Pregnancy associated plasma protein A: an early predictor of fetal growth restriction
DOI:
https://doi.org/10.18203/2320-1770.ijrcog20214652Keywords:
FGR, Pregnancy associated plasma protein-A, Early markerAbstract
Background: The aim of our study was to determine the association of low levels of pregnancy associated plasma protein-A (PAPP-A) levels estimated at 11-13+6weeks of gestation with fetal growth restriction (FGR).
Methods: A prospective observational study of a total of 203 pregnant women with PAPP-A levels were followed up and the outcome data were collected at childbirth.
Results: The incidence of FGR was 7.3%. A significant association was found between low levels of PAPP-A MoM (≤0.49) with FGR (p=0.000) with unadjusted odds ratio of 11.6. At PAPP-A multiples of median (MoM) ≤0.49, FGR had a median (Q1, Q3) of 0.46 (0.42, 1.54) versus 1.87 (0.59, 3.11) which was statistically significant (p=0.05) with moderate strength of prediction [minus 0.58 (95% CI, minus 1.113, minus 0.055), p=0.03]. At the cut-off considered in our study i.e., ≤0.49 MoM, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 73%, 81%, 23%, and 97% respectively with a positive LR of 3.82 and negative LR of 0.32. Karl Pearson’s correlation showed positive correlation (r=0.308, p<0.001) between PAPP-A MoM and birthweight and showed that for every unit increase in PAPP-A MoM, birthweight increased by 0.082 times (approximately 90 gm). We also found an association of low PAPP-A with pre-eclampsia, preterm delivery and increased caesarean delivery births.
Conclusions: We conclude that low PAPP-A MoM levels are good reflectors of placental function and adverse outcomes. PAPP-A, a part of the dual marker, may be extrapolated for suspecting FGR. This could guide in instituting appropriate feto-maternal surveillance.
References
Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther. 2014;36(2):86-98.
ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet Gynecol. 2019;133(2):e97-109.
Laursen LS, Overgaard MT, Soe R, Boldt HB, Sottrup-Jensen L, Giudice LC et al. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS letters. 2001;504(1-2):36-40.
Laursen LS, Kjaer-Sorensen K, Andersen MH, Oxvig C. Regulation of insulin-like growth factor (IGF) bioactivity by sequential proteolytic cleavage of IGF binding protein-4 and 5. Molecular endocrinol. 2007;21(5):1246-57.
Sun IY, Overgaard MT, Oxvig C, Giudice LC. Pregnancy-associated plasma protein A proteolytic activity is associated with the human placental trophoblast cell membrane. J clin endocrinol metabolism. 2002;87(11):5235-40
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine reviews. 1995;16(1):3-34.
Clemmons DR. Role of insulin-like growth factor binding proteins in controlling IGF actions. Molecular cellular endocrinol. 1998;140(1-2):19-24.
Sferruzzi-Perri AN, Owens JA, Pringle KG, Roberts CT. The neglected role of insulin like growth factors in the maternal circulation regulating fetal growth. J physiol. 2011;589(1):7-20.
Bischof P, DuBerg S, Herrmann W, Sizonenko PC. Pregnancy-associated plasma protein-A (PAPP-A) and hCG in early pregnancy. Bri j obstetr gynaecol.1981;88(10):973-5.
RCOG. The Investigation and Management of the Small-for-Gestational-Age Fetus. Greentop Guideline No. 31:RCOG. 2014.
Krantz D, Goetzl L, Simpson JL. 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. Am J Obstet Gynecol. 2004;191(4):1452-8. 4.
Pakniat H, Bahman A, Ansari IJ. The Relationship of Pregnancy-Associated Plasma Protein A and Human Chorionic Gonadotropin with Adverse Pregnancy Outcomes: A Prospective Study. Obstet Gynecol India. 2019;69:412.
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). Am J Obstet Gynecol. 2004;191(4):1446-51.
Smith GC, Shah I, Crossley JA, Aitken DA, Pell JP, Nelson SM et al. Pregnancy associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol. 2006;107(1):161-6.
Spencer CA, Allen VM, Flowerdew G, Dooley K, Dodds L. Low levels of maternal serum PAPP-A in early pregnancy and the risk of adverse outcomes. Prenat Diagn. 2008;28(11):1029-36
Morris RK, Cnossen JS, Langejans M, Robson SC, Kleijnen J, TerRiet G et al. Serum screening with Down’s syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis. BMC pregnancy childbirth. 2008;8:33
Inan C, Varol FG, Erzincan SG, Uzun I, Sutcu H, Sayin CN. Use of prokineticin-1 (PROK1), pregnancy-associated plasma protein A (PAPP-A) and PROK1/PAPP-A ratio to predict adverse pregnancy outcomes in the first trimester: a prospective study. J Maternal-Fetal Neonatal Med. 2018;31:20:2685-92.
Gupta S, Goyal M, Verma D, Sharma A, Bharadwaj N, Kabra M et al. Adverse pregnancy outcome in patients with low pregnancy‐associated plasma protein‐A: The Indian Experience. J Obstet Gynaecol Res. 2015;41:1003-8.
Sovio U, Smith G, Darcy A. First trimester PAPP-A and the risk of fetal growth restriction. Am J Obstet Gynecol. 2014;S112.
Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn. 2002;22(9):778-82.
Lavanya T, Premalatha R, Thakkar NA, Jawahar L, Rajendran PK, Geethanjali E et al. The role of pregnancy associated plasma protein – A level in the first trimester of pregnancy and clinical outcome in an urban referral centre. Int J Reprod Contr Obstet Gynecol. 2019;8:3884-8.
Peterson SE, Simhan HN. First-trimester pregnancy-associated plasma protein A and subsequent abnormalities of fetal growth. Am J Obstet Gynecol. 2008;198(5):e43-5.