Fetal Inflammation and Brain Injury in the Premature Infant: A Complicated Relationship and a Major Postnatal Challenge for Neonatology

October 2025

Introduction

Four recent reports address the potential relationships between fetal systemic inflammation and brain injury, especially white matter injury (WMI), in the premature infant.^1-4 In these reports, fetal systemic inflammation is identified by placental features. The principal placental findings include neutrophilic infiltration into the umbilical cord (funisitis) or chorionic plate vessels (chorionic vasculitis), consistent with a fetal inflammatory and potentially ischemic insult. The clinical correlate, initially described by Romero et al. ,⁵ is intrauterine infection, typically with organisms of the female genital tract, as well as such bacteria as E. coli or B-streptococcus, and a fetal inflammatory response characterized by elevated cytokines, e.g., interleukin-6. Overall, the findings of three of these reports suggest that fetal systemic inflammation may lead to structural brain abnormalities in the premature infant by term equivalent age (TEA) or to impaired neurological development at two years of age or both.^1,2,4 The findings of the fourth report³ suggest particular importance for postnatal illness in determining outcome.

In the following, I will describe briefly the four reports and then consider the overall issue of the potential relations of fetal systemic inflammation (hereafter termed fetal inflammatory response or FIR) and brain injury in the premature infant. Because cerebral WMI is the most common neuropathological feature of brain injury in the premature infant and has been the principal focus of previous reports on determinants of brain abnormality in premature infants, I will emphasize WMI in the discussions to follow.

Fetal Inflammatory Response and Neonatal Brain MRI Abnormalities

The first report, entitled “Impact of fetal inflammatory response on brain MRI abnormalities in extremely preterm infants,”² addressed the relation of “fetal inflammatory response (FIR) severity” to MRI brain abnormalities identified at TEA. A prospective cohort of 141 extremely preterm (<29 weeks gestational age) infants was studied. FIR was present in 59 (42%), with 46 (78% of the FIR group and 33% of the total cohort) exhibiting severe FIR. FIR severity was determined by placental assessment and classified according to criteria established by the Amsterdam Placental Workshop Group Consensus Statement.⁶ MRI was scored according to the Kidokoro criteria.⁷

Abnormal MRI findings were associated with severe FIR (and not with mild FIR or no FIR) and consisted of mild “myelination delay,” “corpus callosum thinning,” and “volume reduction.”² A mild diminution of cerebellar cross-sectional diameter also was noted. The findings suggest a modest impairment of cerebral white matter development and cerebellar growth in infants who had severe FIR. These developmental events are active postnatally in the premature infant and well known to be vulnerable to a variety of postnatal insults.^8,9 Infants with FIR had slightly lower gestational age and five-minute Apgar scores and increased occurrence of symptomatic patent ductus arteriosus. The authors indicate that multivariate linear regression analysis confirmed a significant independent effect of FIR on brain abnormality scores. The final conclusion was that “this study is the first to link FIR severity to MRI brain abnormalities in extremely preterm infants, highlighting FIR as a risk factor for brain injury and delayed maturation.”²

Because space requirements do not allow me to critique this major clinical research effort in detail, the findings strike me as definitive but not marked. Nonetheless, the work sets the stage for future research with more advanced MRI measures.

Fetal Inflammatory Response and Neurodevelopmental Outcomes

The second report addresses a retrospective cohort of infants born <29 weeks (n=559) to determine the neonatal outcome with placental pathologic evidence of FIR.¹ The placental assessment was carried out as described for the study of Mir et al. (just described) and utilized the same rigorous criteria to identify FIR. Neurodevelopmental assessment was carried out at two years of age.

Twenty-eight percent of the group exhibited placental evidence of FIR.¹ Notably, infants with FIR had longer duration of hospitalization, more days on oxygen, and more moderate/severe bronchopulmonary dysplasia. Overall, infants with FIR were not at increased risk of motor or language impairment. However, among infants with severe FIR (“> stage 2 FIR,” 23% of the entire cohort), there was a slightly increased risk for moderate language impairment or death. These infants with severe FIR accounted for 20% of those with moderate neurodevelopmental impairment or death in the entire study cohort, a small but appreciable portion. The authors concluded that an association between severity of FIR and subsequent neurodevelopmental impairment was demonstrated. Admittedly, the relation is not dramatic.

Fetal Inflammatory Response and Death or Cerebral Palsy

The third report addresses data from a multicenter cohort of preterm infants (22 to 26-6/7 weeks’ gestational age, n=6,949).⁴ The composite outcome was death or cerebral palsy identified at 22 to 26 months corrected age. The particular emphasis of this report was the occurrence of funisitis (the well-accepted placental correlate of FIR), considered present if histological examination of the umbilical cord or vessels was documented. Of the total group, 1,057 (28%) had funisitis. On multivariable analysis, exposure to funisitis was associated with a higher risk of death or cerebral palsy (relative risk: 1.23 [1.04, 1.51]), primarily mediated by preterm birth. Concerning cerebral palsy specifically, exposure to funisitis was associated with a higher risk (25.9% vs. 20.9%) (relative risk: 1.23 [1.05, 1.12]). This association was partially (40%) mediated by preterm birth. There was no significant difference in incidence of moderate to severe cerebral palsy or in Bayley cognitive or motor composite scores among those with or without acute funisitis. There was no significant difference in severe intraventricular hemorrhage (IVH) or “white matter injury on neuroimaging” (“sonogram, MRI or CT scan done closest to 36 weeks corrected age and when clinically indicated”).

Thus, in this large cohort, funisitis was associated with a modestly increased risk of death or cerebral palsy and no increased risk of moderate to severe cerebral palsy, lower Bayley cognitive or motor composite scores, severe IVH or apparent WMI. An appreciable role for preterm birth in mediation of these effects was recognized.⁴

Relation of Inflammatory Etiology of Preterm Birth to Neonatal MRI Findings and to Neurodevelopmental Outcome

The fourth report addressed the relations between the presumed etiology of preterm birth and brain injury (assessed by MRI) and neurodevelopmental outcome.³ The prospective cohort was 222 infants born at 24-32 weeks’ gestation. The presumed etiology of preterm birth was defined by placental histopathology, carried out by an “experienced placental pathologist,” for the presence of chorioamnionitis, degree of placental inflammation, and presence of vascular changes (“ischemic and/or hemorrhagic”). Acute histologic chorioamnionitis and maternal vascular malperfusion were identified according to conventional criteria. Importantly, MRI studies were carried out at a median age of 21 days and 89 days (approximately TEA), a major benefit of this report. The presumed etiology of preterm birth as defined by placental histology consisted of inflammatory (38%), vascular (26%), multiple gestation (25%), or idiopathic (11%). Neurodevelopmental follow-up was carried out at 3 years and 4.8 years.

The findings were of considerable interest. Cognitive outcome at 3 years was marginally lower in the inflammatory group relative to the multiple gestation group. However, at 4.5 years, there were no significant associations between preterm birth etiology and cognitive and motor outcomes. Newborns in the idiopathic group had the highest incidence of moderate to severe WMI (35%), whereas infants in the inflammatory group exhibited WMI in only 20%. WMI volumes did not differ across the preterm birth (PTB) etiology groups. The authors conclude that “presumed PTB etiology (using integrated clinical phenotype and placental pathology) suggests that postnatal morbidities are more significant in determining neurodevelopmental outcomes than the initial PTB cause.” A similar conclusion was reached in a comprehensive study of histologic chorioamnionitis by Bierstone et al.¹⁰ Although a commentary accompanying the report of El Shahed et al.³ faulted the study because of the somewhat limited definition of placental inflammation,¹¹ the depth and breadth of the work overall are noteworthy.

Key Mechanistic Questions Raised by the Recent Clinical Reports

These reports raise several important questions that I will address in the following. Firstly, what is the evidence from experimental models to support the notion that fetal inflammation can lead to or contribute to brain injury in the premature infant? Secondly, what are the principal cellular mediators in brain in pathogenesis of such injury? Thirdly, what is the relation between fetal inflammation and the action of injurious postnatal insults? Study of experimental models and of human infants has provided insights into these issues.

            Experimental Studies

Experimental support is available for the notion that fetal systemic inflammation can lead to perinatal brain injury with similarities to that identified postnatally in premature infants, i.e., the encephalopathy of prematurity, especially WMI.^12-19 Two experimental models have been utilized most frequently, i.e., exposure to E. coli or, especially, the lipopolysaccharide of the E. coli cell membrane, or to the pro-inflammatory cytokine, interleukin-1β (IL-1β). The models have included the developing rat, preterm fetal sheep, and preterm rhesus macaque. The consistent findings include elevation of pro-inflammatory cytokines, microglial activation, astrocytosis, subsequent death or injury to premyelinating oligodendrocytes (pre-OLs) and later impairment of oligodendroglial development and/or myelination. These neuropathological results are similar to those observed in premature infants with the neuropathological and imaging characteristics of the encephalopathy of prematurity, especially WMI.^20,21 (Recall that the principal cellular target in cerebral WMI is the pre-OL, the dominant oligodendroglial cell type in the brain of the extremely preterm infant.^20,21 At approximately 30 weeks, the more differentiated immature oligodendrocyte begins ensheathment of axons and differentiates around term to the myelin-producing, MBP+ cell. Of the entire lineage, the pre-OL is the most vulnerable to hypoxia, ischemia, hyperoxia and inflammation because of specific maturation-dependent features, i.e., overexpression of Ca⁺⁺-permeable excitatory amino acid receptors and deficient anti-oxidant defenses.^20,21)

Extrapolation of the experimental findings to the human fetus and premature newborn is difficult. Issues related to (1) cytokine effects on systemic circulatory function and regulation of cerebral blood flow, and (2) exposures to cytokines during time periods of brain development in the animal model that are prolonged relative to the relevant time periods in the human fetus²¹ are among several difficulties concerning relevance. Nonetheless, the models do suggest the distinct possibility that the fetal inflammatory response in the human sets the stage for the occurrence of brain injury postnatally. Importantly, such injury could result from postnatal insults that would not lead to injury in the absence of the inflammatory events initiated in utero. The importance of prenatal inflammation leading to potentiation of injurious postnatal insults (hypoxia, ischemia, hyperoxia) has been well-documented in several experimental models (see later).^22-33

            Human Studies

That the central role of microglia, reactive astrocytes and pro-inflammatory cytokines in cerebral WMI, as shown in the experimental models of WMI, is important in the human infant is supported strongly by human neuropathological studies (see later).^34-37 Pro-inflammatory microglia, acted upon by pathogen-associated molecular products (PAMPs) (e.g., LPS) or by damage-associated molecular products (DAMPs), via Toll-like receptors, release reactive oxygen and nitrogen species and cytokines (e.g., TNF-α) that then act on pre-OLs. Pre-OLs are especially vulnerable to these reactive products because of a delay in development of anti-oxidant and anti-nitrative defenses, as shown in developing human brain.^35,37 Notably, these pro-inflammatory microglia induce formation of toxic reactive astrocytes, which secrete cytokines and molecular products important in the pre-OL maturational failure. Abundant interferon-γ expression has been shown in the reactive astrocytes in premature infants with WMI.³⁶ Moreover, the interferon-γ receptor was shown to be present on pre-OLs, and the degree of oxidative injury to these cells correlated with the degree of interferon-γ expression in astrocytes.³⁶ These observations are of major interest because interferon-γ is especially toxic to pre-OLs in cell culture, and this toxicity is both maturation-dependent and potentiated by TNF-α.²¹ Thus, the studies in experimental models of fetal inflammation described earlier show cellular and molecular features observed in human WMI of the preterm infant.

The particular involvement of microglia in the pathogenesis of WMI in the premature infant likely also relates to a maturation-dependent feature of developing human brain. Thus, microglial cells can be identified in normal human brain very early in development, become abundant in forebrain from 16 to 22 weeks of gestation, and then are concentrated in cerebral white matter, with a deep to superficial gradient.^38,39 In the largest longitudinal study of postmortem human brain, density of microglia reached a peak during the period of greatest vulnerability to WMI (third trimester of gestation) and declined markedly in cerebral white matter after 37 weeks of gestation.³⁸ This observation suggests that a wave of migrating microglia is present in cerebral white matter at the optimum time for activation by inflammatory stimuli, such as fetal systemic inflammation, postnatal hypoxia-ischemia, hyperoxia, sepsis, etc. Microglia not in an active pro-inflammatory state (M2) play important roles in such aspects of brain maturation as oligodendroglial development, myelination, vascularization, synaptic development and neural circuit formation.⁴⁰ Because of these crucial developmental roles of so-called M2 microglia, diversion to a microglial phenotype (M1) with primarily pro-inflammatory functions could contribute to the disturbed maturational events observed in premature brain with WMI. A similar discussion could be generated for the characteristic reactive astrocytes (A1), accompanying M1 microglia, and thereby diverted from the variety of maturational events carried out by non-inflammatory A2 astrocytes.

A critical additional factor of potential relevance to the role of fetal inflammation in the occurrence of postnatal WMI in the preterm infant relates to the potentiation of hypoxic-ischemic insults by inflammation. As noted earlier, landmark experimental studies by Hagberg and coworkers and by others^22-32 have shown potentiation of hypoxic-ischemic brain injury after exposure to fetal inflammation. A similar phenomenon has been shown for hyperoxia-induced injury.³³ Insults not sufficient to lead to injury did so after inflammatory exposure. That a similar phenomenon occurs in the human infant is suggested by the neuropathological observations of Kadhim and coworkers.³⁴ Thus, in a study of 19 cases of periventricular leukomalacia with cytokines in the lesion, “asphyxia” was present in the background. This observation is consistent with the well-known pro-inflammatory effect of hypoxia-ischemia. However, importantly, 8 of the 19 cases with “asphyxia” were complicated by evidence for fetal or neonatal infection. Moreover, brain cytokine immunoreactivity for TNF-α and IL-1β in the PVL cases with infection was at least double the immunoreactivity in the PVL cases without infection. Thus, the possibility of a potentiating interaction between a postnatal hypoxic-ischemic insult and systemic fetal (or neonatal) infection/inflammation is supported.^22-33

Earlier pathological studies suggest that E. coli exposure may be important in some examples of neuroinflammation and perhaps early WMI in premature infants.⁴¹ These findings, of course, are reminiscent of the experimental studies with lipopolysaccharide described earlier. In one neuropathological series, among infants who died at less than 7 days of age, evidence for neuroinflammation (e.g., hypertrophic astrocytes) was identified.⁴¹ (The study predated recognition of M1 and M2 microglia.) Maternal urinary tract infection with fever, presumably related to E. coli infection and therefore endotoxin exposure, was a prominent risk factor. Little to no information concerning prenatal maternal circulatory or metabolic disturbances related to septicemia, etc., was available. An earlier report documented the association of similar neuropathological findings in premature infants who had evidence for Gram-negative organisms in postmortem blood samples.⁴² Although these studies were carried out prior to the era of modern neonatal intensive care and complicating issues related to hypoxia, ischemia, hypercarbia, etc., cannot be assessed, the findings raise the possibility that perinatal E. coli exposure may lead to neuroinflammation and perhaps early WMI.

Conclusions from Experimental and Human Studies

Thus, both experimental and human data suggest that fetal inflammation could lead to microglial activation and reactive astrocytosis and potentiate subsequent hypoxic-ischemic or other insults to produce brain injury, under circumstances in which either insult alone could not lead to injury. The principal mediator of this connection between fetal inflammation and postnatal brain injury is likely microglia.

These data emphasize the potential deleterious importance of prolonged activation of microglia. Thus, seemingly modest postnatal insults relating to hypoxia, ischemia, hyperoxia, pulmonary inflammation with bronchopulmonary dysplasia, mechanical ventilation, sepsis, bacteremia, etc., could serve to prolong injurious microgliosis initiated by fetal systemic inflammation.

How long might prolongation of this neonatal inflammatory state, initiated in utero as part of the fetal inflammatory response, continue? Although neuropathological data in human infants are limited, available information suggests that diffuse white matter gliosis is present for at least many months after the premature period and likely longer.^35,43-45 There is precedent in human neuropathology for microglia to be chronically activated, e.g., after traumatic brain injury. The potential deleterious impact on brain maturation is apparent. The issue of duration of the neonatal inflammatory state and the means to minimize its deleterious effects are clearly central and crucial topics for future research.

Conclusions/Management

Although more data are needed, on the basis of current information my view is that the principal deleterious effect of severe systemic fetal inflammation, apart from provocation of extremely preterm birth, is stimulation of cerebral neuroinflammation, especially in white matter. The major cellular mediators are activated (M1) microglia and likely also reactive (A1) astrocytes. These mediators lead to postnatal injury to pre-Ols in developing cerebral white matter. (They may lead also to impaired maturation because of the diversion from their physiological developmental functions.) Additionally, and perhaps of greater importance, they lead to potentiation of the myriad of postnatal insults characteristic of extremely premature infants in the neonatal intensive setting, as noted in the previous section.

The principal challenges for the neonatologist are (1) identification of the presence of fetal inflammation, (2) vigorous management of the postnatal complications (respiratory, sepsis, etc.) leading to the potentiating insults just described, and (3) institution of therapies directed at inflammatory mediators. Each of these challenges is discussed briefly next.

Identification of Fetal Inflammation

Concerning identification of the presence of fetal inflammation, prenatal diagnosis would be optimal but remains a difficult obstetrical issue. Diagnosis in the newborn can be made by identification of circulating cytokines, especially IL-6 (see earlier). Placental diagnosis is ideal but is not generally available in the first day or so of postnatal life.

Management of Potentiating Insults

Management of potentiating insults is currently the most effective means to prevent brain injury in the affected infant. Such management is detailed in conventional sources. A high degree of diligence in management of the affected infant cannot be overemphasized.

Therapies Directed at Inflammatory Mediators

Therapies directed at inflammatory mediators are currently on the horizon and best discussed elsewhere.^18,19,46 Approaches directed at “activated microglia” include the use of exosomes or nanoparticles, such as dendrimers, to promote a change in such microglia to an anti-inflammatory phenotype.^47-49 An approach that addresses a key inflammatory product, IL-1, has been shown beneficial in term fetal sheep exposed to lipopolysaccharide. Thus, infusion of an IL-1 receptor antagonist was shown to reduce microgliosis, IL-1β expression and to improve oligodendrocyte survival.⁵⁰ This exciting observation would appear to provide a readily applied therapy directed at a key deleterious microglial product.

Future Clinical Research

Future clinical research should include attempts to identify the neuropathology in the infant born after fetal systemic inflammation. Anatomical studies with modern-day immunocytochemical and molecular techniques could help define the cellular phenotypes underlying the brain abnormality in the affected infant. Issues related to specific molecular phenotypes of microglia, astrocytes and pre-Ols would be crucial to elucidate. However, the declining rates of neonatal autopsies⁵¹ suggest that this important goal may be unrealistic.

Advanced MRI measures applied as early as possible, and subsequently, should help determine the principal timing and nature of the brain abnormality in affected living infants, Quantitative diffusion-based imaging would help define the degree to which destructive and dysmaturational events are crucial in determining outcome in these infants. The four reports described at the outset of this commentary report an excellent starting point.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

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