Iranian Society of Gynecology Oncology

Document Type : Original Research Article


1 Department of Obstetrics and Gynecology, Reproductive Health Research Center, Al-Zahra Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

2 Department of Biostatistics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

3 Department of Midwifery, Reproductive Health Research Center, Al-zahra Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran


Background and objective:   The initial diagnosis of predictive markers is essential for the IUGR. High levels of PAPP-A lead to increased levels of free IGF-1, which in turn reflects the function of the placenta and the fetus normal growth. The objective of this study was to compare the level of PAPP-A in pregnancy weeks 11-14 in women with and without intrauterine growth restriction and to assess the ability of this marker to predict adverse outcomes in pregnancy.
Methods:  In this Comparative Cross-sectional study, 227 pregnant women were studied during 2017. Mothers were divided into two main groups with and without intrauterine growth restriction. The relevant data, including birth weight, preeclampsia, gestational diabetes, Apgar score, and PAPP-A, were recorded on special forms. Data analysis was done using SPSS-21 software.
Results: The mean age of participating women in this study was 28.8 ± 5.6 years. The median (IOR) number of gravidity and Gestational weight gain was 1 (1) and 12 (7) kg respectively. The difference in median (IOR) PAPP-A in patients with and without IUGR was statistically significant 0.64(0.57) and 1 (0.57), respectively, P= 0.001.The cut-off point for PAPP-A was 0.73 with a sensitivity=72.2% (95% CI: 64.32-79.16%) and a specify =60.5% (95% CI: 48.65 -71.56%).
Conclusion: The results of this study confirm the relationship between low levels of PAPP-A and adverse outcomes of pregnancy. In the present study, the optimal cut-off point (0.73) is higher than other studies, which can be due to racial and epidemiological differences.


Main Subjects

1. Cunningham FG, Leveno KJ, Bloom SL, Spong CY, Dashe JS, Hoffman BL, et al. Williams obstetrics: McGraw-Hill Medical New York; 2014.
2. ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet Gynecol. 2019;133(2):e97-e109. [DOI:10.1097/AOG.0000000000003070] [PMID]
3. 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(6):681-94. [DOI:10.1111/1471-0528.12172] [PMID]
4. Leijnse JEW, de Heus R, de Jager W, Rodenburg W, Peeters LLH, Franx A, Eijkelkamp N. First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome. Pregnancy Hypertens. 2018;13:87-94. [DOI:10.1016/j.preghy.2018.04.008] [PMID]
5. Abdi F, Aghaie Z, Rahnemaei FA, Alimoradi Z. A systematic review of first trimester biochemical and molecular predictive tests for preeclampsia. Curr Hypertens Rev. 2018;14(1):21-8. [DOI:10.2174/1573402114666180416160425] [PMID]
6. Barrios V, Chowen JA, Martín-Rivada Á, Guerra-Cantera S, Pozo J, Yakar S, et al. Pregnancy-associated plasma protein (PAPP)-A2 in physiology and disease. Cells. 2021;10(12):3576. [DOI:10.3390/cells10123576] [PMID] [PMCID]
7. Sferruzzi-Perri AN, Sandovici I, Constancia M, Fowden AL. Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth. J Physiol. 2017;595(15):5057-93. [DOI:10.1113/JP273330] [PMID] [PMCID]
8. Morris RK, Bilagi A, Devani P, Kilby MD. 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. [DOI:10.1002/pd.5001] [PMID]
9. Kaijomaa M, Ulander VM, Hämäläinen E, Alfthan H, Markkanen H, Heinonen S, Stefanovic V. The risk of adverse pregnancy outcome among pregnancies with extremely low maternal PAPP-A. Prenat Diagn. 2016;36(12):1115-20. [DOI:10.1002/pd.4946] [PMID]
10. Antsaklis P, Fasoulakis Z, Theodora M, Diakosavvas M, Kontomanolis EN. Association of Low Maternal Pregnancy-associated Plasma Protein A with Adverse Perinatal Outcome. Cureus. 2019;11(6):e4912. [DOI:10.7759/cureus.4912] [PMID] [PMCID]
11. Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn. 2011;31(1):7-15. [DOI:10.1002/pd.2637] [PMID]
12. Ong CYT, Liao AW, Spencer K, Munim S, Nicolaides KH. First trimester maternal serum free β human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications. BJOG. 2000;107(10):1265-70. [DOI:10.1111/j.1471-0528.2000.tb11618.x] [PMID]
13. Spencer K, Yu CKH, Cowans NJ, Otigbah C, Nicolaides KH. Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free β-hCG and with second-trimester uterine artery Doppler. Prenat Diagn. 2005;25(10):949-53. [DOI:10.1002/pd.1251] [PMID]
14. Poon LCY, Maiz N, Valencia C, Plasencia W, Nicolaides KH. First-trimester maternal serum pregnancy-associated plasma protein-A and pre-eclampsia. Ultrasound Obstet Gynecol. 2009;33(1):23-33. [DOI:10.1002/uog.6280] [PMID]
15. Goetzinger KR, Singla A, Gerkowicz S, Dicke JM, Gray DL, Odibo AO. The efficiency of first-trimester serum analytes and maternal characteristics in predicting fetal growth disorders. Am J Obstet Gynecol. 2009;201(4):412.e1-.e6. [DOI:10.1016/j.ajog.2009.07.016] [PMID]
16. Grill S, Rusterholz C, Zanetti-Dällenbach R, Tercanli S, Holzgreve W, Hahn S, Lapaire O. Potential markers of preeclampsia-a review. Reprod Biol Endocrino. 2009;7(1):1-14. [DOI:10.1186/1477-7827-7-70] [PMID] [PMCID]
17. Deveci K, Sogut E, Evliyaoglu O, Duras N. Pregnancy-associated plasma protein-A and C-reactive protein levels in pre-eclamptic and normotensive pregnant women at third trimester. J Obstet Gynaecol Res. 2009;35(1):94-8. [DOI:10.1111/j.1447-0756.2008.00835.x] [PMID]
18. Kuc S, Wortelboer EJ, van Rijn BB, Franx A, Visser GHA, Schielen PCJI. Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet Gynecol Surv. 2011;66(4):225-39. [DOI:10.1097/OGX.0b013e3182227027] [PMID]
19. Lean SC, Heazell AEP, Dilworth MR, Mills TA, Jones RL. Placental dysfunction underlies increased risk of fetal growth restriction and stillbirth in advanced maternal age women. Sci Rep. 2017;7(1):9677. [DOI:10.1038/s41598-017-09814-w] [PMID] [PMCID]
20. Carolan M, Frankowska D. Advanced maternal age and adverse perinatal outcome: A review of the evidence. Midwifery. 2011;27(6):793-801. [DOI:10.1016/j.midw.2010.07.006] [PMID]
21. Lončar D, Varjačić M, Arsenijević S. Significance of pregnancy-associated plasma protein A (PAPP-A) concentration determination in the assessment of final outcome of pregnancy. Vojnosanit Pregl. 2013;70(1):46-50. [DOI:10.2298/VSP110530023L] [PMID]
22. Albu AR, Anca AF, Horhoianu VV, Horhoianu IA. Predictive factors for intrauterine growth restriction. J Med Life. 2014;7(2):165-71.
23. Sharma D, Shastri S, Sharma P. Intrauterine Growth Restriction: Antenatal and Postnatal Aspects. Clin Med Insights Pediatr. 2016;10:CMPed.S40070. [DOI:10.4137/CMPed.S40070] [PMID] [PMCID]
24. Ramezani S, Doulabi MA, Saqhafi H, Alipoor M. Prediction of Gestational Diabetes by Measuring the Levels of Pregnancy Associated Plasma Protein-A (PAPP-A) During Gestation Weeks 11-14. J Reprod Infertil. 2020;21(2):130-7.
25. Petry CJ, Ong KK, Hughes IA, Acerini CL, Frystyk J, Dunger DB. Early Pregnancy-Associated Plasma Protein A Concentrations Are Associated With Third Trimester Insulin Sensitivity. J Clin Endocrinol Metab. 2017;102(6):2000-8. [DOI:10.1210/jc.2017-00272] [PMID] [PMCID]
26. Ekin A, Gezer C, Taner CE, Özeren M. The association between low PAPP-A levels at first trimester and poor pregnancy outcomes. Périnat J. 2014;22:142-6. [DOI:10.2399/prn.14.0223007]
27. Gupta S, Goyal M, Verma D, Sharma A, Bharadwaj N, Kabra M, Kapoor S. Adverse pregnancy outcome in patients with low pregnancy-associated plasma protein-A: The Indian Experience. J Obstet Gynaecol Res. 2015;41(7):1003-8. [DOI:10.1111/jog.12662] [PMID]