Dataset Information

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis

ABSTRACT:

Introduction

Preterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.

Population

For objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.

Methods

Placental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.

Results

The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.

Conclusion

Preterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

SUBMITTER: Sullivan G

PROVIDER: S-EPMC8430209 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Inflammasomes are cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and endogenous danger signals. Herein, we determined whether the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis (1) express major inflammasome components; (2) express caspase (CASP)-1 and CASP-4 as well as their active forms; (3) exhibit apoptosis-associated speck-like protein containing a CARD (ASC)/CASP-1 complex formation; and (4) release the mature forms of interleukin (IL)-1? and IL-18. We utilized quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry to determine the messenger RNA (mRNA) and protein expression of major inflammasome components, nucleotide-binding oligomerization domain (NOD) proteins, and the pro- and mature/active forms of CASP-1, CASP-4, IL-1?, and IL-18. The ASC/CASP-1 complex formation was determined using an in situ proximity ligation assay. When comparing the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the mRNA of NLR family pyrin domain-containing protein ( NLRP) 1, NLRP3, NLR family CARD domain-containing protein 4 ( NLRC4), and NOD2 were higher; (2) the NLRP3 protein was increased; (3) the mRNA and active form (p10) of CASP-1 were greater; (4) the mRNA and active form of CASP-4 were increased; (5) the mRNA and mature form of IL-1? were higher; (6) the mature form of IL-18 was elevated; and (7) ASC/CASP-1 complex formation was increased. In conclusion, spontaneous preterm labor with acute histologic chorioamnionitis is characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation of IL-1? and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that supports a role for the inflammasome in the pathological inflammation implicated in spontaneous preterm labor with acute histologic chorioamnionitis.

Project description:Importance:Understanding the role of chorioamnionitis, a major factor leading to preterm birth, in the pathogenesis of neonatal brain injury and adverse neurodevelopmental outcomes may help in identifying potentially modifiable perinatal variables affecting brain health and outcomes among children born preterm. Objective:To evaluate whether histologic chorioamnionitis among neonates born very preterm is associated with intraventricular hemorrhage (IVH) and punctate white matter injury (WMI) or with adverse neurodevelopmental outcomes during early childhood. Design, Setting, and Participants:Prospective cohort study conducted across 3 academic centers (from April 2006 to September 2013 in Canada, from March 2007 to March 2013 in the Netherlands, and from January 2004 to August 2011 in the United States). Children who were born preterm (24-32 weeks' gestation) and who had undergone a placental pathologic evaluation, magnetic resonance imaging as soon as clinically stable, and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) assessments between 18 and 24 months' corrected age (CA) were included. Magnetic resonance imaging scans were assessed for grade of IVH and volume of punctate WMI. Data analysis occurred between December 2016 and January 2018. Final multivariable analyses examining the association of chorioamnionitis with motor and cognitive outcomes accounted for academic center and perinatal and postnatal factors. Main Outcomes and Measures:Punctate WMI volume and IVH detected on neonatal magnetic resonance imaging scans; motor and cognitive outcomes defined using Bayley-III assessments conducted among these children between 18 and 24 months' CA. Results:Of 350 neonates (182 male) in the final cohort, 145 (41.4%) had histologic chorioamnionitis. Gestational age was significantly lower among those with chorioamnionitis (median, 26.4 weeks; interquartile range [IQR], 25.6-27.7 weeks) than among those without chorioamnionitis (median, 28.0 weeks; IQR, 27.0-29.7 weeks). Chorioamnionitis was not associated with IVH or WMI, nor was it associated with worse motor outcomes in univariable or multivariable analyses (adjusted Bayley-III motor score, -2.2; 95% CI, -5.6 to 1.3). Cognitive scores were marginally yet statistically significantly lower among children with chorioamnionitis (median, 105; IQR, 95-110) than among those without chorioamnionitis (median, 105; IQR, 100-115) in the univariable model. This difference was attenuated in the multivariable model (adjusted Bayley-III cognitive score, -3.0; 95% CI, -6.4 to 0.4). Conclusions and Relevance:Histologic chorioamnionitis was not associated with IVH or WMI near birth or with worse cognitive or motor outcomes from 18 to 24 months' CA after accounting for perinatal factors. Postnatal factors attenuated the association between chorioamnionitis and neurodevelopmental outcomes, highlighting the importance of preventing postnatal illness, such as infection, to promote optimal outcomes among children born preterm.