The Relationship of Pregnancy-Associated Plasma Protein A and Human Chorionic Gonadotropin with Adverse Pregnancy Outcomes: A Prospective Study

  • Hamideh Pakniat
  • Atieh Bahman
  • Iman AnsariEmail author
Original Article



This prospective study investigated the relationship between pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG) and adverse pregnancy outcomes in the Iranian population.


Overall, 994 singleton pregnant mothers of 18–35-year old were referred for first-trimester screening tests, including PAPP-A and β-hCG, at the age of 6 days and 11–13 weeks, and were followed until the end of their pregnancy. The adverse pregnancy outcomes, PAPP-A, and β-hCG serum levels were recorded and analyzed. The sensitivity and specificity of the test were measured by calculating the area under the curve of receiver operating characteristic curve (ROC).


The mean serum level of PAPP-A and β-hCG was 1.10 ± 0.69 and 1.09 ± 0.8 MoM, respectively. Pregnancy-associated plasma protein A, regardless of its percentile, showed a significant relationship with the incidence of preeclampsia, preterm birth, and fetal low birth weight (p < 0.001 for each). However, the relationship between PAPP-A and abortion was not significant (p > 0.05). According to ROC, the results indicated that PAPP-A had a significant relationship with the incidence of preeclampsia, preterm birth, and fetal low birth weight (p < 0.001). However, β-hCG levels showed no significant relationship with adverse pregnancy outcomes.


The result of this study revealed that lower level of PAPP-A and β-hCG could be a predictive factor in preterm labor. Also, this study indicated that PAPP-A measurements could be a screening test for adverse pregnancy outcomes, such as preeclampsia, low birth weight and preterm labor.


PAPP-A β-hCG Preeclampsia Preterm labor Low birth weight Abortion 



This work was supported in part by Kowar Hospital Development Research Center, Qazvin University of Medical Sciences. We gratefully acknowledge the Zahra Sadat Mohammadi for assistance with statistical analysis.

Compliance with Ethical Standards

Conflict of interest

The authors declared no conflict of interest.

Ethical Approval

The researchers were committed to the ethical guidelines of the Declaration of Helsinki, and approval for the study was obtained from the Ethical Committee and Institutional Review Board of Qazvin University of Medical Sciences. The data were gathered after obtaining the participants’ informed consents, considering confidentiality and cultural obligations.

Informed consent

Informed consent was obtained from all patients for being included in the study.


This study was funded by Kowsar Research Center, Qazvin University of Medical Sciences.


  1. 1.
    Sweeting A, Park F, Hyett J. The first trimester: prediction and prevention of the great obstetrical syndromes. Best Pract Res Clin Obstet Gynaecol. 2015;29(2):183–93. Scholar
  2. 2.
    Nicolaides KH, Syngelaki A, Poon LC, et al. First-trimester contingent screening for trisomies 21, 18 and 13 by biomarkers and maternal blood cell-free DNA testing. Fetal Diagn Ther. 2014;35(3):185–92. Scholar
  3. 3.
    Cignini P, Savasta LM, Gulino FA, et al. Predictive value of pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet. 2016;293(6):1227–33. Scholar
  4. 4.
    Morris RK, Bilagi A, Devani P, et al. Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. Prenat Diagn. 2017;37(3):253–65. Scholar
  5. 5.
    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. Scholar
  6. 6.
    Huynh L, Kingdom J, Akhtar S. Low pregnancy-associated plasma protein A level in the first trimester. Can Fam Physician. 2014;60(10):899–903.Google Scholar
  7. 7.
    Luewan S, Teja-Intr M, Sirichotiyakul S, et al. Low maternal serum pregnancy-associated plasma protein-A as a risk factor of preeclampsia. Singap Med J. 2018;59(1):55–9. Scholar
  8. 8.
    Hansen YB, Myrhøj V, Jørgensen FS, et al. First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies. Clin Chem Lab Med. 2016;54(1):117–23.CrossRefGoogle Scholar
  9. 9.
    Jelliffe-Pawlowski LL, Baer RJ, Blumenfeld YJ, et al. Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth. BJOG. 2015;122(11):1484–93. Scholar
  10. 10.
    Saraswathy S, Sahai K, Yadav TP, et al. Evaluation of fetal hypermethylated RASSF1A in pre-eclampsia and its relationship with placental protein-13, pregnancy associated plasma protein-A and urine protein. Pregnancy Hypertens. 2016;6(4):306–12. Scholar
  11. 11.
    Sung KU, Roh JA, Eoh KJ, et al. Maternal serum placental growth factor and pregnancy-associated plasma protein A measured in the first trimester as parameters of subsequent pre-eclampsia and small-for-gestational-age infants: a prospective observational study. Obstet Gynecol Sci. 2017;60(2):154–62. Scholar
  12. 12.
    Kharaghani R, Cheraghi Z, Esfahani BO, et al. Prevalence of preeclampsia and eclampsia in Iran. Arch Iran Med. 2016;19(1):64–71. Scholar
  13. 13.
    Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: age-period-cohort analysis. BMJ. 2013;347:f6564.CrossRefGoogle Scholar
  14. 14.
    Thornton C, Dahlen H, Korda A, et al. The incidence of preeclampsia and eclampsia and associated maternal mortality in Australia from population-linked datasets: 2000–2008. Am J Obstet Gynecol. 2013;208:476.e1–5.CrossRefGoogle Scholar
  15. 15.
    Perveen S. Frequency and impact of hypertensive disorders of pregnancy. J Ayub Med Coll. 2014;26:518–21.Google Scholar
  16. 16.
    Pitakkarnkul S, Phaloprakarn C, Wiriyasirivaj B, et al. Seasonal variation in the prevalence of preeclampsia. J Med Assoc Thai. 2011;94:1293–8.Google Scholar
  17. 17.
    Cripe S, O’Brien W, Gelaye B, et al. Perinatal outcomes of southeast asians with pregnancies complicated by gestational diabetes mellitus or preeclampsia. J Immigr Minor Health. 2012;14:747–53.CrossRefGoogle Scholar
  18. 18.
    Moslemi Zadeh N, Naghshvar F, Peyvandi S, et al. PP13 and PAPP-A in the first and second trimesters: predictive factors for preeclampsia? ISRN Obstet Gynecol. 2012;2012:263871. Scholar
  19. 19.
    Crosley EJ, Durland U, Seethram K, et al. First-trimester levels of pregnancy-associated plasma protein A2 (PAPP-A2) in the maternal circulation are elevated in pregnancies that subsequently develop preeclampsia. Reprod Sci. 2014;21(6):754–60. Scholar
  20. 20.
    Patil M, Panchanadikar TM, Wagh G. Variation of PAPP-A level in the first trimester of pregnancy and its clinical outcome. J Obstet Gynaecol India. 2014;64(2):116–9. Scholar
  21. 21.
    Jelliffe-Pawlowski LL, Baer RJ, Currier RJ, et al. Early-onset severe preeclampsia by first trimester pregnancy-associated plasma protein A and total human chorionic gonadotropin. Am J Perinatol. 2015;32(7):703–12. Scholar
  22. 22.
    Yliniemi A, Makikallio K, Korpimaki T, et al. Combination of PAPP-A, fhCGβ, AFP, PlGF, sTNFR1, and maternal characteristics in prediction of early-onset preeclampsia. Clin Med Insights Reprod Health. 2015;9:13–20. Scholar
  23. 23.
    Ozdamar O, Gun I, Keskin U, et al. The role of maternal serumbeta-hCG and PAPP-A levels at gestational weeks 10 to 14 in the prediction of pre-eclampsia. Pak J Med Sci. 2014;30(3):568–73. Scholar
  24. 24.
    Yücel B, Gedikbasi A, Dündar O, et al. The utility of first trimester uterine artery Doppler, placental volume and PAPP-A levels alone and in combination to predict preeclampsia. Pregnancy Hypertens. 2016;6(4):269–73. Scholar
  25. 25.
    O’Gorman N, Wright D, Poon LC, et al. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation. Ultrasound Obstet Gynecol. 2017;49(6):751–5. Scholar
  26. 26.
    Karahasanovic A, Sørensen S, Nilas L. First trimester pregnancy-associated plasma protein A and human chorionic gonadotropin-beta in early and late pre-eclampsia. Clin Chem Lab Med. 2014;52(4):521–5. Scholar
  27. 27.
    Gupta S, Goyal M, Verma D, et al. Adverse pregnancy outcome in patients with low pregnancy-associated plasma protein-A: the Indian experience. J Obstet Gynaecol Res. 2015;41(7):1003–8. Scholar
  28. 28.
    Allen RE, Rogozinska E, Cleverly K, et al. Abnormal blood biomarkers in early pregnancy are associated with preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;182:194–201. Scholar
  29. 29.
    Keikkala E, Koskinen S, Vuorela P, et al. First trimester serum placental growth factor and hyperglycosylated human chorionic gonadotropin are associated with pre-eclampsia: a case control study. BMC Pregnancy Childbirth. 2016;16(1):378.CrossRefGoogle Scholar
  30. 30.
    Kirkegaard I, Uldbjerg N, Petersen OB, et al. PAPP-A, free β-hCG, and early fetal growth identify two pathways leading to preterm delivery. Prenat Diagn. 2010;30(10):956–63. Scholar
  31. 31.
    Gundu S, Kulkarni M, Gupte S, et al. Correlation of first-trimester serum levels of pregnancy-associated plasma protein A with small-for-gestational-age neonates and preterm births. Int J Gynaecol Obstet. 2016;133(2):159–63. Scholar
  32. 32.
    Goetzinger KR, Cahill AG, Kemna J, et al. First-trimester prediction of preterm birth using ADAM12, PAPP-A, uterine artery Doppler, and maternal characteristics. Prenat Diagn. 2012;32(10):1002–7. Scholar
  33. 33.
    D’Antonio F, Rijo C, Thilaganathan B, et al. Association between first-trimester maternal serum pregnancy-associated plasma protein-A and obstetric complications. Prenat Diagn. 2013;33(9):839–47. Scholar
  34. 34.
    Dane B, Dane C, Batmaz G, et al. First trimester maternal serum pregnancy-associated plasma protein-A is a predictive factor for early preterm delivery in normotensive pregnancies. Gynecol Endocrinol. 2013;29(6):592–5. Scholar
  35. 35.
    Quattrocchi T, Baviera G, Pochiero T, et al. Maternal serum PAPP-A as an early marker of obstetric complications? Fetal Diagn Ther. 2015;37(1):33–6. Scholar
  36. 36.
    Kaitu’u-Lino TJ, Bambang K, Onwude J, et al. Plasma MIC-1 and PAPP-a levels are decreased among women presenting to an early pregnancy assessment unit, have fetal viability confirmed but later miscarry. PLoS ONE. 2013;8(9):e72437. Scholar
  37. 37.
    Ranta JK, Raatikainen K, Romppanen J, et al. Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):48–52. Scholar
  38. 38.
    Krauskopf AL, Knippel AJ, Verde PE, et al. Predicting SGA neonates using first-trimester screening: influence of previous pregnancy’s birthweight and PAPP-A MoM. J Matern Fetal Neonatal Med. 2016;29(18):2962–7. Scholar
  39. 39.
    Karagiannis G, Akolekar R, Sarquis R, et al. Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11–13 weeks. Fetal Diagn Ther. 2011;29(2):148–54. Scholar
  40. 40.
    Baer RJ, Lyell DJ, Norton ME, et al. First trimester pregnancy-associated plasma protein-A and birth weight. Eur J Obstet Gynecol Reprod Biol. 2016;198:1–6. Scholar

Copyright information

© Federation of Obstetric & Gynecological Societies of India 2019

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyQazvin University of Medical SciencesQazvinIran
  2. 2.Department of Gynecologic Oncology, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
  3. 3.Medical Students Research CommitteeShahed UniversityTehranIran

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