Association of Histological and Clinical Chorioamnionitis With Neonatal Sepsis Among Preterm Infants: A Systematic Review, Meta-Analysis, and Meta-Regression

Abstract

Chorioamnionitis (CA) is considered a key risk factor for very preterm birth and for developing early onset sepsis (EOS) in preterm infants, but recent data suggest that CA might be protective against late onset sepsis (LOS). We performed a systematic review and meta-analysis of studies exploring the association between CA and sepsis. A comprehensive literature search was performed in PubMed/MEDLINE and EMBASE, from their inception to December 1, 2018. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sources of heterogeneity were analyzed by subgroup and meta-regression analyses. The following categories of sepsis were analyzed: EOS, LOS, unspecified onset sepsis (UOS), culture-proven, and clinical sepsis. CA was subdivided into clinical and histological chorioamnionitis. Funisitis was also analyzed. We found 3,768 potentially relevant studies, of which 107 met the inclusion criteria (387,321 infants; 44,414 cases of CA). Meta-analysis showed an association between any CA and any EOS (OR 4.29, CI 3.63-5.06), any LOS (OR 1.29, CI 1.11-1.54), and any UOS (OR 1.59, CI 1.11-1.54). Subgroup analysis showed that CA was associated with culture-proven EOS (OR 4.69, CI 3.91-5.56), clinical EOS (OR 3.58, CI 1.90-6.76), and culture-proven LOS (OR 1.31, CI 1.12-1.53), but not with clinical LOS (OR 1.52, CI 0.78-2.96). The presence of funisitis did not increase the risk of either EOS or LOS when compared with CA without funisitis. CA-exposed infants had lower gestational age (-1.11 weeks, CI -1.37 to -0.84) than the infants not exposed to CA. Meta-regression analysis showed that the lower gestational age of the CA group correlated with the association between CA and LOS but not with the association between CA and EOS. In conclusion, our data suggest that the positive association between chorioamnionitis and LOS may be modulated by the effect of chorioamnionitis on gestational age.

Keywords: chorioamnionitis; extremely preterm birth; immunomodulation; meta-analysis; meta-regression; neonatal sepsis; systematic review; very preterm birth.

Figure 1

PRISMA diagram of the systematic search.

Figure 2

Random effects meta-analyses of chorioamnionitis and early onset sepsis (EOS), subdivided by definition of chorioamnionitis. (A) Any EOS; (B) culture-proven EOS; (C) clinical EOS; (D) meta-regression comparing culture-proven and clinical EOS. MIAC, microbial invasion of the amniotic cavity.

Figure 3

Random effects meta-analysis of histological chorioamnionitis (CA) and all early onset sepsis (culture proven or clinical).

Figure 4

Random effects meta-analyses of clinical, microbiological, unspecified, and histological/clinical chorioamnionitis (CA) and all early onset sepsis (culture proven or clinical).

Figure 5

Random effects meta-analyses of chorioamnionitis and late onset sepsis (LOS), subdivided by definition of chorioamnionitis. (A) Any LOS; (B) culture-proven LOS; (C) clinical LOS; (D) meta-regression comparing culture-proven and clinical LOS. MIAC, microbial invasion of the amniotic cavity.

Figure 6

Random effects meta-analyses of histological, clinical, microbiological, and unspecified chorioamnionitis (CA) and all late onset sepsis.

Figure 7

Random effects meta-analyses of unspecified onset sepsis (UOS), subdivided by definition of chorioamnionitis. (A) Any UOS; (B) culture-proven UOS; (C) clinical UOS; (D) meta-regression comparing culture-proven and clinical UOS.

Figure 8

Random effects meta-analyses of funisitis (compared with chorioamnionitis without funisitis) and sepsis (culture proven or clinical), subdivided by onset of sepsis.

Figure 9

Meta-regression plot of association between chorioamnionitis and (A) early onset sepsis, and (B) late onset sepsis controlling for difference in gestational age between exposed and non-exposed groups.