These findings highlight the possible relationship between HCA and inflammatory and haematological markers in the maternal, cord and neonatal circulation. In the majority of mothers, HCA was asymptomatic and associated with a modest increase in hsCRP, but not in PCT levels. In umbilical cord blood, HCA was associated with increased PCT and hsCRP, but did not affect cord white cell count or absolute neutrophil count. However, there was a significant increase in inflammatory and haematological markers in infants exposed to HCA without early onset sepsis, peaking at 24 h of age. Histological choriomanionitis may therefore result in sustained inflammatory changes in the neonatal circulation, in the absence of microbiologically diagnosed infection.
The observation of higher CRP but no difference in PCT in the mothers with HCA is in keeping with many previous studies, although data are not uniformly consistent and most studies are on pregnancies complicated by prolonged rupture of membranes 
. The methodology of studies investigating maternal CRP in diagnosing HCA varies, particularly in relation to the CRP cut-off values 
, and there are few data on hsCRP 
. Although there appears to be significant differences in maternal CRP levels in those with and without HCA, the considerable overlap between these groups may limit the clinical utility of CRP in diagnosing HCA 
. In infants exposed to HCA we found significant differences in PCT, and to a lesser extent, hsCRP concentrations cord blood. The discrepant CRP and PCT findings between mothers and infants may reflect differential regulation of CRP and PCT production by placental cytokines 
. In addition the kinetics of CRP and PCT differ; PCT is synthesised more quickly and CRP degrades more slowly 
. Serial CRP and PCT measurements postnatally in infants exposed to HCA may be informative.
Perinatal inflammation is associated with increased umbilical cord inflammatory cytokines including interleukin (IL)-6 and acute phase reactants such as CRP 
, but the impact on inflammatory markers in the early neonatal period is less well-described. Placental inflammation in extremely preterm newborns is associated with elevation in concentrations of acute phase reactants during the first three days after birth 
. Our data suggest that even in infants without obvious evidence of bacterial infection, the response to perinatal inflammation persists postnatally and may be sufficient to cause clinically significant changes in acute phase reactants. The peak CRP occurred on day 1, reflecting the kinetics of CRP production - detectable within 6 h and peaking at approximately 48 h 
Procalcitonin, like CRP, is regulated by cytokines that increase early in HCA 
. In adult intensive care, PCT may have advantages over CRP in differentiating bacterial infection from other causes of inflammation 
. Here we report that cord PCT concentrations were significantly higher in neonates exposed to HCA. Although our study aimed to investigate the more common influences on PCT and neonatal PCT is not routinely measured, our data suggest that gestational age, small for gestational age and length of labour and HCA account for almost half of the variation in cord PCT levels, which therefore may limit its utility in the diagnosis of early neonatal infection. There are few data on PCT and HCA. One study reported that HCA did not influence cord PCT levels, but was associated with a post-natal increase in PCT at 72 h and 7 days 
. Although higher PCT levels are reported in infants who subsequently develop sepsis 
, these studies did not examine placental histology.
Histological chorioamnionitis was associated with increased absolute neutrophil in the first 48 h of life, consistent with other data 
. There was marked overlap in WCC and ANC between HCA and non-HCA groups, limiting their clinical utility in identifying HCA and in diagnosing EOS in HCA-exposed infants.
The strengths of our study include quantification of HCA by an experienced perinatal histopathologist, blinded to outcomes and analysis of parameters commonly used in clinical practice in maternal, fetal and post-natal samples. We acknowledge some limitations, most importantly the non-representative nature of our sample, which reflected the resources available to recruit mothers and infants and to process samples. We therefore enrolled a relative over-representation of moderately preterm infants and of those born by caesarean section. Therefore, and despite the overall sample size, there were fewer cases of HCA than we have previously observed in a more preterm cohort drawn from the same population 
, and thus there was some reduced power and limitation in the number of variables used in regression modelling. The lower frequency of HCA was likely due in part to the over-representation of elective caesarean sections and elective deliveries for multiple pregnancies, and under-representation of spontaneous vaginal deliveries and extremely preterm infants. As HCA predominantly occurred as expected in spontaneous preterm, singleton vaginal deliveries, the findings reflect the overall maternal and neonatal response to HCA, but inclusion of extremely preterm infants would be additionally informative, as this group has a higher incidence of HCA and of neonatal infection. Further studies in a larger unselected preterm population are therefore necessary to confirm our findings. Placental samples were not available from all deliveries, although this is less likely to introduce a systematic bias, as placental histology is part of routine clinical practice in all deliveries less than 34 weeks gestational age and from all placentae successfully collected as part of the study, irrespective of gestational age or clinical features. The higher prevalence of antenatal steroids in the mothers with HCA may have diminished the extent of inflammation, thus dampening the effect of HCA on inflammatory biomarkers. Despite this, our study did find higher CRP concentrations in newborns exposed to HCA. Maternal blood contamination of cord blood samples is also unlikely to have been a major limitation; our sampling protocols aim to reduce maternal blood contamination of cord blood, which largely reflects the fetal circulation at late gestation 
. As postnatal CRP was only measured on infants who were clinically suspected of having sepsis, a significant proportion of neonates did not have CRP measured postnatally, precluding regression analysis of post-natal CRP data. It would be of interest for future studies to investigate inflammatory markers in all infants exposed to HCA, irrespective of whether infection was clinically suspected.
Histological chorioamnionitis has differential effects on maternal and cord/neonatal inflammatory markers. In the newborn exposed to HCA, CRP, white cell count and absolute neutrophil count are increased when compared to newborns without HCA. This may confound the interpretation of these common diagnostic markers of early neonatal sepsis. Further investigations in larger unselected populations of preterm infants, with serial measurement for a longer period of hsCRP and PCT, irrespective of suspected sepsis, would be informative about the effects of HCA on postnatal inflammatory markers and would refine the use of plasma and haematological markers in the diagnosis of neonatal infection.