ReviewInflammatory brain damage in preterm newborns—dry numbers, wet lab, and causal inferences☆
Introduction
The goal of this paper is to integrate three different aspects of the hypothesis that antenatal infection/inflammation is involved in brain white matter damage (WMD) causation in preterm infants. A short background section is followed by “dry numbers” summarizing epidemiologic data without providing details that can be found in previous reviews [1], [2], [3]. The next section is about experimental data from the “wet lab”. We end with the causal inferences we can probably draw based upon the data presented. The overview provided in this paper is neither complete nor exhaustive. Instead, we offer our personal views based on data from observational and experimental studies.
Section snippets
Background
White matter damage can be defined as focal or diffuse on both cranial ultrasound [4] and neonatal magnetic resonance imaging (MRI) [5]. Cerebral palsy (CP), the major motor handicap associated with white matter damage (WMD) in preterm newborns [6], is much more frequent in extremely immature newborns than in infants born at term [7]. So, too, is WMD [8]. These inter-relationships among prematurity, WMD and CP have led epidemiologists to focus on preterm populations in their search for
Dry numbers: the epidemiologic evidence
Modern epidemiology is “occurrence research in medicine” [26]. As such, epidemiologic research has contributed considerably to our current knowledge about WMD/CP occurrence. It has also contributed to our understanding of the association between antenatal infection, inflammatory responses, and WMD/CP risk. In this section, we outline a suggested structure that includes inflammatory responses on the maternal and fetal/neonatal levels (Table 1) and offer examples from among the many studies that
Wet lab: the experimental evidence
Experimental models of WMD have been developed using infectious, hypoxic–ischemic and excitotoxic insults [51]. Some of these experimental data suggest that lipopolysaccharide (LPS)-induced WMD is associated with a much more prominent neuroinflammatory response than damage induced by hypoxia–ischemia [51]. In one rabbit model of remote intrauterine infection [52], focal cystic, but not diffuse WMD was associated with a prominent neuroinflammatory response. However, in light of the potential
Causal inference
In light of the preceding sections that discuss the epidemiologic and experimental evidence, we still need to answer the question, Is infection/inflammation a cause of brain damage in preterm newborns? In this section, we first discuss some basic principles about causal inference based largely on epidemiologic data. We then suggest that one should not look for criteria for what must be a cause, but for evidence in support of the notion that a factor might be a cause. Much of this perspective is
Acknowledgements
Preparation of this article wassupported by grants from the National Institutes of Health (NS040069), Wilhelm Hirte Stiftung, and Hannover Medical School (HiLF).
References (88)
- et al.
White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study
J. Pediatr.
(2003) - et al.
Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm
Lancet
(1999) - et al.
Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques
J. Pediatr.
(1999) - et al.
A review of premature birth and subclinical infection
Am. J. Obstet. Gynecol.
(1992) Pre-term labor: An intra-uterine inflammatory response syndrome?
J. Reprod. Immunol.
(1997)- et al.
Infection and prematurity and the role of preventive strategies
Semin. Neonatol.
(2002) - et al.
Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant
Semin. Pediatr. Neurol.
(1998) - et al.
Immune mechanisms in the pathogenesis of cerebral palsy: implication of proinflammatory cytokines and T lymphocytes
Eur. J. Paediatr. Neurol.
(2002) Pathways of fetal and early neonatal infection
J. Pediatr.
(1961)- et al.
Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years
Am. J. Obstet. Gynecol.
(2000)
Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia
Pediatr. Neurol.
Characteristic neuropathology of leukomalacia in extremely low birth weight infants
Pediatr. Neurol.
High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia
Am. J. Obstet. Gynecol.
Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy
Am. J. Obstet. Gynecol.
Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia
Am. J. Obstet. Gynecol.
Possible correlation between high levels of IL-18 in the cord blood of pre-term infants and neonatal development of periventricular leukomalacia and cerebral palsy
Cytokine
Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions
Lancet
Do white cells matter in white matter damage?
Trends Neurosci.
Patterns of cerebral inflammatory response in a rabbit model of intrauterine infection-mediated brain lesion
Brain Res. Dev. Brain Res.
Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten
J. Neurol. Sci.
Maternal endotoxemia, fetal anomalies, and central nervous system damage: a rat model of a human problem
Am. J. Obstet. Gynecol.
Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain
Schizophr. Res.
Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits
Am. J. Obstet. Gynecol.
The effect of systemic administration of lipopolysaccharide on cerebral haemodynamics and oxygenation in the 0.65 gestation ovine fetus in utero
BJOG
Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide
Brain Res. Dev. Brain Res.
Differential roles of tumor necrosis factor-alpha and interleukin-1 beta in lipopolysaccharide-induced brain injury in the neonatal rat
Brain Res.
Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats
Brain Res.
Mediators of fetal inflammation in extremely low gestational age newborns
Cytokine
Systematic review of chorioamnionitis and cerebral palsy
Ment. Retard. Dev. Disabil. Res. Rev.
Role of the fetus in perinatal infection and neonatal brain damage
Curr. Opin. Pediatr.
Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm
Ment. Retard. Dev. Disabil. Res. Rev.
Neuroimaging in the preterm infant
Ment. Retard. Dev. Disabil. Res. Rev.
Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality
Pediatrics
Cerebral palsy
N. Engl. J. Med.
Changing panorama of cerebral palsy in Sweden: VIII. Prevalence and origin in the birth year period 1991–94
Acta Paediatr.
Psychological findings in preterm children related to neurologic status and magnetic resonance imaging
Pediatrics
Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight
Arch. Dis. Child
Neurology of the Newborn
Infection and preterm labor
Clin. Obstet. Gynecol.
Intrauterine infection and preterm delivery
N. Engl. J. Med.
Intrauterine infection and prematurity
Ment. Retard. Dev. Disabil. Res. Rev.
Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?
Dev. Med. Child Neurol.
Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn
Pediatr. Res.
Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system
Neuropathology
Cited by (150)
Oxytocin as a neuroprotective strategy in neonates: concept and preclinical evidence
2024, Gynecologie Obstetrique Fertilite et SenologiePerinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations
2022, Experimental NeurologyCitation Excerpt :The relationship between PTB, inflammation, brain injury, and CP was first suggested in 1955 by Eastman et al., with the observation that CP was associated with premature delivery and that intrapartum maternal fever was seven times as likely in infants later found to have CP compared with afebrile controls (Eastman and DeLeon, 1955). More recently, reports from clinical and epidemiologic investigations in combination with novel animal studies, continue to suggest strong relationships between maternal and/or fetal inflammation, PTB and brain injury in offspring (Strunk et al., 2014; Bear and Wu, 2016; Wu and Colford, 2001; Dammann and Leviton, 2000; Dammann, 2007; Dammann and Leviton, 2004; Dammann and O’Shea, 2008; Leviton et al., 2005; Leviton et al., 1976; Dammann and Leviton, 2014; Leviton et al., 2018a; Yoon and Romero, 1996; Yoon et al., 1997a; Chaiworapongsa et al., 2002). Despite abundant evidence, there are still significant gaps in our biological understanding of these associations.
Extreme prematurity: Risk and resiliency
2022, Current Problems in Pediatric and Adolescent Health CareSystemic and topical glucocorticoids to prevent BPD
2020, Tantalizing Therapeutics in Bronchopulmonary Dysplasia
- ☆
Based on a lecture given at the Spring Meeting of the Neonatal Society (London, 17 March 2004) and the 3rd Nordic CME in Neonatology (Oslo, 18 March 2004).