Anemias of unknown etiology in the fetus and newborn: the symbiosis of obstetric and neonatal care (literature review and clinical case)
https://doi.org/10.69964/BMCC-2025-2-3-38-49
Abstract
Summary. Congenital anemia represents a significant challenge in perinatal diagnostics due to its high prevalence and the risk of severe complications in both the fetus and the neonate. Therefore, the study and advancement of diagnostic and therapeutic approaches for fetal anemia remain a critical priority in modern perinatology.
Objective. To present a modern approach to the diagnosis and treatment of congenital anemia in the fetus and newborn based on an analysis of current literature data and a clinical case.
Materials and Methods. A literature review over the past 10 years was conducted using databases such as Medline, Scopus, Web of Science, Google Scholar, PubMed, Wiley, and the Cochrane Library. A clinical case of discordant dichorionic twins with severe anemia in one of the fetuses was analyzed.
Results. T he m ain c auses o f c ongenital a nemia w ere c onsidered, i ncluding i soimmunization, fetal blood loss, intrauterine infection, genetic and neoplastic diseases. The key role of non-invasive diagnosis of fetal anemia through the measurement of peak systolic velocity in the middle cerebral artery was emphasized. The effectiveness of intrauterine blood transfusion as the primary treatment method for severe anemia was demonstrated. The clinical case illustrated the complexities of differential diagnosis associated with the potential development of anemia-polycythemia syndrome in dichorionic placentation, as well as the impact of intrauterine infection and umbilical cord pathology on anemia formation. Timely prenatal diagnosis, intrauterine transfusions, and subsequent postnatal treatment ensured a favorable perinatal outcome.
Conclusion. The analysis of literature and the clinical case demonstrate the importance of a timely multidisciplinary and individualized approach to the diagnosis and treatment of congenital anemia using modern ultrasound technologies and intrauterine interventions to improve the prognosis for fetuses and newborns.
About the Authors
I. V. KlimovaRussian Federation
Inna V. Klimova - candidate of Medical Sciences, senior Research Officer of the Department of Ultrasound Diagnostics
22a Pokrovka str., Moscow, 101000
Тel: +7(916)685-92-07
A. E. Panov
Russian Federation
Anton E. Panov - candidate of Medical Sciences, Head of the Ultrasound Diagnostics Department; Physician of the Ultrasound Diagnostics Department
22a Pokrovka str., Moscow, 101000
129327, Moscow, Lenskaya str., 15
Тel: +7 (926) 945-03-58
D. R. Kotsuba
Russian Federation
Daniil R. Kotsuba - ultrasound doctor of the Department of Ultrasound Diagnostics
22a Pokrovka str., Moscow, 101000
Tel: +7 (909) 698-24-12
M. B. Bezlepkina
Russian Federation
Marya B. Bezlepkina - the anesthesiologist-resuscitator, Head of the Neonatal Intensive Care Unit
22a Pokrovka str., Moscow, 101000
M. N. Shakaya
Russian Federation
Marika N. Shakaya - c andidate of M edical Sciences, head of the Neonatology Department
22a Pokrovka str., Moscow, 101000
Tel: +7 (903) 769-61-60
N. A. Makhukova
Russian Federation
Makhukova Natalia Aleks. - Junior Researcher at the Pathology Department
22a Pokrovka str., Moscow, 101000
Tel: +7 (926) 471-68-53
T. A. Yarygina
Russian Federation
Tamara A. Yarygina - candidate of Medical Sciences, Head of the Ultrasound Diagnostics Department; Associate Professor of the Ultrasound Diagnostics Department; Researcher at the Perinatal Cardiology Center
22a Pokrovka str., Moscow, 101000
6 Miklukho-Maklaya str., Moscow, 117198
135 Rublevskoe Shosse, Moscow, 121552
Tel: +7 (903) 004-81-22
References
1. Mari G, Norton ME, Stone J, Berghella V, Sciscione AC, Tate D, et al. Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: The fetus at risk for anemia–diagnosis and management. American Journal of Obstetrics & Gynecology. 2015;212:697–710. https://doi.org/10.1016/j.ajog.2015.01.059
2. Congenital Anemia Due to Fetal Blood Loss and Other Congenital Anemias of the Newborn: Clinical Guidelines. Ministry of Health of the Russian Federation. 2024. (in Russian) https://cr.minzdrav.gov.ru/view-cr/660_2
3. Zaplatnikov A.L., Podzolkova M.N., Ponimanskaya M.A., Denisova Yu.V., Dmitriev A.V., Dementiev A.A. Congenital anemia: diagnostic algorithm. RMZh Mat i Ditya/RMJ Mother and child. 2022;5:358–365. (in Russian) https://doi.org/10.32364/2618-8430-2022-5-4-358-365
4. Abbasi N, Johnson J.-A., Ryan G. Fetal anemia. Ultrasound in Obstetrics & Gynecology. 2017;50:145–53. https://doi.org/10.1002/uog.17555
5. Hendrickson JE, Delaney M. Hemolytic Disease of the Fetus and Newborn: Modern Practice and Future Investigations. Transfus Med Rev. 2016;30:159–64. https://doi.org/10.1016/j.tmrv.2016.05.008
6. Christensen RD, Bahr TM, Ilstrup SJ, Dizon-Townson DS. Alloimmune hemolytic disease of the fetus and newborn: genetics, structure, and function of the commonly involved erythrocyte antigens. J Perinatol. 2023;43:1459–67. https://doi.org/10.1038/s41372-023-01785-3
7. Dudareva Yu.A., Korchagina A.V., Guryeva V.A., Shchanova E.N. Prognostic markers of severe hemolytic disease of the fetus and newborn in Rh isoimmunization.. Byulleten meditsinskoy nauki\ Bulletin of Medical Science 2021;4:5–11. (in Russian) https://doi.org/10.31684/25418475-2021-4-5
8. Lewi L. What fetal medicine specialists should know about the monochorionic placenta. Best Pract Res Clin Obstet Gynaecol. 2022;84:17–32. https://doi.org/10.1016/j.bpobgyn.2022.03.007
9. Sorrenti S, Khalil A, D’Antonio F, D’Ambrosio V, Zullo F, D’Alberti E, et al. Counselling in Fetal Medicine: Complications of Monochorionic Diamniotic Twin Pregnancies. J Clin Med. 2024;13:7295. https://doi.org/10.3390/jcm13237295
10. Tollenaar LSA, Slaghekke F, Middeldorp JM, Lopriore E. Fetal anemia in monochorionic twins: a review on diagnosis, management, and outcome. Expert Rev Hematol. 2023;16:9–16. https://doi.org/10.1080/17474086.2023.2166921
11. Boller MJ, Moore GS, Hung Y-Y, Weintraub MLR, Schauer GM. Fetomaternal hemorrhage: evaluation of recurrence within a large integrated healthcare system. American Journal of Obstetrics & Gynecology. 2021;225:540.e1-540.e8. https://doi.org/10.1016/j.ajog.2021.04.257
12. Derme M, Vasta A, Tibaldi V, Galoppi P, D’Ambrosio V, Di Mascio D, et al. Diagnosis of Spontaneous Massive Fetomaternal Hemorrhage: A Case Report and Literature Review. J Clin Ultrasound. 2025. https://doi.org/10.1002/jcu.24062
13. Mascio DD, Buca D, Rizzo G, Giancotti A, D’Amico A, Leombroni M, et al. VP12.03: Outcome of fetuses with congenital cytomegalovirus infection: a systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology. 2020;56:99–100. https://doi.org/10.1002/uog.22502
14. Olejniczak O, Kornacki J, Boroń D, Gutaj P, Iciek R, Wender-Ożegowska E. Parvovirus B19 Infection in Pregnancy—Course of the Disease, Fetal Complications and Management Tools: A Case Series and Literature Review. Children (Basel). 2024;11:1037. https://doi.org/10.3390/children11091037
15. Munoz JL, Benitez L, Buskmiller C, Nassr AA, Belfort MA, Cortes MS, et al. Clinical Characteristics and Outcomes of Intrauterine Blood Transfusion (IUT) for Infectious Etiologies. Prenat Diagn. 2024;44:1622–7. https://doi.org/10.1002/pd.6671
16. Jamwal M, Aggarwal A, Sharma P, Bansal D, Das R. Congenital dyserythropoietic anemia type IV with high fetal hemoglobin caused by heterozygous KLF1 p.Glu325Lys: first report in an Indian infant. Ann Hematol. 2021;100:281–3. https://doi.org/10.1007/s00277-020-03982-y
17. Prefumo F, Fichera A, Fratelli N, Sartori E. Fetal anemia: Diagnosis and management. Best Pract Res Clin Obstet Gynaecol. 2019;58:2–14. https://doi.org/10.1016/j.bpobgyn.2019.01.001
18. Hamzeh C, Green J, Hamadeh G, Korst LM, Chmait RH. Increased Intrauterine Transfusion Blood Volume Needed to Correct Fetal Anemia due to Placental Chorioangioma. Fetal Diagn Ther. 2025;52:90–6. https://doi.org/10.1159/000541560
19. Jouzova A, Jouza M, Turek J, Gerychova R, Jezova M, Janku P, et al. Sacrococcygeal teratoma — prognosis based on prenatal ultrasound diagnosis, single-center experience and literature review. BMC Pregnancy Childbirth. 2025;25:469. https://doi.org/10.1186/s12884-025-07494-3
20. Rhesus-isoimmunization. Hemolytic disease of the fetus. Clinical recommendations. Ministry of Health of the Russian Federation. 2024. https://cr.minzdrav.gov.ru/view-cr/596_3?ysclid=mbe330l4pt51646989 (in Russian)
21. Mari G. Middle cerebral artery peak systolic velocity: is it the standard of care for the diagnosis of fetal anemia? J Ultrasound Med. 2005;24:697–702. https://doi.org/10.7863/jum.2005.24.5.697
22. Dias T, Ladd S, Mahsud-Dornan S, Bhide A, Papageorghiou AT, Thilaganathan B. Systematic labeling of twin pregnancies on ultrasound. Ultrasound Obstet Gynecol. 2011;38:130–3. https://doi.org/10.1002/uog.8990
23. Sileo FG, Sorrenti S, Giancotti A, Di Mascio D, D’Ambrosio V, Zullo F, et al. Counselling in Fetal Medicine: Uncomplicated Twin Pregnancies. J Clin Med. 2024;13:7355. https://doi.org/10.3390/jcm13237355
24. Steenhaut P, Hubinont C, Steenhaut P, Hubinont C. Perinatal Mortality in Multiple Pregnancy. In: Perinatal Mortality. IntechOpen; 2012. https://doi.org/10.5772/32441
25. Tollenaar LSA, Lopriore E, Oepkes D, Haak MC, Klumper FJCM, Middeldorp JM, et al. Twin anemia polycythemia sequence: knowledge and insights after 15 years of research. Maternal-Fetal Medicine. 2021;3:33–41. https://doi.org/doi:10.1097/FM9.0000000000000065
26. Khalil A, Sotiriadis A, Baschat A, Bhide A, Gratacós E, Hecher K, et al. ISUOG Practice Guidelines (updated): role of ultrasound in twin pregnancy. Ultrasound in Obstet and Gynecology. 2025;65:253–76. https://doi.org/10.1002/uog.15821
27. Slaghekke F, Kist WJ, Oepkes D, Pasman SA, Middeldorp JM, Klumper FJ, et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther. 2010;27:181–90. https://doi.org/10.1159/000304512
28. Multiple Pregnancy. Clinical Guidelines. Ministry of Health of the Russian Federation. 2024. https://cr.minzdrav.gov.ru/view-cr/638_2 (in Russian) Accessed 2 Jun 2025.
29. Tollenaar LSA, Lopriore E, Middeldorp JM, Haak MC, Klumper FJ, Oepkes D, et al. Improved prediction of twin anemia-polycythemia sequence by delta middle cerebral artery peak systolic velocity: new antenatal classification system. Ultrasound Obstet Gynecol. 2019;53:788–93. https://doi.org/10.1002/uog.20096
30. Khalil A, Gordijn S, Ganzevoort W, Thilaganathan B, Johnson A, Baschat AA, et al. Consensus diagnostic criteria and monitoring of twin anemia–polycythemia sequence: Delphi procedure. Ultrasound in Obstetrics & Gynecology. 2020;56:388–94. https://doi.org/10.1002/uog.21882
31. Lopriore E, Slaghekke F, Oepkes D, Middeldorp JM, Vandenbussche FPHA, Walther FJ. Hematological characteristics in neonates with twin anemia-polycythemia sequence (TAPS). Prenat Diagn. 2010;30:251–5. https://doi.org/10.1002/pd.2453
32. Fishel-Bartal M, Weisz B, Mazaki-Tovi S, Ashwal E, Chayen B, Lipitz S, et al. Can middle cerebral artery peak systolic velocity predict polycythemia in monochorionic- diamniotic twins? Evidence from a prospective cohort study. Ultrasound Obstet Gynecol. 2016;48:470–5. https://doi.org/10.1002/uog.15838
33. Zilliox M, Koch A, Favre R, Sananes N. Unusual twin anemia-polycythemia sequence in a dichorionic diamniotic pregnancy. J Gynecol Obstet Hum Reprod. 2019;48:359–61. https://doi.org/10.1016/j.jogoh.2019.02.005
34. Yoshimura Y, Ozawa K, Goto Hi, Yamazaki Y, Isohata H, Ochiai D. Twin Anemia-Polycythemia Sequence With Spontaneous Resolution in Dichorionic Diamniotic Twin Pregnancy: A Case Report and a Review of the Literature. Cureus. 16:e73563. https://doi.org/10.7759/cureus.73563
35. Kanagaretnam D, Nayyar R, Zen M. Twin anemia polycythemia sequence in dichorionic diamniotic twins: A case report and review of the literature. Clinical Case Reports. 2021;9:e04184. https://doi.org/10.1002/ccr3.4184
36. Cavazza MC, Lai AC, Sousa S, Pina R. Dichorionic pregnancy complicated by a twin-to-twin transfusion syndrome. BMJ Case Rep. 2019;12:e231614. https://doi.org/10.1136/bcr-2019-231614
37. Lanna M, Faiola S, Casati D, Rustico MA. Twin-twin transfusion syndrome in dichorionic twin pregnancy: rare but not impossible. Ultrasound Obstet Gynecol. 2019;54:417–8. https://doi.org/10.1002/uog.20195
38. Quintero R, Kontopoulos EV, Barness E, Steffensen TS, Hilbelink D, Chmait R, et al. Twin-twin transfusion syndrome in a dichorionic-monozygotic twin pregnancy: The end of a paradigm? Fetal Pediatr Pathol. 2010;29:81–8. https://doi.org/10.3109/15513811003615013
39. Murata S, Takano M, Kagawa Y, Fujiwara M, Sumie M, Nakata M. Twin-twin transfusion syndrome in a monozygotic pregnancy with obvious lambda sign in first-trimester ultrasound. Taiwan J Obstet Gynecol. 2016;55:904–6. https://doi.org/10.1016/j.tjog.2015.04.010
40. Bolshakova A.S., Yarygina T.A., Sakalo V.A., Gladkova K.A., Barkov I.Yu., Sadelov I.O. Observation of a monozygotic twin discordant for multiple developmental anomalies. Akusherstvo i ginekologiya/Obstetrics and Gynecology.2023;12:205–12.(In Russian) https://doi.org/10.18565/aig.2023.286
41. Qu JZZ, Leung TY, Jiang P, Liao GJW, Cheng YKY, Sun H, et al. Noninvasive prenatal determination of twin zygosity by maternal plasma DNA analysis. Clin Chem. 2013;59:427–35. https://doi.org/10.1373/CLINCHEM.2012.194068
42. Maisonneuve E, Ben M’Barek I, Leblanc T, Da Costa L, Friszer S, Pernot F, et al. Managing the Unusual Causes of Fetal Anemia. Fetal Diagn Ther. 2020;47:156–6. https:// doi.org/10.1159/0005015544
43. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med. 2000;342:9–14. https://doi.org/10.1056/nejm200001063420102
Review
For citations:
Klimova I.V., Panov A.E., Kotsuba D.R., Bezlepkina M.B., Shakaya M.N., Makhukova N.A., Yarygina T.A. Anemias of unknown etiology in the fetus and newborn: the symbiosis of obstetric and neonatal care (literature review and clinical case). Bulletin of maternal and child care. 2025;2(3):38-49. (In Russ.) https://doi.org/10.69964/BMCC-2025-2-3-38-49