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

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 HRV 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 dG; term~145 dG) in isobaric chambers. At 138dG, isolated hearts were studied using a Langendorff preparation. We calculated basal iFHRV matrix indices across five signal-analytical domains from the systolic peaks within 15 min segments in each heart. Significance was assumed at p<0.05. Maternal hypoxia yielded chronic fetal PaO2 values of 11.5±0.6 (mean+SEM) relative to controls of 20.9±0.5 mmHg. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4-fold increases in the Grid transformation as well as the AND similarity index (sgridAND, informational domain) and a 4-fold reduction in the Scale dependent Lyapunov exponent slope (invariant domain). We also detected a 2-fold reduction in the Recurrence quantification analysis, percentage of laminarity and recurrences and maximum diagonal line (dlmax, geometric domain) and in the Multiscale time irreversibility asymmetry index (energetic domain). dlmax and sgridAND correlated with left ventricular end-diastolic pressure across both groups (R 2 =0.32 and R 2 =0.63, respectively). 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 lower complexity in iFHRV. Key points summary 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 carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy. Indices of iFHRV may improve fetal health surveillance by helping to diagnose prediction of fetal hypoxia and acidaemia during antenatal or intra-partum fetal compromise.