White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: Lessons from experimental ovine models☆
Section snippets
Introduction: Fetal inflammatory response syndrome and brain injury
Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is an important risk factor for white matter injury in the fetal brain [1]. In chorioamnionitis the fetal epithelial organs (i.e. skin, lung, gut) are exposed to intraamniotic microorganisms or endotoxins. These inflammatory stimuli cause local inflammation in the epithelial organs which may evolve systemically, resulting in fetal sepsis and subsequent FIRS. Alternatively, fetal sepsis and FIRS may
FIRS and brain injury — clinical evidence
Chorioamnionitis is an infection of the placental membranes and amniotic fluid and is a frequent cause of preterm birth (before 37 weeks of gestation) [5]. Around 60% of all preterm deliveries are related to intra-uterine inflammation with the incidence of chorioamnionitis increasing with decreasing gestational age [5], [6], [7]. Chorioamnionitis manifests clinically as maternal fever, uterine tenderness and maternal and fetal tachycardia in which the treatment consists of administration of
Animal models
To study the effects of intra-uterine inflammation on fetal brain injury and development, various experimental animal models have been developed [13], [35], [36], [37]. Animal models of maternal inflammation and perinatal brain injury through intranasal, intra-venous, intra-peritoneal, and intra-cervical administration or injections in the uterine wall and uterine horns with different agents, such as viruses, bacteria or bacterial components (LPS) have been described in mice [37], [38], [39],
Pro-inflammatory cytokines
Intra-uterine exposure to infection/inflammation induces a rapid increase in pro-inflammatory cytokines in the maternal serum [67], amniotic fluid [68], [69], fetal serum [70], [71] and in the fetal central nervous system [70], [72]. Although cytokines are physiologically expressed in the normal developing brain [73], it is now clear that dysregulation of the cytokine expression is a major trigger for adverse neurodevelopmental complications [74], [75], [76]. Pro-inflammatory cytokines can
Summary and conclusion
FIRS, induced either by chorioamnionitis or fetal sepsis, is a strong predictor for adverse neurodevelopmental outcomes in both preterm and term infants. Emerging evidence suggest that fetal inflammation can not only lead to white matter injury and cerebral palsy but can also contribute to the development of adult onset diseases such as schizophrenia [34], [74]. The ovine models of intra-amniotic and intravenous administration of LPS, mimicking chorioamnionitis and fetal sepsis respectively,
Conflict of interest
None of the authors have a conflict of interest.
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2022, Experimental NeurologyCitation Excerpt :The remaining oligodendrocyte precursors exhibit dysregulated maturation by failing to myelinate axons (Yap & Perlman, 2020; Buser et al., 2012). Additionally, the immature oligodendrocytes are more susceptible to further neuroinflammatory damage from free radicals and excitotoxicity (Kuypers et al., 2012; Yap & Perlman, 2020; Volpe et al., 2011; Chau et al., 2014). Though much work has been done to understand the pathophysiology of PBI in the setting of chorioamnionitis, the underlying molecular mechanisms eliciting inflammation through the placental-fetal-brain axis remain unknown and therefore lack therapies to mitigate CNS injury.
Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model
2021, American Journal of Obstetrics and GynecologySuccessful use of an artificial placenta–based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation
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2020, Seminars in Fetal and Neonatal MedicineCitation Excerpt :Pro-inflammatory cytokines may cause direct injury to oligodendrocytes and neurons, while causing secondary injury through microglial activation. In addition, these cytokines may influence the integrity of the newborn's blood-brain barrier, further exposing the brain to developmental insults [21,22]. Many co-morbidities in the preterm newborn such as necrotizing enterocolitis (NEC), late onset sepsis, and bronchopulmonary dysplasia (BPD) are also associated with brain damage, adding to the complexity of interactions that result in brain injury.
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Sources of financial support: Veni BWK 016.096.141 from the Dutch Scientific Research Organization and the Research School for Oncology and Developmental Biology (GROW), Maastricht University.
Condensation: This review summarizes the clinical and experimental evidence on the effects of chorioamnionitis and fetal sepsis on fetal brain injury.