Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening

Published:January 20, 2023DOI:


      • High PAPP-A or free β-hCG levels lead to anxiety despite low risk for trisomies.
      • The significance of extremely high PAPP-A or free β-hCG remains unclear.
      • Most pregnancies with extremely increased PAPP-A or free β-hCG have good outcomes.
      • Counselling in patients with extremely high PAPP-A or free β-hCG should be favorable.



      Extreme levels of either PAPP-A or free β-hCG may be a serious clinical concern. A multicentre study was carried out to determine the frequency and clinical consequences of high (minimum 2,0 MoM) maternal (PAPP)-A and free beta hCG.


      A total number of 8591 patients with singleton pregnancies between 11 + 0–13 + 6 weeks of gestation were enrolled. A total number of 612 cases with first trimester serum level of PAPP-A corresponding to ≥ 2,0 MoM and/or free β-hCG to ≥ 2,0 MoM were included in the statistical analysis. All serum samples were analysed with Roche (Cobas) or Kryptor (Brahms) devices. A retrospective analysis of perinatal outcomes was conducted.


      Values of PAPP-A ≥ 2,0 MoM and free β-hCG < 2.0 MoM were detected in 48,5% of patients (n = 297), free β-hCG ≥ 2,0 MoM and PAPP-A concentration < 2,0 MoM in 38,1% of patients (n = 233) and both PAPP-A and free β-hCG ≥ 2,0 multiple of median in 13,4% of patients (n = 82). The highest PAPP-A and free β-hCG concentrations were 19,2 MoM and 16,3 MoM respectively. Patients with both PAPP-A and free β-hCG above 2,0 MoM had a slightly higher (but statistically not significant) prevalence of history of low birthweight (8,3%).


      Pregnancy outcomes in women with normal ultrasound findings and high PAPP-A /free β-hCG concentration are good. Higher prevalence of pregnancy complications was not detected in either extremely high PAPP-A and free β-hCG concentration groups. In cases of normal ultrasound and isolated high (even extreme) biochemical markers levels the counselling should be comforting.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Ong C.Y.T.
        • Liao A.W.
        • Spencer K.
        • Munim S.
        • Nicolaides K.H.
        First trimester maternal serum free beta human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications.
        BJOG. 2000; 107: 1265-1270
        • Smith G.C.
        • Stenhouse E.J.
        • Crossley J.A.
        • Aitken D.A.
        • Cameron A.D.
        • Connor J.M.
        Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth.
        J Clin Endocrinol Metab. 2002; 87: 1762-1767
        • Shiefa S.
        • Amargandhi M.
        • Bhupendra J.
        • Moulali S.
        • Kristine T.
        First Trimester Maternal Serum Screening Using Biochemical Markers PAPP-A and Free beta-hCG for Down Syndrome, Patau Syndrome and Edward Syndrome.
        Indian J Clin Biochem. 2013; 28: 3-12
        • Tul N.
        • Pusenjak S.
        • Osredkar J.
        • Spencer K.
        • Novak-Antolic Z.
        Predicting complications of pregnancy with first-trimester maternal serum free-betahCG, PAPP-A and inhibin-A.
        Prenat Diagn. 2003; 23: 990-996
        • Bale L.K.
        • Conover C.A.
        Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A.
        J Endocrinol. 2005; 186: 325-331
        • Gomes M.S.
        • Carlos-Alves M.
        • Trocado V.
        • Arteiro D.
        • Pinheiro P.
        Prediction of adverse pregnancy outcomes by extreme values of first trimester screening markers.
        Obstet Med. 2017; 10: 132-137
        • Giorgetti C.
        • Vanden Meerschaut F.
        • De Roo C.
        • Saunier O.
        • Quarello E.
        • Hairion D.
        • et al.
        Multivariate analysis identifies the estradiol level at ovulation triggering as an independent predictor of the first trimester pregnancy-associated plasma protein-A level in IVF/ICSI pregnancies.
        Hum Reprod. 2013; 28: 2636-2642
        • Bonne S.
        • Sauleau E.
        • Sananes N.
        • Akaladios C.
        • Rongières C.
        • Pirrello O.
        Influence of medically assisted reproduction techniques on crown-rump length and biochemical markers of trisomy 21 in the first trimester of pregnancy.
        Fertil Steril. 2016; 105: 410-416
        • Szymusik I.
        • Kosinski P.
        • Kosinska-Kaczynska K.
        • Warzecha D.
        • Karwacka A.
        • Kaczynski B.
        • et al.
        The first trimester aneuploidy biochemical markers in IVF/ICSI patients have no additional benefit compared to spontaneous conceptions in the prediction of pregnancy complications.
        J Perinat Med. 2018; 46: 953-959
        • Yigiter A.B.
        • Kavak Z.N.
        • Bakirci N.
        • Gokaslan H.
        Effect of smoking on pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, and nuchal translucency in the first trimester of pregnancy.
        Adv Ther. 2006; 23: 131-138
        • Dugoff L.
        • Hobbins J.C.
        • Malone F.D.
        • Porter T.F.
        • Luthy D.
        • Comstock C.H.
        • 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: 1446-1451
        • Krantz D.
        • Goetzl L.
        • Simpson J.L.
        • Thom E.
        • Zachary J.
        • Hallahan T.W.
        • et al.
        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: 1452-1458
        • Yaron Y.
        • Ochshorn Y.
        • Heifetz S.
        • Lehavi O.
        • Sapir Y.
        • Orr-Urtreger A.
        First trimester maternal serum free human chorionic gonadotropin as a predictor of adverse pregnancy outcome.
        Fetal Diagn Ther. 2002; 17: 352-356
        • Lawrence J.B.
        • Oxvig C.
        • Overgaard M.T.
        • Sottrup-Jensen L.
        • Gleich G.J.
        • Hays L.G.
        • et al.
        The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A.
        Proc Natl Acad Sci U S A. 1999; 96: 3149-3153
        • Turner J.M.
        • Kumar S.
        Low First Trimester Pregnancy-Associated Plasma Protein-A Levels Are Not Associated with an Increased Risk of Intrapartum Fetal Compromise or Adverse Neonatal Outcomes: A Retrospective Cohort Study.
        J Clin Med. 2020; 9: 1108
        • Ziolkowska K.
        • Dydowicz P.
        • Sobkowski M.
        • Tobola-Wrobel K.
        • Wysocka E.
        • Pietryga M.
        The clinical usefulness of biochemical (free beta-hCg, PaPP-a) and ultrasound (nuchal translucency) parameters in prenatal screening of trisomy 21 in the first trimester of pregnancy.
        Ginekol Pol. 2019; 90: 161-166
        • Cuckle H.
        • Arbuzova S.
        • Spencer K.
        • Crossley J.
        • Barkai G.
        • Krantz D.
        • et al.
        Frequency and clinical consequences of extremely high maternal serum PAPP-A levels.
        Prenat Diagn. 2003; 23: 385-388