General characteristics of innate immunity and fetal host response to infection

The innate immune system is primitive and critical for survival. Therefore, during fetal life it develops first before the adaptive im­mune system. It is the first line of defence particularly in the im­mature fetus.

Several biological pathways of intrauterine infection/inflamma- tion leading to fetal and perinatal brain damage have been docu­mented. These pathways clarify the multiple links between maternal and perinatal inflammation, cerebral palsy, and other associated complications. Three newer concepts related to infection/inflam- mation and perinatal brain damage may be considered to put these pathways in perspective:

1. Inflammatory responses of both the fetus and the mother to ascending or blood-b orne intrauterine infections are medi­ated by each individual’s genetically controlled inflammatory process (4).

2. Infection may precede pregnancy or be established very early in pregnancy. Endometrial or decidual infection may remain clin­ically unrecognized and may even persist from one pregnancy to the next (5).

3. The end results of infection/inflammation include cellulitis, abscess formation, thrombosis, embolization, ischaemia, and infarction, but also cell damage from reactive oxygen species and other damaging molecules, altered immune recognition, and apoptosis. The brain-damaging mechanisms may persist and cause damage after the original harmful processes have been removed or corrected (5, 6).

Within the brain, cytokines may also attenuate the fetal blood­brain barrier (7, 8) and mediate transendothelial migration of leuco­cytes and inflammatory damage. The brain phagocytes, microglial cells, express interleukin (IL)-1β, IL-6, and TNF-α in response to stimulation by lipopolysaccharide (9). TNF- α, IL- 1β, and interferon­gamma exert a direct neurotoxic effect on oligodendrocytes progen­itors (10-12), which are destined at maturity to myelinate the axons (white matter) of neural cells, and induce gliosis and release of ni­tric oxide leading to mitochondrial dysfunction and cellular energy failure (13).

Developmental vulnerability to infection-driven brain damage

Several developmental anatomical, metabolic, and immuno- endocrinological factors, act synergistically to promote fetal tissue injury. Developing neurons are vulnerable to insults during the period of neuronal and glial mitosis, the stage of orderly cel­lular migration, and during the formation and organization of the microarchitecture. The premyelination stage appears to be the pe­riod of maximum susceptibility of the oligodendrocyte. In addition, the germinal matrix zone is another developmental structure with increased vulnerability to injury.

The germinal matrix zone is a transient embryonic tissue of the de­veloping fetal brain located immediately adjacent to the lateral vent­ricles and spanning across the vascular boundaries of the cerebral circulation. It involutes at about 32 weeks of gestation. Between 23 and 32 weeks, the motor nerve cells and their axons (white matter) in the matrix are perfused by a loose network of fragile and imma­ture blood vessels, which are supported by only a single cell layer of endothelium with no muscularis or muscle coats.

Collectively, the incompletely developed vascular supply of the cerebral white matter (14), dysregulation of cerebral blood flow related to immaturity (15, 16), and the vulnerability of the oligo­dendroglial precursors to attack by free radicals (17, 18) predispose the preterm brain to pressure-passive circulation and ischaemic in­jury. The end result is a fatal accumulation of reactive oxygen species and apoptotic death ofthe oligodendroglia resulting in neuronal loss.

The developmental predisposition, maturity-dependent patho­physiological mechanisms, and oligodendrocyte vulnerability dis­cussed previously may exert their effects on the premature brain to produce a set of clinical disorders including neonatal depression, periventricular leucomalacia (PVL), cerebral palsy, and IVH. The mechanism through which infection drives fetal brain damage in the term and near-term infant is less well defined but is likely to involve the inflammatory cascade acting synergistically with other factors. Respiratory morbidity in the form of bronchopulmonary dysplasia has also been linked with fetal exposure to intrauterine infection.

Periventricular leucomalacia and cerebral palsy

PVL is the main precursor lesion of cerebral palsy and predicts 60-100% of cases in affected preterm infants (19). It consists of two major components, namely focal, which is located deep in the white matter and characterized by a localized but non-s elective necrosis of all cellular elements with subsequent cyst formation, and the diffuse component, characterized by a more diffuse but se­lective injury directed at the oligodendrocyte precursors (20). The inflammatory mediators of infection and hypoxia-ischaemia exert a direct neurotoxic damage on the oligodendroglial precursors through the generation of reactive oxygen species.

Intraventricular haemorrhage

Fetuses with fetal systemic inflammatory response syndrome (FSIRS) or severe hypoxia-ischaemia lose their autoregulatory capacity required to maintain steady cerebral blood flow (15). The resultant dramatic alterations in the cerebral blood flow may rup­ture the tenuous germinal matrix vasculature with bleeding into the matrix and subsequent extension through the single ependymal cell layer, which separates the matrix zone from the lateral ventricle into the ventricles resulting in IVH (32). Alternatively, the inflam­matory adhesion of leucocytes to the fragile vessels of the matrix zone may lead to vascular damage and bleeding into the germinal matrix. Subsequent ventriculomegaly arising from IVH may further compress adjacent periventricular capillaries causing ischaemia and further white matter damage. Infants with chorioamnionitis and raised amniotic fluid IL-6 have a three- to fourfold increase in the risk of IVH compared to their peers without membrane inflamma­tion (33-35).