Skip to main content
Log in

Negative Pregnancy Test in Patients with Trophoblastic Diseases

  • Management of Gestational Trophoblastic Diseases (A Cheung, Section Editor)
  • Published:
Current Obstetrics and Gynecology Reports Aims and scope Submit manuscript

Abstract

Quantitative and qualitative human chorionic gonadotrophin (hCG) assays are widely used to detect pregnancy state and abnormal trophoblastic lesions. At least five different forms of hCG have been characterized and different trophoblastic diseases produce different forms of hCG in varying proportions. Because of the difference in antibody specificity in various commercial automated immunoassays of HCG, discordant results may be obtained by laboratories using different hCG assays, with a falsely low or negative result obtained if the assay does not recognize the hCG variants produced from the trophoblastic tissue. On the other hand, significantly elevated hCG concentration can paradoxically lead to false-negative results in two-site immunometric assay due to high-dose hook effect. Clinicians managing patients with trophoblastic lesions should be aware of these limitations of current hCG assays and clinical laboratories should have measures to avoid analytical false negative hCG results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Cole LA. hCG, five independent molecules. Clin Chim Acta Int J Clin Chem. 2012;413(1–2):48–65. doi:10.1016/j.cca.2011.09.037.

    Article  CAS  Google Scholar 

  2. Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol: RB&E. 2010;8:102. doi:10.1186/1477-7827-8-102.

    Article  Google Scholar 

  3. Iles RK. Ectopic hCGbeta expression by epithelial cancer: malignant behaviour, metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol. 2007;260–262:264–70. doi:10.1016/j.mce.2006.02.019.

    Article  PubMed  Google Scholar 

  4. Zhang HJ, Siu MK, Yeung MC, Jiang LL, Mak VC, Ngan HY, et al. Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma. Carcinogenesis. 2011;32(5):765–71. doi:10.1093/carcin/bgr033.

    Article  CAS  PubMed  Google Scholar 

  5. Cheung AN, Chan KK. Perplexing hCG profile after evacuation of hydatidiform mole. Lancet. 2012;379(9811):98–100. doi:10.1016/S0140-6736(11)61518-3.

    Article  PubMed  Google Scholar 

  6. Cole LA. New discoveries on the biology and detection of human chorionic gonadotropin. Reprod Biol Endocrinol: RB&E. 2009;7:8. doi:10.1186/1477-7827-7-8.

    Article  Google Scholar 

  7. Wu JT, Christensen SE. Effect of different test designs of immunoassays on "hook effect" of CA 19–9 measurement. J Clin Lab Anal. 1991;5(3):228–32.

    Article  CAS  PubMed  Google Scholar 

  8. Charrie A, Charriere G, Guerrier A. Hook effect in immunometric assays for prostate-specific antigen. Clin Chem. 1995;41(3):480–1.

    CAS  PubMed  Google Scholar 

  9. Ohashi S, Kaji H, Abe H, Chihara K. "Paradoxical" GH suppression by secretagogues in acromegaly? Horm Metab Res. 1993;25(7):393–4. doi:10.1055/s-2007-1002128.

    Article  CAS  PubMed  Google Scholar 

  10. St-Jean E, Blain F, Comtois R. High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas. Clin Endocrinol. 1996;44(3):305–9.

    Article  CAS  Google Scholar 

  11. Levinson SS. Hook effect with lambda free light chain in serum free light chain assay. Clin Chim Acta; Int J Clin Chem. 2010;411(21–22):1834–6. doi:10.1016/j.cca.2010.07.027.

    Article  CAS  Google Scholar 

  12. Miles LE, Lipschitz DA, Bieber CP, Cook JD. Measurement of serum ferritin by a 2-site immunoradiometric assay. Anal Biochem. 1974;61(1):209–24.

    Article  CAS  PubMed  Google Scholar 

  13. Fernando SA, Wilson GS. Studies of the 'hook' effect in the one-step sandwich immunoassay. J Immunol Methods. 1992;151(1–2):47–66.

    Article  CAS  PubMed  Google Scholar 

  14. Butch AW. Dilution protocols for detection of hook effects/prozone phenomenon. Clin Chem. 2000;46(10):1719–21.

    CAS  PubMed  Google Scholar 

  15. Cole TG, Johnson D, Eveland BJ, Nahm MH. Cost-effective method for detection of "hook effect" in tumor marker immunometric assays. Clin Chem. 1993;39(4):695–6.

    CAS  PubMed  Google Scholar 

  16. Al-Mahdili HA, Jones GR. High-dose hook effect in six automated human chorionic gonadotrophin assays. Ann Clin Biochem. 2010;47(Pt 4):383–5. doi:10.1258/acb.2010.090304.

    Article  CAS  PubMed  Google Scholar 

  17. O'Reilly SM, Rustin GJ. Mismanagement of choriocarcinoma due to a false low HCG measurement. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 1993;3(3):186–8.

    Article  Google Scholar 

  18. Flam F, Hambraeus-Jonzon K, Hansson LO, Kjaeldgaard A. Hydatidiform mole with non-metastatic pulmonary complications and a false low level of hCG. Eur J obstet Gyneco Reprod Biol. 1998;77(2):235–7.

    Article  CAS  Google Scholar 

  19. Tabas JA, Strehlow M, Isaacs E. A false negative pregnancy test in a patient with a hydatidiform molar pregnancy. New Engl J Med. 2003;349(22):2172–3. doi:10.1056/NEJM200311273492221.

    Article  CAS  PubMed  Google Scholar 

  20. Levavi H, Neri A, Bar J, Regev D, Nordenberg J, Ovadia J. "Hook effect" in complete hydatidiform molar pregnancy: a falsely low level of beta-HCG. Obstet Gynecol. 1993;82(4 Pt 2 Suppl):720–1.

    CAS  PubMed  Google Scholar 

  21. Wheeler CA, Davis S, Degefu S, Thorneycroft IH, O'Quinn AG. Ovarian choriocarcinoma: a difficult diagnosis of an unusual tumor and a review of the hook effect. Obstet Gynecol. 1990;75(3 Pt 2):547–9.

    CAS  PubMed  Google Scholar 

  22. Cervinski MA, Gronowski AM. Reproductive-endocrine point-of-care testing: current status and limitations. Clin Chem lab Med: CCLM / FESCC. 2010;48(7):935–42. doi:10.1515/CCLM.2010.183.

    Article  CAS  Google Scholar 

  23. Olaniyan OB, Momoh JA. Negative urine hCG in choriocarcinoma. Int J Gynaecol Obstet: Off Org Int Fed Gynaecol Obstet. 2007;98(1):59–60. doi:10.1016/j.ijgo.2007.03.040.

    Article  CAS  Google Scholar 

  24. Meyer T, Cole LA, Richman PI, Mitchell HD, Myers J, Rustin GJ. High levels of hCG in choriocarcinoma can result in renal failure and a false-negative pregnancy test in men. Clin Oncol. 2001;13(4):301–3.

    CAS  Google Scholar 

  25. Er TK, Jong YJ, Tsai EM, Huang CL, Chou HW, Zheng BH, et al. False-negative pregnancy test in hydatidiform mole. Clin Chem. 2006;52(8):1616–8. doi:10.1373/clinchem.2006.068056.

    Article  CAS  PubMed  Google Scholar 

  26. Yadav YK, Fatima U, Dogra S, Kaushik A. Beware of "hook effect" giving false negative pregnancy test on point-of-care kits. J Postgrad Med. 2013;59(2):153–4. doi:10.4103/0022-3859.113838.

    Article  CAS  PubMed  Google Scholar 

  27. Hunter CL, Ladde J. Molar Pregnancy with False Negative beta-hCG Urine in the Emergency Department. Western J Emerg Med. 2011;12(2):213–5.

    Google Scholar 

  28. Pang YP, Rajesh H, Tan LK. Molar pregnancy with false negative urine hCG: the hook effect. Singap Med J. 2010;51(3):e58–61.

    CAS  Google Scholar 

  29. Ofinran O, Papaioannou S, Kandavel V, Shrivastava S, Hall S, Tzafettas J. Negative pregnancy test: could it be a molar pregnancy? J Obstet Gynaecol: J Inst Obstet Gynaecol. 2007;27(8):857–8. doi:10.1080/01443610701780800.

    Article  CAS  Google Scholar 

  30. Pretlove SJ, Lovell KH, Thompson PJ, Reid WM. Beware the negative pregnancy test. J Obstet Gynaecol: J Inst Obstet Gynaecol. 2002;22(4):442. doi:10.1080/014436102320261168.

    Article  Google Scholar 

  31. Griffey RT, Trent CJ, Bavolek RA, Keeperman JB, Sampson C, Poirier RF. "Hook-like effect" causes false-negative point-of-care urine pregnancy testing in emergency patients. J Emerg Med. 2013;44(1):155–60. doi:10.1016/j.jemermed.2011.05.032.

    Article  PubMed  Google Scholar 

  32. Gronowski AM, Cervinski M, Stenman UH, Woodworth A, Ashby L, Scott MG. False-negative results in point-of-care qualitative human chorionic gonadotropin (hCG) devices due to excess hCGbeta core fragment. Clin Chem. 2009;55(7):1389–94. doi:10.1373/clinchem.2008.121210.

    Article  CAS  PubMed  Google Scholar 

  33. Cole LA, Kardana A, Park SY, Braunstein GD. The deactivation of hCG by nicking and dissociation. J Clin Endocrinol Metab. 1993;76(3):704–10.

    CAS  PubMed  Google Scholar 

  34. Hancock BW. hCG measurement in gestational trophoblastic neoplasia: a critical appraisal. J Reprod Med. 2006;51(11):859–60.

    PubMed  Google Scholar 

  35. Cole LA, Kohorn EI. The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing cancers. J Reprod Med. 2006;51(10):793–811.

    CAS  PubMed  Google Scholar 

  36. Sturgeon CM, Berger P, Bidart JM, Birken S, Burns C, Norman RJ, et al. Differences in recognition of the 1st WHO international reference reagents for hCG-related isoforms by diagnostic immunoassays for human chorionic gonadotropin. Clin Chem. 2009;55(8):1484–91. doi:10.1373/clinchem.2009.124578.

    Article  CAS  PubMed  Google Scholar 

  37. Whittington J, Fantz CR, Gronowski AM, McCudden C, Mullins R, Sokoll L, et al. The analytical specificity of human chorionic gonadotropin assays determined using WHO International Reference Reagents. Clin Chim Acta; Int J Clin Chem. 2010;411(1–2):81–5. doi:10.1016/j.cca.2009.10.009.

    Article  CAS  Google Scholar 

  38. Cole LA, DuToit S, Higgins TN. Total hCG tests. Clin Chim Acta; Int J Clin Chem. 2011;412(23–24):2216–22. doi:10.1016/j.cca.2011.08.006.

    Article  CAS  Google Scholar 

  39. Cole LA, Shahabi S, Butler SA, Mitchell H, Newlands ES, Behrman HR, et al. Utility of commonly used commercial human chorionic gonadotropin immunoassays in the diagnosis and management of trophoblastic diseases. Clin Chem. 2001;47(2):308–15.

    CAS  PubMed  Google Scholar 

  40. Cole LA, Sutton JM, Higgins TN, Cembrowski GS. Between-method variation in human chorionic gonadotropin test results. Clin Chem. 2004;50(5):874–82. doi:10.1373/clinchem.2003.026989.

    Article  CAS  PubMed  Google Scholar 

  41. Cole LA. Hyperglycosylated hCG, a review. Placenta. 2010;31(8):653–64. doi:10.1016/j.placenta.2010.06.005.

    Article  CAS  PubMed  Google Scholar 

  42. Cole LA, Butler SA, Khanlian SA, Giddings A, Muller CY, Seckl MJ, et al. Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia. Gynecol Oncol. 2006;102(2):151–9. doi:10.1016/j.ygyno.2005.12.045.

    Article  CAS  PubMed  Google Scholar 

  43. Cole LA, Khanlian SA, Muller CY, Giddings A, Kohorn E, Berkowitz R. Gestational trophoblastic diseases: 3. Human chorionic gonadotropin-free beta-subunit, a reliable marker of placental site trophoblastic tumors. Gynecol Oncol. 2006;102(2):160–4.

    Article  CAS  PubMed  Google Scholar 

  44. Marcillac I, Troalen F, Bidart JM, Ghillani P, Ribrag V, Escudier B, et al. Free human chorionic gonadotropin beta subunit in gonadal and nongonadal neoplasms. Cancer Res. 1992;52(14):3901–7.

    CAS  PubMed  Google Scholar 

  45. Salzberger M, Nelken D. The Immunologic Pregnancy Test. Some Reasons Forfalse-Positive and False-Negative Results. Am J Obstet Gynecol. 1963;86:899–902.

    CAS  PubMed  Google Scholar 

  46. Mitchell H, Seckl MJ. Discrepancies between commercially available immunoassays in the detection of tumour-derived hCG. Mol Cell Endocrinol. 2007;260–262:310–3. doi:10.1016/j.mce.2006.09.003.

    Article  PubMed  Google Scholar 

  47. Mehra R, Huria A, Gupta P, Mohan H. Choriocarcinoma with negative urinary and serum beta human chorionic gonadotropin (betaHCG)–a case report. Indian J Med Sci. 2005;59(12):538–41.

    Article  PubMed  Google Scholar 

  48. Hussa RO, Rinke ML, Schweitzer PG. Discordant human chorionic gonadotropin results: causes and solutions. Obstet Gynecol. 1985;65(2):211–9.

    CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Chun-Wing Yeung and Annie NY Cheung declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chun-Wing Yeung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yeung, CW., Cheung, A.N.Y. Negative Pregnancy Test in Patients with Trophoblastic Diseases. Curr Obstet Gynecol Rep 3, 102–106 (2014). https://doi.org/10.1007/s13669-013-0067-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13669-013-0067-2

Keywords

Navigation