Incidence Of Fetal Breathing Movements Research Articles

Brief hypoxia in late gestation sheep causes prolonged disruption of fetal electrographic, breathing behaviours and can result in early labour.

Brief episodes of severe fetal hypoxia can arise in late gestation as a result of interruption of normal umbilical blood flow Systemic parameters and blood chemistry indicate complete recovery within 1-2 hours, although the long-term effects on fetal brain functions are unknown Fetal sheep were subjected to umbilical cord occlusion (UCO) for 10 min at 131 days of gestation, and then monitored intensively until onset of labour or delivery (<145 days of gestation) Normal patterns of fetal behaviour, including breathing movements, episodes of high and low voltage electorcortical activity, eye movements and postural (neck) muscle activity, were disrupted for 3-10days after the UCO Preterm labour and delivery occurred in a significant number of the pregnancies after UCO compared to the control (sham-UCO) cohort. Complications arising from antepartum events such as impaired umbilical blood flow can cause significant fetal hypoxia. These complications can be unpredictable, as well as difficult to detect, and thus we lack a detailed understanding of the (patho)physiological changes that occur between the antenatal in utero event and birth. In the present study, we assessed the consequences of brief (∼10min) umbilical cord occlusion (UCO) in fetal sheep at ∼0.88 gestation on fetal plasma cortisol concentrations and fetal behaviour [electrocortical (EcoG), electo-oculargram (EOG), nuchal muscle electromyography (EMG) and breathing activities] in the days following UCO. UCO caused a rapid onset of fetal hypoxaemia, hypercapnia, and acidosis; however, by 6h, all blood parameters and cardiovascular status were normalized and not different from the control (Sham-UCO) cohort. Subsequently, the incidence of fetal breathing movements decreased compared to the control group, and abnormal behavioural patterns developed over the days following UCO and leading up to the onset of labour, which included increased high voltage and sub-low voltage ECoG and EOG activities, as well as decreased nuchal EMG activity. Fetuses subjected to UCO went into labour 7.9±3.6 days post-UCO (139.5±3.2 days of gestation) compared to the control group fetuses at 13.6±3.3 days post-sham UCO (144±2.2 days of gestation; P < 0.05), despite comparable increases in fetal plasma cortisol and a similar body weight at birth. Thus, a single transient episode of complete UCO late in gestation in fetal sheep can result in prolonged effects on fetal brain activity and premature labour, suggesting persisting effects on fetal cerebral metabolism.

Pulmonary feedback and gestational age-dependent regulation of fetal breathing movements

Prenatal lung development requires fetal breathing movements (FBM). To investigate the dependence of FBM on feedback originating from the lung, we hypothesized that pneumonectomy stimulates FBM. Time-dated fetal sheep underwent bilateral pneumonectomy, unilateral pneumonectomy, or sham surgery at 125-130 days gestation. The incidence of FBM decreased in sham-operated fetuses at 142 days versus 130 days (p = 0.013), but was unchanged across all gestational ages in bilaterally pneumonectomized fetuses (p > or = 0.52). In unilaterally pneumonectomized fetuses, the incidence of FBM remained unchanged until 139 days and was higher than that of the bilaterally pneumonectomized fetuses at 130-136 days gestation (p < or = 0.03). The amplitude of integrated diaphragmatic electromyographic activity (integralEMG(di)) and total respiratory output (frequency of breathing x integralEMG(di)) were lower in pneumonectomized fetuses versus sham-operated fetuses at later gestational ages (p < 0.05). These decreases in integralEMG(di) and total respiratory output were most pronounced at 142 days in bilaterally pneumonectomized fetuses versus sham-operated fetuses (p = 0.006 and 0.016, respectively). Low-voltage electrocortical activity (ECoG) increased, and high-voltage ECoG decreased, in unilaterally pneumonectomized fetuses compared with sham-operated fetuses (p = 0.04). In conclusion, we provide new evidence that feedback from the fetal lung modulates the incidence and various components of phrenic nerve output, suggesting a positive feedback mechanism between FBM and lung development.

The effect of magnesium sulfate on the behavioral activities of fetal goats.

To investigate fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during administration of magnesium sulfate to fetal goats. The fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during 6 hours of continuous magnesium sulfate infusion into the fetal jugular vein were examined in 8 chronically instrumented fetal goats at 124-131 days of gestation. Fetal breathing movements were defined as repetitive negative fluctuations of the fetal tracheal pressure. Fetal electrocortical activities were assessed by visual analysis of periods of high-voltage and low-voltage electrocortical activities. Continuous infusion of magnesium sulfate for 6 hours significantly increased the fetal plasma magnesium concentration from 2.8 +/- 1.2 to 8.3 +/- 2.6 mg/dL without significant changes in fetal arterial blood gases. The incidence of fetal heart rate accelerations during magnesium infusion was significantly decreased from that found during the control periods. After 2 hours of infusion, the incidence of fetal breathing movements significantly decreased from 33.9% +/- 20.5% to 1.2% +/- 1.4% and remained at this level during the remaining 4 hours of magnesium infusion. The percentage of time that the fetuses were found to have low-voltage electrocortical activities decreased from 51.6% +/- 9.0% to 40.4% +/- 8.2% after 2 hours of infusion but recovered to 49.9% +/- 12.0% by 6 hours of magnesium infusion. We concluded that fetal magnesium sulfate administration affected fetal heart rate accelerations and fetal breathing movements continuously but electrocortical activities only temporarily during 6 hours of observations.

The effect of methadone treatment on the quantity and quality of human fetal movement

Objective: To evaluate the effect of daily maternal methadone maintenance treatment on the quality and quantity of fetal movement. Methods: At 34–37 weeks gestation, real-time ultrasound recordings were obtained from 17 methadone treated and 17 non-opioid-dependent mothers at two time points relative to the methadone mothers' daily dose of methadone. The first observation was just prior to the mother taking her daily dose (Time A) and the second was 1-h postdose (Time B). The incidence and pattern of fetal breathing movements (FBMs), fetal trunk movements (FTMs) and total fetal activity (TFA) were obtained from these ultrasounds. Results: A time by group effect was found for measures of FBM and TFA, Fs(1,32)=6.06 and 4.94, P<0.05. At Time A and Time B for these measures t-tests showed no difference in the incidence of FBM (47.9% vs. 55.4%) and TFA (56% vs. 64%) at Time A between the methadone and comparison groups; however, at Time B the incidence of FBM (16.6% vs. 53.5%) and TFA (27% vs. 65%) was decreased for the methadone group. In addition, there was a between-group difference for two qualitative measures of fetal breathing. A slower rate of fetal breathing (40.3 vs. 47.2 breaths/min) and fewer FBMs per breathing episode (51.7 vs. 92.4) were found for the methadone group regardless of time since the mothers' daily dose. Conclusion: Taken together these results suggest that daily maternal methadone maintenance treatment altered both quantitative and qualitative measures of fetal activity that have been found to be related to normal fetal development.

Effect of intermittent umbilical cord occlusion on fetal respiratory activity and brain adenosine in late-gestation sheep.

It was hypothesized that intermittent umbilical cord occlusion (UCO) would inhibit ovine fetal breathing movements (FBM) in association with increased cerebral adenosine levels. To test this hypothesis, on two successive days during late gestation (133-134 days; term = 146 days), microdialysis samples were collected from the brains of 10 chronically instrumented fetal sheep during 2-h periods of complete UCO induced every 30 min (Day 1: 2-min UCOs; Day 2: 4-min UCOs). Control fetuses (n = 10) underwent no UCO. Tracheal pressure was measured throughout. This regimen resulted in a decrease in fetal arterial PO2 (PaO2) during each UCO to 7.3 +/- 0.8 mmHg (P<0.01; Day 1) and 8.4 +/- 1.1 mmHg (P<0.01; Day 2). Throughout each UCO period, fetal arterial pH (pHa) decreased to 7.28 +/- 0.02 (P<0.01; Day 1) and 7.11 +/- 0.07 (P<0.01; Day 2). The hourly incidence of FBM decreased significantly only on Day 2, from 38.6 +/- 4.1% to 4.1 +/- 1.6% (P<0.01). The frequency of deep isolated inspiratory efforts increased from 4.7 +/- 2.0 h(-1) to 17.6 +/- 6.1 h(-1) (P<0.05; Day 1) and from 2.2 +/- 0.9 h(-1) to 33.6 +/- 4 h(-1) (P<0.01; Day 2). The amplitude of both FBM and deep isolated inspiratory efforts increased during the UCO periods on both days. The concentration of cerebral extracellular fluid (ECF) adenosine during UCO increased by 219 +/- 215% (P<0.05; Day 1) and 172 +/- 107% (P<0.05; Day 2) over the baseline periods. In conclusion, the severity of the inhibitory effect of repeated UCO on FBM depends, in part, on the length of the occlusions. The inhibition of FBM during intermittent UCO may be mediated by the increase in ECF adenosine in the fetal brain. Furthermore, FBM and deep isolated inspiratory efforts appear to be regulated by different mechanisms.

Fetal behavioural state changes following maternal fluoxetine infusion in sheep

Clinical depression is diagnosed in 5–15% of women during pregnancy, increasing the risk of negative outcomes. Fluoxetine (FX), a selective serotonin reuptake inhibitor, is prescribed during pregnancy. In adults, FX alters sleep patterns with single doses decreasing total sleep time and rapid eye movement sleep. The effects of FX on sleep in the fetus are unknown. However, 5-hydroxytryptophan, the precursor of serotonin, has been reported to prolong high-voltage (HV) electrocortical (ECoG) activity and increase the incidence of fetal breathing movements (FBM) in the sheep fetus. We hypothesize that FX exposure will decrease the incidence of LV ECoG in the fetus. Twenty-one pregnant sheep were surgically prepared for chronic study of blood gases, ECoG activity, eye movements and FBM. After 3 days of recovery, ewes received a 70-mg bolus i.v. infusion of FX or sterile water followed by continuous infusion at a rate of 0.036 mg/min for 8 days. The incidence of low-voltage (LV) ECoG decreased from 54±4% on the preinfusion day to 45±5% on infusion day 1 in the FX group and remained decreased throughout the infusion period. In addition, the incidence of both eye movements and FBM was decreased on infusion day 1 compared to preinfusion day in the FX group. HV ECoG increased from 39±3% on preinfusion day to 68±14% on FX infusion day 1 and remained elevated throughout the infusion period. These data show that maternal FX administration alters fetal behavioural state.

The adenosine A(1)-receptor antagonist 8-CPT reverses ethanol-induced inhibition of fetal breathing movements.

Administration of either ethanol or adenosine inhibits fetal breathing movements (FBM), eye movements, and low-voltage electrocortical activity (LV ECoG). The concentration of adenosine in ovine fetal cerebral extracellular fluid increases during ethanol-induced inhibition of FBM. The purpose of this study was to determine the effect of a selective adenosine A(1)-receptor antagonist, 8-cyclopentyltheophylline (8-CPT) on the incidence of FBM during ethanol exposure. After a 2-h control period, seven pregnant ewes received a 1-h intravenous infusion of ethanol (1 g/kg maternal body wt), followed 1 h later by a 2-h fetal intravenous infusion of either 8-CPT (3.78 +/- 0.08 microg. kg(-1). min(-1)) or vehicle. Ethanol reduced the incidence of FBM from 44.0 +/- 10.4 to 2.7 +/- 1.3% (P < 0.05) and 51.2 +/- 7.6 to 11.9 +/- 5.0% (P < 0.05) in fetuses destined to receive 8-CPT or vehicle, respectively. In the vehicle group, FBM remained suppressed for 7 h. In contrast, during the first hour of 8-CPT infusion, FBM returned to baseline (31 +/- 11%) and was not different from control throughout the rest of the experiment. Ethanol also decreased the incidence of both low-voltage electrocortical activity and eye movements, but there were no differences in the incidences of these behavioral parameters between the 8-CPT and vehicle groups throughout the experiment. These data are consistent with the hypothesis that adenosine, acting via A(1) receptors, may play a role in the mechanism of ethanol-induced inhibition of FBM.

Temporal changes in fetal cardiovascular, behavioural, metabolic and endocrine responses to maternally administered dexamethasone in the late gestation fetal sheep.

To determine the primary (0-12 h) and secondary (12-24 h) effects of dexamethasone on fetal heart rate, short term heart rate variation, blood pressure, breathing movements and electrocortical activity, blood gas exchange, metabolism and adrenocortical function in the late gestation sheep fetus. Comparison of the effects of a single maternally administered intramuscular injection of dexamethasone (12 mg) with those of saline vehicle from 1 h before injection to 24 h post-injection. Fetal cardiovascular and behavioural parameters were recorded continuously. Fetal and maternal blood samples were taken at regular intervals for blood gas, glucose and lactate, cortisol and adrenocorticotrophin measurements. Sixteen chronically instrumented singleton fetal sheep at 127-133 days of gestation (term is about 147 days). During the primary phase short term heart rate variation fell (P < 0.001), and this was associated with a transient fall in the incidence of fetal breathing movements, a fall in fetal heart rate and a rise in fetal blood pressure. By 12 h there was a significant increase in short term heart rate variation (P < 0.001) and a rise in fetal heart rate, but blood pressure and fetal breathing movements had returned to normal. Dexamethasone significantly reduced fetal PaO2 throughout most of the experimental period, particularly 1 h post-injection (P < 0.005). Fetal and maternal plasma cortisol and adrenocorticotrophin concentrations fell significantly from 1 h post-injection. The effects of dexamethasone on fetal heart rate variation are more complex than previously described with both a fall and an increase observed depending on the time at which heart rate variation was measured after injection. Dexamethasone also caused a significant fall in fetal PaO2, and although this was not to hypoxic levels in normoxic fetuses it does raise questions about the potential impact of dexamethasone on chronically hypoxic fetuses.

Effects of pregnanolone on behavioural parameters and the responses to GABA A receptor antagonists in the late gestation fetal sheep

Placental progesterone metabolites may suppress fetal behaviour by interacting with GABA A receptors. In an initial study, the effect of 5 β-pregnan-3 α-ol-20-one (pregnanolone) given as a bolus (2.5 and 5.0 mg) or infused at a rate of 25 mg/h was investigated in unanaesthetized, catheterized fetal sheep, 127–135 days gestation. The incidence of fetal breathing movements (FBM) and behavioural arousal activity, defined as nuchal muscle electromyographic (EMG) activity during low voltage electrocortical (LV ECoG) activity were suppressed by pregnanolone administered as a bolus, while the pregnanolone infusion produced a significant decrease in arousal and EOG activity, and an increase in the presence of HV ECoG. The effect of pregnanolone on fetal behaviour and arousal induced by the GABA A antagonist picrotoxin was also investigated. Picrotoxin was given as a bolus (≈300 μg/kg) and pregnanolone was subsequently administered as a bolus (5.0 mg), and behavioural parameters were recorded and analysed. The incidence of arousal and FBM were 1.1±1.6 min/10 min and 2.5±2.3 min/10 min, respectively, before picrotoxin treatment and increased during the 10–20 and 20–30 min epochs after picrotoxin treatment (arousal: 5.0±2.2 and 6.5±3.6 min/10 min, respectively, n=6, P<0.05; FBM: 7.3±3.2 and 9.3±1.2 min/10 min, respectively, n=6, P<0.05.). The picrotoxin-induced increases in arousal and FBM were significantly suppressed ( n=6, P<0.05) by pregnanolone treatment to 1.6±1.5 min/10 min and 4.6±2.3 min/10 min, respectively. We conclude that; (i) the GABA A active steroid pregnanolone suppresses basal and picrotoxin-induced fetal arousal and FBM; and (ii) steroid sensitive GABA A receptors may regulate fetal behaviour and breathing.

Effects of Antenatal Thyrotropin-Releasing Hormone on Fetal Heart Rate and Breathing Movements

Objective: To determine the effect of maternally administered thyrotropin-releasing hormone (TRH) on fetal heart rate (FHR) pattern and fetal breathing movements (FBM). Methods: Prospective observational study of 75 pregnant women between 26 and 34 weeks’ gestation in whom pharmacological fetal lung maturation was clinically indicated. Forty-minute recordings were made of FBM or FHR patterns before and after drug administration. Twenty-five received TRH 400 µg as an intravenous bolus, 25 TRH 400 µg in 50 ml 0.9% saline as an intraveous infusion, and 25 acted as controls. Recordings were processed digitally to calculate the change in FHR (n = 45) and FBM parameters (n = 30). The main outcome measures for FHR were number of accelerations and decelerations, baseline rate, overall and short-term variation and duration of high and low variability, while for FBM they were rate, breath-to-breath interval and incidence. Results between groups were compared by analysis of variance. Results: There was no significant change in FHR, accelerations or variation in any of the groups. Similarly, there was no change in the incidence of FBM. TRH administered as a bolus produced a small statistically but not clinically significant increase in breathing rate (mean Δ = 35 breaths/h, p = 0.004), which was not seen in the TRH infusion and control groups. Conclusions: Maternally administered TRH as used to enhance fetal lung maturation has no clinically significant direct effect on FHR or FBM patterns.

Effect of arginine vasopressin on breathing movements of chronically instrumented fetal lambs.

In hypoxic conditions, fetal breathing movements (FBM) are reportedly inhibited with simultaneous elevation of the plasma level of catecholamines and arginine vasopressin (AVP). Although some kinds of catecholamines are reported to inhibit FBM, the effects of AVP on FBM are still unknown. The present study was undertaken to elucidate whether or not AVP has an inhibitory effect on FBM and electrocortical activities in chronically instrumented fetal lambs. Arginine vasopressin was injected slowly into the fetal external jugular vein via a catheter over a 30 minute period at an infusion rate of 4.9 approximately 10.0 mIU/minute/body. In 15 fetuses (36 estimations) the mean fetal age, mean estimated fetal body weight, and mean infusion dose were 132.4 +/- 4.5 days, 3.4 +/- 0.3 kg and 1.7 +/- 0.3 mIU/kg/min. The infusion caused a persistent decrease in the fetal heart rate and an increase in the fetal arterial pressure during the 30 minute period. The infusion of AVP resulted in a significant decrease in the incidence of FBM from 36.1 +/- 14.8% to 12.4 +/- 14.9% (p <0.01). However, there were no significant differences in the incidence of the low voltage fast (LVF) activity before and during infusion of AVP. AVP has an inhibitory effect on FBM. The mechanism of this inhibition was not a direct suppression of the CNS as there was a dissociation between FBM and the electrocortical activity during infusion of AVP.

The effect of hypercapnia and hypercapnia associated with central cooling on breathing in unanesthetized fetal lambs.

In utero breathing activity is present periodically, but it must become continuous at birth. We investigated the effect of hypercapnia and of hypercapnia combined with central cooling on fetal breathing in seven chronically instrumented fetal lambs of 131-134-d gestation, using an extracorporeal membrane oxygenation (ECMO) system to control fetal blood gases and fetal temperature. During fetal hypercapnia (from a partial pressure of arterial CO2 (Paco2) 6.18 +/- 0.11 kPa to Paco2 7.39 +/- 0.15 kPa) frequency, amplitude, and incidence of fetal breathing movements during low voltage electrocortical activity (LV ECoG) increased significantly compared with isocapnic control on ECMO, but breathing remained absent during high voltage electrocortical activity (HV ECoG). During hypercapnia accompanied by central cooling (Paco2 7.90 +/- 0.13 kPa, temperature decreased by 2.1 degrees C) there were similar changes in fetal breathing movements during LV ECoG, but in four out of seven fetuses fetal breathing movements continued throughout HV ECoG. Hypercapnia accompanied by central cooling can thus override the inhibitory effects of HV ECoG on fetal breathing movements. This may be due to changes in sensitivity to CO2 produced by an increase in afferent input to the CNS.

Maternal theophylline administration and breathing movements in late-gestation human fetuses

To investigate the relation between maternal administration of theophylline and breathing movements during late gestation in human fetuses. After a 1-hour control period, 17 women with normally grown fetuses at 33-38 weeks' gestation were given 400 mg of sustained-release theophylline orally. Maternal plasma theophylline and glucose concentrations were measured every hour, and the incidence of fetal breathing movements and breathing rates were measured continuously during the next 8 hours. Results were compared with those of a similar control group that did not receive theophylline. The maternal plasma theophylline concentration increased to detectable levels after 1 hour, reached therapeutic levels of 6.9 +/- 0.4 micrograms/mL (standard error of the mean) after 6 hours, and thereafter averaged 8.3 +/- 0.3 micrograms/mL, significantly higher than initial control values (P < .05). The mean glucose concentration was unchanged during the first 6 hours (79.2 +/- 1.1 mg/dL) and then decreased somewhat, averaging 75.8 +/- 1.1 mg/dL in the 7-8 hour period. The incidence of fetal breathing increased 26.4 +/- 1.9% after 5 hours and remained elevated during the next 3 hours at levels significantly higher than in the initial control period (P < .05) and higher than in the control group that did not receive theophylline. The mean hourly breathing rate averaged 40.9 +/- 1.3 breaths per minute after ingestion of theophylline, a nonsignificant change. Ingestion of theophylline by pregnant women in late gestation is associated with an increase in fetal breathing movements. Theophylline has been used widely in the management of asthma in pregnancy, and the assessment of fetal breathing movements is used routinely for evaluation of fetal status. Therefore, account must be taken of changes in breathing movements caused by maternal theophylline administration.

Fetal breathing is not inhibited by ethanol exposure during prolonged reduced uterine blood flow

When prolonged hypoxemia is induced in fetal sheep by reducing uterine blood flow, fetal breathing movements (FBM) return to normal incidence after their initial decrease. Ethanol also inhibits FBM. These experiments were designed to determine the role of fetal oxygenation status in affecting ethanol-induced inhibition of FBM. A 1-h maternal infusion of 1 g ethanol/kg maternal body weight was given to animals following 20 h of reduced uterine blood flow (RUBF; n = 9), as well as to normoxemic (n = 9) fetal sheep, and the effect on FBM, electrocortical activity (ECoG), and electroocular activity (EOG) was determined. In normoxemic fetuses, the incidence of FBM decreased from 26.1 +/- 5.5% to 2.8 +/- 1.6% (p < 0.05) with ethanol, subsequently returning to baseline values over 6 h, but there was no effect of ethanol on FBM incidence in RUBF fetuses (32.8 +/- 9.1%). Ethanol increased the incidence of intermediate ECoG from 16.6 +/- 2.9% to 49.0 +/- 9.8% (p < 0.01) in normoxemic fetuses, but there was no change in RUBF fetuses. We conclude that the adaptive mechanism(s) invoked by fetal sheep during prolonged RUBF abolishes its ability to respond behaviourally to ethanol.

Fetal breathing is not inhibited by ethanol exposure during prolonged reduced uterine blood flow

When prolonged hypoxemia is induced in fetal sheep by reducing uterine blood flow, fetal breathing movements (FBM) return to normal incidence after their initial decrease. Ethanol also inhibits FBM. These experiments were designed to determine the role of fetal oxygenation status in affecting ethanol-induced inhibition of FBM. A 1-h maternal infusion of 1 g ethanol/kg maternal body weight was given to animals following 20 h of reduced uterine blood flow (RUBF; n = 9), as well as to normoxemic (n = 9) fetal sheep, and the effect on FBM, electrocortical activity (ECoG), and electroocular activity (EOG) was determined. In normoxemic fetuses, the incidence of FBM decreased from 26.1 +/- 5.5% to 2.8 +/- 1.6% (p < 0.05) with ethanol, subsequently returning to baseline values over 6 h, but there was no effect of ethanol on FBM incidence in RUBF fetuses (32.8 +/- 9.1%). Ethanol increased the incidence of intermediate ECoG from 16.6 +/- 2.9% to 49.0 +/- 9.8% (p < 0.01) in normoxemic fetuses, but there was no change in RUBF fetuses. We conclude that the adaptive mechanism(s) invoked by fetal sheep during prolonged RUBF abolishes its ability to respond behaviourally to ethanol.

Fetal breathing movements in late diabetic pregnancy: relationship to fetal heart rate patterns and Braxton Hicks' contractions.

In type-1 diabetic pregnancy, the occurrence of fetal breathing movements (FBM) was studied in relation to the fetal heart rate patterns (HRPs) A and B and to Braxton Hicks' contractions. Simultaneous 2-h recordings of fetal heart rate and body, eye and breathing movements were available for analysis (n = 44). These recordings were made in 20 fetuses of diabetic women at 32-38 weeks of gestation. Uterine activity was monitored at 36 and 38 weeks. For all recordings combined, the median incidences of FBM during HRPs A and B were 23% and 41%, respectively (NS). At low overall breathing activity (< 50% of total observation time), FBM were more numerous during HRP B than during HRP A in 83% of the recordings. However, if the overall breathing activity exceeded 50% of time FBM were preferentially made during HRP A in 93% of the recordings. This relationship was most pronounced at 38 weeks. These results corroborate our previous findings in the healthy near-term fetus. They show even more clearly that the state-dependent occurrence of FBM depends on the fetus' drive to breathe. During the recordings, breathing activity remained unchanged at all gestational ages studied, in contrast to the gradual decline in FBM seen in normal pregnancy. Braxton Hicks's contractions had no effect on FBM, which differs from the specific distribution of FBM during uterine contractions as previously found in uncomplicated pregnancies. We conclude that FBM in late diabetic pregnancy are not influenced by Braxton Hicks' contractions and that they do not show a clear-cut state-dependency. The (neural) mechanism underlying FBM differs from that in normal pregnancy.

Alpha 1‐ and alpha 2‐adrenoreceptor actions of phentolamine and prazosin on breathing movements in fetal sheep in utero.

1. We studied the effects of systemic administration of the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine and the selective alpha 1-adrenoreceptor antagonist prazosin on fetal breathing movements (FBM) and electrocortical activity (ECoG) in fetal sheep. In one group of fetuses (group I; n = 7) the effects of phentolamine were measured during normoxia and hypoxia. In the second group of fetuses (group II; n = 8) the effects of either phentolamine, or combined phentolamine and prazosin, or prazosin alone, were measured during normoxia. 2. In group I fetuses, the incidence of FBM increased after phentolamine treatment. An increase in the incidence and mean episode duration of low-voltage ECoG (LV-ECoG) was also measured after phentolamine treatment. These effects of phentolamine persisted during hypoxia. 3. In group II fetuses a pronounced decrease in the incidence of FBM occurred after administration of prazosin following either phentolamine or saline pretreatment. These effects of prazosin on FBM were independent of an effect on ECoG activity. 4. We conclude that catecholamines have a stimulatory role on FBM mediated via an alpha 1-adrenoreceptor mechanism. Phentolamine leads to an increase in FBM by preferentially antagonizing presynaptic alpha 2-adrenoreceptors over postsynaptic alpha 1-adrenoreceptors. This influence of phentolamine on FBM may be secondary to its effect on ECoG. Promotion of LV-ECoG by catecholamines is mediated via an alpha 1-independent mechanism.

Effect of inhibition of prostaglandin synthesis on breathing movements and pulmonary blood flow in fetal sheep

During transition from fetal to extrauterine life, respiration increases in incidence and magnitude as pulmonary blood flow dramatically increases. To determine whether alterations in pulmonary blood flow in utero are directly related to alterations in fetal breathing movements (FBM), we studied six chronically instrumented fetal sheep late in gestation to assess the effects of continuous FBM caused by a 4-h infusion of meclofenamate, a prostaglandin synthase inhibitor, on mean pulmonary blood flow to the fetus. We found a striking increase in FBM from 46 +/- 15% (SD) of the time during control to > 85% of the time by 1 h (P < 0.001), with the fetuses exhibiting continuous FBM by the last 1 h of infusion. The mean pulmonary blood flow also increased significantly during the first 90 min of the infusion as the incidences of FBM were increasing (26 +/- 14 and 56 +/- 23 ml.min-1.kg-1 for control and infusion, respectively; P < 0.01). Despite the simultaneous initial increase in FBM and mean pulmonary blood flow, the increase in left pulmonary artery blood flow was not sustained and decreased back to baseline by 2 h, even though the incidence of FBM continued to increase at this time. During the infusion, the mean pulmonary blood flow was not different between the presence or absence of FBM. There were no changes in fetal heart rate or pulmonary or systemic blood pressures during the infusion nor in arterial pH or blood gas tensions. We conclude that this increase in mean pulmonary blood flow in utero was not solely related to the increase in breathing movements.

Hypoxic inhibition of breathing in fetal sheep: relationship to brain adenosine concentrations

Because hypoxic inhibition of fetal breathing may be caused by a rise in central adenosine levels, the effects of O2 deficiency on fetal brain adenosine concentrations were determined at levels of hypoxia that inhibited fetal breathing. Under halothane anesthesia, the brains of fetal sheep (0.8 term) were implanted with guide cannulas exteriorized through a Silastic rubber window in the uterus and flank of the ewe. At least 4 days after surgery, a microdialysis probe was inserted into a cannula with the membrane tip placed in the rostral brain stem. During 1 h of isocapnic hypoxia, mean fetal arterial PO2 was reduced from 24.0 +/- 0.9 Torr (control) to 13 +/- 0.6 Torr and arterial pH fell progressively from 7.354 +/- 0.007 to 7.273 +/- 0.023. Hypoxia decreased the incidence of fetal breathing movements from 33 +/- 5.2 to 5 +/- 2.2 min/h, with a normal incidence (29 +/- 3.5 min/h) during the hour after arterial PO2 returned to control values. Adenosine concentrations in microdialysis perfusate under control conditions averaged approximately 35 nM, increased up to 2.3-fold during the hour of O2 deficiency, and fell toward control values when normoxia was restored. We conclude that fetal brain adenosine levels are increased at levels of O2 deficiency that inhibit fetal breathing, which are results consistent with a role for adenosine in hypoxic inhibition of fetal breathing.

Relationship between plasma adenosine concentration and breathing movements in growth-retarded fetuses

The purpose of this study was to investigate the relationship between plasma adenosine concentration and breathing movements in growth-retarded fetuses. We measured the incidence of fetal breathing movements and breathing rate immediately before cordocentesis in 26 growth-retarded fetuses at 31 to 38 weeks' gestation. Blood retrieved by cordocentesis was then analyzed for umbilical venous plasma adenosine concentration, blood gases, and pH. In growth-retarded fetuses with hypoxia and acidosis plasma adenosine concentration was elevated and the incidence of fetal breathing movements was reduced. The change in plasma adenosine concentration correlated inversely and significantly with the incidence of fetal breathing movements. Decreased breathing movements correlate with elevated plasma adenosine concentration in fetuses. We postulate that the enhanced adenosine formation in growth-retarded fetuses may modulate the inhibition of fetal breathing movements.