Preterm birth is a major cause of perinatal mortality and long-term morbidity. Chorioamnionitis is a common cause of preterm birth. Clinical chorioamnionitis, characterised by maternal fever, leukocytosis, tachycardia, uterine tenderness, and preterm rupture of membranes, is less common than subclinical/histologic chorioamnionitis, which is asymptomatic and defined by inflammation of the chorion, amnion, and placenta. Chorioamnionitis is often associated with a fetal inflammatory response. The fetal inflammatory response syndrome (FIRS) is defined by increased systemic inflammatory cytokine concentrations, funisitis, and fetal vasculitis. Clinical and epidemiological studies have demonstrated that FIRS leads to poor cardiorespiratory, neurological, and renal outcomes. These observations are further supported by experimental studies that have improved our understanding of the mechanisms responsible for these outcomes. This paper outlines clinical and experimental studies that have improved our current understanding of the mechanisms responsible for chorioamnionitis-induced preterm birth and explores the cellular and physiological mechanisms underlying poor cardiorespiratory, neural, retinal, and renal outcomes observed in preterm infants exposed to chorioamnionitis.

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.

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.