Review: Neuroinflammation in intrauterine growth restriction

doi:10.1016/j.placenta.2016.11.012

Placenta

Volume 54, June 2017, Pages 117-124

https://doi.org/10.1016/j.placenta.2016.11.012 Get rights and content

Abstract

Disruption to the maternal environment during pregnancy from events such as hypoxia, stress, toxins, inflammation, and reduced placental blood flow can affect fetal development. Intrauterine growth restriction (IUGR) is commonly caused by chronic placental insufficiency, interrupting supply of oxygen and nutrients to the fetus resulting in abnormal fetal growth. IUGR is a major cause of perinatal morbidity and mortality, occurring in approximately 5–10% of pregnancies. The fetal brain is particularly vulnerable in IUGR and there is an increased risk of long-term neurological disorders including cerebral palsy, epilepsy, learning difficulties, behavioural difficulties and psychiatric diagnoses. Few studies have focused on how growth restriction interferes with normal brain development in the IUGR neonate but recent studies in growth restricted animal models demonstrate increased neuroinflammation. This review describes the role of neuroinflammation in the progression of brain injury in growth restricted neonates. Identifying the mediators responsible for alterations in brain development in the IUGR infant is key to prevention and treatment of brain injury in these infants.

Introduction

Intrauterine growth restriction (IUGR) is a major cause of perinatal morbidity and mortality and occurs in approximately 5–10% of pregnancies [1], [2] with even higher rates (21%) reported in the developing world [3]. IUGR is generally defined as a fetus that fails to achieve appropriate growth potential due to genetic or environmental factors. It is characterised by fetal weight dropping over time across growth percentiles; by birth most IUGR infants weigh less than the 10th percentile for gestational age. Chronic placental insufficiency is a common cause of IUGR. Placental insufficiency or utero-placental dysfunction results in insufficient blood flow to the placenta during pregnancy and inadequate supply of nutrients and oxygen to support normal growth of the fetus. Thus, the fetus develops in a chronic hypoxic environment. Placental insufficiency can result in changes fetal metabolism, hormones, hematology, immunology and cardiovascular function.

The adverse fetal environment can significantly affect the developing brain. In a chronic hypoxic environment, fetal circulatory redistribution occurs; blood flow is selectively redirected to the brain and away from other organs to maximise oxygen and nutrient supply. This type of growth restriction is referred to as ‘brain-sparing’ or asymmetric IUGR because the body is disproportionately smaller than the head. Asymmetrical IUGR is the most common form of growth restriction affecting 70–80% of all IUGR infants with disruption to fetal growth occurring mainly in the third trimester. Symmetric IUGR accounts for 20–25% of all IUGR fetuses and is characterised by a global growth restriction throughout pregnancy. Brain-sparing has been regarded as a protective mechanism in the IUGR fetus to protect and promote brain development but recent evidence has challenged this idea (reviewed in Ref. [4]). Several studies have demonstrated that asymmetric IUGR infants i.e. those with ‘brain-sparing’, have worse neurodevelopmental outcomes than symmetric IUGR infants [5], [6], [7], [8], [9], [10].

Section snippets

Brain injury in IUGR

The fetal brain is particularly vulnerable to the effects of IUGR [11]. Long-term neurological disorders such as cerebral palsy (CP) and epilepsy, as well as learning and attention difficulties, neurobehavioural disabilities, and other cognitive issues have been attributed to restricted growth of the fetus [12], [13], [14], [15]. A four-to six-fold increase in CP has been shown in IUGR neonates [14] with others reporting up to a 30-fold increase [16]. The long-term care of a child with

Mechanisms of neuronal injury

Few studies have focused on the detailed mechanisms of brain injury in the IUGR neonate which is surprising given the high proportion of IUGR infants who exhibit adverse long-term neurological outcomes [18], [19]. There is a considerable paucity of data from human autopsy tissue of the pathology of the human IUGR brain. A classical study of six term IUGR infants demonstrated a reduction in myelin lipids and DNA content (used as an estimate of cell number) in cerebrum-brainstem and cerebellum

Inflammation in the IUGR brain

Recent studies in animal models of growth restriction have reported increased numbers of activated microglia and astrogliosis, indicative of inflammatory responses in the IUGR brain (Table 1) [22], [23], [24], [25], [26], [27], [31], [39], [40]. Neuroinflammation encompasses a number of processes including increased numbers of activated microglia, elevated production of proinflammatory cytokines (particularly interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α)) [41], [42], [43],

Proinflammatory cytokines

Proinflammatory cytokines are shown to play a critical role in acute HI brain injury and may cause and/or exacerbate brain damage to the fetal and neonatal brain. The on-going presence of increased levels of proinflammatory cytokines contributes to white matter damage as well as neuronal damage after acute neonatal HI [41], [48], [53], [55], [56]. In the preterm infant, the occurrence of CP has been attributed, at least partially, to increased levels of proinflammatory cytokines in the brain

Activated microglia

Microglia are the first inflammatory cells that respond to hypoxic events in the neonatal brain [72]. Microglial cells are resident macrophages in the brain and are present in large numbers in the developing brain. Microglia are involved in cellular pruning during both normal development and pathological conditions. Resting (ramified) microglia in the neonate have multiple processes with a small cell body [73]. Microglial cells function to defend against infections or toxic substances released

Conclusion

Chronic deprivation of oxygen and nutrients to the developing fetus through altered placental function has dramatic consequences on fetal brain development. Activation of inflammatory pathways both systemically and in the brain are thought to play a key role in altered brain development and may contribute to the poor neurodevelopmental outcomes associated with chronic placental insufficiency [67], [68]. Understanding how the IUGR brain is damaged by examining where inflammation is occurring,

Funding

This work was supported by The University of Queensland Medicine and Biomedical Sciences Emerging Leaders grant and Royal Brisbane and Women's Hospital Foundation research grant.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Acknowledgements

This review was generated as part of the Queensland Perinatal Consortium Inaugural Conference held on July 15th, 2016 in Brisbane, Queensland Australia. The conference was supported by an Intra-Faculty Collaborative Workshop grant from the Faculty of Medicine, The University of Queensland. The authors thank Sydney Peterson for assistance with Table 1.

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IUGR newborns show a vulnerable immature brain exposed to exaggerated inflammation uncontrolled by the microglia [160]. Research on neuroinflammation reveals growing evidence of early molecular impact of IUGR condition on the perinatal brain [161]. Despite human birth cohorts and animal data, literature reporting neurocognitive outcomes at adulthood is scarce.
Intrauterine growth restriction (IUGR) affects 10–15% of all pregnancies worldwide. IUGR may result from maternal, placental or fetal origin. Maternal malnutrition before and during pregnancy represents the most prevalent non-genetic or placental cause. IUGR reflects an abnormal adaptive fetal growth in a deleterious environment. Individuals born after IUGR are more susceptible to develop diseases related to subsequent stressors through a lifetime. Animal models help to decipher the underlying causes of dysregulated pathways and molecular modifications conditioning health and disease in adult offspring born after IUGR. The aim of this review is to summarize current knowledge on long term consequences of IUGR, integrating animal models and human studies for a better care of IUGR-born individuals in a life course perspective.

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Review: Neuroinflammation in intrauterine growth restriction

Abstract

Introduction

Section snippets

Brain injury in IUGR

Mechanisms of neuronal injury

Inflammation in the IUGR brain

Proinflammatory cytokines

Activated microglia

Conclusion

Funding

Conflict of interest statement

Acknowledgements

J. Pediatr.

Int. J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci.

Semin. Perinatol.

Lancet

Eur. J. Paediatr. Neurol. EJPN Off. J. Eur. Paediatr. Neurol. Soc.

NeuroImage

Brain Res.

Behav. Brain Res.

Neurobiol. Dis.

Exp. Neurol.

Neuroscience

Int. J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci.

Int. J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci.

Int. J. Dev. Neurosci.

J. Neuroimmunol.

Neuroscience

Neuroscience

Brain Res.

Behav. Brain Res.

Pediatr. Neurol.

Brain Dev.

Brain Res.

Dev. Brain Res.

Exp. Neurol.

Brain Res.

Brain Res.

Dev. Brain Res.

Australia's Mothers and Babies 2004 Cat. No. PER 34

Intrauterine growth retardation, health and nutrition emerging and reemerging issues in developing countries 2020

Focus

Brain-sparing in intrauterine growth restriction: considerations for the neonatologist

Neonatology

Cerebral blood perfusion and neurobehavioral performance in full-term small-for-gestational-age fetuses

Am. J. Obstet. Gynecol.

Neurodevelopmental outcome in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution

Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol.

Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing

Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol.

Middle versus anterior cerebral artery Doppler for the prediction of perinatal outcome and neonatal neurobehavior in term small-for-gestational-age fetuses with normal umbilical artery Doppler

Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol.

What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population

Am. J. Epidemiol.

Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review

BJOG Int. J. Obstet. Gynaecol.

Neuropsychological outcome of children with intrauterine growth restriction: a 9-year prospective study

Pediatrics

Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks' gestation

Am. J. Obstet. Gynecol.

Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction

Pediatr. Res.

Brain growth gains and losses in extremely preterm infants at term

Cereb. Cortex

Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury

J. Neurosurg. Pediatr.

Brain injury caused by chronic fetal hypoxemia is mediated by inflammatory cascade activation

Reprod. Sci.

Prenatal ischemia and white matter damage in rats

J. Neuropathol. Exp. Neurol.

Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats

Pediatr. Res.