Intra-amniotic infections are associated with an increased risk of preterm delivery, which, in turn, may be associated with neurological sequelae in former preterm infants [
80]. Microbial presence in the amniotic fluid may elicit maternal and fetal inflammatory response that are then responsible for neonatal complications. The association between elevated inflammatory cytokines IL-1β and IL-6 in the amniotic fluid and subsequent white matter injury has been noted in preterm infants [
81]. Elevated levels of inflammatory cytokines in the cord blood including IL-1β, IL-6 IL-8, and TNF-α have also been shown to correlate with neonatal cerebral lesions as detected by MRI after parturition in human premature infants [
82]. Furthermore, clinical evidence shows that elevated inflammatory response in the perinatal period has been demonstrated to correlate with long-term neonatal morbidities including cerebral palsy [
83], psychomotor deficits [
8], and non-neurological diseases including necrotizing enterocolitis (NEC) [
84], bronchopulmonary dysplasia [
85], and chronic lung disease [
86,
87] in preterm neonates. However, as previously mentioned, antenatal exposure to infection may not necessarily be associated with an increased risk of adverse outcomes [
11‐
14] and may even have a preconditioning effect [
15,
16] since antenatal assessment of inflammation may be associated with a maternal response during pregnancy and may not truly reflect inflammatory response of the fetus. Dammann et al. [
35] has suggested that cord blood and postnatal serum cytokine levels may reflect different waves of inflammatory responses in the fetal and neonatal circulation respectively and that cytokine levels in the blood may change drastically in the postnatal period. Nelson et al. [
14] demonstrated that elevated inflammatory cytokines TNF-α, IL-1, IL-6, IL-8, along with interferon-γ (IFN-γ), vasoactive intestinal peptide, substance P, and calcitonin gene-related peptides in the neonatal blood correlated with PVL, ventriculomegaly, and severe germinal matric hemorrhage assessed by ultrasonography. Hecht et al. [
88] also demonstrated that the elevation of several blood proteins, cytokines, and chemokine adhesion molecules was associated with white matter lesions. However, Kuban et al. [
89] has noted that transient elevation of any single inflammation-associated cytokine in the blood did not predict cerebral palsy, but recurrent elevation within the first two postnatal weeks increased risk of adverse outcomes in preterm infants. Interestingly, risks of diparesis and hemiparesis were significantly increased when at least four inflammatory blood proteins were elevated during the first two postnatal weeks [
89]. While these blood biomarkers may potentially predict brain lesions in the preterm infants, Ellison et al. [
90] reported that that plasma levels of IL-6, IL-8, IL-10, TNF-α, and IFN-γ were not associated with cerebral spinal fluids of these cytokines nor did such plasma levels reflect brain injury as assessed by MRI. It is suggested, however, that cerebral spinal fluid (CSF) cytokine levels may be a more accurate predictor of cerebral white matter injury as preterm infants with white matter injury had higher CSF levels of IL-6, IL-10, and TNF-α. While elevation of various blood markers has been shown to be associated with white matter injury, these markers are diverse in classification and not necessarily predictive of white matter injury. Expression levels of many of these blood biomarkers are intertwined, thus making it difficult to pinpoint one biomarker that is specific for assessing brain injury. As mentioned previously, dysregulation of the immune system [
40], causing an imbalance in the pro- and anti-inflammatory response, suggests that more than one biomarker may be involved in this process. In addition, the possibility of other organ injuries may interfere with blood assessments that reduce the accuracy in assessing brain injury based only on biomarkers in bodily fluids. Such biochemical assessments, however, may serve as useful screening tools for preterm infants at high risks of developing adverse neurological diseases. The emergence of the imaging techniques to assess brain injury has become prevalent in the clinic; the use of imaging biomarkers may provide a more accurate approach to assess inflammation/injury that is more specific to the brain.