Conrad R. Chao

Effects of single and multiple courses of antenatal glucocorticoids in preterm newborns less than 30 weeks' gestation

BACKGROUNDnWe compared outcomes between neonates receiving either single course, multiple courses, or no antenatal glucocorticoid exposure.nnnMETHODSnWe retrospectively identified neonates whose mothers received a single course (SIN) of dexamethasone, multiple (2-3) weekly courses (MULT), or no (NO) glucocorticoids. Multiple gestations and infants with chromosomal abnormalities or not receiving a full course of antenatal dexamethasone were excluded from the study. The incidences of the following outcomes were examined: respiratory distress syndrome (RDS), Grades III or IV intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, and in-hospital death. Means were compared with analysis of variance and outcome variable frequencies with chi-square test.nnnRESULTSnA total of 147 infants were included in the analysis. There were no differences in the gestational age or growth parameters among the groups. As anticipated, infants exposed to antenatal glucocorticoids had a significantly lower incidence of morbidities (BPD, NEC, and IVH) than the unexposed infants. There were no differences in the incidence of RDS, IVH, BPD, NEC, ROP, PDA, sepsis, or death between the SIN and MULT groups.nnnCONCLUSIONnA single course of antenatal glucocorticoid therapy is associated with improved neonatal outcomes in infants less than 30 weeks gestation. Multiple courses were not shown to confer additional benefits, but further investigation is required to definitively address the need for weekly treatment.

Cardiovascular effects of cocaine during pregnancy

Cocaine administration during pregnancy results in major maternal cardiovascular effects that in some cases exceed those observed in the nonpregnant state. Animal studies have shown increases in heart rate and blood pressure and decreases in regional organ blood flow. Fetal effects include arterial hypoxemia, increases in blood pressure and heart rate, and increases in cerebral blood flow that may be related not only to hypertension and hypoxemia, but also to direct effects on cerebral blood vessels. Fetal intestinal blood flow is decreased. These effects may be related to the clinical consequences of cocaine use during pregnancy.

Anticholinergic suppression of ovine fetal swallowing activity

OBJECTIVEnFetal swallowing contributes importantly to amniotic fluid volume regulation as the primary route of fluid resorption, reaching 500 to 1000 ml/day near term. Near-term ovine fetal swallowing activity occurs predominantly during low-voltage electrocortical activity. In view of the potential to pharmacologically alter electrocortical activity, we hypothesized that fetal administration of a centrally acting cholinergic antagonist may be used to modulate fetal swallowing activity. To explore cholinergic modulation of swallowing activity, we examined fetal swallowing and electrocortical activity in response to central and peripheral cholinergic suppression by atropine sulfate.nnnSTUDY DESIGNnSingleton ovine fetuses (n = 6) were chronically prepared with vascular catheters and thyrohyoid, nuchal, and thoracic esophageal electromyogram and biparietal electrocortical electrodes. Swallowing and electrocortical activity were monitored for 2 hours before and after intravenous injection (1 ml of 0.15 mol/L sodium chloride) of atropine sulfate (1 mg/kg). On a subsequent day an identical study was performed with use off atropine methyl nitrate (3 mg/kg), an atropine analog that does not cross the blood-brain barrier.nnnRESULTSnAtropine sulfate decreased low-voltage electrocortical activity (56% +/- 5% to 14% +/- 4%), increased high-voltage electrocortical activity (40% +/- 5% to 81% +/- 5%), and did not change intermediate electrocortical activity (4% +/- 1% to 5% +/- 1%). Fetal swallowing activity decreased from 46 +/- 12 to 12 +/- 2 swallows per hour after atropine sulfate administration. Atropine methyl nitrate had no discernible effect on either fetal electrocortical or swallowing activity. Fetal arterial pressure, plasma osmolality, pH, PCO2, and PO2 did not change.nnnCONCLUSIONSnCentral cholinergic antagonism suppresses low-voltage fetal electrocortical and swallowing activity in the ovine fetus. Studies exploring spontaneous or induced fetal swallowing should consider the behavioral state of the fetus when conclusions are drawn about changes in the swallowing activity.

Nitric oxide modulates spontaneous swallowing behavior in near-term ovine fetus

Human and ovine fetuses demonstrate an enhanced rate of swallowing, an activity critical for amniotic fluid regulation. Fetal swallowing may be modulated by both systemic and central factors. Nitric oxide (NO) is a central neuromodulator that has been localized to brain regions regulating thirst and swallowing. We sought to determine if NO contributes to the regulation of spontaneous ovine fetal swallowing. Six time-dated pregnant ewes with singleton fetuses (129 ± 1 day) were chronically prepared with fetal vascular and lateral ventricle catheters and electrocorticogram (ECoG) and esophageal electromyogram electrodes. After a 2-h control period, fetuses were given lateral ventricle injection of NO synthase inhibitor nitro-l-arginine methyl ester (l-NAME) and monitored for 2 h. NO precursor l-arginine was then injected into the lateral ventricle, and fetuses were monitored for a final 2 h. All fetuses received an additional control study of fetal swallowing before and after lateral ventricle injection of artificial cerebrospinal fluid (aCSF). Data were analyzed with repeated-measures ANOVA and paired t-test ( P < 0.05). Suppression of a central NO with central l-NAME significantly reduced mean (±SE) spontaneous fetal swallowing (1.2 ± 0.1-0.6 ± 0.1 swallows/min low-voltage ECoG; P < 0.01). Restoration of central NO by l-arginine significantly increased fetal swallowing to pre-l-NAME levels (1.2 ± 0.1 swallows/min low voltage). There were no changes in fetal swallowing during the control study of aCSF. Fetal ECoG activity and blood pressure did not change during the study or control aCSF injection. We conclude that NO is an important neuromodulator of fetal swallowing activity. Central NO synthase activity may contribute to the heightened level of spontaneous fetal swallowing and thus amniotic fluid regulation.Human and ovine fetuses demonstrate an enhanced rate of swallowing, an activity critical for amniotic fluid regulation. Fetal swallowing may be modulated by both systemic and central factors. Nitric oxide (NO) is a central neuromodulator that has been localized to brain regions regulating thirst and swallowing. We sought to determine if NO contributes to the regulation of spontaneous ovine fetal swallowing. Six time-dated pregnant ewes with singleton fetuses (129 +/- 1 day) were chronically prepared with fetal vascular and lateral ventricle catheters and electrocorticogram (ECoG) and esophageal electromyogram electrodes. After a 2-h control period, fetuses were given lateral ventricle injection of NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) and monitored for 2 h. NO precursor L-arginine was then injected into the lateral ventricle, and fetuses were monitored for a final 2 h. All fetuses received an additional control study of fetal swallowing before and after lateral ventricle injection of artificial cerebrospinal fluid (aCSF). Data were analyzed with repeated-measures ANOVA and paired t-test (P < 0.05). Suppression of a central NO with central L-NAME significantly reduced mean (+/-SE) spontaneous fetal swallowing (1.2 +/- 0.1-0.6 +/- 0.1 swallows/min low-voltage ECoG; P < 0.01). Restoration of central NO by L-arginine significantly increased fetal swallowing to pre-L-NAME levels (1.2 +/- 0.1 swallows/min low voltage). There were no changes in fetal swallowing during the control study of aCSF. Fetal ECoG activity and blood pressure did not change during the study or control aCSF injection. We conclude that NO is an important neuromodulator of fetal swallowing activity. Central NO synthase activity may contribute to the heightened level of spontaneous fetal swallowing and thus amniotic fluid regulation.

Pregnancy enhances cocaine-induced stimulation of uterine contractions in the chronically instrumented rat☆☆☆★★★

OBJECTIVEnOur purpose was to test whether cocaine stimulates uterine activity in nonpregnant and pregnant rats.nnnSTUDY DESIGNnThe carotid artery and jugular vein were chronically catheterized, and a microballoon probe was inserted into the uterine cavity of 15 pregnant and 14 nonpregnant female rats. Conscious animals received a bolus dose of either cocaine or saline solution intravenously. Cardiovascular and uterine contractile responses were studied.nnnRESULTSnCocaine (2.5 mg/kg) induced a marked increase in uterine activity and arterial blood pressure in both pregnant and nonpregnant animals without producing systemic toxicity. The maximum change in uterine contractions was greater in the pregnant group than in the nonpregnant group, and blood pressure responses were transient in both.nnnCONCLUSIONnThis study is the first demonstration that cocaine stimulates the rat uterus in vivo, with a greater increase in contractions in pregnant compared with nonpregnant animals. These differences are not related to the hemodynamic response or pharmacokinetic profile of cocaine.

N-methyl-D-aspartate glutamate receptor mediates spontaneous and angiotensin II-stimulated ovine fetal swallowing

Background: In adult rats N-methyl-D-aspartate (NMDA) receptors have been implicated in the central control of body fluid homeostasis, as intracerebroventricular (ICV) injection of NMDA receptor antagonists suppresses stimulated drinking behavior. Fetal swallowing occurs at a significantly higher rate as compared to adult drinking, contributing to amniotic fluid volume regulation and fetal gastrointestinal development. The aim of present study was to determine the role of central NMDA receptors in the modulation of fetal swallowing activity. Methods: Eight time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and ICV catheters, electrocorticogram (ECoG), and esophageal electromyogram electrodes and studied at 130 ± 1 days gestation. Following an initial 2-hour baseline period (time 2h), the NMDA receptor antagonist, dizocipline (1 mg), was injected ICV. At time 4h, the dose of dizocipline was repeated, together with angiotensin II (AngII, 6.5 μg). Fetal swallowing was monitored for 2 hours after each injection. Four of these fetuses also received an identical control study (on an alternate day) in which dizocipline was replaced with artificial cerebrospinal fluid (aCSF). Results: ICV dizocipline injection nearly abolished spontaneous fetal swallowing activities (0.6 ± 0.1 to 0.2 ± 0.1 swallous/min; P < .001). ICV AngII in the presence of dizocipline did not demonstrate a dipsogenic effect on fetal swallowing (0.1 ± 0.1; P < .001) In the control study, ICV injection of aCSF did not change fetal swallowing activity (1.0 ± 0.1 swallows/min), while ICV AngII resulted in a significant increase inf etal swallowing (2.0 ± 0.1 swallows/min; P < .001). Conclusions: This study demonstrates that central NMDA-glutamate receptor-mediated activity contributes to the high rate of spontaneous and AngII-stimulated fetal swallowing. We speculate that reduced NMDA receptor expression within the forebrain dispogenic neurons may account for observed differences in drinking activities between the fetus/neonate and the adult.

Influence of fetal to neonatal transition on nitric oxide synthase expression in the nucleus tractus solitarius in sheep.

Transition from fetal to newborn life is accompanied by a marked rise in circulating norepinephrine (NE) concentrations though arterial blood pressure does not substantively change. Nitric oxide (NO) plays an important role in the central regulation of sympathetic tone in the nucleus tractus solitarius (NTS) and neuronal NO synthase (nNOS) expression is functionally regulated in the brain. The purpose of these studies was to determine the influence of transition at birth on nNOS expression in the brainstem nuclei, particularly in the NTS, associated with changes in arterial pressure and plasma NE concentration. Experiments were performed using time-dated gestational ewes with twin fetuses. Arterial blood pressure was recorded and arterial blood NE concentrations were measured in the term fetus (gestational 147-148 days) and newborn lambs (4 h of postnatal age). The fetal and newborn animals were then perfused with 4% paraformaldehyde. Sections of the medulla were examined by using both immunolabeling with a polyclonal antibody directed against nNOS and nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry, a marker for expression of nNOS. Micrographs were quantified using a microscope with reticule grid to measure the number of positive cells containing color staining in the brainstem nuclei. Plasma NE concentration in the newborn was more than two-fold greater compared to fetal values but mean arterial blood pressure was similar between fetus and newborn. The nNOS positive cells and NADPHd positive cells were significantly increased in the medial NTS (mNTS) of the newborn compared to fetus. nNOS immunoreactivity and NADPHd reactivity tended to increase in the rostral ventral medulla (RVM) in newborn, but were not altered in other brainstem nuclei during the transition from fetal to newborn life. The results suggest that nNOS expression in the mNTS is predominately enhanced at 4 h of neonatal age vs. the term fetus. We conclude that elevated circulating NE is associated with up-regulation of nNOS in the mNTS which may serve a protective role in central regulation of neonatal arterial blood pressure.