Department of Physiology, Fetal Physiology and Neuroscience Group, The University of Auckland, Auckland, New Zealand.
The Department of Obstetrics and Gynaecology, Mie University, Mie, Japan.
J Physiol. 2024 Dec;602(23):6553-6569. doi: 10.1113/JP284560. Epub 2023 Jul 11.
Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury.
出生前缺氧缺血（HI）是导致死产和幸存者严重神经发育障碍的关键风险因素，包括脑瘫，尽管目前尚无可靠的生物标志物来检测可能经历过短暂严重 HI 的高危胎儿。我们研究了早产胎儿羊在 0.7 孕周（相当于早产儿）至 0.8 孕周（相当于足月儿）出生后 3 周内 HI 后胎儿心率变异性（FHRV）的时频域测量值。我们之前已经表明，这与严重的白质和灰质损伤的延迟发展有关，包括囊性白质损伤（WMI），类似于人类早产儿的损伤。HI 与 FHRV 的时频域测量值的抑制以及恢复后前 3 天的昼夜节律性降低有关。相比之下，在恢复的最后 2 周内，FHRV 的多个测量值的昼夜节律性被夸大，这是通过早晨最低点的 FHRV 降低更大介导的，但傍晚高峰没有变化。这些数据表明，FHRV 测量的时间会影响其诊断效用。我们进一步提出，FHRV 的昼夜节律变化可能是产前 HI 和不断发展的脑损伤的低成本、易于应用的生物标志物。关键点：出生前缺氧缺血（HI）是死产和幸存者残疾的关键风险因素，尽管目前尚无可靠的产前脑损伤生物标志物。在早产胎儿羊中，已知导致 3 周后严重白质和灰质损伤延迟发展的急性 HI 与恢复后前 3 天内多个 FHRV 时频域测量值的早期抑制以及其昼夜节律的丧失有关。在 HI 恢复的最后 2 周内，观察到频域 FHRV 测量值的昼夜节律被夸大。FHRV 的早晨最低点较低，傍晚高峰没有变化。FHRV 的昼夜节律变化可能是产前 HI 和不断发展的脑损伤的低成本、易于应用的生物标志物。
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