First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Abstract

Key points We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction. Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy. Therefore, the isolated fetal heart has intrinsic variability and carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy. Abstract Fetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic heart rate variability (iHRV), devoid of any external influences, exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n = 6) or hypoxia (10% inspired O2, n = 9) for the last third of gestation (105–138 days of gestation (dG); term ∼145 dG) in isobaric chambers. At 138 dG, isolated hearts were studied using a Langendorff preparation. We calculated basal intrinsic FHRV (iFHRV) indices reflecting iFHRV's variability, predictability, temporal symmetry, fractality and chaotic behaviour, from the systolic peaks within 15 min segments in each heart. Significance was assumed at P < 0.05. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4‐fold increases in the Grid transformation as well as the AND similarity index (sgridAND) and a 4‐fold reduction in the scale‐dependent Lyapunov exponent slope. We also detected a 2‐fold reduction in the Recurrence quantification analysis, percentage of laminarity (pL) and recurrences, maximum and average diagonal line (dlmax, dlmean) and the Multiscale time irreversibility asymmetry index. The iHRV measures dlmax, dlmean, pL and sgridAND correlated with left ventricular end‐diastolic pressure across both groups (average R2 = 0.38 ± 0.03). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a time scale‐dependent higher complexity in iFHRV.

Transient effects of forebrain ischemia on fetal heart rate variability in fetal sheep

“…For example, it is broadly believed that the appearance of "normal" FHRV is an expression of an intact central nervous system, requiring essentially all components to be functioning, including the cerebral cortex, midbrain, and medulla as well as the autonomic efferent pathways (15). The contribution of both sympathetic and parasympathetic efferents to FHRV is well established (16)(17)(18)(19)(20)(21), and recently the presence of intrinsic sinoatrial nodal rhythms has been confirmed in the fetus (22). Although it is intuitive that higher centers in the forebrain influence autonomic outflow, and therefore make at least an indirect contribution to FHRV, this has never been systematically tested.…”

Heart Rate Variability in the Perinatal Period: A Critical and Conceptual Review

“…However, HRV may reflect much more than the autonomic regulation of cardiac activity. On the one hand, it has been recently discovered, in ovine models, that the fetal heart has already an intrinsic sinoatrial node activity that can affect HRV and that can be affected by adverse conditions (e.g., chronic hypoxia) in the last trimester of pregnancy (Frasch et al, 2020). On the other hand, HRV seems to be greatly influenced by information coming from the whole organism (e.g., the gut or the immune system) through systemic afferent pathways, such as the vagus nerve (Frasch, 2020).…”

“…This focused review is divided into three sections: (1) the first section describes briefly the HRV metrics and examines the relationship between ANS and HRV in fetuses and newborns; (2) the second section examines the technology available in the NICU, how to monitor HRV efficiently, and the usefulness of real-time HRV; and (3) the third and final section will summarize the main findings and outline future perspectives for the clinical use of real-time HRV in the neonatal field, with a brief subsection about its usefulness in low-income countries. (Hoyer et al, 2013(Hoyer et al, , 2019Uhrikova et al, 2015;Pichot et al, 2016;Massaro et al, 2017;Shaffer and Ginsberg, 2017;Herry et al, 2019;Oliveira et al, 2019b;Patural et al, 2019;Frasch et al, 2020). From the work of the Task Force for HRV analysis in 1996, which constitutes the foundation for the majority of the papers on HRV, many metrics are developed to describe HRV, and they can be classified into three categories: time-domain, frequency-domain, and non-linear metrics ( Table 1).…”

A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows

“…Nonetheless, the importance of ANS and vagus nerve regulation in fetal and neonatal development is still underrepresented (Sadler, 2012;Moore et al, 2016). Moreover, except the third trimester du Plessis, 2018, 2019), literature usually lacks an analysis of potential "critical windows" TABLE 1 | Summary of the HRV metrics cited in the main text (Brändle et al, 2015;Massaro et al, 2017;Oliveira et al, 2019;Patural et al, 2019;Frasch et al, 2020a).…”