Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. β-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (β-adrenergic blockade; n = 10) or saline ( n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.

Hypoxia-ischaemia (HI) is a major contributor to preterm brain injury, although there are currently no reliable biomarkers for identifying infants who are at risk. We tested the hypothesis that fetal heart rate (FHR) and FHR variability (FHRV) would identify evolving brain injury after HI. Fetal sheep at 0.7 of gestation were subjected to either 15 (n = 10) or 25 min (n = 17) of complete umbilical cord occlusion or sham occlusion (n = 12). FHR and four measures of FHRV [short-term variation, long-term variation, standard deviation of normal to normal R-R intervals (SDNN), root mean square of successive differences) were assessed until 72 h after HI. All measures of FHRV were suppressed for the first 3-4 h in the 15 min group and 1-2 h in the 25 min group. Measures of FHRV recovered to control levels by 4 h in the 15 min group, whereas the 25 min group showed tachycardia and an increase in short-term variation and SDNN from 4 to 6 h after occlusion. The measures of FHRV then progressively declined in the 25 min group and became profoundly suppressed from 18 to 48 h. A partial recovery of FHRV measures towards control levels was observed in the 25 min group from 49 to 72 h. These findings illustrate the complex regulation of FHRV after both mild and severe HI and suggest that the longitudinal analysis of FHR and FHRV after HI may be able to help determine the timing and severity of preterm HI.

Key points •Therapeutic hypothermia needs to be started as early as possible in the first 6 h after acute injury caused by hypoxia–ischaemia (HI), but the severity and timing of HI are often unclear. In this study we evaluated whether measures of heart rate variability (HRV) might provide early biomarkers of HI. •The duration but not magnitude of suppression of HRV power and conversely increased sample entropy of the heart rate were associated with severity of HI, such that changes in the first 3 h did not discriminate between groups. •Relative changes in HRV power bands showed different patterns between groups and therefore may have the potential to evaluate the severity of HI. •Aberrant fetal heart rate patterns and increased arginine vasopressin levels in the first hour after moderate and severe HI were correlated with loss of EEG power after 3 days’ recovery, suggesting potential utility as early biomarkers of outcome. Abstract Therapeutic hypothermia is partially neuroprotective after acute injury caused by hypoxia–ischaemia (HI), likely because the timing and severity of HI are often unclear, making timely recruitment for treatment challenging. We evaluated the utility of changes in heart rate variability (HRV) after HI as biomarkers of the timing and severity of acute HI. Chronically instrumented fetal sheep at 0.85 gestational age were exposed to different durations of umbilical cord occlusion to produce mild (n = 6), moderate (n = 8) or severe HI (n = 8) or to sham occlusion (n = 5). Heart rate (HR) and HRV indices were assessed until 72 h after HI. All HI groups showed suppressed very low frequency HRV power and elevated sample entropy for the first 3 h; more prolonged changes were associated with greater severity of HI. Analysis of relative changes in spectral power showed that the moderate and severe groups showed a shift towards higher HRV frequencies, which was most marked after severe HI. This shift was associated with abnormal rhythmic HR patterns including sinusoidal patterns in the first hour after HI, and with elevated plasma levels of arginine vasopressin, which were correlated with subsequent loss of EEG power by day 3. In conclusion, absolute changes in HRV power in the first 3 h after acute HI were not significantly related to the severity of HI. The intriguing relative shift in spectral power towards higher frequencies likely reflects greater autonomic dysfunction after severe HI. However, sinusoidal HR patterns and elevated vasopressin levels may have utility as biomarkers of severe HI.

Fetal heart rate variability (FHRV) is a key index of intrapartum well-being. Both arms of the autonomic system regulate FHRV under normoxic conditions in the antenatal period. However, autonomic control of FHRV during labor when the fetus is exposed to repeated, brief hypoxemia during uterine contractions is poorly understood. We have previously shown that the sympathetic nervous system (SNS) does not regulate FHRV during labor-like hypoxia. We therefore investigated the hypothesis that the parasympathetic system is the key mediator of intrapartum FHRV. 26 chronically instrumented fetal sheep at 0.85 of gestation received either bilateral cervical vagotomy (n=7), atropine sulfate (n=7) or sham treatment (control, n=12), followed by three 1-min complete umbilical cord occlusions (UCOs) separated by 4-min reperfusion periods. Parasympathetic blockade reduced three measures of FHRV before UCOs (all p<0.01). Between UCOs, atropine and vagotomy were associated with marked tachycardia (both p<0.005), suppressed measures of FHRV (all p<0.01) and abolished FHRV on visual inspection compared to the control group. Tachycardia in the atropine and vagotomy groups resolved over the first 10 min after the final UCO, in association with evidence that the SNS contribution to FHRV progressively returned during this time. Our findings support that SNS control of FHRV is acutely suppressed for at least 4 minutes after a deep intrapartum deceleration, and takes 5-10 minutes to recover. The parasympathetic system is therefore likely to be the key mediator of FHRV once frequent FHR decelerations are established during labor.

The interpretation of fetal heart rate (FHR) patterns is the only available method to continuously monitor fetal well‐being during labour. One of the most important yet contentious aspects of the FHR pattern is changes in FHR variability (FHRV). Some clinical studies suggest that loss of FHRV during labour is a sign of fetal compromise so this is reflected in practice guidelines. Surprisingly, there is little systematic evidence to support this observation. In this review we methodically dissect the potential pathways controlling FHRV during labour‐like hypoxaemia. Before labour, FHRV is controlled by the combined activity of the parasympathetic and sympathetic nervous systems, in part regulated by a complex interplay between fetal sleep state and behaviour. By contrast, preclinical studies using multiple autonomic blockades have now shown that sympathetic neural control of FHRV was potently suppressed between periods of labour‐like hypoxaemia, and thus, that the parasympathetic system is the sole neural regulator of FHRV once FHR decelerations are present during labour. We further discuss the pattern of changes in FHRV during progressive fetal compromise and highlight potential biochemical, behavioural and clinical factors that may regulate parasympathetic‐mediated FHRV during labour. Further studies are needed to investigate the regulators of parasympathetic activity to better understand the dynamic changes in FHRV and their true utility during labour.