Chorioamnionitis, maternal fever, and neonatal encephalopathy

Neonatal encephalopathy (NE) in the term infant is usually clinically diagnosed by the presence of seizures, abnormalities of conscious state or tone, or feeding or respiratory difficulties of a central origin. Although commonly attributed to peripartum hypoxia and ischaemia, evidence for the presence of these is often lacking, and many other antepartum and intrapartum associations have been described.1,2 Many infants with NE go on to show a range of neurodevelopmental sequelae including cerebral palsy (CP), but again while a causative association is often assumed, the signs of NE may simply be those of a preexisting cerebral pathology. The amniotic membranes and fluid provide an effective barrier for the fetus against most bacteria and fungi. Preterm or prolonged rupture of the membranes results in an increasing risk to the mother and fetus for infection and a consequent inflammatory response, chorioamnionitis (CA). CA is clinically diagnosed by the presence of maternal fever, usually, but not always, in the presence of ruptured membranes and uterine tenderness. Raised levels of inflammatory markers are seen in maternal blood, amniotic fluid, and often in fetal blood and cerebrospinal fluid, especially in the preterm infant. Pathological diagnosis involves the examination of placental tissue and membranes, but such precision is usually lacking in large epidemiological studies, which depend on a recorded clinical diagnosis. In term infants, a number of studies have shown inconsistent results for an association between CA and NE, after confounding factors have been taken into account. Shalak et al. found an association but not independently of fetal acidosis and not with fever.3 Longer-term studies seem to show a clear and independent association between CA and CP (odds ratio [OR] 3.8, population attributable risk 11%). 4 In the preterm infant, CA seems to increase the risk for the development of periventricular leucomalacia and subsequent CP. Recent work indicates that the likely mechanism is inflammatory damage to pre-oligodendrocytes, resulting in poorer myelination later.5 While this is less likely to be the mechanism in term infants, inflammatory markers have been identified in the neonatal period in blood of infants who later developed CP.6 Numerous studies have consistently shown that maternal fever, defined at various levels, is associated with both NE (OR 3.5–4.7) and subsequent risk for developing CP (OR 9.3), particularly spastic quadriplegia (OR 19). 7 The mechanisms by which this occurs is unclear, but Tomimatsu et al. have shown that hyperthermia during hypoxia–ischaemia in a mouse model promotes a rise in caspase-3 at 36 hours, with subsequent increase in cerebral apoptosis.8 Maintaining normothermia or inducing hypothermia during and post hypoxia–ischaemia has been shown in this and other studies to be neuroprotective. Blume et al.’s case–control study in this issue aims to disentangle the possible causative effects of two peripartum associations of NE, CA, and maternal fever. By linking anonymized routinely collected data from a birth registry and an obstetric database, they were able to conduct a population-based case– control study to examine the associations between maternal fever and clinical CA with NE. By linking the databases, the authors were able to harness the power of large numbers, avoiding some of the biases innate to small hospital-based studies, and allowing some powerful statistical models to be generated to address confounders. The limitations of the study are common to most large epidemiological studies, and include uncertain definitions and an inability to check on the validity of reported data. Nevertheless, they were able to conclude from their analyses that both CA (OR 5.4) and isolated maternal fever (OR 3.1) were independently and significantly associated with NE. This would support the idea that they act through different mechanisms, as the experimental work would indicate, and that different approaches to prevention of NE and CP may be needed, depending on which factor predominated.