No sympathy for the hypoxic: the role of fetal oxygenation in autonomic dysfunction

Uteroplacental insufficiency, defined as the failure of the placenta to adequately supply nutrients to the developing fetus, can result from insufficient blood flow to the placenta, and thereby deficient fetal oxygenation. Chronic uteroplacental insufficiency risks neonatal metabolic acidosis, cerebral palsy, early neonatal death and fetal growth restriction, and may often necessitate an early delivery. Fetal heart rate variability (FHRV) is routinely employed to assess fetal well-being and profound, prolonged reductions in FHRV are thought to represent acute fetal compromise (Serra et al. 2008). The regulation of fetal heart rate fluctuates throughout gestation as the allostatic balance of sympathetic and parasympathetic influences shifts. Normoxic human pregnancies show an ontogenic transition towards sympathetic dominance in the third trimester (Schneider et al. 2010), accompanied by a rise in overall heart rate variability and short term variability. This is absent in human pregnancies complicated by uteroplacental dysfunction (Ferrario et al. 2009). However, the pathophysiology underlying suppression of sympathetic influences on FHRV in the late-gestation fetus remain unclear. There is thus a need to investigate the longitudinal mechanisms behind reduced FHRV in the setting of uteroplacental insufficiency. In this issue of The Journal of Physiology, Shaw et al. examined indices of the autonomic control of fetal heart rate and showed that chronic hypoxia during pregnancy alters fetal heart rate variability by reducing sympathetic tone as the fetus approaches term (Shaw et al. 2018). The authors studied the autonomic control of fetal heart rate variability in fetal sheep over the last third of pregnancy. The fetal femoral artery was cannulated for blood gas measurements, hormone quantification and fetal arterial pressure monitoring to assess the interval between each fetal heart beat for direct measurement of sympathetic and parasympathetic control of heart rate variability, in a way that is not possible in human fetuses non-invasively. Isobaric chambers were employed to maintain pregnant sheep for 16 days in hypoxic conditions. The reported reductions in fetal femoral arterial and seen in their model recapitulate the clinical hypoxic and metabolic defects seen in human pregnancies, complicated by intrauterine growth restriction. By analysing FHRV over the 16 days towards term, and comparing normoxic and hypoxic fetuses, Shaw et al. show that FHRV is reduced, predominantly due to dysregulation of sympathetic control of fetal heart rate. Interestingly, there was an increase in the low frequency (LF) component of FHRV in quiet sleep during the first 48 h of hypoxia, representing the characteristic response to acute hypoxia. However, this sympathetic hyperactivity was followed by a decrease in sympathetic influence on HFRV after approximately 72 h, as evidenced by a marked reduction in LF. Therefore, in the early phases of uteroplacental dysfunction, inappropriately elevated LF components of FHRV may serve as a biomarker of hypoxia-driven autonomic dysregulation of the control of fetal heart rate that precipitates the decline. In stark contrast to the increasing influence on fetal heart rate in normoxic sheep, the chronically hypoxic fetus suffered from an overall sympathetic suppression while parasympathetic indices of FHRV were unaffected as they approached term. This study also confirms previous work showing a more significant fall in heart rate in hypoxic vs. normoxic fetuses, which is not due to a reflex rise in arterial blood pressure (Allison et al. 2016). The findings in normal fetal sheep reported by Shaw et al. are in agreement with data obtained in patients, demonstrating a progressive increase in LF power in normal human pregnancy, particularly shifting towards sympathetic dominance during the third trimester (Ferrario et al. 2009; Schneider et al. 2010). However, while previous studies demonstrated that sympathetic suppression, rather than parasympathetic dysregulation, acts to reduce FHRV in intrauterine growth restriction, the mechanisms and temporal dynamics of this suppression were unresolved. In summary, the paper by Shaw et al. suggests that progressive reductions in fetal heart rate variability are related to fetal exposure to chronic hypoxia, mediated through fetal sympathetic nervous system dysregulation. Together with previous reports, these new findings underscore the validity of FHRV in predicting uteroplacental dysfunction while further suggesting that chronic (and not acute) fetal hypoxia may lead to sympathetic suppression. In addition to pointing to autonomic dysregulation in the sympathetic nervous system as the aetiology of the decrease in HFRV, this study provides unique insight into the timeline of autonomic dysfunction in the setting of chronic hypoxia. None Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. National Institute of Health NIH1DP2HL132356 to M.V.