First trimester serum PAPP-A is associated with placenta accreta: a retrospective study



Our objective of this study was to investigate whether first trimester serum pregnancy-associated plasma protein-A (PAPP-A) differed amongst pregnancies with placenta previa-accreta and non-adherent placenta previa and healthy pregnancies by a retrospective cohort analysis.


A total of 177 pregnant females were included in the study, as follows: 35 cases of placenta previa-accreta, 30 cases of non-adherent placenta previa, and 112 cases of BMI and age matched, healthy pregnant controls. PAPP-A multiples of the median (MoM) were acquired from laboratory data files in 1 January 2017–30 September 2019. The probable maternal serum biochemical predictor of placenta accreta was analyzed by using multiple logistic regression analysis.


PAPP-A MoM of placenta previa-accreta group was significantly higher than those of the non-adherent placenta previa group and control group (p = 0.009 < 0.05, p < 0.001). Serum PAPP-A was found to be significantly positively associated with placenta accreta after adjusted gestational week at time of blood sampling, BMI, age, smoking, and previous cesarean section history (OR: 3.51; 95% CI: 1.77–6.94; p = 0.0003 < 0.05). In addition, smoking (OR: 9.17; 95% CI: 1.69–49.62; p = 0.010 < 0.05) and previous cesarean section history (OR: 2.75; 95% CI: 1.23–6.17; p = 0.014 < 0.05) were also significantly associated with placenta accreta.


Increased first trimester serum PAPP-A was significantly positively associated with placenta accreta, suggesting that the potential role of PAPP-A in identifying pregnancies at high risk for placenta accreta. Smoking and previous cesarean section history may be the risk factors for accreta in placenta previa patients.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.



Pregnancy-associated plasma protein-A


Body mass index


Multiples of the median


  1. 1.

    Su HW, Yi YC, Tseng JJ, Chen WC, Chen YF, Kung HF, Chou MM (2017) Maternal outcome after conservative management of abnormally invasive placenta. Taiwan J Obstetr Gynecol 56(3):353–357.

    Article  Google Scholar 

  2. 2.

    Higgins MF, Monteith C, Foley M, O’Herlihy C (2013) Real increasing incidence of hysterectomy for placenta accreta following previous caesarean section. Eur J Obstet Gynecol Reprod Biol 171(1):54–56.

    Article  PubMed  Google Scholar 

  3. 3.

    Silver RM (2015) Abnormal placentation: placenta previa, vasa previa, and placenta accreta. Obstet Gynecol 126(3):654–668.

    Article  PubMed  Google Scholar 

  4. 4.

    Tikkanen M, Paavonen J, Loukovaara M, Stefanovic V (2011) Antenatal diagnosis of placenta accreta leads to reduced blood loss. Acta Obstet Gynecol Scand 90(10):1140–1146.

    Article  PubMed  Google Scholar 

  5. 5.

    Comstock CH, Love JJ Jr, Bronsteen RA, Lee W, Vettraino IM, Huang RR, Lorenz RP (2004) Sonographic detection of placenta accreta in the second and third trimesters of pregnancy. Am J Obstet Gynecol 190(4):1135–1140.

    Article  PubMed  Google Scholar 

  6. 6.

    Brown BP, Meyers ML (2020) Placental magnetic resonance imaging Part II: placenta accreta spectrum. Pediatr Radiol 50(2):275–284.

    Article  PubMed  Google Scholar 

  7. 7.

    SfM-FM PC, Belfort MA (2010) Placenta accreta. Am J Obstet Gynecol 203(5):430–439.

    Article  Google Scholar 

  8. 8.

    Yu N, Cui H, Chen X, Chang Y (2017) First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction. Taiwan J Obstetr Gynecol 56(3):358–361.

    Article  Google Scholar 

  9. 9.

    Buke B, Akkaya H, Demir S, Sagol S, Simsek D, Basol G, Barutcuoglu B (2018) Relationship between first trimester aneuploidy screening test serum analytes and placenta accreta. J Maternal-fetal Neonatal Med 31(1):59–62.

    CAS  Article  Google Scholar 

  10. 10.

    Thompson O, Otigbah C, Nnochiri A, Sumithran E, Spencer K (2015) First trimester maternal serum biochemical markers of aneuploidy in pregnancies with abnormally invasive placentation. BJOG Int J Obstetr Gynaecol 122(10):1370–1376.

    CAS  Article  Google Scholar 

  11. 11.

    Pilalis A, Souka AP, Antsaklis P, Daskalakis G, Papantoniou N, Mesogitis S, Antsaklis A (2007) Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11–14 weeks’ gestation. Ultrasound Obstetr Gynecol 29(2):135–140.

    CAS  Article  Google Scholar 

  12. 12.

    Pijnenborg R, Dixon G, Robertson WB, Brosens I (1980) Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1(1):3–19.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, Silver R, Pergament E, Platt LD, Filkins K, Johnson A, Mahoney M, Hogge WA, Wilson RD, Mohide P, Hershey D, Wapner R, First Trimester Maternal Serum B, Fetal Nuchal Translucency Screening Study G (2004) Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. AmJ Obstetr Gynecol 191(4):1452–1458.

    CAS  Article  Google Scholar 

  14. 14.

    Yaron Y, Cherry M, Kramer RL, O’Brien JE, Hallak M, Johnson MP, Evans MI (1999) Second-trimester maternal serum marker screening: maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome. Am J Obstet Gynecol 181(4):968–974.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Khong TY (2008) The pathology of placenta accreta, a worldwide epidemic. J Clin Pathol 61(12):1243–1246.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Livrinova V, Petrov I, Samardziski I, Jovanovska V, Boshku AA, Todorovska I, Dabeski D, Shabani A (2019) Clinical importance of low level of PAPP-A in first trimester of pregnancy—an obstetrical dilemma in chromosomally normal fetus. Open Access Macedonian J Med Sci 7(9):1475–1479.

    Article  Google Scholar 

  17. 17.

    Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, Hankins G, Berkowitz RL, Merkatz I, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Vidaver J, D’Alton ME (2004) First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol 191(4):1446–1451.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Di Mascio D, Cali G, D’Antonio F (2019) Updates on the management of placenta accreta spectrum. Minerva Ginecol 71(2):113–120.

    Article  PubMed  Google Scholar 

  19. 19.

    Jauniaux E, Jurkovic D (2012) Placenta accreta: pathogenesis of a 20th century iatrogenic uterine disease. Placenta 33(4):244–251.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Fitzpatrick KE, Sellers S, Spark P, Kurinczuk JJ, Brocklehurst P, Knight M (2012) Incidence and risk factors for placenta accreta/increta/percreta in the UK: a national case-control study. PLoS ONE 7(12):e52893.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Walter AJ, McCullough AE, Patel MD, Cornella JL (1999) Placenta increta presenting as delayed postabortal hemorrhage. Obstet Gynecol 93(5 Pt 2):846.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Silver RM, Barbour KD (2015) Placenta accreta spectrum: accreta, increta, and percreta. Obstet Gynecol Clin North Am 42(2):381–402.

    Article  PubMed  Google Scholar 

  23. 23.

    Dombrowski MP, Bottoms SF, Saleh AA, Hurd WW, Romero R (1995) Third stage of labor: analysis of duration and clinical practice. Am J Obstet Gynecol 172(4 Pt 1):1279–1284.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Leijnse JEW, de Heus R, de Jager W, Rodenburg W, Peeters LLH, Franx A, Eijkelkamp N (2018) First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome. Pregnancy Hypertens 13:87–94.

    Article  PubMed  Google Scholar 

  25. 25.

    Zelop C, Nadel A, Frigoletto FD Jr, Pauker S, MacMillan M, Benacerraf BR (1992) Placenta accreta/percreta/increta: a cause of elevated maternal serum alpha-fetoprotein. Obstet Gynecol 80(4):693–694

    CAS  PubMed  Google Scholar 

  26. 26.

    Hung TH, Shau WY, Hsieh CC, Chiu TH, Hsu JJ, Hsieh TT (1999) Risk factors for placenta accreta. Obstet Gynecol 93(4):545–550.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Dreux S, Salomon LJ, Muller F, Goffinet F, Oury JF, Sentilhes L (2012) Second-trimester maternal serum markers and placenta accreta. Prenatal Diagn 32(10):1010–1012.

    CAS  Article  Google Scholar 

  28. 28.

    Garrido-Gomez T, Ona K, Kapidzic M, Gormley M, Simon C, Genbacev O, Fisher SJ (2017) Severe pre-eclampsia is associated with alterations in cytotrophoblasts of the smooth chorion. Development 144(5):767–777.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Christians JK, Beristain AG (2016) ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts. Cell Adhes Migr 10(1–2):147–153.

    CAS  Article  Google Scholar 

  30. 30.

    Di Lorenzo G, Ceccarello M, Cecotti V, Ronfani L, Monasta L, Vecchi Brumatti L, Montico M, D’Ottavio G (2012) First trimester maternal serum PIGF, free beta-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta 33(6):495–501.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Kupferminc MJ, Tamura RK, Wigton TR, Glassenberg R, Socol ML (1993) Placenta accreta is associated with elevated maternal serum alpha-fetoprotein. Obstet Gynecol 82(2):266–269

    CAS  PubMed  Google Scholar 

  32. 32.

    Vyshka G, Capari N, Shaqiri E (2010) Placenta increta causing hemoperitoneum in the 26th week of pregnancy: a case report. J Med Case Rep 4:412.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shellhaas CS, Gilbert S, Landon MB, Varner MW, Leveno KJ, Hauth JC, Spong CY, Caritis SN, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai BM, Langer O, Gabbe SG, Eunice Kennedy Shriver National Institutes of H, Human Development Maternal-Fetal Medicine Units N (2009) The frequency and complication rates of hysterectomy accompanying cesarean delivery. Obstet Gynecol 114(2 Pt 1):224–229.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Silver RM, Landon MB, Rouse DJ, Leveno KJ, Spong CY, Thom EA, Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O’Sullivan MJ, Sibai B, Langer O, Thorp JM, Ramin SM, Mercer BM, National Institute of Child H, Human Development Maternal-Fetal Medicine Units N (2006) Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol 107(6):1226–1232.

    Article  PubMed  Google Scholar 

  35. 35.

    Kingdom JC, Hobson SR, Murji A, Allen L, Windrim RC, Lockhart E, Collins SL, Soleymani Majd H, Alazzam M, Naaisa F, Shamshirsaz AA, Belfort MA, Fox KA (2020) Minimizing surgical blood loss at cesarean hysterectomy for placenta previa with evidence of placenta increta or placenta percreta: the state of play in 2020. Am J Obstet Gynecol.

    Article  PubMed  Google Scholar 

  36. 36.

    Ruiz-Perez R, Delgado Lopez-Cozar E, Jimenez-Contreras E (2010) Principles and criteria used by the National Evaluation Committee of Research Activity (CNEAI-Spain) for the assessment of scientific publications: 1989–2009. Psicothema 22(4):898–908

    PubMed  Google Scholar 

  37. 37.

    Luo L, Sun Q, Ying D, Wu X, Yan P, Yang Y, Chen Z (2019) Scoring system for the prediction of the severity of placenta accrete spectrum in women with placenta previa: a prospective observational study. Arch Gynecol Obstet 300(3):783–791.

    Article  PubMed  Google Scholar 

  38. 38.

    Genbacev O, Zhou Y, Ludlow JW, Fisher SJ (1997) Regulation of human placental development by oxygen tension. Science 277(5332):1669–1672.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Tantbirojn P, Crum CP, Parast MM (2008) Pathophysiology of placenta creta: the role of decidua and extravillous trophoblast. Placenta 29(7):639–645.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Usta IM, Hobeika EM, Musa AA, Gabriel GE, Nassar AH (2005) Placenta previa-accreta: risk factors and complications. Am J Obstet Gynecol 193(3 Pt 2):1045–1049.

    Article  PubMed  Google Scholar 

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This study was supported by the Research Fund for Academician Lin He New Medicine, China (No. JYHL2018FMS15).

Author information




FGW and DMM conceived and designed the study. FGW and LXZ participated in the design. FGW drafted the manuscript. FGW, YPW, and JSW performed the statistical analysis. SXC participated in the chart making and collecting information in revised the manuscript. FR and HS participated in the design of the study and revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Liangxi Zhu or Dongmei Man.

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The authors declare that they have no competing interests.

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The study was approved by the Human Ethics Committee of the Affiliated Hospital of Jining Medical University (Shandong, China) (2019-zr-016).

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Wang, F., Chen, S., Wang, J. et al. First trimester serum PAPP-A is associated with placenta accreta: a retrospective study. Arch Gynecol Obstet (2021).

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  • PAPP-A
  • First trimester serum
  • Placenta accreta
  • Association