The Iranian Journal of Obstetrics, Gynecology and Infertility

The Iranian Journal of Obstetrics, Gynecology and Infertility

Diagnostic Value of Pregnancy-Associated Plasma Protein A in Women with Intrauterine Fetal Growth Restriction

Document Type : Original Article

Authors
Nasrin Mansouri 1
Ali Azizi 2
Maryam Ayni 3
1 Assistant Professor, Department of Obstetrics and Gynecology, Clinical Research Center of Imam Reza Hospital, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
2 Associate Professor, Department of Community Medicine, Social Development and Health Promotion Research Center, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
3 General Physician, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
10.22038/ijogi.2025.87532.6417
Abstract
Introduction: Intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity and mortality as well as long-term growth and health problems. This study was conducted with aim to investigate the diagnostic value of pregnancy-associated plasma protein A (PAPP-A) in assessing the risk of IUGR.
Methods: This retrospective case-control study was conducted from 2020 to 2023 on 80 singleton pregnancies with IUGR as the case group and 80 uncomplicated pregnancies as the control group. Serum PAPP-A and β-hCG levels were measured in the first trimester of gestation (weeks 11–13) and expressed as multiples of the median (MoM). Uterine artery Doppler was assessed by mean pulsatility index (PI). Logistic regression and receiver operating characteristic (ROC) curves were used to determine odds ratio (OR), sensitivity, and specificity. Data analysis was performed using SPSS statistical software (version 27) and Chi-square, Fisher's exact and independent t-tests. P<0.05 was considered significant.
Results: The mean PAPA-A level in women with IUGR infants (0.83±0.37) was significantly lower than that in the control group (1.17±0.95) (P < 0.002) and the mean uterine artery PI was higher (1.85 vs. 1.42, P < 0.001). High PI (>95th percentile) predicted IUGR with an odds ratio of 5.5 (95% CI: 3.1-9.8) and PAPA-A was 0.52 (95% CI: 0.34-0.84).
Conclusion: In first trimester screening, in addition to assessing the risk of Down syndrome, serum PAPA-A levels and uterine artery Doppler can be used to assess the risk of IUGR.
Keywords
Diagnostic Value
Intrauterine Growth Restriction
Pregnancy
Pregnancy-Associated Plasma Protein A
Uterine artery Doppler
Subjects
  1. Baschat AA. Pathophysiology of fetal growth restriction: implications for diagnosis and surveillance. Obstetrical & gynecological survey 2004; 59(8):617-27.
  2. Sharma D, Shastri S, Sharma P. Intrauterine growth restriction: antenatal and postnatal aspects. Clinical medicine insights: pediatrics 2016;10:CMPed-S40070.
  3. Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal diagnosis and therapy 2014; 36(2):86-98.
  4. D'Agostin M, Morgia CD, Vento G, Nobile S. Long-term implications of fetal growth restriction. World journal of clinical cases 2023; 11(13):2855.
  5. Kagan KO, Wright D, Nicolaides KH. First‐trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell‐free DNA testing. Ultrasound in Obstetrics & Gynecology 2015; 45(1):42-7.
  6. Giudice LC, Conover CA, Bale L, Faessen GH, Ilg K, Sun I, et al. Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. The Journal of Clinical Endocrinology & Metabolism 2002; 87(5):2359-66.
  7. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. 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). American journal of obstetrics and gynecology 2004; 191(4):1446-51.
  8. Spencer K, Cowans NJ, Nicolaides KH. Low levels of maternal serum PAPP‐A in the first trimester and the risk of pre‐eclampsia. Prenatal Diagnosis: Published in Affiliation With the International Society for Prenatal Diagnosis 2008; 28(1):7-10.
  9. Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. The Journal of Clinical Endocrinology & Metabolism 2002; 87(4):1762-7.
  10. Derbent AU, Yanik FF, Simavli S, Atasoy L, Ürün E, Kuşçu ÜE, et al. First trimester maternal serum PAPP‐A and free β‐HCG levels in hyperemesis gravidarum. Prenatal diagnosis 2011; 31(5):450-3.
  11. Karagiannis G, Akolekar R, Sarquis R, Wright D, Nicolaides KH. Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11–13 weeks. Fetal diagnosis and therapy 2011; 29(2):148-54.
  12. Sabbaghchi M, Jalali R, Mohammadi M. A Systematic Review and Meta‐analysis on the Prevalence of Low Birth Weight Infants in Iran. Journal of pregnancy 2020; 2020(1):3686471.
  13. Gonen G, Akpak YK, Muhcu M. Investigation of Association with First-Trimester Free Human Chorionic Gonadotropin-ß, Pregnancy-Associated Plasma Protein-A, and Adverse Pregnancy Outcomes. Gynecology Obstetrics & Reproductive Medicine 2022; 28(1):7-15.
  14. Gordijn SJ, Beune IM, Thilaganathan BT, Papageorghiou A, Baschat AA, Baker PN, et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound in Obstetrics & Gynecology 2016; 48(3):333-9.
  15. Mlynarczyk M, Chauhan SP, Baydoun HA, Wilkes CM, Earhart KR, Zhao Y, et al. The clinical significance of an estimated fetal weight below the 10th percentile: a comparison of outcomes of< 5th vs 5th–9th percentile. American journal of obstetrics and gynecology 2017; 217(2):198-e1.
  16. Papamichail M, Fasoulakis Z, Daskalakis G, Theodora M, Rodolakis A, Antsaklis P. Importance of low pregnancy associated plasma protein-A (PAPP-A) levels during the first trimester as a predicting factor for adverse pregnancy outcomes: a prospective cohort study of 2636 pregnant women. Cureus 2022; 14(11).
  17. Fatima A, Aich A, Jamjute P. Association of low pregnancy-associated plasma protein A with the timing of delivery in babies with intrauterine growth restriction, babies showing suboptimal growth on serial scans, and well-grown babies. International Journal of Reproduction, Contraception, Obstetrics and Gynecology 2025; 14(7):2238–44.
  18. Kazemi Aski S, Sharami SH, Tavangar A, Kazemnezhad E, Dalil Heirati SF, Etezadi A. Comparison of Pregnancy-Associated Plasma Protein-A Levels in Women with and Without Intrauterine Growth Restriction. Journal of Obstetrics, Gynecology and Cancer Research 2024; 9(1):14-21.
  19. Dey M, Choudhury P, Chawla S, Dhume P, Goel S, Shah A, et al. Pregnancy-Associated plasma Protein-A: its significance as a single biomarker for adverse obstetric outcomes. Gynecology Obstetrics & Reproductive Medicine 2023; 29(3):146-51.
  20. Cristodoro M, Messa M, Tossetta G, Marzioni D, Dell’Avanzo M, Inversetti A, et al. First trimester placental biomarkers for pregnancy outcomes. International Journal of Molecular Sciences 2024; 25(11):6136.
  21. Hong J, Kumar S. Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction. Clinical Science 2023; 137(8):579-95.
  22. Zhong Y, Zhu F, Ding Y. Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis. BMC pregnancy and childbirth 2015; 15(1):191.
  23. Antsaklis P, Fasoulakis Z, Theodora M, Diakosavvas M, Kontomanolis EN, Kontomanolis E. Association of low maternal pregnancy-associated plasma protein A with adverse perinatal outcome. Cureus 2019; 11(6).
  24. Turrado Sánchez EM, de Miguel Sánchez V, Macía Cortiñas M. Correlation between PAPP-A levels determined during the first trimester and birth weight at full-term. Reproductive Sciences 2023; 30(11):3235-42.
  25. Gonen G, Akpak YK, Muhcu M. Investigation of Association with First-Trimester Free Human Chorionic Gonadotropin-ß, Pregnancy-Associated Plasma Protein-A, and Adverse Pregnancy Outcomes. Gynecology Obstetrics & Reproductive Medicine 2022; 28(1):7-15.
  26. Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. Association of extreme first-trimester free human chorionic gonadotropin-β, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. American journal of obstetrics and gynecology 2004; 191(4):1452-8.
  27. Saruhan Z, Ozekinci MU, Simsek M, Mendilcioglu I. Association of first trimester low PAPP-A levels with adverse pregnancy outcomes. Clinical and experimental obstetrics & gynecology 2012; 39(2):225-8.
  28. Morssink LP, Kornman LH, Hallahan TW, Kloosterman MD, Beekhuis JR, De Wolf BT, et al. Maternal serum levels of free β‐hCG and PAPP‐A in the first trimester of pregnancy are not associated with subsequent fetal growth retardation or preterm delivery. Prenatal Diagnosis: Published in Affiliation With the International Society for Prenatal Diagnosis 1998; 18(2):147-52.
  29. Parker JD, Schoendorf KC, Kiely JL. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Annals of epidemiology 1994; 4(4):271-8.
  30. Diabelková J, Rimárová K, Urdzík P, Dorko E, Houžvičková A, Andraščíková Š, et al. Risk factors associated with low birth weight. Cent Eur J Public Health 2022; 30(88):S43-9.
  31. Bui K, Nguyen L, Phung TT. 240 Risk Factors Associated with Term and Preterm Low Birth Weight in Thai Nguyen, Vietnam. Journal of Investigative Medicine 2006; 54(1):S121.
  32. Gaccioli F, Aye IL, Sovio U, Charnock-Jones DS, Smith GC. Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers. American journal of obstetrics and gynecology 2018; 218(2):S725-37.
  33. Bai X, Li W, Ding W, Chan OK, Leung MB, Lau SL, et al. New first trimester circulating angiogenic biomarkers in predicting early-onset and late-onset fetal growth restriction: a case-control study. BMC Pregnancy and Childbirth 2025; 25(1):562.
  34. Melchiorre K, Leslie K, Prefumo F, Bhide A, Thilaganathan B. First‐trimester uterine artery Doppler indices in the prediction of small‐for‐gestational age pregnancy and intrauterine growth restriction. Ultrasound in Obstetrics and Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology 2009; 33(5):524-9.
The Iranian Journal of Obstetrics, Gynecology and Infertility
Volume 28, Issue 8
October 2025
Pages 10-19