Abstract:
INTRODUCTION: Inflammation-induced remodelling of gestational tissues that
underpins spontaneous preterm birth (sPTB, delivery < 37 weeks’ gestation)
may vary by race and context. To explore relationships between markers of
these pathological processes, we (a) characterised the cervicovaginal fluid (CVF)
cytokine profiles of pregnant South African women at risk of PTB; (b) determined
CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of
metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these
markers for sPTB.
METHOD OF STUDY: The concentrations of 10 inflammatory cytokines and MMP-9
and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring
women at high risk of PTB. We studied CVF sampled at three gestational time
points (GTPs): GTP1 (20–22 weeks, n = 37), GTP2 (26–28 weeks, n = 40), and
GTP3 (34–36 weeks, n = 29) and analysed for changes in protein concentrations
and predictive capacities (area under the ROC curve (AUC) and 95% confidence
interval (CI)) for sPTB.
RESULTS: There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered
preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after
assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas
GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term
women with an average AUC = 0.73. At GTP2, IL-1b (18-fold, p < 0.0001), IL-8 (4-
fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p =
0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm
compared with term women with an average AUC = 0.80. By contrast, IL-10 was
associated with term delivery with an AUC (95% CI) = 0.75 (0.55–0.90). At GTP3, IL-1b (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03),
and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term
women with an average AUC = 0.85. Elevated IL-1b was associated with delivery
within 14 days of assessment with AUC = 0.85 (0.67–0.96). Overall, elevated
MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing
women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1
at all GTPs (r ≥ 0.61, p < 0.01) for women delivering at term was only observed at
GTP1 for those who delivered preterm (r = 0.70, p < 0.03).
CONCLUSIONS: In this cohort, sPTB is associated with gestation-dependent
increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and
dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1b)
and ECM remodelling proteins rise significantly in the final 2 weeks before the
onset of labour when sPTB is imminent. The signalling mechanisms for these
ECM remodelling observations remain to be elucidated.
