Abstract
Early spontaneous preterm birth is associated with inflammation/infection and shortening of the cervix. We hypothesised that cervico-vaginal production of trappin2/elafin (peptidase inhibitor 3) and cathelicidin antimicrobial peptide (cathelicidin), key components of the innate immune system, are altered in women who have a spontaneous preterm birth. The aim was to determine the relationship between cervico-vaginal fluid (CVF) trappin2/elafin and cathelicidin protein concentrations with cervical length in woman at risk of spontaneous preterm birth. Trappin2/elafin and cathelicidin were measured using ELISA in longitudinal CVF samples (taken between 13 to 30 weeks' gestation) from 74 asymptomatic high risk women (based on obstetric history) recruited prospectively. Thirty six women developed a short cervix (<25 mm) by 24 weeks' and 38 women did not. Women who developed a short cervix had 2.71 times higher concentrations of CVF trappin2/elafin from 14 weeks' versus those who did not (CI 1.94–3.79, p<0.0005). CVF trappin2/elafin before 24 weeks' was 1.79 times higher in women who had a spontaneous preterm birth <37 weeks' (CI: 1.05–3.05, p = 0.034). Trappin2/elafin (>200 ng/ml) measured between 14+0–14+6 weeks' of pregnancy predicted women who subsequently developed a short cervix (n = 11, ROC area = 1.00, p = 0.008) within 8 weeks. Cathelicidin was not predictive of spontaneous delivery. Vitamin D status did not correlate with CVF antimicrobial peptide concentrations. Raised CVF trappin2/elafin has potential as an early pregnancy test for prediction of cervical shortening and spontaneous preterm birth. This justifies validation in a larger cohort.
Highlights
Preterm birth is a global healthcare problem associated with significant neonatal morbidity and mortality and substantial healthcare costs [1,2]
The novel demonstration that the cervico-vaginal fluid (CVF) trappin2/elafin concentration is raised prior to cervical shortening in women at high risk of Spontaneous preterm birth (sPTB) is indicative of an altered innate immune status early in pregnancy in these women
The substantive difference between cases and controls suggests that measurement of trappin2/elafin may be a useful biomarker for identifying women at high risk of cervical shortening; i.e. those who could benefit from additional surveillance and intervention
Summary
Preterm birth is a global healthcare problem associated with significant neonatal morbidity and mortality and substantial healthcare costs [1,2]. Spontaneous preterm birth (sPTB) accounts for approximately three quarters of all premature deliveries and the need for early identification of at-risk women is widely recognised, since this would facilitate management and instigation of appropriate interventions. Several families of AMPs (e.g. whey acidic proteins, trappin2/ elafin, transferrins and human a and b defensins) have been identified in the female reproductive tract [7,8,9]. The PI3 gene produces a spliced protein (117 aa; 12.3 kDa) which is cleaved intracellularly to a mature protein (9.9 kDA, Trappin 2). This can be secreted and tethered to the extracellular matrix via an exposed cementoin domain. Trappin can be further processed via extracellular tryptases to soluble elafin (6 kDA), a smaller molecule which is no longer tethered to the extracellular matrix [10,11]
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