Obstetrics, Gynecology and Reproduction

Advanced search

RhD-induced immunogenetic disparity between mother and fetus: medical importance and economic effect of using molecular genetic technology

Full Text:


Introduction. Here we discuss the problem of timely diagnostics and prevention of Rh-immunization of pregnant women as well as fetal hemolytic disease, which remains currently relevant, despite the existence of proven diagnostic, therapeutic and preventive methods.

Aim: to assess the medico-economic efficiency of non-invasive prenatal diagnostics of using fetal Rh factor (rhesus D antigen, RhD) in maternal blood – a fetal RhD-genotyping.

Materials and Methods. A retrospective observational study was conducted to analyze determining fetal Rh-factor in the blood samples from 4109 Rh-negative pregnant women observed in the 41 medical facilities of the Ulyanovsk region in the years 2018–2020. The fetal RhD level was determined by polymerase chain reaction at gestational age of ≥ 10 weeks. To assess testrelated medical effectiveness, there were examined sensitivity, specificity, predictive value of positive and negative data as well as diagnostic accuracy. The data collected during the study were compared with those obtained after delivery. To assess the economic efficiency, the difference between the cost of immunization and the cost of determining the fetal Rh factor level was determined.

Results. A positive and negative fetal Rh-factor was detected in 67.26 % (n = 2793) and 32.74 % (n = 1316) cases, respectively. Diagnostic accuracy of the test system "Test-RhD" was 99.40 %, sensitivity – 99.84 %, specificity – 97.51 %, the prognostic value of a positive result was 99.43 %, the predictive value of a negative result – 99.28 % with low rate of false positive and false negative data. It was shown that our study allows to avoid unnecessary immunization costs for all Rh-negative pregnant women.

Conclusion. Analysis of the diagnostic characteristics and cost-effectiveness of the RhD test evidences about high medical significance of the method described and allows to recommend its wider application.

About the Authors

A. G. Konopliannikov
Pirogov Russian National Research Medical University, Health Ministry of Russian Federation
Russian Federation

Aleksandr G. Konopliannikov – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Pediatric Faculty

1 Ostrovityanova Str., Moscow 117997

A. N. Toropovskii
TestGen LLC
Russian Federation

Andrei N. Toropovskii – MD, PhD, General Director

9 44th InzhenernyProezd, Ulyanovsk 432072

D. A. Viktorov
Samara State Medical University, Health Ministry of Russian Federation
Russian Federation

Denis A. Viktorov – MD, PhD (Biology), Associate Professor, Department of General and Molecular  Biology

89 Chapaevskaya Str., Samara 443099

Yu. V. Myakisheva
Samara State Medical University, Health Ministry of Russian Federation
Russian Federation

Yulia V. Myakisheva – MD, Dr Sci Med, Head of the Department of General and Molecular Biology

89 Chapaevskaya Str., Samara 443099

R. F. Burganova
Ulyanovsk Regional Clinical Hospital
Russian Federation

Ramilya F. Burganova – MD, Head of Clinical Diagnostic Laboratory

7 Third International Str., Ulyanovsk 432063

A. V. Solovyev
Samara State Medical University, Health Ministry of Russian Federation
Russian Federation

Alexey V. Solovyev – MD, PhD (Biology), Associate Professor, Department of General and Molecular Biology

89 Chapaevskaya Str., Samara 443099

A. V. Kazakova
Samara State Medical University, Health Ministry of Russian Federation
Russian Federation

Anna V. Kazakova – MD, Dr Sci Med, Head of the Department of Obstetrics and Gynecology № 2

89 Chapaevskaya Str., Samara 443099

V. B. Marinovskaya
Samara State Medical University, Health Ministry of Russian Federation
Russian Federation

Victoria B. Marinovskaya – MD, Medical Resident, Department of Obstetrics and Gynecology

89 Chapaevskaya Str., Samara 443099


1. Konoplyannikov A.G., Pavlova N.G. Isoserological incompatibility of the blood of the mother and the fetus. Hemolytic disease of the fetus and newborns. In: Obstetrics. National leadership. Eds. G.M. Savelieva, V.N. Serova, G.T. Sukhikh, V.E. Radzinsky. [Izoserologicheskaya nesovmestimost' krovi materi i ploda. Gemoliticheskaya bolezn' ploda i novorozhdennyh. V kn.: Akusherstvo. Nacional'noe rukovodstvo. Pod red. G.M. Savel'evoj, V.N. Serova, G.T. Suhih, V.E. Radzinskogo]. Moscow: GEOTAR-Media, 2015. 324–34. (In Russ.).

2. Rh sensitization. Hemolytic disease of the fetus. Clinical guidelines (protocol). [Rezus-sensibilizaciya. Gemoliticheskaya bolezn' ploda. Klinicheskie rekomendacii (protokol)]. Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2017. 15 p. (In Russ.).

3. Jensen M.P., Damkjaer M.B., Clausen F.B. et al. Targeted Rhesus immunoglobulin for RhD-negative women undergoing an induced abortion: A clinical pilot study. Acta Obstet Gynecol Scand. 2019;98(9):1164–71.

4. Obstetrics: national guidelines. Eds. G.M. Savelyeva, G.T. Sukhikh, V.N. Serova, V.E. Radzinsky. [Akusherstvo: nacional'noe rukovodstvo. Pod red. G.M. Savel'evoj, G.T. Suhih, V.N. Serova, V.E. Radzinskogo]. Moscow: GEOTAR-Media, 2018. 1088 p. (In Russ.).

5. Trubnikova L.I., Toropovsky A.N., Zhmyrko E.V. et al. Experience in the introduction of non-invasive perinatal sex and Rh-factor studies of the fetus at an early stage using the blood of pregnant woman. [Opyt vnedreniya ne invazivnogo perinatal'nogo issledovaniya pola i rezus-faktora ploda na rannem sroke po krovi beremennoj zhenshchiny]. Ul'yanovskij mediko-biologicheskij zhurnal. 2015;(2):71–9. (In Russ.).

6. Polikarpov A.V., Alexandrova G.A., Golubev N.A. et al. The main indicators of the health of mothers and children, the activities of the child protection and obstetric services in the Russian Federation. [Osnovnye pokazateli zdorov'ya materi i rebyonka, deyatel'nost' sluzhby ohrany detstva i rodovspomozheniya v Rossijskoj Federacii. Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2018. 169 p. (In Russ.).

7. Khabarov S.V., Denisova O.V., Devichensky V.M. Role of molecular genetic non-invasive laboratory diagnostics in prevention of Rh-conflict pregnancy. [Rol' molekulyarno-geneticheskoj neinvazivnoj laboratornoj diagnostiki v profilaktike rezus-konfliktnoj beremennosti]. Medicinskij alfavit. 2019;3(22):78–83. (In Russ.).

8. Mikhailov A.V. Ultrasound-guided intrauterine interventions during pregnancy. In: Clinical guidelines for ultrasound diagnostics. [Vnutrimatochnye vmeshatel'stva pod ul'trazvukovym kontrolem vo vremya beremennosti. V kn.: Klinicheskoe rukovodstvo po ul'trazvukovoj diagnostike. Pod red. V.V. Mit'kova Moscow, 1996. Vol. 2. 280–99. (In Russ.).

9. Deka D., Dadhwal V., Sharma A.K. et al. Perinatal survival and procedure-related complications after intrauterine transfusion for red cell alloimmunization. Arch Gynecol Obstet. 2016;293(5):967–73.

10. Tkachenko A.V., Kostenko T.I., Sviridova N.I. et ak. Prevention of Rh isoimmunization in pregnant women. [Uglov N.D. Profilaktika rezus-izoimmunizacii beremennyh zhenshchin]. Lekarstvennyj vestnik. 2018;12(3):27–30. (In Russ.).

11. Bennardello F., Coluzzi S., Curciarello G. et al.; Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) and Italian Society of Gynaecology and Obstetrics (SIGO) working group. Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn. Blood Transfus. 2015;13(1):109–34.

12. Babovic I., Plesinac S., Radojicic Z. et al. Middle cerebral artery Doppler in prediction degree of fetal anemia and the best timing for the second intrauterine intravascular transfusion in red cell alloimmune disease. Clin Exp Obstet Gynecol. 2015;42(6):792–6.

13. Irugova E.Z., Sherkhova A.Z., Bereketova M.A., Nakhusheva A.R. Rh-conflict during pregnancy. [Rezus-konflikt pri beremennosti]. Estestvennye i tekhnicheskie nauki. 2019;(12):131–4. (In Russ.).

14. Van der Schoot, de Haas M., Clausen F.B. Genotyping to prevent Rh disease: Has the time come? Curr Opin Hematol. 2017;24(6):544–50.

15. Mahdavi S., Karami F., Sabbaghi S. Non-invasive prenatal diagnosis of foetal gender through maternal circulation in first trimester of pregnancy. J Obstet Gynaecol. 2019;39(8):1071–4.

16. Wienzek-Lischka S., Bachmann S., Fröhner V., Bein G. Potential of next-generation sequencing in noninvasive fetal molecular blood group genotyping. Transfus Med Hemother. 2020;47(1):14–22.

17. Orzińska A., Guz K., Mikula M. et al. Prediction of fetal blood group and platelet antigens from maternal plasma using next-generation sequencing. Transfusion. 2019;59(3):1102–7.

18. Addai-Mensah O., Afriyie E.Y., Sakyi S.A. et al. Fetal Rhesus D genotyping and sex determination from maternal plasma of Rhesus D-negative antenatal population: the usefulness of conventional polymerase chain reaction in resource-limited settings. Obstet Gynecol Int. 2020;2020:4913793.

19. Tyumina O.V., Tikhonova O.M., Klyuchnikov D.Yu., Melnikov V.A. Medical and economical efficacy evaluation of non-invasive prenatal fetal Rh factor screening. [Ocenka mediko-ekonomicheskoj effektivnosti prenatal'nogo neinvazivnogo skrininga rezus-faktora ploda]. Voprosy ginekologii, akusherstva i perinatologii. 2017;16(6):3–35. (In Russ.).

20. Soothill P.W., Finning K., Latham T. et al. Use of cffDNA to avoid administration of anti-D to pregnant women when the fetus is RhD-negative: implementation in the NHS. BJOG. 2015;122(12):1682–6.

21. Hu P., Liang D., Chen Y. et al. An enrichment method to increase cell-free fetal DNA fraction and significantly reduce false negatives and test failures for non-invasive prenatal screening: A feasibility study. J Transl Med. 2019;17(1):124.

22. Bearak J., Popinchalk A., Alkema L., Sedgh G. Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. Lancet Global Health. 2018;6(4):e380–e389.

23. Sarfmago P., Yang H., Llewellyn A. et al. High-throughput non-invasive prenatal testing for fetal rhesus D status in RhD-negative women not known to be sensitised to the RhD antigen: a systematic review and economic evaluation. Health Technol Assess. 2018;22(13):1–172.

24. Yang H., Llewellyn A., Walker R. et al. High-throughput, non-invasive prenatal testing for fetal rhesus D status in RhD-negative women: a systematic review and meta-analysis. BMC Med. 2019;17(1):37.

25. De Haas M., Thurik F.F., van der Ploeg C.P.B. et al. Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. BMJ. 2016;355:i5789.

26. Haimila K., Sulin K., Kuosmanen M. et al. Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women: outcome of the first two years of a national program in Finland. Acta Obstet Gynecol Scand. 2017;96(10):1228–33.

27. Bohmova J., Lubusky M., Holuskova I. et al. Two reliable methodical approaches for non-invasive RHD genotyping of a fetus from maternal plasma. Diagnostics (Basel). 2020;10(8):564.

28. Kravchenko E.N., Ozhereleva M.A. Genetic and molecular cell technologies in diagnostics Rh factor fetus in pregnant women with Rh-negative blood. [Geneticheskie i molekulyarno-kletochnye tekhnologii v diagnostike rezus-faktora ploda u beremennyh s rezus-otricatel'noj krov'yu]. Problemy reprodukcii. 2016;22(5):39–43. (In Russ.).

29. Takahashi K., Migita O., Sasaki A. et al. Amplicon sequencing-based noninvasive fetal genotyping for RHD-positive D antigen-negative alleles. Clin Chem. 2019;65(10):1307–16.

30. Toropovsky A.N., Nikitin A.G., Viktorov D.A., Konoplyannikov A.G. Non-invasive prenatal diagnosis of fetal sex and Rh factor (results of a multicenter study). [Neinvazivnaya prenatal'naya diagnostika pola i rezus-faktora ploda (rezul'taty mnogocentrovogo issledovaniya). Doktor.Ru. 2016;(8–9):38–43. (In Russ.).

For citation:

Konopliannikov A.G., Toropovskii A.N., Viktorov D.A., Myakisheva Yu.V., Burganova R.F., Solovyev A.V., Kazakova A.V., Marinovskaya V.B. RhD-induced immunogenetic disparity between mother and fetus: medical importance and economic effect of using molecular genetic technology. Obstetrics, Gynecology and Reproduction. 2021;15(5):525-533. (In Russ.)

Views: 227

ISSN 2313-7347 (Print)
ISSN 2500-3194 (Online)