Abstract
ObjectiveTo determine the relationship between high vaginal pro-inflammatory cytokines and cervical shortening in women at high risk of spontaneous preterm labor and to assess the influence of cervical cerclage and vaginal progesterone on this relationship.MethodsThis prospective longitudinal observational study assessed 112 women with at least one previous preterm delivery between 16 and 34 weeks’ gestation. Transvaginal cervical length was measured and cervico-vaginal fluid sampled every two weeks until 28 weeks. If the cervix shortened (<25 mm) before 24 weeks’ gestation, women (cases) were randomly assigned to cerclage or progesterone and sampled weekly. Cytokine concentrations were measured in a subset of cervico-vaginal fluid samples (n = 477 from 78 women) by 11-plex fluid-phase immunoassay.ResultsAll 11 inflammatory cytokines investigated were detected in cervico-vaginal fluid from women at high risk of preterm birth, irrespective of later cervical shortening. At less than 24 weeks’ gestation and prior to intervention, women destined to develop a short cervix (n = 36) exhibited higher cervico-vaginal concentrations than controls (n = 42) of granulocyte-macrophage colony-stimulating factor [(GM-CSF) 16.2 fold increase, confidence interval (CI) 1.8–147; p = 0.01] and monocyte chemotactic protein-1 [(MCP-1) 4.8, CI 1.0–23.0; p = 0.05]. Other cytokines were similar between cases and controls. Progesterone treatment did not suppress cytokine concentrations. Interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ and tumour necrosis factor (TNF)-α concentrations were higher following randomization to cerclage versus progesterone (p<0.05). Cerclage, but not progesterone treatment, was followed by a significant increase in cervical length [mean 11.4 mm, CI 5.0–17.7; p<0.001].ConclusionsAlthough GM-CSF and MCP-1 cervico-vaginal fluid concentrations were raised, the majority of cervico-vaginal cytokines did not increase in association with cervical shortening. Progesterone treatment showed no significant anti-inflammation action on cytokine concentrations. Cerclage insertion was associated with an increase in the majority of inflammatory markers and cervical length.
Highlights
Preterm birth is a major challenge facing modern obstetrics, with a global prevalence of 9.6% and over a million annual neonatal deaths [1]
Spontaneous preterm labour (SPTL), which accounts for 75% of these births, is likely to be initiated by a variety of factors [2], thereby hindering accurate identification of at-risk women
A total of 1223 women were assessed for eligibility and 112 women were enrolled into this observational study (Figure 1)
Summary
Preterm birth is a major challenge facing modern obstetrics, with a global prevalence of 9.6% and over a million annual neonatal deaths [1]. Current clinical management is disparate [3,4,5,6,7,8,9,10,11] and the effectiveness of interventions such as cervical cerclage and progesterone to improve neonatal outcome remain to be proven. This may, in part, reflect an ineffective understanding of the cellular mechanisms involved and mis-categorization of patient risk status resulting in inappropriate treatment. In the most recent systematic review [22], IL-6 has been shown to be strongly associated with
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