Main Article Content
Objective: To assess the role of first and second-trimester screening biomarkers pregnancy-associated plasma protein-A(PAPP-A), free beta-human chorionic gonadotropin(free ß-hCG), estriol, alpha-fetoprotein and total β-hCG in the early diagnosis of intrahepatic cholestasis of pregnancy (ICP).
Materials and Methods: Patients with ICP admitted to Mersin University Hospital for delivery between 2015 and 2019 and had first and second-trimester aneuploidy screening tests performed in the same facility were retrospectively assessed. Randomly 60 pregnant women without comorbid conditions during the same period were included as controls. Data regarding demographic characteristics, laboratory values including free ß-hCG and PAPP-A in first-trimester screening and total ß-hCG, estriol and alpha- fetoprotein in second-trimester screening were compared.
Results: There were 46 eligible patients with ICP. In first trimester screening, it was found that PAPP-A MoM was significantly lower (0.89±0.55 vs. 1.94±0.73; p=0.035) while free ß-hCG MoM was significantly higher in ICP group when compared to controls (1.84±0.59 vs. 0.99±0.47; p=0.018). In second trimester screening, no significant difference was detected in aneuploidy markers between groups. For prediction of ICP development, first trimester free β-hCG >1.44 MoM was found to have a sensitivity of 50%, a specificity of 80% and positive and negative predictive values of 33% and 88.9% respectively. Similarly first trimester PAPP-A values <1.075 MoM was found to have 80% and 75% sensitivity and specificity with positive and negative predictive values of 75% and 44% respectively.
Conclusion: Low PAPP-A MoM value and elevated free ß-hCG in first trimester seem to be associated with ICP development.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Kulhan M, Kulhan NG, Nayki U, et al. Intrahepatic cholestasis of pregnancy and fetal outcomes. Mini review. Arch Med Sci Civil Dis 2017; 2: e85-6.
Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120-33.
Ozkan S, Ceylan Y, Ozkan OV, et al. Review of a challenging clinical issue: intrahepatic cholestasis of pregnancy. World J Gastroenterol 2015; 21: 7134-41
Tayyar A, Temel Yuksel I, et al. Maternal copeptin levels in intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 2017 Jun 14: 1–5.
Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 2014; 59: 1482-91.
Karaahmet E, Ay Gungor ANC, Topaloglu N, et al. Revalence of psychiatric disorders during pregnancy and their effect on birth weight. Arch Med Sci Civil Dis 2016; 1: e24-9.
Arrese M, Macias RIR, Briz O, et al. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med 2008; 10: e9.
Hancerliogullari N, Aktulay A, Engin-Ustun Y, et al. Pregnancy-associated plasma protein a levels are decreased in obstetric cholestasis. Clin Exp Obstet Gynecol 2015;42: 617-8.
Kang JH, Farina A, Park JH, et al. Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity. Prenat Diagn 2008; 28: 704-9.
Gutaj P, Wender-Ożegowska E, Brązert J. Maternal lipids associated with large-for-gestational-age birth weight in women with type 1 diabetes: results from a prospective single center study. Arch Med Sci 2017; 13: 753-9.
Goetzinger KR, Cahill AG, Macones GA, et al. Association of first-trimester low PAPP-A levels with preterm birth. Prenat Diagn 2010; 30: 309-13
Blumenfeld YJ, Baer RJ, Druzin ML, et al. Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption. Am J Obs Gynecol 2014; 211: 144.e1–144.e9, Perinatal Journal 2014;22(3):142-146, Turk J Obstet Gynecol. 2020 Mar; 17(1): 40–45).
AJOG. The association between first-trimester levels of PAPP-A and perinatal complications , volume 191,Issue 6, Suplement , S78, December 01, 2004.
Sirikunalai P, Wanapirak C, Sirichotiyakul S, et al. Associations between maternal serum free beta human chorionic gonadotropin (β-hCG) levels and adverse pregnancy outcomes. J Obstet Gynaecol. 2016;36(2):178-82.
Aksan Desteli G, Sahin-Uysal N, Cok T, et al. First trimester maternal serum PAPP-A levels and associated pregnancy complications in intrahepatic cholestasis of pregnancy. Clin Exp Obstet Gynecol. 2016;43(5):673-677.
Akobeng AK. Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr 2007; 6:644-647
Tayyar AT, Tayyar A, Atakul T, Yayla , et al. Could first- and second-trimester biochemical markers for down syndrome have a role in predicting intrahepatic cholestasis of pregnancy? Arch Med Sci. 2018;14(4):846–50.
Handschuh K, Guibourdenche J, Guesnon M, et al. Modulation of PAPP-A expression by PPARgamma in human first trimester trophoblast. Placenta 2006; 27 Suppl A:S127-34.
Bowman CJ, Streck RD, Chapin RE. Maternal-placental insulin-like growth factor (IGF) signaling and its importance to normal embryo-fetal development. Birth Defects Res B Dev Reprod Toxicol 2010; 89: 339-49.
Clemmons DR. 1998. Role of insulin-like growth factor binding proteins in controlling IGF actions. Mol Cell Endocrinol 140: 19–24
Irwin JC, Suen LF, Martina NA, et al. Role of the IGF system in trophoblast invasion and pre-eclampsia. Hum Reprod 1999;14: 90–96
Chełchowska M, Gajewska J, Mazur J, et al. Serum pregnancy-associated plasma protein A levels in the first, second and third trimester of pregnancy: relation to newborn anthropometric parameters and maternal tobacco smoking. Arch Med Sci 2016; 12: 1256-62
Gagnon A, Wilson RD, Audibert F, et al. Obstetrical complications associated with abnormal maternal serum markers analytes. J Obstet Gynaecol Can 2008; 30: 918-49
Kawamura I, Takeshita S, Fushimi M, et al. Stimulation of choleresis by insulin-like growth factor-I in rats. Endocr J 2000; 47: 249-55.
Mabuchi M, Kawamura I, Fushimi M, et al. Choleretic actions of insulin like growth factor I, prednisolone, and ursodeoxycholic acid in rats. Dig Dis Sci 2003; 48: 1398-405.
Hagenbuch B, Dawson P. The sodium bile salt cotransport family SLC10. Pflugers Arch 2004; 447: 566-70.
Vallejo M, Briz O, Serrano MA, et al. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol 2006; 44:1150-7.
Glantz A, Reilly SJ, Benthin L, et al. Intrahepatic cholestasis of pregnancy: amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology 2008; 47: 544-51.
Raty R, Anttila L, Virtanen A, et al. Maternal midtrimester free beta-HCG and AFP serum levels in spontaneous singleton pregnancies complicated by gestational diabetes mellitus, pregnancy-induced hypertension or obstetric cholestasis. Prenat Diagn 2003; 23: 1045-8.
Turkcapar F, Engin-Üstün Y, Simsek OY, et al. First and second trimester biochemical markers in familial Mediterranean fever. Eur Rev Med Pharmacol Sci. 2013;17(13):1820–3.
Cohen JL, Smilen KE, Bianco AT, et al. Predictive value of combined serum biomarkers for adverse pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol. 2014;181:89–94.
Türkmen GG, Timur H, Yilmaz Z, et al. Effect of intrahepatic cholestasis of pregnancy on maternal serum screening tests. J Neonatal-Perinatal Med.2016;9(4):411–5
Eloranta ML, Heinonen S, Kirkinen P. Intrahepatic cholestasis of pregnancy has no effect on maternal serum second trimester alpha-fetoprotein and hCG. Acta Obstet Gynecol Scand. 2000;79(7):548–52
Yuan X, Long W, Liu J, et al. Associations of serum markers screening for Down’s syndrome with pregnancy outcomes: a Chinese retrospective cohort study. Clin Chim Acta. 2019;489:130–5.
Reyes H, Ribalta J, González MC, et al. Sulfobromophthalein clearance tests before and after ethinyl estradiol administration, in women and men with familial history of intrahepatic cholestasis of pregnancy. Gastroenterology 1981; 81: 226-231
Barth A, Klinger G, Rost M. Influence of ethinyloestradiol propanolsulphonate on serum bile acids in healthy volunteers. Exp Toxicol Pathol 2003; 54: 381-386
Leslie KK, Reznikov L, Simon FR, et al. Estrogens in intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2000;95(3):372–6.
Milkiewicz P, Gallagher R, Chambers J, et al. Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment. J Gastroenterol Hepatol 2003; 18: 1283-1286
Fisk NM, Bye WB, Storey GN. Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital.Aust N Z J Obstet Gynaecol 1988; 28: 172-176