Inflammation, brain damage and visual dysfunction in preterm infants
Introduction
We have previously proposed that brain white matter damage (WMD) might be more common among preterm than term infants, because what leads to prematurity might also contribute to WMD.1 We believe the most plausible common antecedents are perinatal remote infection2 and the subsequent fetal/neonatal inflammatory response.3
Just as we have recently expanded this concept of common antecedents to include neonatal pulmonary disorders,4 we expand it now to include visual dysfunction. In essence, we suggest that inflammation contributes to both WMD, which often leads to central (i.e. brain origin) visual dysfunctions5 and retinopathy of prematurity (ROP), which leads to retinal visual dysfunctions.
Fig. 1 is the centerpiece of this paper. Each of the six boxes (A–F) in Fig. 1 is accompanied by a specific section in the text.
The top row boxes (A, C, E) relate to inflammatory processes. The bottom row boxes (B, D, F) relate to outcome phenomena. We do not suggest that the sequence of A through F represents the exact sequence of events in our scenario. Nor do we specify any sequential order. All we want to convey is a ‘big picture’ of how inflammatory challenges might be involved in long term developmental disabilities. We will focus on the eye and on vision, while keeping the brain in mind. In the final section, not depicted as a box in the figure, we will offer a few thoughts about future research.
Section snippets
White matter damage and retinopathy of prematurity
Among preterm infants, the possibility of damage to the brain and eye is a major concern. For a general overview, the reader is referred to recent reviews of neonatal brain damage,6 ROP7 and other ophthalmological issues in preterm infants.8 Because we will frequently refer to WMD and ROP before we formally arrive at their appropriate section in the text below, these two entities will be briefly defined here. For their relationship with each other and with developmental disabilities, please
Box A: prenatal factors
Much progress has been made over the past decades regarding the aetiological characterisation of infection-associated prematurity.17 In this volume, for example, the focus is on differences between term and preterm birth in the setting of infection/inflammation. The initial proposal that prenatal maternal infection contributes to perinatal brain damage18 has been further expanded to include inflammatory cytokines as the link between the inflammatory stimulus and WMD.1, 19, 20 By and large, a
Box B: preterm birth
Not all preterm birth is equal. The aetiology of prematurity can (and probably should) be conveniently organised by what leads to maternal hospitalisation and subsequent preterm delivery. Such ‘initiators’ of premature delivery (IOPD) are preterm labour (PTL), prelabour rupture of membranes (PROM), pregnancy-induced hypertension (PIH) and other catastrophes such as placental abruption or cord prolapse.29 This view remains controversial.30, 31
We do not hold that any of the IOPD entities is the
Box C: peri-/neonatal infection and/or inflammation
Neonatal infection and sepsis are major clinical problems associated with a high risk of mortality.37 Part of this risk might not be due to the infection itself, but to the potentially adverse effects of the accompanying systemic inflammatory response syndrome (SIRS) instead. Among survivors, neonatal infection and sepsis are also associated with WMD38, 39 and ROP.40, 41, 42, 43
Neonatal non-infectious inflammation might further increase the inflammatory burden. For example,
Box D: white matter damage, retinopathy and cerebral visual impairment
We have not been able to find convincing evidence that neonatal WMD and ROP are associated. This lack of association most probably reflects their different risk patterns. For example, WMD might be associated with both antenatal and postnatal infection/inflammation, while the inflammatory component of ROP might be restricted to either one of these time periods. Such scenarios must remain speculative until large studies are conducted that are designed to look at both risk patterns in both
Box E: sustained inflammation
Usually, the exposure to infection/inflammation is viewed as being a singular event. However, we consider exposure to inflammation more likely to be a continuous challenge for the preterm infant, starting before birth (Box A), continuing throughout the neonatal period (Box C) and perhaps even continuing thereafter (Box E).
Many groups have identified up-regulated pro-inflammatory cytokine expression in the brains of deceased newborns.53, 54, 55, 56, 57, 58, 59 Pro-inflammatory cytokines have a
Box F: developmental disabilities
Most recent studies suggest that the vast majority of surviving extremely preterm infants will suffer considerable impairment at school age.63, 64, 65 While some of these cognitive and learning limitations appear to be a consequence of visual perceptual impairments attributed to WMD,66, 67, 68 others might be due to the motor impairments attributed to WMD.69, 70 Obviously, these two pathways from WMD to cognitive/learning limitations are by no means mutually exclusive.
The visual46, 71 and
Future research issues
At several points in this article, we felt it necessary to indicate the lack of data. Indeed, much needs to be done in this field. A research agenda should target the elucidation of infection/inflammation-induced damage to the eye and visual brain pathways of preterm infants. Here, we offer only a few suggestions for such an agenda.
First, future experimental work could build upon the excellent work done in the area of ROP pathogenesis involving angiogenic growth factors that act as mediators
Acknowledgements
Support for the writing of this paper came from NIH (UO1 NS 40069-01A2) and the Wilhelm Hirte Stiftung, Hannover, Germany.
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2020, Seminars in Fetal and Neonatal MedicineCitation Excerpt :Therefore, the role of intra-amniotic neuroinflammation does not seem to be limited to preterm neonates, a concept that is important given that most cases of cerebral palsy derive from infants born at term. Briefly, the evidence in support of this concept indicates that 1) proven intra-amniotic infection is present in at least 25% of all preterm deliveries [209–215] and in 61% of patients with clinical chorioamnionitis at term [216]; 2) a fetal inflammatory response (diagnosed by the presence of funisitis, elevated concentrations of IL-6 or C-reactive protein in umbilical cord blood) is present in a large fraction of patients with intra-amniotic infection [9,217,218]; 3) there is a strong association between intra-amniotic infection/inflammation and the subsequent development of white matter lesions of the neonatal brain [219–237]; 4) a fetal inflammatory response (diagnosed by funisitis) increases the risk of both periventricular leukomalacia and cerebral palsy [9,20,192–195,238–262]; 5) intrauterine infection with bacteria or intra-amniotic administration of LPS can induce a fetal systemic inflammatory response, neuroinflammation, and lesions resembling periventricular leukomalacia with gliosis and neuronal injury [193,223–225,228,263–265], and this neuroinflammatory process can be observed in animals delivered preterm as well as in those who delivered at term [233,266]; 6) intrauterine administration of bacterial endotoxin has been used to generate an animal model of cerebral palsy, in which there is neuroinflammation [267,268]; and 7) down-regulation of fetal neuroinflammation with the administration of anti-inflammatory agents (e.g. N-acetyl-cysteine) or stem cell-related products can reverse the neuroinflammatory process and the phenotype in animals [269–278]. The relative contributions of fetal inflammation and postnatal inflammation have been the subject of investigation.
Microbes and the womb: Does it matter?
2020, The Developing Microbiome: Lessons from Early LifeThe Intestinal Microbiome
2018, Avery's Diseases of the Newborn: Tenth EditionThe Intestinal Microbiome
2017, Avery's Diseases of the Newborn, Tenth Edition