Maternal serum levels of C-reactive protein at early pregnancy to predict fetal growth restriction and preterm delivery: A prospective cohort study

Abstract

Background: A considerable evidence suggests that maternal inflammation dysregulation may play as a risk factor for both maternal and neonatal outcomes.


Objective: The study’s objectives were designed to evaluate the correlation between serum C-reactive protein (CRP) levels, as an inflammation factor, preterm delivery, and small for gestational age (SGA) births.


Materials and Methods: This prospective cohort study was conducted on 120 singleton pregnant women with gestational age less than 20 wk. Maternal CRP serum concentration was measured before 20 wk gestation. Patients were followed-up until the delivery and final outcomes of pregnancy were recorded in terms of preterm delivery and SGA births.


Results: Serum CRP levels in participants with normal fetuses and SGA births were 4.09 ± 1.35 mg/l and 6.04 ± 3.29 mg/l, respectively (p = 0.19), while in cases of preterm delivery, it was 9.63 ± 5.78 mg/l (p < 0.001). By using receiver operating characteristic (ROC) curve, serum CRP levels (cut-off point 5.27 mg/l, area 0.836) had acceptable diagnostic accuracy value in distinguishing preterm delivery (sensitivity (75%), specificity (86.1%), positive predictive value (37.5%), negative predictive value (96.87%), accuracy (85%)) and serum CRP levels (cut-off point 6.67 mg/l, area 0.673) in distinguishing SGA births (sensitivity (50%), specificity (91.2%), positive predictive value (23.07%), and negative predictive value (97.19%), and accuracy (89.16 %)).


Conclusion: Higher maternal serum CRP levels measured early in pregnancy may associate with higher risk of preterm delivery and SGA.


Key words: C-reactive protein, Small for gestational age, Preterm birth.

References
[1] Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. Longitudinal profiling of inflammatory cytokines and C−reactive protein during uncomplicated and preterm pregnancy. Am J Reprod Immunol 2014; 72: 326–336.

[2] Pearce BD, Nguyen PH, Gonzalez-Casanova I, Qian Y, Omer SB, Martorell R, et al. Pre-pregnancy maternal plasma cytokine levels and risks of small-for- gestational-age at birth. J Matern Fetal Neonatal Med 2016; 29: 4065–4069.

[3] Ferguson KK, Kamai EM, Cantonwine DE, Mukherjee B, Meeker JD, McElrath TF. Associations between repeated ultrasound measures of fetal growth and biomarkers of maternal oxidative stress and inflammation in pregnancy. Am J Reprod Immunol 2018; 80: e13017.

[4] Georgiou HM, Thio YS, Russell C, Permezel M, Heng YJ, Lee S, et al. Association between maternal serum cytokine profiles at 7-10 weeks’ gestation and birth weight in small for gestational age infants. Am J Obstet Gynecol 2011; 204: 415. E1–e12.

[5] Park H, Park KH, Kim YM, Kook SY, Jeon SJ, Yoo HN. Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: a retrospective study. BMC Pregnancy and Childbirth 2018; 18: 146–154.

[6] Ryu HK, Moon JH, Heo HJ, Kim JW, Kim YH. Maternal c−reactive protein and oxidative stress markers as predictors of delivery latency in patients experiencing preterm premature rupture of membranes. Int J Gynecol Obstet 2017; 136: 145–150.

[7] Alijahan R, Hazrati S, Mirzarahimi M, Pourfarzi F, Ahmadi Hadi P. Prevalence and risk factors associated with preterm birth in Ardabil, Iran. Iran J Reprod Med 2014; 12: 47–56.

[8] Darling AM, McDonald CR, Conroy AL, Hayford KT, Liles WC, Wang M, et al. Angiogenic and inflammatory biomarkers in mid-pregnancy and small-for-gestational-age outcomes in Tanzania. Am J Obstet Gynecol 2014; 211: 509: e1–e8.

[9] Bakalis SP, Poon LC, Vayna AM, Pafilis I, Nicolaides KH. C-reactive protein at 11–13 weeks’ gestation in spontaneous early preterm delivery. J Maternal Fetal Neonat Med 2012; 25: 2475–2478.

[10] Musilova I, Kacerovsky M, Stepan M, Bestvina T, Pliskova L, Zednikova B, et al. Maternal serum Creactive protein concentration and intra-amniotic inflammation in women with preterm prelabor rupture of membranes. PloS One 2017; 12: e0182731.

[11] Cotechini T, Komisarenko M, Sperou A, Macdonald- Goodfellow S, Adams MA, Graham CH. Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia. J Exp Med 2014; 211: 165–179.

[12] Kumarathasan P, Vincent R, Das D, Mohottalage S, Blais E, Blank K, et al. Applicability of a highthroughput shotgun plasma protein screening approach in understanding maternal biological pathways relevant to infant birth weight outcome. J Proteomics 2014; 100: 136–146.

[13] Ghezzi F, Franchi M, Raio L, Di Naro E, Bossi G, D’Eril GV, et al. Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery. Am J Obstet Gynecol 2002; 186: 268–273.

[14] Garcia-Flores V, Romero R, Miller D, Xu Y, Done B, Veerapaneni C, et al. Inflammation-induced adverse pregnancy and neonatal outcomes can be improved by the immunomodulatory peptide exendin-4. Front Immunol 2018; 9: 1291–1311.

[15] Vecchié A BA, Carbone F, Maggi D, Ferraiolo A, Carloni B, et al. C-reactive protein levels at the midpregnancy can predict gestational complications. Biomed Res Int 2018; 2018: 1070151. 1–8.

[16] Hvilsom GB, Thorsen P, Jeune B, Bakketeig LS. Creactive protein: a serological marker for preterm delivery? Acta Obstet Gynecol Scand 2002; 81: 424–429.

[17] Grgic G, Skokic F, Bogdanovic G. C-reactive protein as a biochemical marker of idiopathic preterm delivery. Med Arch 2010; 64: 132–134.

[18] Shahshahan Z, Rasouli O. The use of maternal C-reactive protein in the predicting of preterm labor and tocolytic therapy in preterm labor women. Adv Biomed Res 2014; 3: 154–162.

[19] Ozer KT, Kavak ZN, Gökaslan H, Elter K, Pekin T. Predictive power of maternal serum and amniotic fluid CRP and PAPP-A concentrations at the time of genetic amniocentesis for the preterm delivery. Eur J Obstet Gynecol Reprod Biol 2005; 122: 187–190.

[20] Bullen BL, Jones NM, Holzman CB, Tian Y, Senagore PK, Thorsen P, et al. C-reactive protein and preterm delivery: clues from placental findings and maternal weight. Reprod Sci 2013; 20: 715–722.

[21] Pitiphat W, Gillman MW, Joshipura KJ, Williams PL, Douglass CW, Rich-Edwards JW. Plasma C-reactive protein in early pregnancy and preterm delivery. Am J Epidemiol 2005; 162: 1108–1113.

[22] Ertas IE, Kahyaoglu S, Yilmaz B, Ozel M, Sut N, Guven MA, et al. Association of maternal serum high sensitive C−reactive protein level with body mass index and severity of pre−eclampsia at third trimester. J Obstet Gynaecol Res 2010; 36: 970–977.

[23] Briana DD, Liosi S, Gourgiotis D, Boutsikou M, Marmarinos A, Baka S, et al. Fetal concentrations of the growth factors TGF-α and TGF-β1 in relation to normal and restricted fetal growth at term. Cytokine 2012; 60: 157–161.

[24] Conde−Agudelo A, Papageorghiou AT, Kennedy SH, Villar J. Novel biomarkers for predicting intrauterine growth restriction: a systematic review and meta−analysis. BJOG 2013; 120: 681–694.

[25] Ernst GD, de Jonge LL, Hofman A, Lindemans J, Russcher H, Steegers EA, et al. C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal complications: the Generation R Study. Am J Obstet Gynecol 2011; 205: 132. e1–e12.

[26] Lindner U, Tutdibi E, Binot S, Monz D, Hilgendorff A, Gortner L. Levels of cytokines in umbilical cord blood in small for gestational age preterm infants. Klin Pädiatr 2013; 225: 70–74.