Research Article: Non-invasive prediction of preterm birth in women with cervical insufficiency or an asymptomatic short cervix (≤25 mm) by measurement of biomarkers in the cervicovaginal fluid

Date Published: July 10, 2017

Publisher: Public Library of Science

Author(s): Ha-Na Yoo, Kyo Hoon Park, Eun Young Jung, Yu Mi Kim, Song Yi Kook, Se Jeong Jeon, Brenda A Wilson.

http://doi.org/10.1371/journal.pone.0180878

Abstract

To determine whether various proteins in the cervicovaginal fluid (CVF) known to be involved in immune regulation, alone or in combination with clinical risk factors, can predict spontaneous preterm delivery (SPTD) in women with cervical insufficiency or a short cervix (≤25 mm).

This retrospective cohort study included 62 asymptomatic women with cervical insufficiency (n = 27) or an asymptomatic short cervix (n = 35) at 18–27 weeks. CVF swab samples were taken for assays of vitamin D binding protein (VDBP), interleukin (IL)-8, matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and Dickkopf-related protein 3 (DKK3) before cervical examination, and maternal blood was collected for the determination of the C-reactive protein (CRP) level. The primary outcome measurement was SPTD at <32 weeks of gestation. Logistic regression analysis and receiver operating characteristic curves were used for the statistical analyses. The rate of SPTD at <32 weeks was 40.3% (25/62). The CVF levels of VDBP, TIMP-1, and DKK3, but not IL-8 and MMP-9, were significantly higher in the women who had SPTD at <32 weeks than in those who did not deliver spontaneously at <32 weeks. The women who had SPTD at <32 weeks had a significantly more advanced cervical dilatation at presentation and a higher level of serum CRP. Using the stepwise regression analysis, a prediction model was developed by combining various proteins in the CVF and clinical factors, resulting in the inclusion of cervical dilatation, CVF VDBP, and use of corticosteroids (area under curve, 0.909). In women with cervical insufficiency or a short cervix, VDBP, TIMP-1, and DKK3 in the CVF may be useful as non-invasive predictors of SPTD at <32 weeks. A combination of these markers and clinical factors appears to improve the predictability of SPTD compared with the markers alone.

Partial Text

Cervical insufficiency complicates 0.1–1% of all pregnancies and is thought to be the main cause of second trimester pregnancy loss or early preterm birth [1–3]. Despite the clinical relevance of cervical insufficiency, little is known regarding the pathophysiology involved and the preterm risk assessment tools, especially those involving non-invasive methods. Such information is relevant for the development of more-effective treatments targeting individual risks and for patient counseling.

Of the 64 women who fulfilled the inclusion criteria, 2 women received a history-indicated cerclage, leaving 62 women in the final analysis, including 27 women with cervical insufficiency and 35 women with an asymptomatic short cervix. The median gestational age at the time of sampling was 22+5 weeks (range, 18+0 to 27+6 weeks). SPTD at <32 weeks of gestation occurred in 40.3% (25/62) of the patients. The principal findings of this study are as follows: (i) In women with cervical insufficiency or a short cervix, VDBP, TIMP-1, and DKK3 in the CVF may be useful as non-invasive predictors of SPTD at <32 weeks; (ii) a combination of these markers and clinical factors appears to improve predictability of SPTD in comparison to the markers alone; and (iii) the median CVF levels of VDBP, MMP-9, TIMP-1, and DKK3 were significantly higher in the women with cervical insufficiency than in those with a short cervix. To our knowledge, this is the first study to demonstrate the distinctive changes in various proteins present in the cervicovaginal compartment between women with cervical insufficiency/short cervix who had SPTD at <32 weeks and delivered 32 weeks later. Similar results regarding pro-inflammatory cytokines and VDBP were also documented in the CVF of women with preterm labor and intact membranes [6, 8, 13]. In conclusion, VDBP, TIMP-1, and DKK3 in the CVF may be useful as non-invasive predictors of SPTD in women with cervical insufficiency or a short cervix. A combination of these markers and clinical factors appears to improve the predictability of SPTD compared with markers alone. Further large prospective studies are needed to determine whether our prediction model as a management strategy can be used to identify the patients who would benefit from cerclage.   Source: http://doi.org/10.1371/journal.pone.0180878

 

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