About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
Logout
Obstetrics and Gynegology2021№6
The complement system during physiological...

The complement system during physiological pregnancy

DOI
https://dx.doi.org/10.18565/aig.2021.6.14-20

Sidorova I.S., Nikitina N.A., Unanyan A.L., Ageev M.B., Kokin  A.A.

1) Obstetrics and Gynecology Department No 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of the Russian Federation, Moscow, Russia; 2) Intensive Care Unit, Branch (Maternity Hospital), V.V. Veresaev City Clinical Hospital, Moscow Healthcare Department, Moscow, Russia
This literature review analyzes the studies published over the past 10 years on the role of the complement system in the physiological development of pregnancy. The complement system belongs to the factors of innate immunity and plays an important role in maintaining homeostasis and developing a normal pregnancy. The paper presents the currently available data on changes in complement factors from preimplantation to full term. Many authors recognize that normal pregnancy develops after the moderate activation of the system of the complement, which is accompanied by the higher expression of its regulatory proteins in both maternal blood flow and the placenta. By the end of the third trimester, there are increases in the concentration of C3, C4d, C9, sC5b-9, anaphylatoxins C3a, C4a, C5a, regulatory factor H, as well as the C4d/C4, C3a/C3 ratios. Adequate placentation is accompanied by local expression of regulatory proteins, such as DAF (CD55), CD59, and MCP (CD46), which block the formation of C3 and C5 convertases and the assembly of MAC on the cell membrane surface. In addition, the investigators studied the role of the complement system in the processes of implantation and placentation, development of fetal organs and systems, and preparation for childbirth, as well as the risk of pregnancy complications and postnatal diseases in both the mother and her baby when complementary homeostasis is disrupted.
Conclusion. Clinical trials using complement biomarkers in serum, urine, and placenta have shown a direct relationship between complement system dysregulation and adverse pregnancy outcomes, such as preeclampsia, fetal growth retardation, miscarriage, and preterm birth.

Keywords

complement system
complement activation
pregnancy
placentation
neurogenesis
Full text (in Russian)

References

  1. Cavaillon J.M., Sansonetti P., Goldman M. 100th Anniversary of Jules Bordet's Nobel Prize: tribute to a founding father of immunology. Front. Immunol. 2019; 10: 2114. https://dx.doi.org/10.3389/fimmu.2019.02114.
  2. Girardi G., Lingo J.J., Fleming S.D., Regal J.F. Essential role of complement in pregnancy: from implantation to parturition and beyond. Front. Immunol. 2020; 11: 1681. https://dx.doi.org/10.3389/fimmu.2020.01681.
  3. Lokki A.I., Heikkinen-Eloranta J., Jarva H., Saisto T., Lokki M.L., Laivuori H., Meri S. Complement activation and regulation in preeclamptic placenta. Front. Immunol. 2014; 5: 312. https://dx.doi.org/10.3389/fimmu.2014.00312.
  4. Pierik E., Prins J.R., van Goor H., Dekker G.A., Daha M.R., Seelen M.A.J., Scherjon S.A. Dysregulation of complement activation and placental dysfunction: a potential target to treat preeclampsia? Front. Immunol. 2020 Jan 15; 3098. https://dx.doi.org/10.3389/fimmu.2019.03098.
  5. Regal J.F., Gilbert J.S., Burwick R.M. The complement system and adverse pregnancy outcomes. Mol. Immunol. 2015; 67(1): 56-70. https://dx.doi.org/10.1016/j.molimm.2015.02.030.
  6. Kouser L., Madhukaran S.P., Shastri A., Saraon A., Ferluga J., Al-Mozaini M., Kishore U. Emerging and novel functions of complement protein C1q. Front. Immunol. 2015; 6: 317. https://dx.doi.org/10.3389/fimmu.2015.00317.
  7. Csomor E., Bajtay Z., Sándor N., Kristóf K., Arlaud G.J., Thiel S., Erdei A. Complement protein C1q induces maturation of human dendritic cells. Mol. Immunol. 2007; 44(13): 3389-97. https://dx.doi.org/10.1016/j.molimm.2007.02.014.
  8. Dunkelberger J.R., Song W.C. Complement and its role in innate and adaptive immune responses. Cell Res. 2010; 20(1): 34-50. https://dx.doi.org/10.1038/cr.2009.139.
  9. Markiewski M.M., Nilsson B., Ekdahl K.N., Mollnes T.E., Lambris J.D. Complement and coagulation: strangers or partners in crime? Trends Immunol. 2007; 28(4): 184-92. https://dx.doi.org/10.1016/j.it.2007.02.006.
  10. Burwick R.M., Feinberg B.B. Complement activation and regulation in preeclampsia and HELLP syndrome. Am. J. Obstet. Gynecol. 2020 Sep 25: S0002-9378(20)31129-7. https://dx.doi.org/10.1016/j.ajog.2020.09.038.
  11. Yu L., Wang L., Chen S. Endogenous toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 2010; 14(11): 2592-603. https://dx.doi.org/10.1111/j.1582-4934.2010.01127.x.
  12. Spaans F., de Vos P., Bakker W.W., van Goor H., Faas M.M. Danger signals from ATP and adenosine in pregnancy and preeclampsia. Hypertension. 2014; 63(6): 1154-60. https://dx.doi.org/10.1161/HYPERTENSIONAHA.114.03240.
  13. Fuzzi B., Rizzo R., Criscuoli L., Noci I., Melchiorri L., Scarselli B. et al. HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur. J. Immunol. 2002; 32(2): 311-5. https://dx.doi.org/10.1002/1521-4141(200202)32:2<311::AID-IMMU311>3.0.CO;2-8.
  14. Moffett A., Colucci F. Uterine NK cells: active regulators at the maternal-fetal interface. J. Clin. Invest. 2014; 124(5): 1872-9. https://dx.doi.org/10.1172/JCI68107.
  15. Girardi G. Complement activation, a threat to pregnancy. Semin. Immunopathol. 2018; 40(1): 103-11. https://dx.doi.org/10.1007/s00281-017-0645-x.
  16. Hawksworth O.A., Coulthard L.G., Mantovani S., Woodruff T.M. Complement in stem cells and development. Semin. Immunol. 2018; 37: 74-84. https://dx.doi.org/10.1016/j.smim.2018.02.009.
  17. Contro E., Bernabini D., Farina A. Cell-free fetal DNA for the prediction of pre-eclampsia at the first and second trimesters: a systematic review and meta-analysis. Mol. Diagn. Ther. 2017; 21(2): 125-35. https://dx.doi.org/10.1007/s40291-016-0245-9.
  18. Tempfer C.B., Bancher-Todesca D., Zeisler H., Schatten C., Husslein P., Gregg A.R. Placental expression and serum concentrations of cytokeratin 19 in preeclampsia. Obstet. Gynecol. 2000; 95(5): 677-82. https://dx.doi.org/10.1016/s0029-7844(00)00797-3.
  19. Derzsy Z., Prohászka Z., Rigó J. Jr., Füst G., Molvarec A. Activation of the complement system in normal pregnancy and preeclampsia. Mol. Immunol. 2010; 47(7-8): 1500-6. https://dx.doi.org/10.1016/j.molimm.2010.01.021.
  20. Albieri A., Kipnis T., Bevilacqua E. A possible role for activated complement component 3 in phagocytic activity exhibited by the mouse trophoblast. Am. J. Reprod. Immunol. 1999; 41(5): 343-52. https://dx.doi.org/10.1111/j.1600-0897.1999.tb00448.x.
  21. Baines M.G., Millar K.G., Mills P. Studies of complement levels in normal human pregnancy. Obstet. Gynecol. 1974; 43: 806-10.
  22. Richani K., Soto E., Romero R., Espinoza J., Chaiworapongsa T., Nien J.K. et al. Normal pregnancy is characterized by systemic activation of the complement system. J. Matern. Fetal Neonatal Med. 2005; 17(4): 239-45. https://dx.doi.org/10.1080/14767050500072722.
  23. Mor G., Cardenas I., Abrahams V., Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann. N. Y. Acad. Sci. 2011; 1221(1): 80-7. https://dx.doi.org/10.1111/j.1749-6632.2010.05938.x.
  24. Bulla R., Bossi F., Agostinis C., Radillo O., Colombo F., De Seta F., Tedesco F. Complement production by trophoblast cells at the feto-maternal interface. J. Reprod. Immunol. 2009; 82(2): 119-25. https://dx.doi.org/10.1016/j.jri.2009.06.124.
  25. Agostinis C., Bulla R., Tripodo C., Gismondi A., Stabile H., Bossi F. et al. An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development. J. Immunol. 2010; 185(7): 4420-9. https://dx.doi.org/10.4049/jimmunol.0903215.
  26. Singh J., Ahmed A., Girardi G. Role of complement component C1q in the onset of preeclampsia in mice. Hypertension. 2011; 58(4): 716-24. https://dx.doi.org/10.1161/HYPERTENSIONAHA.111.175919.
  27. Reichhardt M.P., Lundin K., Lokki A.I., Recher G., Vuoristo S., Katayama S. et al. Complement in human pre-implantation embryos: attack and defense. Front. Immunol. 2019; 10: 2234. https://dx.doi.org/10.3389/fimmu.2019.02234.
  28. Gonzalez J.M., Franzke C.W., Yang F., Romero R., Girardi G. Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice. Am. J. Pathol. 2011; 179(2): 838-49. https://dx.doi.org/10.1016/j.ajpath.2011.04.024.
  29. Magdalon J., Mansur F., Teles E., Silva A.L., de Goes V.A., Reiner O., Sertié A.L. Complement system in brain architecture and neurodevelopmental disorders. Front. Neurosci. 2020; 14: 23. https://dx.doi.org/10.3389/fnins.2020.00023.
  30. Gorelik A., Sapir T., Haffner-Krausz R., Olender T., Woodruff T.M., Reiner O. Developmental activities of the complement pathway in migrating neurons. Nat. Commun. 2017; 8: 15096. https://dx.doi.org/10.1038/ncomms15096.
  31. Girardi G., Fraser J., Lennen R., Vontell R., Jansen M., Hutchison G. Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO)--conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development. Mol. Psychiatry. 2015; 20(8): 1017-26. https://dx.doi.org/10.1038/mp.2014.110.
  32. Sekar A., Bialas A.R., de Rivera H., Davis A., Hammond T.R., Kamitaki N. et al. Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly M.J., Carroll M.C., Stevens B., McCarroll S.A. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530(7589):177-83. https://dx.doi.org/10.1038/nature16549.
  33. Fagan K., Crider A., Ahmed A.O., Pillai A. Complement C3 expression is decreased in autism spectrum disorder subjects and contributes to behavioral deficits in rodents. Mol. Neuropsychiatry. 2017; 3(1): 19-27. https://dx.doi.org/10.1159/000465523.
  34. Orsini F., De Blasio D., Zangari R., Zanier E.R., De Simoni M.G. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front. Cell. Neurosci. 2014; 8: 380. https://dx.doi.org/10.3389/fncel.2014.00380.
  35. Jacob A., Alexander J.J. Complement and blood-brain barrier integrity. Mol. Immunol. 2014; 61(2): 149-52. https://dx.doi.org/10.1016/j.molimm.2014.06.039.
  36. Woodruff T.M., Ager R.R., Tenner A.J., Noakes P.G., Taylor S.M. The role of the complement system and the activation fragment C5a in the central nervous system. Neuromolecular Med. 2010; 12(2): 179-92. https://dx.doi.org/10.1007/s12017-009-8085-y.
  37. Sisa C., Agha-Shah Q., Sanghera B., Carno A., Stover C., Hristova M. Properdin: a novel target for neuroprotection in neonatal hypoxic-ischemic brain injury. Front. Immunol. 2019; 10: 2610. https://dx.doi.org/10.3389/fimmu.2019.02610.
  38. van der Linde D., Konings E.E., Slager M.A., Witsenburg M., Helbing W.A., Takkenberg J.J., Roos-Hesselink J.W. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 2011; 58(21): 2241-7. https://dx.doi.org/10.1016/j.jacc.2011.08.025.
  39. Olson K.N., Redman L.M., Sones J.L. Obesity "complements" preeclampsia. Physiol. Genomics. 2019; 51(3): 73-6. https://dx.doi.org/10.1152/physiolgenomics.00102.2018.
  40. Fiorentino T.V., Hribal M.L., Andreozzi F., Perticone M., Sciacqua A., Perticone F., Sesti G. Plasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals. Nutr. Metab. Cardiovasc. Dis. 2015; 25(5): 510-7. https://dx.doi.org/10.1016/j.numecd.2015.02.007.

Received 12.03.2021

Accepted 02.04.2021

About the Authors

Iraida S. Sidorova, Dr. Med. Sci., Professor, Academician of the RAS, Merited Scholar of the Russian Federation, Department of Obstetrics and Gynecology № 1,
N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: sidorovais@yandex.ru.
ORCID: 0000-0003-2209-8662. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Natalya A. Nikitina, Dr. Med. Sci., Professor at the Department of Obstetrics and Gynecology № 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov
First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: natnikitina@list.ru. ORCID: 0000-0001-8659-9963. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Ara L. Unanyan, Dr. Med. Sci., Professor, Professor of the Department of Obstetrics and Gynecology No. 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). Tel.: +7(903)960-35-26. E-mail: 9603526@mail.ru. ORCID: 0000-0002-2283-2356.
8-2 Trubetskaya str., Moscow, 119991, Russia.
Mikhail B. Ageev, Ph.D., Teaching Assistant at the Department of Obstetrics and Gynecology №1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: mikhaageev@yandex.ru. ORCID: 0000-0002-6603-804X. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Albert A. Kokin, Head of the Department of Anesthesiology and Intensive Care, Maternity Hospital affiliated to the V.V. Veresaev Clinical Hospital of Moscow City Health Department. E-mail: Alberkokin@yandex.ru. ORCID: 0000-0001-7615-4530.
127247, Russia, Moscow, 800th anniversary of Moscow str., 22.

For citation: Sidorova I.S., Nikitina N.A., Unanyan A.L., Ageev M.B., Kokin A.A. The complement system during physiological pregnancy.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 6: 14-20 (in Russian)
https://dx.doi.org/10.18565/aig.2021.6.14-20

Similar Articles

№9 / 2024
Drapkina Yu.S., Makarova N.P., Kalinin A.P., Vasiliev R.A., Amelin V.V.
Experience in machine learning application to predict pregnancy loss after assisted reproductive technologies
№7 / 2024
Igitova M.B., Kazanina A.B., Cherkasova T.M., Yavorskaya S.D., Dmitrienko K.V., Dolgova N.S.
Pregnancy after in vitro fertilization: obstetric and perinatal risks
№6 / 2024
Ziganshin A.M., Tagirov M.R., Dikke G.B.
Clinical case of hemorrhagic stroke in a pregnant woman
№9 / 2024
Tyutyunnik V.L., Mirzabekova D.D., Mikhailova O.I., Kan N.E., Krasnyi A.M.
Correlation of perinatal outcomes in preeclampsia with the dynamics of CD16+ monocyte content in peripheral blood
№1 / 2025
Serov V.N., Pasman N.M., Pismak M.A., Vagner Yu.N.
Prevention of preeclampsia with low-molecular-weight heparins
By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.