Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant

This review synthesizes the literature supporting the hypothesis that infection during or even before pregnancy remote from the fetal brain leads to neonatal white matter damage (NWMD) and its long-term sequelae, including cerebral palsy. First, a framework of five dimensions is presented, including the spectrum of NWMD, its relationship with gestational age, its clinical spectrum, the expressions and correlates of infection, and the mother/child dyad. Second, a summary of the plethora of support for the remote infection/NWMD-hypothesis is presented by drawing on studies published over the past three decades. Although an epidemiological perspective is prominent, we invoke molecular explanations (especially the cytokine hypothesis) for observed associations. Third, the article concludes with a section on future studies needed to characterize and eliminate (pre-) pregnancy infections in the mother and to identify and evaluate potentially neuroprotective strategies in the fetus.