Elsevier

Early Human Development

Volume 88, Issue 12, December 2012, Pages 931-936
Early Human Development

White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: Lessons from experimental ovine models

https://doi.org/10.1016/j.earlhumdev.2012.09.011Get rights and content

Abstract

Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is closely related to the development of white matter injury in the fetal brain. Large epidemiological studies support the link between FIRS and fetal brain injury with a clear association between the presence of in utero inflammation and neurodevelopmental complications such as cerebral palsy, autism and cognitive impairments later in life.

Translational animal models of chorioamnionitis and fetal sepsis are essential in understanding the underlying pathophysiological mechanisms of fetal brain injury after exposure to intra-uterine inflammation. Concerning this aspect, ovine models have high translational value since neurodevelopment in sheep closely resembles the human situation.

In this article, we will review clinical and experimental evidence for the link between FIRS and white matter injury in the fetal brain. With respect to experimental findings, we will particularly focus on the lessons learned from ovine models of chorioamnionitis and fetal sepsis. We also highlight two key players implied in the pathophysiology of white matter injury after in utero exposure to inflammation.

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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    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.

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