(73) Pro-inflammatory vaginal cytokines, early PTB, and infectious morbidity in patients with asymptomatic cervical shortening

Objective: There is a critical need to improve risk-stratification of individuals with an asymptomatic short cervical length (CL).

Study Design: Secondary analysis of a multicenter, unmasked RCT of pessary vs. usual care, 2017-2021. Participants with singleton pregnancies, an asymptomatic CL ≤20mm (16+0-23+6 wks), no prior PTB, and a vaginal swab at enrollment were included. 12 cytokines were quantified using a Luminex assay. The primary outcome was PTB < 35 wks. Secondary outcomes were PTB < 32, < 28, and < 24 wks and maternal (chorio) and neonatal (sepsis ± pneumonia) infectious morbidity. Each cytokine was classified as ‘high’ or ‘low’ using a numeric cut point that optimized the sensitivity and specificity for PTB < 35 wks. A pro-inflammatory cytokine score was calculated for each patient by adding +1 point per high pro-inflammatory (IL-1𝛂, IL-1β, IL-2, IL-6, IL-8, GM-CSF, TNF-𝛂, VEGF) and +1 point per low anti-inflammatory (IL-1RA, IL-4, IL-10, G-CSF) cytokine. Data were analyzed by logistic regression; AUC analyses evaluated outcome prediction of clinical-only, cytokine-only, and clinical+cytokine models.

Results: 531 of 544 RCT participants met inclusion criteria; 37% had PTB < 35 wks; 7% had maternal and 22% had neonatal infectious morbidity. Cytokines were collected at a median 21.7 (IQR 20.7, 23.0) wks. Cytokine scores ranged 1-9 [median 4, IQR (3,5)] and were higher for those with PTB < 35 wks vs. >35 wks (4.7 vs. 4.0, p< 0.001). In regressions, the composite cytokine score was associated with PTB < 35, < 32, < 28, and < 24 wks and maternal and neonatal infectious morbidity. Outcome prediction in clinical+cytokine models did not statistically improve vs. clinical-only models (Table). In Kaplan-Meier analysis, higher cytokine scores were associated with earlier delivery (Figure; log-rank p < 0.001).

Conclusion:

A mid-trimester pro-inflammatory vaginal cytokine milieu is associated with PTB and infectious morbidity in patients with asymptomatic short CL. Non-invasive vaginal cytokine quantification may be an additional way to identify which individuals have pathologic vs. incidental CL shortening.