Denervation of peripheral chemoreceptors decreases breathing movements in fetal sheep

The role of the peripheral chemoreceptors in the control of fetal breathing movements has not been fully defined. To determine whether denervation of the peripheral chemoreceptors affects fetal breathing movements, we studied 14 chronically catheterized fetal sheep from 120 to 138 days of gestation. In seven fetuses the chemoreceptors were denervated by bilateral section of the vagus and carotid sinus nerves; in seven others, sham operations were performed. We compared several variables during two study periods: 0-5 and 6-13 days after operation. In the denervated fetuses there were significant decreases in the incidence and amplitude of fetal breathing movements during both study periods. There were no differences between the two groups in incidence of low-voltage electrocortical activity, arterial pH and blood gas tensions, fetal heart rate, mean arterial blood pressure, or duration of survival after operation or birth weight. We conclude that denervation of the peripheral chemoreceptors decreases fetal breathing movements. These results indicate that the peripheral chemoreceptors are active during fetal life and participate in the control of fetal breathing movements.     

Influence of Doppler ultrasound on fetal activity.

A randomised and double blind study of 100 subjects and 50 controls was performed to confirm or refute a report from Cardiff in 1975 that continuous Doppler ultrasound, as used in fetal heart rate monitoring, increases fetal movement by over 90%. The results showed such an effect to be most unlikely (power greater than 0.99). A total of 150 pregnant mothers recorded fetal movements for 30 minutes while connected to a specially modified cardiotocograph, the ultrasound being switched on at random for either the first or second 15 minutes in 100 of the patients. The mean difference in 15 minute movement count, with and without ultrasound, among the 100 patients was 0.2 of a movement (SD 12.7; p greater than 0.6 by two tailed Wilcoxon matched pairs signed ranks test). The control group showed a mean difference of 2.6 movements (SD 12.1; p greater than 0.2). Results of a pilot study suggested that the observations in the earlier report may have been influenced by mechanisms unrelated to ultrasound.     

Power spectrum analysis of fetal heart rate variability using the abdominal maternal electrocardiogram

A signal analysis procedure is described for obtaining the power spectrum of the fetal and maternal heart rates as recorded from the abdomen. This technique, which includes the subtraction of an averaged maternal ECG waveform using a cross-correlation function and the fast Fourier transform algorithm, enables the detection of all the fetal QRS complexes in spite of their coincidence with the maternal ECGs. The power spectrum of the fetal heart rates (FHR) obtained from 15 women at 32–41 weeks gestation were studied and two indices were measured which are related to the long term and short term variabilities in the FHR signal. It was found that quantitative evaluation of the FHR variability can be obtained using power spectrum analysis.     

Computer analysis of antepartum fetal heart rate: 1. Baseline determination

A consequent and reproducible determination of baseline is an essential prerequisite for objective interpretation of fetal heart rate. A fully automated off-line method of baseline determination has been developed and tested on 50 normal antepartum fetal heart rate recordings of two hours duration. The method is constructed around two functional units, a digital filter and a trim function, which interact in an iterative process. The results were evaluated in comparison with automated baseline determination according to Dawes and coworkers. A panel of 3 experts agreed that in 14 of the 50 recordings (28%), the new developed procedure resulted in a substantially better baseline fit. In the remaining 34 recordings (72%), baseline fit from both methods was judged as equivalent. The described procedure of baseline determination provides a solid base for automated detection of accelerations and decelerations in fetal heart rate recordings. It enables the study of the relation between the fetal heart rate pattern and fetal movements. Finally, it provides an objective tool for analysis of variables within the fetal heart rate with the highest predictive value with respect to fetal outcome.     

Effect of hyperoxia (PaO2 50-90 mmHg) on fetal breathing movements in the unanaesthetized fetal sheep

Hypoxia inhibits fetal breathing movements but after birth it stimulates breathing. These differences have long been thought to involve central nervous inhibitory mechanisms. Such mechanisms might exert a tonic inhibition of fetal breathing movements at normal fetal PaO2 and the rise in PaO2 at birth might lift this inhibitory effect. To test this hypothesis 7 fetal sheep were chronically instrumented at 125-130 days for recording electrocortical activity (ECoG), and the electromyograph (EMG) activity of the diaphragm and neck muscles. Catheters were placed in a fetal carotid and a brachial artery and in the fetal trachea. For an extracorporeal membrane oxygenation system a 12 F gauge silastic catheter was placed in the right atrium for draining fetal blood and a 9.6 F gauge catheter was placed in a carotid artery to return oxygenated blood. Three days after operation the fetuses were connected to the extracorporeal membrane oxygenation system and fetal PaO2 was raised to 65.2 +/- 4.4 mmHg (SEM) for 6 to 19 h without changing pH or PaCO2. Neither the incidence of high voltage ECoG (48.5 +/- SEM 2.0% vs 52.8 +/- 3.3%) nor of fetal breathing movements (37.3 +/- 2.6% vs 23.8 +/- 5.9%) changed during the periods of hyperoxia. Since fetal breathing movements did not become continuous, we conclude that the lower PaO2 in the fetus compared to the neonate does not exert a tonic inhibitory influence on fetal breathing movements.     

Increased oxygen consumption associated with breathing activity in fetal lambs

To examine the relationship between fetal O2 consumption and fetal breathing movements, we measured O2 consumption, umbilical blood flow, and cardiovascular and blood gas data before, during, and after fetal breathing movements in conscious chronically catheterized fetal lambs. During fetal breathing movements, O2 consumption increased by 30% from a control value of 7.7 +/- 0.7 (SE) ml X min-1 X kg-1. Umbilical blood flow was 210 +/- 21 ml X min-1 X kg-1 before fetal breathing movements; in 9 of 16 samples it increased by 52 +/- 12 ml X min-1 X kg-1, while in the other 7 it decreased by 23 +/- 9 ml X min-1 X kg-1. Umbilical arterial and venous O2 partial pressures and pH fell during fetal breathing movements, and the fall was greater when umbilical blood flow was decreased. Partial CO2 pressure rose in both vessels, and again the increase was greatest when umbilical blood flow fell during fetal breathing movements. Also associated with a fall in umbilical blood flow was the transition from low-amplitude irregular to large-amplitude regular fetal breathing movements. It is concluded that fetal breathing movements increase fetal O2 demands and are associated with a transient deterioration in fetal blood gas status, which is most severe during large-amplitude breathing movements.     

Fetal breathing movements and other tests of fetal wellbeing: a comparative evaluation.

Sixty pregnant women whose fetuses were considered to be at high risk were intensively studied with fetal and placental function tests. Fetal breathing movements were studied with real-time ultrasound and the amount of time spent breathing and the variability of the breath-to-breath interval were measured. A reduction in the amount of time the fetus spent making breathing movements and decreased variability were indicative of fetal compromise. When these results were compared with those of other tests of fetal wellbeing measurement of fetal breathing movements and ultrasound assessment of growth were more sensitive tests of fetal wellbeing than the biochemical measures (urinary oestrogen, human placental lactogen, pregnancy-specific beta-1-glycoprotein, and unconjugated oestriol concentrations) or fetal heart rate. The predictive value was highest with serum unconjugated oestriol but the results of other tests were similar. Study of fetal breathing movements or an ultrasonic assessment of growth may provide a better screening test for fetal compromise than biochemical estimations.     

Changes in antepartum heart rate patterns with progressive deterioration of the fetal condition

In this paper changes in antepartum fetal heart rate (FHR) patterns are described, that occur with progressive deterioration of the fetal condition. The data on the relationship between heart rate patterns and fetal blood gas and pH values are reviewed. A possible rank ordering is presented in which changes in FHR pattern, body movements and blood flow velocity wave form patterns occur with progressive deterioration of the fetal condition.It is concluded that in small-for-date fetuses changes in heart rate and movement patterns are rather late signs of impairment, coinciding with fetal hypoxaemia. In general, heart rate variation falls below the norm at the same time as decelerations occur; there are, however, large inter-fetal differences. In general, abnormal Doppler velocity wave form patterns precede the occurrence of heart rate decelerations. Their impact on the timing of delivery is, however, still uncertain. The advantages of a numerical analysis of FHR patterns include identification of fetuses with low FHR variation, precision of the actual fetal condition and (at early gestation) longitudinal follow-up of fetuses with abnormal heart rate patterns.     

The nature of very low frequency component of the heart rate variability and the role of sympathetic-parasympathetic interactions

A method of separate monitoring "instant" changes of the VLF, LF and HF power spectral components of heart rate variability, has been developed. The power of the LF and HF spectral components were proved to be continuously changing. The period of these power fluctuations could stay within 15 to 150 sec. Comparison of the heart rate variability spectrum with LF and HF spectral components power fluctuations' spectrums has shown that the frequencies of the LF and HF spectral components power fluctuations stay within the VLF range. The co-operative spectrum form of these fluctuations repeats the form of the VLF peak. In cases when the LF and HF spectral components power fluctuations' periods do not coincide, VLF has two peaks. The frequency of one VLF peak coincides with frequency of the HF power fluctuations, and the frequency of another--with the frequency of LF power fluctuations.     

Cardiovascular, metabolic and endocrine effects of chemical sympathectomy and of adrenal demedullation in fetal sheep

A procedure in fetal sheep for causing peripheral sympathectomy by regular intravascular guanethidine sulphate administration and for causing adrenal demedullation by intragland injection of acid formalin is reported. Demedullation substantially removed adrenaline from the fetal circulation, but has a small effect only on noradrenaline. Plasma noradrenaline levels were depressed by 50% when demedullated fetuses were also subject to peripheral sympathectomy by guanethidine sulphate treatment. This provides some evidence that the paraganglia in the sheep fetus contributes to resting plasma catecholamines. Furthermore the ability of adrenal demedullation to increase markedly this pool of extra-adrenal chromaffin tissue indicates that in the fetus adrenal activity regulates the growth of these para-aortic bodies. In response to sympathectomy plasma vasopressin concentrations rose substantially, whilst adrenal demedullation caused a small rise. Demedullation and sympathectomy depressed fetal plasma glucose and elevated plasma cortisol. In both sympathectomised and adrenal demedullated fetuses resting heart rate and blood pressure was not depressed. However in those with a depleted peripheral nervous system periods of cardiovascular instability were apparent after 2-3 days of treatment with guanethidine sulphate. Hence there were regular episodes where fetal blood pressure and heart rate fell sharply followed 60-90s later by very large increases in blood pressure sustained for up to 10 min and associated with substantial production of plasma vasopressin and catecholamines. These results show that fine cardiovascular control in the fetus requires an intact sympathetic system as the endocrine system is too slow responding to effectively maintain reflex vascular control.     

Relationship between accelerations and decelerations in heart rate and skeletal muscle activity in fetal sheep

Accelerations in fetal heart rate have been shown to be closely related to fetal body movements and are indicative of well-being in the human fetus. We have examined the association of accelerations and decelerations in heart rate with skeletal muscle activity in 8 fetal sheep between 125 and 145 days' gestation. Accelerations/decelerations were defined as transient increases/decreases in fetal heart rate of greater than or equal to 10 beats/min. lasting for 5 s or longer. For accelerations (n = 1180), the mean duration was 18.8 +/- 1.5 s (SEM) and the mean amplitude was 25.3 +/- 1.2 beats/min; for decelerations (n = 237), the mean duration was 17.4 +/- 1.6 s and the mean amplitude was 18.7 +/- 1.0 beats/min. Electromyograms were recorded from the nuchal muscles and antagonistic muscle groups of the fetal forelimb and hindlimb. Electromyogram activity occurred during 88.4 +/- 2.8% of accelerations and 60.6 +/- 7.7% of decelerations. There was a 36.6% reduction in the number of accelerations following fetal paralysis with gallamine, but no change in their amplitude or duration. It is concluded that accelerations in heart rate are highly associated with skeletal muscle activity in fetal sheep. The majority of these occur as a result of central neuronal output rather than as a consequence of fetal movement.     

An estimate of fetal autonomic state by time-frequency analysis of fetal heart rate variability.

In this study we present a noninvasive method that enables the investigation of the fetal heart rate (FHR) fluctuations. The objective was to design a quantitative measurement to assess the fetal autonomic nervous system and to investigate its development as a function of the gestational age. Our Medical Physics group has developed a complex algorithm for online beat-to-beat detection of the fetal ECG (FECG), extracted from the maternal abdominal ECG signal. We used our previously acquired FECG data, which includes noninvasive recordings of 200 maternal abdominal ECG signals. From these, we chose 35 cases of healthy pregnancies that we divided into three groups according to gestational age: Group 1, 23 +/- 2 wk; Group 2, 32 +/- 1 wk; and Group 3, 39 +/- 1 wk. The FHR variability was analyzed by a time-frequency decomposition based on a continuous wavelet transform. We showed that, independent of the gestational age, most of the FHR power is concentrated in the very-low-frequency range (0.02-0.08 Hz) and in the low-frequency range (0.08-0.2 Hz). In addition, there is power in the high-frequency range that correlates with the frequency range of fetal respiratory motion (0.4-1.7 Hz). In the intermediate-frequency range (0.2-0.4 Hz), the power is significantly smaller. The changes in the average power spectrum in relation to gestation time were carefully and quantitatively examined. The results imply that there is a neural organization during the last trimester of the pregnancy, and the sympathovagal balance is reduced with the gestational age.     

Criteria for the design of fetal heart rate analysis systems

Criteria are described for the automated analysis of fetal pulse intervals, fetal movements and of uterine contractions measured externally, antenatally and interactively on-line, for implementation on a personal computer interfaced to an appropriate fetal monitor, and tested on 10,000 records. Measurements of short and longer term fetal heart rate variation are compared; both are required to identify sinister records. Recall and display of records acquired on the same patient over several weeks has proved a useful diagnostic aid.     

Combined one- and two-dimensional ultrasound system for monitoring fetal breathing movements.

A combined one- and two-dimensional ultrasonic system for monitoring respiratory movements in the human fetus has been developed. A real-time cross-sectional image of the fetal chest at the level of the fetal heart can be obtained, and a time motion recording of fetal respiratory movements can then be written on a strip-chart recorder. Combining the features of one-dimensional and two-dimensional systems produces an accurate means of investigating fetal breathing movements.     

Genioglossus and alae nasi activity in fetal sheep

The functional development of two upper airway dilating muscles, the alae nasi and the genioglossus, has been studied in fetal sheep in utero from 112-140 days gestation. Before electrocortical differentiation phasic activity was present in both muscles for long periods, mostly when breathing movements were present. After 120 days gestation phasic genioglossal and alae nasi activity occurred only during periods of low voltage electrocortical activity. During high voltage episodes there was no phasic activity and tonic activity was not sustained. Although present during periods of breathing movements genioglossus activity was rarely synchronous with the diaphragm. The alae nasi showed both respiratory and non-respiratory related activity. Hypoxia abolished both alae nasi and genioglossus activity but whereas alae nasi rapidly developed an inspiratory rhythm during 5% CO2 administration this was not the case with the genioglossus and inspiratory activity was not always seen in the genioglossus even during 10% CO2 administration. It is concluded that there are fundamental differences between the control of genioglossus and alae nasi activity in the fetal sheep. The alae nasi behaves as an inspiratory muscle responding to hypoxia and hypercapnia as would be expected but the genioglossus shows no inspiratory activity during normal unstimulated fetal breathing. Thus the neural mechanisms for activation of inspiratory activity appear to be present late in gestation. However it is possible for the genioglossus to develop an inspiratory rhythm under conditions of much increased respiratory drive.     

Effects of morphine and naloxone on fetal heart rate and movement in the pig.

To test the hypothesis that an increasing opioid tonus is involved in decreases in fetal heart rate (FHR) and movement (FM) during late gestation, we studied the effects of intravenous bolus injections of morphine (1 mg) and naloxone (1 mg) on FHR and FM in the fetal pig. Twenty-one fetuses (1 per sow) were catheterized at 90-104 days of gestation (median 100 days). Recordings of FHR (electrocardiograph or Doppler-derived signals) and FM (ultrasonography) were made from 15 min before to 45 min after treatment. Morphine administration significantly decreased FHR, but it increased FHR variation and forelimb movements (LM). LM were clustered, and this stereotyped behavior has never before been observed in any mammalian fetus. Naloxone administration increased gross body movements and FHR without significant changes in FHR variation. It is concluded that FHR and motility are under opioidergic control in the pig fetus. Both morphine and naloxone induce hypermotility, suggesting that naloxone does not act as a pure opioid antagonist in the fetal pig.     

Effects of maternal indomethacin administration on fetal breathing movements in sheep

To determine the role of prostaglandins in the control of fetal breathing movements, we infused indomethacin (5 mg/ml; 25 mg/kg per day) into the maternal femoral vein for 70 h in 5 pregnant ewes. There was a significant increase in the incidence and amplitude of fetal breathing movements beginning within 2 h reaching a peak at 8-10 h. It then diminished and was no longer present by 20-70 h despite continued indomethacin infusion. Maternal glucose concentrations were increased at 8 and 16 h following the initiation of indomethacin infusion. The data suggested that the previously reported effects of cyclo-oxygenase inhibitor on fetal breathing movements are transient and do not continue beyond 20 h.     

Stimulation of breathing movements in fetal sheep by inhibitors of prostaglandin synthesis

We studied the effects of inhibitors of prostaglandin synthesis on fetal breathing movements on 17 occasions in 11 lambs (gestational age 125-141 days). We gave 12 h infusions of sodium mechlofenamate (8.6-22.2 mg.kg-1) in 13 studies and indomethacin (21.8-38.8 mg.kg-1) in four studies. Results were similar with both agents and did not correlate with drug dosage. There were no changes in fetal arterial blood pressure, pH or blood gas tensions. We assessed fetal breathing movements by measurements of tracheal pressure for a control period of 224 h prior to and 208 h during the infusion of inhibitors of prostaglandin synthesis; their administration caused a marked stimulation of fetal breathing movements judged from the following four variables: (1) incidence of fetal breathing movements increased from 38.4 to 69.2% of the time (P < 0.001); (2) average amplitude of change in tracheal pressure during fetal breathing movements increased from 4.1 to 6.0 torr (P < 0.01); (3) maximal amplitude of change in tracheal pressure during fetal breathing movements increased from 8.8 to 13.4 torr (P < 0.01); and (4) the duration of the longest continuous episode of fetal breathing movements increased from 37 to 229 min (P < 0.05). Two fetuses had electrocorticogram (ECoG) recordings. In control periods, fetal breathing movements occurred only during low voltage, high frequency ECoG activity; however, during infusions of inhibitors of prostaglandin synthesis, fetal breathing movements occurred also during high voltage, low frequency ECoG activity. We conclude that inhibitors of prostaglandin synthesis stimulate fetal breathing movement in fetal sheep. These results suggest that a component of the prostaglandin system is a factor which inhibits breathing movements during fetal life.     

Developmental changes of the glycolytic enzymes in the human fetal heart

The ontogeny of hexokinase, phosphofructokinase, phosphoglucoisornerase, aldolase, pyruvate kinase and lactate dehydrogenase activities which are associated with glycolysis, an important energy yielding process, has been studied in human fetal heart for periods ranging from 13 weeks to above 33 weeks of gestation. Hexokinase, phosphoglucoisomerase and pyruvate kinase activities show similar developmental profiles exhibiting maximum activity at 25–28 weeks ofgestation. Phosphofructokinase activity, on the other hand, shows a minimum at this period and exhibits a peak value at early stages (13–16 weeks of gestation). Though considerable activity for aldolase is observed at an early period, it declines thereafter, but again increases in the later period. The probable role and correlations of these glycolytic enzymes with energy demand and general functional development in human fetal heart in ontogeny are evaluated.     

Indomethacin antagonizes the ethanol-induced suppression of breathing activity but not the suppression of brain activity in the near-term fetal sheep

The effect of indomethacin on the ethanol-induced suppression of fetal breathing movements, low-voltage electrocortical (ECoG) activity, and electro-ocular (EOG) activity was studied in the near-term fetal sheep. Ten conscious instrumented pregnant ewes (between 129 and 131 days of gestation; term, 147 days) received 1-h maternal intravenous infusion of 1 g ethanol/kg total body weight and simultaneous fetal treatment with either indomethacin (2 mg/kg fetal body weight/h) (n = 5) or an equivalent volume of phosphate buffer (n = 5) intravenously for 9 h. Fetal ECoG activity, EOG activity, and fetal breathing movements were monitored continuously over the experimental periods. In animals treated with ethanol and buffer (n = 5), fetal breathing movements were suppressed for 8 h and low-voltage ECoG and EOG activity was suppressed for 2 h below preinfusion levels. In animals treated with ethanol and indomethacin (n = 5), fetal breathing movements were elevated for 13 h but low-voltage ECoG and EOG activity remained suppressed for 3 h below preinfusion levels. The data suggests that indomethacin can antagonize the ethanol-induced suppression of fetal breathing movements, but does not alter the ethanol-induced suppression of ECoG or EOG activity.