The Relationship Among Intra-Amniotic Inflammatory Response, The Progression of Inflammation in Chorionic Plate and Early-Onset Neonatal Sepsis

Abstract

Background: The chorionic plate (CP) has been denigrated by the well-known route of the extraplacental membranes from the decidua parietalis through the chorion to the amnion in the progression of ascending intrauterine infection among preterm births (PTBs). However, considering previous studies reporting the relationship among intra-amniotic inflammatory response (IAIR), the progression of inflammation in extraplacental membranes and early-onset neonatal sepsis (EONS), and the anatomic connection between extraplacental membranes and CP, there is a good chance that IAIR would be more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP would be associated with a significant increase in EONS in neonates delivered due to either PTL or preterm-PROM. Unfortunately, there is no information about the relationship among IAIR, the progression of inflammation in CP, and EONS among spontaneous PTBs. The objective of the current study is to examine this issue. Method: The study population included 309 singleton pregnant women-delivered preterm neonates with the following conditions: (1) gestational age (GA) at delivery: 20.0~36.9 weeks; (2) spontaneous PTBs: PTL (151 cases) or preterm-PROM (158 cases); (3) available results of placental histologic examination; (4) without congenital anomaly; and (5) delivery within 60 h of amniocentesis. We examined IAIR, and the frequency of intra-amniotic inflammation (IAI) and EONS according to the progression of inflammation in CP [i.e., stage-0, inflammation-free CP; stage-1, inflammation restricted to subchorionic fibrin (SCF); stage-2, inflammation in connective tissue (CT) of CP but without chorionic vasculitis; and stage-3, chorionic vasculitis]. IAIR was determined by amniotic fluid (AF) matrix metalloproteinase-8 (MMP-8) concentration (ng/ml), and IAI was defined as an elevated AF MMP-8 concentration (≥23 ng/ml). EONS included either suspected or proven EONS. Results: (1) Each stage (stage-0 to stage-3) was present in 69.3% (214/309), 15.9% (49/309), 11.0% (34/309), and 3.9% (12/309) of the study population. (2) AF MMP-8 concentrations continuously elevated according to the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; median (ng/ml), range (ng/ml); 6.0 (0.3-4202.7) vs. 153.9 (0.3-6142.6) vs. 464.9 (5.8-3929.0) vs. 1,780.4 (35.1-5019.5); Kruskal-Wallis test, P < 0.001 and Spearman's rank-correlation test, P < 0.000001, r = 0.553]. (3) Moreover, the frequency of IAI and EONS gradually increased with the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; IAI, 30.5% (64/210) vs. 70.2% (33/47) vs. 96.7% (29/30) vs. 100% (12/12); EONS, 3.5% (7/200) vs. 25.5% (12/47) vs. 32.3% (10/31) vs. 40.0% (4/10); each for Pearson's chi-square test, P < 0.000001 and linear-by-linear association, P < 0.000001]. (4) Of note, multiple logistic regression analysis demonstrated that a more advanced stage in the progression of inflammation within CP was associated with a higher odds ratio (OR) for EONS [stage-1 vs. stage-2 vs. stage-3; OR, 7.215, 95% confidence-interval (CI) (2.177-23.908) vs. OR, 10.705, 95% CI (2.613-43.849) vs. OR, 27.189, 95% CI (2.557-289.124)] compared with stage-0 even after the adjustment for potential confounding variables. Conclusion: IAIR is more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP is an independent risk factor for EONS in spontaneous PTBs. This finding suggests that CP may be another playground for the progression of ascending intrauterine infection in addition to extraplacental membranes, and the progression of inflammation in CP may be used for the prediction of EONS in spontaneous PTBs.

Keywords: ascending intra-uterine infection; chorionic plate inflammation; early-onset neonatal sepsis; intra-amniotic inflammatory response; preterm birth.

Figure 1

Amniotic fluid (AF) MMP-8 concentrations according to the progression of inflammation within chorionic plate (CP) [stage-0, inflammation-free CP vs. stage-1, inflammation restricted to subchorionic fibrin (SCF) vs. stage-2, inflammation in the connective tissue (CT) of CP without chorionic vasculitis vs. stage-3, chorionic vasculitis; median, range, 6.0 ng/ml (0.3–4202.7 ng/ml) vs. 153.9 ng/ml (0.3–6142.6 ng/ml) vs. 464.9 ng/ml (5.8–3929.0 ng/ml) vs. 1780.4 ng/ml (35.1–5019.5 ng/ml)] among preterm gestations. Each P-value is shown in the graph. AF MMP-8 concentration results were available in 299 patients, and those were not examined in 10 patients due to the limited amount of remaining AF.

Figure 2

The frequency of intra-amniotic inflammation (IAI) (A) and positive amniotic fluid (AF) culture (B) according to the progression of inflammation within chorionic plate (CP) [i.e., stage-0, inflammation-free CP vs. stage-1, inflammation restricted to subchorionic fibrin (SCF) vs. stage-2, inflammation in the connective tissue (CT) of CP without chorionic vasculitis vs. stage-3, chorionic vasculitis] among preterm gestations. Each P-value is shown in the graph. AF culture results were available in 303 patients. IAI results were available in 299 patients, and those were not examined in 10 patients due to the limited amount of AF remaining.

Figure 3

The frequency of suspected or proven early-onset neonatal sepsis (EONS) (A) and proven EONS (B) according to the progression of inflammation within chorionic plate (CP) [i.e., stage-0, inflammation-free CP vs. stage-1, inflammation restricted to subchorionic fibrin (SCF) vs. stage-2, inflammation in the connective tissue (CT) of CP without chorionic vasculitis vs. stage-3, chorionic vasculitis] among preterm gestations. Each P-value is shown in the graph. Twenty-one neonates were excluded from the analysis of suspected or proven EONS among 309 cases because they died shortly after delivery as a result of extremely prematurity (n = 11) or had no information about EONS in the medical records (n = 10) and thus could not be evaluated with respect to the presence or absence of EONS.