A distinctive pattern of recurrent rapid falls in fetal heart rate, called decelerations, are commonly associated with uterine contractions during labour. These brief decelerations are mediated by vagal activation. The reflex triggering this vagal response has been variably attributed to a mechanoreceptor response to fetal head compression, to baroreflex activation following increased blood pressure during umbilical cord compression, and/or a Bezold–Jarisch reflex response to reduced venous return from the placenta. Although these complex explanations are still widespread today, there is no consistent evidence that they are common during labour. Instead, the only mechanism that has been systematically investigated, proven to be reliably active during labour and, crucially, capable of producing rapid decelerations is the peripheral chemoreflex. The peripheral chemoreflex is triggered by transient periods of asphyxia that are a normal phenomenon associated with all uterine contractions. This should not cause concern as the healthy fetus has a remarkable ability to adapt to these repeated but short periods of asphyxia. This means that the healthy fetus is typically not at risk of hypotension and injury during uncomplicated labour even during repeated brief decelerations. The physiologically incorrect theories surrounding decelerations that ignore the natural occurrence of repeated asphyxia probably gained widespread support to help explain why many babies are born healthy despite repeated decelerations during labour. We propose that a unified and physiological understanding of intrapartum decelerations that accepts the true nature of labour is critical to improve interpretation of intrapartum fetal heart rate patterns.

Acute post-asphyxial encephalopathy occurring around the time of birth remains a major cause of death and disability. The recent seminal insight that allows active neuroprotective treatment is that even after profound asphyxia (the “primary” phase), many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Although many of these secondary processes are potentially injurious, they appear to be primarily epiphenomena of the “execution” phase of cell death. Animal and human studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible but before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, has been associated with potent, long-lasting neuroprotection. Recent clinical trials show that while therapeutic hypothermia significantly reduces morbidity and mortality, many babies still die or survive with disabilities. The challenge for the future is to find ways of improving the effectiveness of treatment. In this review, we will dissect the known mechanisms of hypoxic-ischemic brain injury in relation to the known effects of hypothermic neuroprotection.

Hypoxia–ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic–ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia–ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.

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The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic-ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5-2 min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour.

Sympathetic nervous system (SNS)-mediated peripheral vasoconstriction plays a key role in initial maintenance of blood pressure during rapid-onset asphyxia in the mammalian fetus, but it is attenuated after the first few minutes. It is unclear whether the SNS response is sustained during the brief, but frequently repeated, episodes of asphyxia characteristic of labor. In the present study, 14 fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 7) or sham injection (control; n = 7), followed 4-5 days later by repeated 2-min episodes of complete umbilical cord occlusion every 5 min for up to 4 h or until mean arterial blood pressure (MAP) fell to <20 mmHg for two successive occlusions. In controls, umbilical cord occlusions were associated with a rapid initial fall in fetal heart rate (FHR) and femoral blood flow (FBF), with initial hypertension, followed by progressive development of hypotension during ongoing occlusions. Sympathectomy was associated with attenuation of the initial rise in MAP during umbilical cord occlusion, and after the onset of hypotension, a markedly more rapid fall of MAP to the nadir, with a correspondingly slower fall in FBF (P < 0.05). In contrast, MAP and FHR between successive occlusions were higher after sympathectomy (P < 0.05). There was no significant difference in the number of occlusions before terminal hypotension (6-OHDA; 16.1 ± 2.2 vs. control; 18.7 ± 2.3). These data show that SNS activity provides ongoing support for fetal MAP during prolonged exposure to brief repeated asphyxia.

This study examined the hypothesis that repeated episodes of brief but severe hypoxia would not attenuate the chemoreflex-mediated rapid initial fall in fetal heart rate (FHR) and, further, that greater hypoxic stress, as shown by hypotension and metabolic acidosis, would be associated with an enhanced chemoreflex response. Chronically instrumented, near-term fetal sheep received 1 min total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8) or every 2.5 min (1:2.5 group; n = 8) until mean arterial blood pressure fell to <20 mmHg on two successive occlusions. Umbilical cord occlusion caused variable decelerations, with sustained hypertension in the 1:5 group and little change in acid-base status (pH 7.34 +/- 0.03 after 4 h). In contrast, the 1:2.5 group showed progressive hypotension and metabolic acidemia (pH 6.92 +/- 0.04 after the last occlusion). The 1:2.5 group showed a significant increase in the rate of initial fall in FHR during the occlusion series, which was greater than the 1:5 group in the last 30 min of the occlusion series (9.4 +/- 1.4 vs. 3.5 +/- 0.3 beats.min(-1).s(-1); P < 0.01), with a greater fall in FHR (71.9 +/- 6.5 vs. 47.0 +/- 8.7 beats/min; P < 0.05). In summary, this study demonstrated that repetitive laborlike cord occlusions, which led to severe fetal compromise, were associated with an increase in the slope and magnitude of the initial FHR deceleration. These findings support the concept of the chemoreflex as a central, robust component of fetal adaptation to severe hypoxia.

Key pointsr Fetal heart rate variability and changes in the ST segment of the electrocardiogram are used clinically during labour to identify fetuses at risk of severe metabolic acidosis or death.r Sympathetic nervous system activity contributes to heart rate variability in healthy normoxic fetuses, and is critical for the rapid haemodynamic adaptations to repeated episodes of asphyxia induced by brief complete umbilical cord occlusions at rates consistent with active labour.r We now show that chemical sympathectomy did not alter fetal heart rate variability between episodes of brief repeated asphyxia or elevation of the ST segment during asphyxia.r The lack of influence of the sympathetic system on fetal heart rate variability between episodes of brief asphyxia suggests that measures of fetal heart rate variability are unlikely to help monitor changes in sympathetic nervous system activity during active labour.Abstract Changes in fetal heart rate variability (FHRV) and ST segment elevation (measured as the T/QRS ratio) are used to evaluate fetal adaptation to labour. The sympathetic nervous system (SNS) is an important contributor to FHRV under healthy normoxic conditions, and is critical for rapid support of blood pressure during brief labour-like asphyxia. However, although it has been assumed that SNS activity contributes to FHRV during labour; this has never been tested, and it is unclear whether the SNS contributes to the rapid increase in T/QRS ratio during brief asphyxia. Thirteen chronically instrumented fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 6) or sham treatment (control; n = 7), followed 4-5 days later by 2 min episodes of complete umbilical cord occlusion repeated every 5 min for up to 4 h, or until mean arterial blood pressure fell to <20 mmHg for two successive occlusions. FHRV was decreased before occlusions in the 6-OHDA group (P < 0.05) and 2-4.5 h during recovery after occlusions (P < 0.05) compared to the control group. During each occlusion there was a rapid increase in T/QRS ratio. Between successive occlusions the T/QRS ratio rapidly returned to baseline, and FHRV increased above baseline in both groups (P < 0.05), with no significant effect of sympathectomy on FHRV or T/QRS ratio. In conclusion, these data show that SNS activity does not mediate the increase in FHRV between repeated episodes of brief umbilical cord occlusion or the transient increase in T/QRS ratio during occlusions. Abbreviations 6-OHDA, 6-hydroxydopamine; FHR, fetal heart rate; FHRV, fetal heart rate variability; MAP, mean arterial pressure; RMSSD, root mean square of successive RR intervals; SDNN, standard deviation of RR intervals; SNS, sympathetic nervous system; STV, short-term variation.