Review
Inflammatory brain damage in preterm newborns—dry numbers, wet lab, and causal inferences

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Abstract

Epidemiologic observations support the contention that infection, inflammation, and neonatal white matter damage (WMD) are associated. We also have documentation from multiple experimental models that infection/inflammation can damage developing white matter. Based on these observations in humans and animals, we offer causal inferences using widely accepted causal criteria and the multivariable model of causation. As much as we want to, however, we are reluctant to state unequivocally that inflammation causes WMD in humans born much before term. The main reason is that we lack convincing evidence that inflammation precedes WMD (temporal evidence). We also need more (and more detailed) observational studies clarifying the presumed infection→inflammation→WMD sequence before we can initiate intervention trials to reduce the risk of WMD.

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).

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    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).

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