The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth

Abstract

Acute chorioamnionitis is a well-established lesion of the placenta in cases with intra-amniotic infection. In contrast, the clinicopathological significance of chronic chorioamnionitis is unclear. This study was conducted to determine the frequency and severity of chronic chorioamnionitis in normal pregnancy and in various pregnancy complications. Placentas from the following patient groups were studied: (1) term not in labor (n=100), (2) term in labor (n=100), (3) preterm labor (n=100), (4) preterm prelabor rupture of membranes (n=100), (5) preeclampsia at term (n=100), (6) preterm preeclampsia (n=100), and (7) small-for-gestational-age at term (n=100). Amniotic fluid CXCL10 concentration was measured in 64 patients. CXCL9, CXCL10, and CXCL11 mRNA expressions in the chorioamniotic membranes were assessed using real-time quantitative reverse transcription-PCR. The frequency of chronic chorioamnionitis in the preterm labor group and the preterm prelabor rupture of membranes group was 34 and 39%, respectively, which was higher than that of normal-term placentas (term not in labor, 19%; term in labor, 8%; P<0.05 each). The frequency of chronic chorioamnionitis in the preeclampsia at term group, preterm preeclampsia group, and small-for-gestational-age group was 23, 16, and 13%, respectively. Concomitant villitis of unknown etiology was found in 38 and 36% of preterm labor cases and preterm prelabor rupture of membranes cases with chronic chorioamnionitis, respectively. Interestingly, the median gestational age of preterm chronic chorioamnionitis cases was higher than that of acute chorioamnionitis cases (P<0.05). The median amniotic fluid CXCL10 concentration was higher in cases with chronic chorioamnionitis than in those without, in both the preterm labor group and preterm prelabor rupture of membranes group (P<0.05 and P<0.01, respectively). CXCL9, CXCL10, and CXCL11 mRNA expression in the chorioamniotic membranes was also higher in cases with chronic chorioamnionitis than in those without chronic chorioamnionitis (P<0.05). We propose that chronic chorioamnionitis defines a common placental pathological lesion among the preterm labor and preterm prelabor rupture of membranes groups, especially in cases of late preterm birth. Its association with villitis of unknown etiology and the chemokine profile in amniotic fluid suggests an immunological origin, akin to transplantation rejection and graft-versus-host disease in the chorioamniotic membranes.

Figure 1

Histological characteristics of chronic chorioamnionitis (CCA). (a, b): Stage 1 inflammation showing infiltration of lymphocytes limited to the chorionic trophoblast layer (a). CD3 immunostaining demonstrates that the majority of these cells are T cells (b). (c, d): Stage 2 inflammation is characterized by infiltration of lymphocytes into the chorioamniotic connective tissue layer (H&E, c), which are largely CD3+ T cells (d).

Figure 2

Frequency of chronic chorioamnionitis (CCA) in different obstetrical settings. Frequency of CCA in PTL (34%) and PPROM (39%) groups are significantly higher compared to TNL (19%) and TIL (8%) groups. The difference in frequency between TNL and TIL cases was also statistically significant. The frequency of CCA in each group ranged from 8% to 39%. TNL: term not in labor, TIL: term in labor, PTL: preterm labor, PPROM: preterm prelabor rupture of the membranes, TPE: preeclampsia at term, PPE: preterm preeclampsia, SGA: small-for-gestational-age at term. * p<0.05, **: p<0.01, ***: p<0.001.

Figure 3

Frequency of villitis of unknown etiology (VUE) in each group with chronic chorioamnionitis (CCA). (a) Frequency of VUE in each group ranged from 13% (PPE group) to 25% (TPE group). (b) Concomitant VUE was found in 38.2% and 35.9% of PTL and PPROM cases with CCA, respectively, but in 9.1% and 6.6% of PTL and PPROM cases without CCA, respectively. TNL: Term not in labor, TIL: term in labor, PTL: preterm labor, PPROM: preterm prelabor rupture of the membranes, TPE: preeclampsia at term, PPE: preterm preeclampsia, SGA: small-for-gestational-age at term.

Figure 4

Comparisons of amniotic fluid CXCL10 according to the presence of chronic chorioamnionitis (CCA), acute chorioamnionitis (ACA), and villitis of unknown etiology (VUE). (a) While CCA cases have significantly higher amniotic fluid CXCL10 concentration, it is not elevated in cases with ACA. (b) CCA cases with concomitant VUE have higher amniotic fluid CXCL10 concentrations compared to cases without inflammation.

Figure 5

mRNA expressions of CXCL9, CXCL10, and CXCL11 in the chorioamniotic membranes. CXCL9 (a), CXCL10 (b), and CXCL11 (c) mRNA expressions are significantly higher in chronic chorioamnionitis (CCA) positive cases, but not in acute chorioamnionitis (ACA) positive cases when compared to cases without inflammation.

Figure 6

Comparisons of amniotic fluid (AF) CXCL10 concentration (a) and mRNA expressions of CXCL9 (b), CXCL10 (c), and CXCL11 (d) in the chorioamniotic membranes (CAM) according to the severity of chronic chorioamnionitis (CCA). Severity of CCA was graded as 1: grade 1/stage 1 inflammation, 2: grade 1/stage 2 or grade 2/stage 1 inflammation, and 3: grade 2/stage 2 inflammation. The comparisons reveal that even mild CCA is associated with significantly increased amniotic fluid CXCL10 concentration and CXCL9 mRNA expression in the chorioamniotic membranes.