![The World Congress on Controversies in Obstetrics, Gynecology and Infertility (COGI). Click here to learn more.]({"type":"image" , "src" : "/sda/112382/JournalAd-COGI2024-Leaderboard.jpg"})
https://orcid.org/0000-0002-8602-9714
Dear Editor,
In clinical practice, comparison of total human chorionic gonadotropin (hCG) changes in serum and determining the difference rate are essential steps for clinical decisions. Management strategies depend on the clinical significance of the change in particularly challenging cases of ectopic pregnancy, including interstitial and cervical pregnancies (Garzon et al. Citation2019). After methotrexate treatment, a drop in serum total hCG, which is greater than 15%, is clinically significant in the management of ectopic pregnancy (ACOG Practice Bulletin 2018). However, some critical factors, such as between-method, biological, and analytical variations may contribute to the difference in total hCG results. The clinician should be aware of these sources of variation for appropriate clinical management because fertility and reproductive outcomes may range widely according to surgical, medical, and expectant management approaches (Baggio et al. Citation2021). On the other hand, total hCG measurement is also crucial for germ cell tumours, early diagnosis, and the treatment response of gestational trophoblastic neoplasia (Ngan et al. Citation2021).
There are two essential cornerstone strategies for a reliable and clinically comparable total hCG results. The first is the standardisation of total hCG measurement methods, and the second is the minimisation of the variation sources. Between-method variation is a common problem in the follow-up of patients with total hCG results from different laboratories. Reference standard calibrator use may decrease between-method variation. Therefore, a working group for the standardisation of hCG was established by the IFCC in 1994 (Gronowski and Grenache Citation2009). Subsequently, in 2001 WHO approved the standards developed for six different hCG variants by the IFCC as the 1st WHO International Reference Reagents (IRRs) (Gronowski and Grenache Citation2009). But today, the 3rd or 4th WHO standards are used instead of the first IRRs for hCG calibration. The purity of the 3rd or 4th WHO standard differs from the first IRRs. Different calibrator content and various analytical specificity of the immunoassays are causes of inter-method variation. Consequently, the first WHO IRRs should be used by all laboratories for hCG standardisation.
The molecular heterogeneity of hCG is another problem in standardisation. There are many molecular variants of hCG, such as intact hCG, nicked hCG, free β-subunit hCG, free α-subunit hCG, hyperglycosylated hCG, and beta core fragment hCG, which are all detectable in serum and urine by different methods. In a study by Sturgeon et al., it was found that type of the molecular variant affects the rate of between-method variation (Sturgeon et al. Citation2009). In this study, the between-method variation for intact hCG was 12.3%, 37% for beta-hCG, and 57% for hCG beta core fragment (Sturgeon et al. Citation2009).
In the case of different results from the same laboratory, analytical and biological variations are significant sources of total variation since there is no between-method variation. The analytical variation reflects the variation between different methods. Moreover, biological variation ranges for total hCG were reported as 11.9–48.5% for first-trimester pregnancies (Sennels et al. Citation2011). It may also be helpful to report the change value (RCV) for hCG, which is calculated from both biological variation and analytical variation (Coşkun et al. Citation2021). Hence, clinicians can compare the percentage change between two total hCG results with the RCV to determine whether the change is clinically significant.
The first crucial step for more comparable total hCG results is the standardisation of the molecular variant detected by immunoassays. The second step is using the same WHO IRR in all laboratories. We believe that overcoming these steps with an interdisciplinary approach will significantly contribute to the gynecologists’ clinical approach and decision-making, thus decreasing unanticipated complications.
Acknowledgments
The study received no financial funding.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
- Baggio, S., et al., 2021. Fertility and reproductive outcome after tubal ectopic pregnancy: comparison among methotrexate, surgery and expectant management. Archives of Gynecology and Obstetrics, 303 (1), 259–268.
- Coşkun, A., et al., 2021. Personalized reference intervals in laboratory medicine: a new model based on within-subject biological variation. Clinical chemistry, 67 (2), 374–384.
- Committee on Practice Bulletins—Gynecology. 2018. ACOG Practice Bulletin No. 191: Tubal ectopic pregnancy. Obstet Gynecol, 131 (2), e65–e77.
- Garzon, S., et al., 2019. Laparoscopic reversible occlusion of uterine arteries and cornuostomy for advanced interstitial pregnancy. Minimally invasive Therapy & Allied Technologies, 28 (6), 359–362. Epub 2018
- Gronowski, A.M. and Grenache, D.G., 2009. Characterization of the hCG variants recognized by different hCG immunoassays: an important step toward standardization of hCG measurements. Clinical chemistry, 55 (8), 1447–1449.
- Ngan, H.Y.S., et al., 2021. Diagnosis and management of gestational trophoblastic disease: 2021 update. International journal of Gynaecology and Obstetrics, 155 (Suppl 1), 86–93.
- Sturgeon, C.M. et al., 2009. Differences in recognition of the 1st WHO international reference reagents for hCG-related isoforms by diagnostic immunoassays for human chorionic gonadotropin. Clinical chemistry, 55 (8), 1484–1491.
- Sennels, H.P., Jørgensen, F.S. and Sørensen, S., 2011. Biological variation of free beta chorionic gonadotropin and pregnancy-associated plasma protein A in first trimester pregnancies. Clinical chemistry and Laboratory Medicine, 49 (2), 291–295.