Research Article: Vitamin D-binding protein in cervicovaginal fluid as a non-invasive predictor of intra-amniotic infection and impending preterm delivery in women with preterm labor or preterm premature rupture of membranes

Date Published: June 7, 2018

Publisher: Public Library of Science

Author(s): Song Yi Kook, Kyo Hoon Park, Ji Ae Jang, Yu Mi Kim, Hyunsoo Park, Se Jeong Jeon, Brenda A. Wilson.

http://doi.org/10.1371/journal.pone.0198842

Abstract

To determine whether vitamin D-binding protein (VDBP) in cervicovaginal fluid (CVF) is independently predictive of intra-amniotic infection and imminent spontaneous preterm delivery (SPTD, delivery within 48 hours) in women with preterm labor with intact membranes (PTL) or preterm premature rupture of membranes (PPROM).

This was a single-center retrospective cohort study. CVF samples for VDBP assays were obtained along with serum C-reactive protein (CRP) levels immediately after amniocentesis in consecutive women with PTL (n = 148) or PPROM (n = 103) between 23.0 and 34.0 weeks of gestation. VDBP levels in CVF were determined by enzyme-linked immunosorbent assay kits. The primary outcome measures were intra-amniotic infection [defined as positive amniotic fluid (AF) culture] and SPTD within 48 hours after sampling.

In the multivariable analysis, elevated VDBP levels in CVF samples of PTL women were significantly associated with intra-amniotic infection and imminent preterm delivery, even after adjusting for potential confounders (e.g., gestational age at sampling, parity, and serum CRP). However, these relationships were not found in women with PPROM. In women with PTL, the areas under receiver operating characteristic curves of CVF VDBP level for predicting intra-amniotic infection and imminent preterm delivery were 0.66 and 0.71, with cut-off values of 1.76 μg/mL (sensitivity of 64.3% and specificity of 78.4%) and 1.37 μg/mL (sensitivity of 65.4% and specificity of 72.6%), respectively. The CVF VDBP levels were significantly higher in women with PPROM than in those with PTL.

VDBP in the CVF independently predicts intra-amniotic infection and imminent preterm delivery in women with PTL, whereas in women with PPROM, an elevated VDBP level in CVF is not associated with increased risks of these two outcome variables.

Partial Text

Spontaneous preterm labor and intact membranes (PTL) or spontaneous preterm premature rupture of the membranes (PPROM) accounts for approximately 70 to 80% of all preterm births, and preterm birth, owing to these causes in particular, is strongly associated with significant neonatal morbidity, mortality, and long-term disability [1–3]. Evidence suggests that the impact of preterm birth on adverse neonatal outcomes is directly related to the degree of prematurity and the occurrence of subclinical intra-uterine infection [4–6]. Therefore, the ability to predict the risk of spontaneous preterm delivery (SPTD) and intra-uterine infection more precisely, especially using non-invasive methods, has important clinical implications in terms of the treatment strategy (e.g., administration of medications [i.e., corticosteroid, antibiotics, and magnesium for neuroprotection] and transfer to a tertiary center) and the counseling of patients with PTL or PPROM.

This retrospective cohort study was carried out at Seoul National University Bundang Hospital (Seongnam, Republic of Korea) from November 2008 to September 2015. The ethics committee at Seoul National University Bundang Hospital approved the study (IRB no. B-1105/128-102). The study population consisted of consecutive singleton pregnant women diagnosed with either spontaneous PTL (n = 148) or PPROM (n = 103) at 23 +0 to 34 +0 weeks of gestation. The inclusion criteria were as follows: (1) a live fetus was delivered; (2) an aliquot of CVF sample available for analysis; (3) amniocentesis performed to determine the microbial and inflammatory status of the AF at the time of enrollment; and (4) CVF collected at the time of amniocentesis. The exclusion criteria were multiple pregnancies, major fetal congenital anomalies, prior cervical cerclage, evidence of clinical chorioamnionitis at the time of presentation, and active labor at admission (defined as cervical dilatation greater than 3 cm by sterile speculum examination) in cases of PPROM. The diagnosis of PPROM was made on the basis of clinical findings of either a pool of AF in the posterior fornix or leakage of fluid through the cervix on sterile speculum examination, and a positive nitrazine test. PPROM was defined as the spontaneous rupture of membranes occurring prior to 37 weeks of gestation and before the onset of uterine contractions. Preterm labor was defined as the presence of regular uterine contractions, with a frequency of at least two contractions every 10 minutes, and cervical change that required hospitalization. Gestational age was calculated based on the last menstrual period and the first trimester or second trimester (≤20 weeks) ultrasound results, when available. During the study period, amniocentesis for retrieval of the AF and CVF sampling were immediately offered to patients who were admitted with either PTL or PPROM at our institution. The patients provided written informed consent for the collection and use of the CVF samples for research purposes. The primary outcome measures were a positive AF culture result and SPTD within 48 hours of sampling.

During the study period, a total of 251 women with PTL (n = 148) or a diagnosis of PPROM (n = 103) met the eligibility criteria and were included in the final analysis. The mean (SD) gestational ages at sampling were 29.9 (2.9) weeks for the PTL group and 30.3 (3.1) weeks for the PPROM group (P = 0.140), while the mean (SD) gestational ages at delivery were 35.1 (4.3) weeks for the PTL group and 31.9 (2.6) weeks for the PPROM group (P < 0.001). Positive AF culture results were obtained in 9.4% (14/148) of the women with PTL and in 42.7% (44/103) of the women with PPROM. Table 1 shows the types of microorganisms isolated from the AF of women with PTL and PPROM. Polymicrobial invasion was present in 12 cases [85% (12/14)] for the women with PTL and in 26 cases [59% (26/44)] for the women with PPROM. For the analyses of the relationship between SPTD within 48 hours and the covariates, we excluded 12 patients because of iatrogenic deliveries (two for PTL and three for PPROM) and transfer to another hospital within 48 hours (three for PTL and four for PPROM). SPTD within 48 hours occurred in 18% (26/143) of women with PTL and 27% (28/96) of women with PPROM. The principal findings of this study are as follows: (i) in women with PTL, the CVF VDBP level independently predicts intra-amniotic infection and imminent preterm delivery; (ii) however, an elevated CVF VDBP level in women with PPROM was not independently associated with increased risks of either intra-amniotic infection or imminent preterm delivery; and (iii) CVF VDBP levels were significantly higher in women with PPROM than in those with PTL. This study confirms the findings of previous studies conducted in women with PTL by Liong et al. [13, 14] and Hitti et al. [11] and extends the findings to women with PPROM. In conclusion, we demonstrated that the level of VDBP in the CVF independently predicted intra-amniotic infection and imminent preterm delivery in women with PTL and that elevated CVF VDBP levels were not associated with increased risks of these two outcome variables in women with PPROM. Further studies are needed to determine the source of VDBP in the CVF and to elucidate the role of VDBP in maternal blood and AF as it relates to SPTD and intra-amniotic infection.   Source: http://doi.org/10.1371/journal.pone.0198842

 

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