by 1-way ANOVA. Fr and AS significantly impaired glucose tolerance, as demonstrated by OGTT (21% and 24% increase in AUC, respectively; P=0.0006). Fr and AS reduced expression of insulin receptor (39.5% and 33% reduction, respectively; P=0.02) and peroxisome proliferator-activated receptor γ (45.2% and 47%, respectively; P=0.039), whereas Fr alone reduced expression of protein kinase B (36.9% reduction; P=0.048) and resulted in an increase in adipocyte size and leptin concentrations (40% increase; P=0.03). AS, but not Fr, reduced male fetal weight (16.5% reduction; P=0.04) and female fetal fasting blood glucose concentration at cull (20% reduction; P=0.02) compared with CD. AS significantly reduced the length of pregnancy compared with the CD and Fr groups (1.25 d shorter; P=0.02). Fr and AS consumption were associated with maternal metabolic dysfunction in mice. AS was also associated with reduced fetal growth and fetal hypoglycemia. Therefore, ASBs may not be a beneficial alternative to sugar-sweetened beverages during pregnancy.

Maternal selenium deficiency during pregnancy in mice increases thyroid hormone concentrations, alters placental function and reduces fetal growth.

Inappropriate intake of key micronutrients in pregnancy is known to alter maternal endocrine status, impair placental development and induce fetal growth restriction. Selenium is an essential micronutrient required for the function of approximately 25 important proteins. However, the specific effects of selenium deficiency during pregnancy on maternal, placental and fetal outcomes are poorly understood. The present study demonstrates that maternal selenium deficiency increases maternal triiodothyronine and tetraiodothyronine concentrations, reduces fetal blood glucose concentrations, and induces fetal growth restriction. Placental expression of key selenium-dependent thyroid hormone converting enzymes were reduced, whereas the expression of key placental nutrient transporters was dysregulated. Selenium deficiency had minimal impact on selenium-dependent anti-oxidants but increased placental copper concentrations and expression of superoxide dismutase 1. These results highlight the idea that selenium deficiency during pregnancy may contribute to thyroid dysfunction, causing reduced fetal growth, that may precede programmed disease outcomes in offspring. Selenium is a trace element fundamental to diverse homeostatic processes, including anti-oxidant regulation and thyroid hormone metabolism. Selenium deficiency in pregnancy is common and increases the risk of pregnancy complications including fetal growth restriction. Although altered placental formation may contribute to these poor outcomes, the mechanism by which selenium deficiency contributes to complications in pregnancy is poorly understood. Female C57BL/6mice were randomly allocated to control (>190µgkg-1 , n=8) or low selenium (<50µgkg-1 , n=8) diets 4weeks prior to mating and throughout gestation. Pregnant mice were killed at embryonic day 18.5 followed by collection of maternal and fetal tissue. Maternal and fetal plasma thyroid hormone concentrations were analysed, as was placental expression of key selenoproteins involved in thyroid metabolism and anti-oxidant defences. Selenium deficiency increased plasma tetraiodothyronine and triiodothyronine concentrations. This was associated with a reduction in placental expression of key selenodependent deiodinases, DIO2 and DIO3. Placental expression of selenium-dependent anti-oxidants was unaffected by selenium deficiency. Selenium deficiency reduced fetal glucose concentrations, leading to reduced fetal weight. Placental glycogen content was increased within the placenta, as was Slc2a3mRNA expression. This is the first study to demonstrate that selenium deficiency may reduce fetal weight through increased maternal thyroid hormone concentrations, impaired placental thyroid hormone metabolism and dysregulated placental nutrient transporter expression. The study suggests that the magnitude of selenium deficiency commonly reported in pregnant women may be sufficient to impair thyroid metabolism but not placental anti-oxidant concentrations.

Fetal biometry for guiding the medical management of women with gestational diabetes mellitus for improving maternal and perinatal health.

Gestational diabetes mellitus (GDM) is a common medical condition that complicates pregnancy and causes adverse maternal and fetal outcomes. At present, most treatment strategies focus on normalisation of maternal blood glucose values with use of diet, lifestyle modification, exercise, oral anti-hyperglycaemics and insulin. This has been shown to reduce the incidence of adverse outcomes, such as birth trauma and macrosomia. However, this involves intensive monitoring and treatment of all women with GDM. We propose that using medical imaging to identify pregnancies displaying signs of being affected by GDM could help to target management, allowing low-risk women to be spared excessive intervention, and facilitating better resource allocation. We wanted to address the following question: in women with gestational diabetes, does the use of fetal imaging plus maternal blood glucose concentration to indicate the need for medical management compared with glucose concentration alone reduce the risk of adverse perinatal outcomes? We searched Cochrane Pregnancy and Childbirth's Trials Register (29 January 2019), ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) (both on 29 January 2019), and reference lists of retrieved studies. Randomised controlled trials, including those published in abstract form only. Studies using a cluster-randomised design and quasi-randomised controlled trials were both eligible for inclusion, but we didn't identify any. Cross-over trials were not eligible for inclusion in our review.We included women carrying singleton pregnancies who were diagnosed with GDM, as defined by the trials' authors. The intervention of interest was the use of fetal biometry on imaging methods in addition to maternal glycaemic values for indicating the use of medical therapy for GDM. The control group was the use of maternal glycaemic values alone for indicating the use of such therapy. Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors extracted data and checked them for accuracy. Three randomised controlled trials met the inclusion criteria for our systematic review - the studies randomised a total of 524 women.We assessed the three included studies as being at a low to moderate risk of bias; the nature of the intervention made it difficult to achieve blinding of participants and personnel and none of the trial reports contained information about methods of allocation concealment (and were therefore assessed as being at an unclear risk of selection bias).In all studies, the intervention was the use of fetal biometry on ultrasound to identify fetuses displaying signs of fetal macrosomia, and the use of this information to indicate the use of medical anti-hyperglycaemic treatments. Those pregnancies were subject to more stringent blood glucose targets than those without signs of fetal macrosomia.Maternal outcomesThe use of fetal biometry in addition to maternal blood glucose concentration (compared with maternal blood glucose concentration alone) may make little or no difference to the incidence of caesarean delivery (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.59 to 1.10; 2 trials, 428 women; low-certainty evidence). We are unclear about the results for hypertensive disorders of pregnancy (RR 0.80, 95% CI 0.34 to 1.89; 2 trials, 325 women) due to very low-certainty evidence. The included trials did not report on development of type 2 diabetes in the mother or maternal hypoglycaemia.Fetal and neonatal outcomesThe use of fetal biometry may make little or no difference to the incidence of neonatal hypoglycaemia (RR 0.90, 95% CI 0.57 to 1.42; 3 trials, 524 women; low-certainty evidence). Very low-certainty evidence means that we are unclear about the results for large-for-gestational age (RR 0.81, 95% CI 0.38 to 1.74; 3 trials, 524 women); shoulder dystocia (RR 0.33, 95% CI 0.01 to 7.98; 1 trial, 96 women); a composite measure of perinatal morbidity or mortality (RR 1.00, 95% CI 0.21 to 4.71; 1 study, 96 women); or perinatal mortality (RR 0.33, 95% CI 0.01 to 7.98; 1 trial, 96 women). This review is based on evidence from three trials involving 524 women. The trials did not report some important outcomes of interest to this review, and the majority of our secondary outcomes were also unreported. The available evidence ranged from low- to very low-certainty, with downgrading decisions based on limitations in study design, imprecision and inconsistency.There is insufficient evidence to evaluate the use of fetal biometry (in addition to maternal blood glucose concentration values) to assist in guiding the medical management of GDM, on either maternal or perinatal health outcomes, or the associated costs.More research is required, ideally larger randomised studies which report the maternal and infant short- and long-term outcomes listed in this review, as well as those outcomes relating to financial and resource implications.

Prolonged Prepregnant Maternal High-Fat Feeding Reduces Fetal and Neonatal Blood Glucose Concentrations by Enhancing Fetal β-Cell Development in C57BL/6 Mice.

The main objective of this study was to investigate the effect of maternal obesity on offspring’s glucose metabolism during the perinatal period. Maternal obesity was established by feeding C57BL/6 mice with a high-fat (HF) diet before or during pregnancy. Our results showed that prolonged prepregnant HF feeding but not HF feeding during pregnancy significantly reduced fetal and neonatal blood glucose concentrations. Remarkably, elevated blood insulin concentrations and increased activation of insulin signaling were observed in fetuses and neonates from prepregnant HF-fed dams. In addition, significantly larger β-cell areas were observed in pancreases of fetuses and neonates from prepregnant HF-fed dams. Although there was no significant change in placental cross-sectional area or GLUT 1 expression, prepregnant HF feeding significantly enhanced the expression of genes that control placental fatty acid supply. Interestingly, reducing fatty acid supply to the placenta and fetus by placental-specific knockout of adipose triglyceride lipase not only reduced fetal β-cell area and blood insulin concentration but also attenuated prepregnant HF feeding–induced reduction in offspring blood glucose concentrations during the perinatal period. Together, these results indicate that placental and fetal fatty acid supply plays an important role in fetal β-cell development, insulin secretion, and glucose metabolism. Prolonged prepregnant maternal HF feeding resembles pregravid maternal obesity in mice, which reduces fetal and neonatal blood glucose concentrations by enhancing fetal β-cell development and insulin secretion.

Impact of thermal stress on placental function and fetal physiology.

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternal- fetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period.

Importance of genetic differences in developmental programming: gene by environment interactions in models of maternal dietary restriction

Importance of genetic differences in developmental programming: gene by environment interactions in models of maternal dietary restriction

The Herbal Medicine Tokishakuyakusan Increases Fetal Blood Glucose Concentrations and Growth Hormone Levels and Improves Intrauterine Growth Retardation Induced by Nω-Nitro-L-arginine Methyl Ester

Nω-Nitro-L-arginine methyl ester (L-NAME) induces a pre-eclampsia-like syndrome in pregnant rats. We have previously reported the anti-hypertensive effects of several Japanese traditional (Kampo) medicines in this model, and one of these, Tokishakuyakusan (TS), also improved intrauterine growth retardation (IUGR). In the present study, we characterized the effect of TS on IUGR. TS administration reversed the decrease in fetal body weight and fetal blood glucose concentration induced by the infusion of L-NAME. Growth hormone (GH) levels in the fetal blood, which were decreased by L-NAME infusion, were also significantly elevated by TS; however, levels of GH releasing hormone (GHRH) and insulin-like growth factor I (IGF-I) were unchanged and only slightly changed, respectively. Treatment with L-NAME with or without TS had no apparent effect on GH, GHRH, and IGF-I levels of dams. In an immunocytochemical study, the number of GH-positive cells in the fetal pituitary gland was significantly increased in TS-treated rats. These data suggest that enhanced proliferation of somatotrope cells of the pituitary gland and the resultant increase in GH secretion in the fetus may be involved in the improvement of IUGR by TS.

Placentomal differentiation may compensate for maternal nutrient restriction in ewes adapted to harsh range conditions1

Maternal nutrient restriction from early to midgestation can lead to fetal growth retardation, with long-term impacts on offspring growth, physiology, and metabolism. We hypothesized that ewes from flocks managed under markedly different environmental conditions and levels of nutrition might differ in their ability to protect their own fetus from a bout of maternal nutrient restriction. We utilized multiparous ewes of similar breeding, age, and parity from 2 flocks managed as 1) ewes adapted to a nomadic existence and year-long, limited nutrition near Baggs, WY (Baggs ewes), and 2) University of Wyoming ewes with a sedentary lifestyle and continuous provision of more than adequate nutrition (UW ewes). Groups of Baggs ewes and UW ewes were fed 50 (nutrient restricted) or 100% (control fed) of National Research Council recommendations from d 28 to 78 of gestation, then necropsied, and fetal and placental data were obtained. Although there was a marked decrease (P < 0.05) in fetal weight and blood glucose concentrations in nutrient-restricted vs. control fed UW ewes, there was no difference in these fetal measurements between nutrient-restricted and control-fed Baggs ewes. Nutrient-restricted and control-fed UW ewes exhibited predominantly type A placentomes on d 78, but there were fewer (P c0.05) type A and greater (P < 0.05) numbers of type B, C, and D placentomes in nutrient-restricted than control-fed Baggs ewes. Placental efficiency (fetal weight/placentomal weight) was reduced (P = 0.04) in d 78 nutrient-restricted UW ewes when compared with control-fed UW ewes. In contrast, nutrient-restricted and control-fed Baggs ewes exhibited similar placental efficiencies on d 78. This is the first report of different placental responses to a nutritional challenge during pregnancy when ewes were selected under different management systems. These data are consistent with the concept that Baggs ewes or their conceptuses, which were adapted to both harsh environments and limited nutrition, initiated conversion of type A placentomes to other placentomal types when subjected to an early to mid-gestational nutrient restriction, whereas this conversion failed to occur in UW ewes. This early placentomal conversion in the Baggs ewes may function to maintain normal nutrient delivery to their developing fetuses during maternal nutrient restriction.

Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth.

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.

Maternal undernutrition from early- to mid-gestation leads to growth retardation, cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep.

Early gestation is critical for placentomal growth, differentiation, and vascularization, as well as fetal organogenesis. The fetal origins of adult disease hypothesis proposes that alterations in fetal nutrition and endocrine status result in developmental adaptations that permanently change structure, physiology, and metabolism, thereby predisposing individuals to cardiovascular, metabolic, and endocrine disease in adult life. Multiparous ewes were fed to 50% (nutrient restricted) or 100% (control fed) of total digestible nutrients from Days 28 to 78 of gestation. All ewes were weighed weekly and diets adjusted for individual weight loss or gain. Ewes were killed on Day 78 of gestation and gravid uteri recovered. Fetal body and organ weights were determined, and numbers, morphologies, diameters, and weights of all placentomes were obtained. From Day 28 to Day 78, restricted ewes lost 7.4% of body weight, while control ewes gained 7.5%. Maternal and fetal blood glucose concentrations were reduced in restricted versus control pregnancies. Fetuses were markedly smaller in the restricted group than in the control group. Further, restricted fetuses exhibited greater right- and left-ventricular and liver weights per unit fetal weight than control fetuses. No treatment differences were observed in any gross placentomal measurement. However, caruncular vascularity was enhanced in conceptuses from nutrient-restricted ewes but only in twin pregnancies. While these alterations in fetal/placental development may be beneficial to early fetal survival in the face of a nutrient restriction, their effects later in gestation as well as in postnatal life need further investigation.

Fetal cyclic motor activity in diabetic pregnancies: sensitivity to maternal blood glucose.

Spontaneous fetal movement in the last third of human gestation is dominated by irregular oscillations on a scale of minutes (cyclic motility, CM). The core properties of these oscillations are stable during the third trimester of gestation in normal fetuses, but disrupted by poorly controlled maternal diabetes. Here we investigated whether fetal CM is linked to short-term instabilities in maternal glucose metabolism. The fetuses of 40 mothers with type I (n = 28) or gestational (n = 12) diabetes were studied one to six times between 27 and 40 postmenstrual weeks of gestation. Fetal movement and maternal blood glucose concentration were measured during two separate periods of fetal activity in each session. Fetal CM was quantified with spectral analysis. Early in the third trimester, changes in the rate of oscillation in fetal CM between the two periods of activity were inversely related to changes in maternal blood glucose levels. Fetal CM was unrelated to concurrent maternal blood glucose levels at any point in the third trimester. The pattern of results suggests that disruption of the temporal organization of spontaneous fetal motor activity in pregnancies complicated by maternal diabetes represents an acute response to fluctuations in the metabolic environment rather than an alteration of CM development.

Metabolic effects of IGF-I in the growth retarded fetal sheep.

It has been shown that IGF-I has an anabolic effect in the normal fetus. However, there is evidence to suggest that there may be IGF-I resistance in the growth retarded fetus. Therefore, we investigated the effects of acute IGF-I infusion to chronically catheterised fetal sheep. At 128 days gestation, fetuses underwent a 4 h infusion of IGF-I (50 microg/kg/h). Three groups of animals were studied. Nine normally grown fetuses were studied as controls. Embolised animals (n=8) received microspheres into the uterine vasculature, and animals with spontaneous intra-uterine growth retardation (IUGR animals) (n=6) were fetuses found at post mortem to be spontaneously growth restricted. The effects of IGF-I infusion on feto-placental carbohydrate and protein metabolism were similar in our control group to previous similar experiments. IGF-I infusion decreased fetal blood glucose, oxygen, urea and amino-nitrogen concentrations, and inhibited placental lactate production. The same fetal blood metabolite concentrations also fell during IGF-I infusion in the embolised fetuses, but the effect on placental lactate production was not seen. The only effect of IGF-I infusion in the spontaneous IUGR animals was a fall in fetal blood amino-nitrogen concentrations. We conclude that fetal IGF-I infusion does not have the same anabolic effects in the growth retarded fetus as the normal fetus. In addition, the effects of IGF-I were different in the two growth retarded groups. Our data support previous evidence that the growth retarded fetus has altered IGF-I sensitivity, and this may vary depending on the cause, severity and duration of growth retardation.

Effects of maternal dexamethasone therapy on fetal lung development in the rhesus monkey.

A large body of evidence demonstrates that antenatal glucocorticoids can accelerate fetal lung maturation. The purpose of this study was to delineate the optimal dose of dexamethasone and to determine whether a single- or multiple-injection regimen of the same total dexamethasone dosage was more effective in accelerating pulmonary development. Pregnant rhesus monkeys were injected with varying doses of dexamethasone or vehicle as either a single-bolus injection or as four separate injections, each spaced 12 hours apart. All maternal treatments were begun exactly 72 hours prior to delivery, and all fetuses were delivered by cesarean section at 135 +/- 1 days gestation. When a single injection of dexamethasone was used, fetal liver weight increased in a dose-related fashion. Fetal and maternal cortisol and fetal blood glucose concentrations were also influenced by increasing dexamethasone dosages. Fetal pulmonary phospholipids, however, were unchanged at all steroid doses examined. Multiple injections of dexamethasone generally produced more pronounced effects, even though the total dexamethasone dose remained the same. Thus, liver weight and fetal and maternal cortisol, glucose, and insulin levels were significantly influenced by the multiple administration of dexamethasone. In addition, total lung phosphatidylcholine, surfactant phosphatidylcholine, the surfactant-phosphatidylcholine-to-total-phosphatidylcholine ratio, and the surfactant-disaturated-phosphatidylcholine-to-total-lung-disaturated- phosphatidylcholine ratio were elevated after the multiple-injection regimen. A total dose of 0.5 mg dexamethasone/kg maternal body weight given in four separate injections appeared to produce the most beneficial results. These data suggest that low-dose, antenatal glucocorticoid treatment can effectively accelerate the biochemical maturation of the fetal lung.

Fetal metabolic responses to hypoxia.

It has been known for may years that hypoxaemia in the fetus induces a number of biophysical, cardiovascular, endocrine and metabolic responses by the fetus, some of which are not sustained if the period of hypoxaemia is extended. For instance, fetal breathing and body movements and the circulating concentrations of many of the stress-related hormones return to control levels during prolonged periods of hypoxaemia. In particular, circulating fetal blood glucose concentrations gradually return to control levels, after an initial increase. The initial increase is primarily due to a catecholamine-mediated increase in glucose production from glycogen stores leading to a marked reduction in glycogen content. During prolonged periods of hypoxaemia, however, the decrease in fetal blood glucose concentrations is principally due to a decrease in the activity of the major enzymes responsible for glycogenolysis and not to a total depletion of glycogen stores. It is suggested that the decrease in enzyme activity could be due to a prostaglandin E2-mediated antagonism of catecholamine-activated glycogenolysis. In contrast, fetal blood lactate concentrations increase to a plateau after 4-5 h of hypoxaemia and remain at this elevated level for the duration of the hypoxaemia. Circulating lactate concentrations do not increase further, despite production by hypoxic tissues remaining high, due to an increase in lactate clearance by the placenta; under normal conditions the placenta releases lactate into the fetal circulation. It is considered that many of these changes are important adaptive responses which allow the fetus to survive in a sub-optimal intrauterine environment.

Maternal insulin-like growth factor-I infusion alters feto-placental carbohydrate and protein metabolism in pregnant sheep.

Insulin-like growth factor-I (IGF-I) in the maternal circulation may have a role in the regulation of placental function and fetal growth, but its mechanisms of action are not known. We studied the effects of maternal IGF-I infusion (30 micrograms/kg.h for 4 h) in eight chronically catheterized pregnant sheep. IGF-I infusion caused an increase in fetal blood glucose concentrations, but no change in placental or fetal glucose uptake. Maternal plasma insulin concentrations fell. Placental lactate production increased by 56%, with most of this lactate taken up by the fetus. Maternal and fetal blood amino nitrogen concentrations fell, but fetal protein oxidation was unchanged. IGF-I infusion did not change feto-placental oxygenation, placental blood flow, or placental transfer by simple or facilitated diffusion. The metabolic effects of maternal IGF-I infusion in part oppose those of fetal IGF-I. We hypothesize that the balance of maternal and fetal IGF-I concentrations contributes to the regulation of substrate distribution between mother, placenta and fetus, and may thus mediate the nutritional regulation of fetal growth.

Effect of ethanol on immature ovine fetal breathing movements, fetal prostaglandin E2, and myometrial activity

In the mature ovine fetus, ethanol decreases fetal breathing movements (FBM), which is temporally related to increased prostaglandin E2 (PGE2) concentration, decreases blood glucose concentration, increases blood lactate concentration, and decreases uterine electromyographic (EMG) activity. The objective of this study was to determine the effects of ethanol on these variables in the immature fetal sheep. Experiments were conducted in pregnant ewes at 85-94 days of gestation (full term 147 days) that received a 1-h maternal infusion of 1 g ethanol/kg maternal body wt (n = 9) or an equivalent volume of saline (n = 5). The maximal maternal and fetal blood ethanol concentrations for the ethanol regimen were 1.305 +/- 0.165 and 1.458 +/- 0.137 mg/ml, respectively. Maternal infusion of ethanol (or saline) did not change the incidence of FBM, fetal plasma PGE2 concentration, heart rate, blood pressure, blood gases and pH, or uterine EMG activity. Ethanol decreased (P < 0.05) fetal blood glucose concentration from 1.18 +/- 0.10 to 0.87 +/- 0.07 and 0.89 +/- 0.09 mM at 1 and 3 h, respectively, but did not alter blood lactate concentration compared with saline infusion. These data support the hypothesis that the effects of ethanol on FBM, fetal plasma PGE2 and blood lactate concentrations, and uterine EMG activity are gestational age dependent.

Insulin-like growth factor 1 alters feto-placental protein and carbohydrate metabolism in fetal sheep.

Insulin-like growth factor 1 (IGF-1) is an anabolic hormone in postnatal life and may be an important endocrine regulator of fetal growth. However, its effects on fetal metabolism in vivo have not previously been determined. We studied the effect of 50 micrograms/h.kg IGF-1 infusion in 12 chronically catheterized fetal sheep. Fetal blood amino nitrogen concentrations fell 10% and maternal 7%, consistent with a rise in feto-placental amino acid uptake. Fetal amino acid oxidation, measured by fetal urea production fell by 30% (44.4 +/- 10.5 to 30.9 +/- 8.0 mumol/min). Fetal and maternal blood glucose concentrations both fell by 0.1 mM, consistent with increased feto-placental glucose uptake. Placental lactate production fell 30% (114 +/- 15 to 78 +/- 11 mumol/min), as did fetal and uterine lactate uptake. There was no change in umbilical or uterine blood flows, nor in placental transfer by simple or facilitated diffusion. We conclude that IGF-1 has anabolic effects on feto-placental protein and carbohydrate metabolism. Circulating IGF-1 may in part mediate the regulation of fetal growth in response to fetal nutrient supply.