The predictive role of maternal serum and cervicovaginal fluid vitamin D-binding protein for preterm birth and latency period

Abstract

Aim

Adverse perinatal outcomes have been linked to alterations in vitamin D-binding protein (VDBP) levels. We assessed the predictive value of serum and cervicovaginal fluid VDBP for preterm birth, as well as to measure VDBP in threatened preterm labor (TPL) and preterm premature rupture of membranes (PPROM).

Methods

A total of 138 pregnant women were divided into three groups in this prospective case-control study: TPL(n=59), PPROM (n=43) and control (n=36). Also, all patients were divided into two groups according to whether the latency period was shorter (n=48) or longer than 48 hours (n=90). The VDBP levels were measured using an enzyme-linked immunosorbent assay kit and compared between groups.

Results

Cervicovaginal fluid and serum VDBP levels were lower in the TPL and PPROM groups than controls. Cervicovaginal fluid VDBP<0.63ng/ml predicted preterm birth with 81.58% sensitivity and 53.23% specificity (AUC=0.713, p<0.001). Serum VDBP≤ 0.26ng/ml predicted preterm birth with 61.84% sensitivity and 64.52% specificity (AUC=0.629, p=0.008). No significant difference was detected between serum and cervicovaginal fluid VDBP levels for predicting preterm birth (p=0.018). Moreover, cervicovaginal fluid VDBP>0.44ng/ml predicted latency period≤48 hours with 43.75% sensitivity and 94.44% specificity (AUC=0.694, p<0.001), while serum VDBP did not predict a latency period shorter than 48 hours (AUC=0.515, p=0.771).

Conclusions

Both serum and cervicovaginal VDBP may be valuable markers for predicting preterm birth. Although no difference was found between serum and cervicovaginal VDBP in terms of predictive role, cervicovaginal fluid VDBP may be one step ahead of serum VDBP with the ability to predict a short latency period

Keywords

cervicovaginal vitamin D-binding protein - latency period - preterm birth - serum vitamin D-binding protein

• References

• 1 Walani SR. Global burden of preterm birth. Int J Gynaecol Obstet 2020; 150: 31-33
• 2 Beck S, Wojdyla D, Say L. et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 2010; 88: 31-38
• 3 Kook SY, Park KH, Jang JA. et al. 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. PLoS ONE 2018; 13: e0198842
• 4 D'Silva AM, Hyett JA, Coorssen JR. First trimester protein biomarkers for risk of spontaneous preterm birth: identifying a critical need for more rigorous approaches to biomarker identification and validation. Fetal Diagn Ther 2020; 47: 497-506
• 5 Jung EY, Park KH, Han BR. et al. Measurement of interleukin 8 in cervicovaginal fluid in women with preterm premature rupture of membranes: A comparison of amniotic fluid samples. Reprod Sci 2017; 24: 142-147
• 6 Ryu A, Park KH, Oh KJ. et al. Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes. Acta Obstet Gynecol Scand 2013; 92: 517-524
• 7 Liong S, Di Quinzio MK, Heng YJ. et al. Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes. Reproduction 2013; 145: 137-147
• 8 Karras SN, Dursun E, Alaylıoglu M. et al. Upregulation of irisin and vitamin D-binding protein concentrations by increasing maternal 25-hydrovitamin d concentrations in combination with specific genotypes of vitamin D-binding protein polymorphisms. Nutrients 2021; 14: 90
• 9 Ma R, Gu Y, Zhao S. et al. Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies. Am J Physiol Endocrinol Metab 2012; 303: E928-E935
• 10 Creswell L, Rolnik DL, Lindow SW. et al. Preterm birth: Screening and prediction. Int J Womens Health 2023; 15: 1981-1997
• 11 Ramachandran A, Clottey KD, Gordon A. et al. Prediction and prevention of preterm birth: Quality assessment and systematic review of clinical practice guidelines using the AGREE II framework. Int J Gynaecol Obstet 2024; 166: 932-942
• 12 Georges HM, Norwitz ER, Abrahams VM. Predictors of inflammation-mediated preterm birth. Physiology (Bethesda) 2025; 40
• 13 Norman AW. 1α,25(OH)₂ Vitamin D3, vitamin D nuclear receptor (VDR) and plasma vitamin D-binding protein (DBP) structures and ligand shape preferences for genomic and rapid biological responses. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Amsterdam: Elsevier; 2008: 749-778
• 14 Lisowska-Myjak B, Jóźwiak-Kisielewska A, Łukaszkiewicz J. et al. Vitamin D-binding protein as a biomarker to confirm specific clinical diagnoses. Expert Rev Mol Diagn 2020; 20: 49-56
• 15 Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: more than vitamin D binding. Best Pract Res Clin Endocrinol Metab 2015; 29: 773-786
• 16 Karras SN, Wagner CL, Castracane VD. Understanding vitamin D metabolism in pregnancy: From physiology to pathophysiology and clinical outcomes. Metabolism 2018; 86: 112-123
• 17 Fernando M, Ellery SJ, Marquina C. et al. Vitamin D-binding protein in pregnancy and reproductive health. Nutrients 2020; 12: 1489
• 18 Tahsin T, Khanam R, Chowdhury NH. et al. Vitamin D deficiency in pregnancy and the risk of preterm birth: a nested case-control study. BMC Pregnancy Childbirth 2023; 23: 322
• 19 Hou H, Zhang JY, Chen D. et al. Altered decidual and placental catabolism of vitamin D may contribute to the aetiology of spontaneous miscarriage. Placenta 2020; 92: 1-8
• 20 Gharesi-Fard B, Zolghadri J, Kamali-Sarvestani E. Alteration in the expression of proteins in unexplained recurrent pregnancy loss compared with in the normal placenta. J Reprod Dev 2014; 60: 261-267
• 21 Albejante MC, Kunz TCM, Ferreira MFC. et al. Proteinuria is associated with urinary loss of cubilin and vitamin D-binding protein in patients with preeclampsia. Sci Rep 2020; 10: 3956
• 22 Wookey AF, Chollangi T, Yong HE. et al. Placental vitamin D-binding protein expression in human idiopathic fetal growth restriction. J Pregnancy 2017; 2017: 5120267
• 23 Pereira L, Reddy AP, Jacob T. et al. Identification of novel protein biomarkers of preterm birth in human cervical-vaginal fluid. J Proteome Res 2007; 6: 1269-1276