Unresolved issues regarding etiopathogenesis of preeclampsia as a neurogenic neuroimmune phenomenon of the perinatal period
Sidorova I.S., Managadze I.D.
The issue of preeclampsia, a severe protein-dependent hypertensive complication of the second half of pregnancy which is the leading cause of maternal and perinatal morbidity and mortality worldwide, continues to show fluctuating trends. It remains a significant concern and raises a wide range of unresolved questions, including etiopathogenesis, the search for potential biomarkers, as well as prognostic, diagnostic and therapeutic approaches. This review suggests that preeclampsia should be regarded as a phenomenon of stress-induced maladaptation during the perinatal period, involving a conflict between the mother and the fetus, associated with impairments in neurocorticogenesis and the development of the structures and functions of higher nervous activity, as well as the integrity and permeability of the blood-brain barrier (BBB). This is reflected in changes in the levels of neuron-specific proteins (NSPs) in maternal blood serum, alongside the process of complement-mediated destructive gestational endotheliosis induced by maternal agonistic autoantibodies.
The review includes papers on this topic available in the PubMed, Google Scholar and eLibrary databases, published from 2016 to 2026.
Conclusion. The article opens up new areas of research into the etiopathogenetic mechanisms of preeclampsia as a neurogenic neuroimmune phenomenon, and explores the potential for identifying innovative, prognostically valuable diagnostic and therapeutic targets. The paper also discusses early predictors of neurological complications in children born to mothers with preeclampsia. The obtained findings may transform both approaches to the monitoring and management of pregnancy and our understanding of the etiopathogenetic nature of preeclampsia as a whole.
Authors’ contributions. Sidorova I.S. – developing the concept and design of the study, editing the text; Sidorova I.S., Managadze I.D. – collecting and analyzing the literature data, writing the text.
Conflicts of interest. The authors declare that there are no conflicts of interest.
Funding. The study was conducted without sponsorship.
Generative Artificial Intelligence. The authors did not use any AI tools to generate the text of the article.
For citation: Sidorova I.S., Managadze I.D. Unresolved issues regarding etiopathogenesis of
preeclampsia as a neurogenic neuroimmune phenomenon of the perinatal period.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (7): 13-23 (in Russian)
https://dx.doi.org/10.18565/aig.2025.346
Keywords
References
- Сидорова И.С., Манагадзе И.Д. Современная концепция развития преэклампсии: новые данные. Акушерство и гинекология. 2025; 2: 5-13. https://dx.doi.org/10.18565/aig.2024.272 [Sidorova I.S., Managadze I.J. Modern concept of the development of preeclampsia: new data. Obstetrics and Gynecology. 2025; (2): 5-13 (in Russian). https://dx.doi.org/10.18565/aig.2024.272].
- Kostović I., Sedmak G., Judaš M. Neural histology and neurogenesis of the human fetal and infant brain. Neuroimage. 2019; 188: 743-73. https://dx.doi.org/10.1016/j.neuroimage.2018.12.043
- Сидорова И.С., Манагадзе И.Д. Современные представления о преэклампсии с учетом роли нейронспецифических белков головного мозга плода. Акушерство и гинекология. 2025; 1: 5-11. https://dx.doi.org/10.18565/aig.2024.221 [Sidorova I.S., Managadze I.J. Current understanding of preeclampsia with regard to the role of fetal brain neuron-specific proteins. Obstetrics and Gynecology. 2025; (1): 5-11 (in Russian). https://dx.doi.org/10.18565/aig.2024.221].
- Kadry H., Noorani B., Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020; 17(1): 69. https://dx.doi.org/10.1186/s12987-020-00230-3
- Burwick R.M., Feinberg B.B. Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Am. J. Obstet. Gynecol. 2022; 226(2S): S1059-70. https://dx.doi.org/10.1016/j.ajog.2020.09.038
- Collier A.Y., Smith L.A., Karumanchi S.A. Review of the immune mechanisms of preeclampsia and the potential of immune modulating therapy. Hum. Immunol. 2021; 82(5): 362-70. https://dx.doi.org/10.1016/j.humimm.2021.01.004
- Cheng S., Norris W., Kalkunte S., Jash S., Richardson L.R., Sharma S. Evidence for complement activation in preeclampsia placenta and its presence in circulation. Am. J. Reprod. Immunol. 2025; 93(5): e70076. https://dx.doi.org/10.1111/aji.70076
- Maeda K.J., McClung D.M., Showmaker K.C., Warrington J.P., Ryan M.J., Garrett M.R. et al. Endothelial cell disruption drives increased blood-brain barrier permeability and cerebral edema in the Dahl SS/jr rat model of superimposed preeclampsia. Am. J. Physiol. Heart Circ. Physiol. 2021; 320(2): H535-48. https://dx.doi.org/10.1152/ajpheart.00383.2020
- Friis T., Wikström A.K., Acurio J., León J., Zetterberg H., Blennow K. et al. Cerebral biomarkers and blood-brain barrier integrity in preeclampsia. Cells. 2022; 11(5): 789. https://dx.doi.org/10.3390/cells11050789
- Bergman L., Hastie R., Zetterberg H., Blennow K., Schell S., Langenegger E. et al. Evidence of neuroinflammation and blood-brain barrier disruption in women with preeclampsia and eclampsia. Cells. 2021; 10(11): 3045. https://dx.doi.org/10.3390/cells10113045
- Papapanagiotou A., Daskalaki M.A., Gargalionis A.N., Margoni A., Domali A., Daskalakis G. et al. The role of angiogenetic factors in preeclampsia. Int. J. Mol. Sci. 2025; 26(21): 10431. https://dx.doi.org/10.3390/ijms262110431
- Burwick R.M., Rodriguez M.H. Angiogenic biomarkers in preeclampsia. Obstet. Gynecol. 2024; 143(4): 515-23. https://dx.doi.org/10.1097/AOG.0000000000005532
- Escudero C., Kupka E., Ibañez B., Sandoval H., Troncoso F., Wikström A.K. et al. Brain vascular dysfunction in mothers and their children exposed to preeclampsia. Hypertension. 2023; 80(2): 242-56. https://dx.doi.org/10.1161/HYPERTENSIONAHA.122.19408
- Bergman L., Torres-Vergara P., Penny J., Wikström J., Nelander M., Leon J. et al. Investigating maternal brain alterations in preeclampsia: the need for a multidisciplinary effort. Curr. Hypertens Rep. 2019; 21(9): 72. https://dx.doi.org/10.1007/s11906-019-0977-0
- Canjels L.P.W., Jansen J.F.A., Alers R.J., Ghossein-Doha C., van den Kerkhof M., Schiffer V.M.M.M. et al. Blood-brain barrier leakage years after pre-eclampsia: dynamic contrast-enhanced 7-Tesla MRI study. Ultrasound Obstet. Gynecol. 2022; 60(4): 541-8. https://dx.doi.org/10.1002/uog.24930
- Mahendra V., Clark S.L., Suresh M.S. Neuropathophysiology of preeclampsia and eclampsia: a review of cerebral hemodynamic principles in hypertensive disorders of pregnancy. Pregnancy Hypertens. 2021; 23(3): 104-11. https://dx.doi.org/10.1016/j.preghy.2020.10.013
- Li J., Zheng M., Shimoni O., Banks W.A., Bush A.I., Gamble J.R. et al. Development of novel therapeutics targeting the blood-brain barrier: from barrier to carrier. Adv. Sci. (Weinh). 2021; 8(16): 2101090. https://dx.doi.org/10.1002/advs.202101090
- Li W., Pan R., Qi Z., Liu K.J. Current progress in searching for clinically useful biomarkers of blood-brain barrier damage following cerebral ischemia. Brain Circ. 2018; 4(4): 145-52. https://dx.doi.org/10.4103/bc.bc_11_18
- Misan N., Michalak S., Rzymski P., Poniedziałek B., Kapska K., Osztynowicz K. et al. Molecular indicators of blood-brain barrier breakdown and neuronal injury in pregnancy complicated by fetal growth restriction. Int. J. Mol. Sci. 2022; 23(22): 13798. https://dx.doi.org/10.3390/ijms232213798
- Zhang Y., Zhao H.J., Xia X.R., Diao F.Y., Ma X., Wang J. et al. Hypoxia-induced and HIF1α-VEGF-mediated tight junction dysfunction in choriocarcinoma cells: Implications for preeclampsia. Clin. Chim. Acta. 2019; 489: 203-11. https://dx.doi.org/10.1016/j.cca.2017.12.010
- Miller E.C. Preeclampsia and cerebrovascular disease: the maternal brain at risk. Hypertension. 2019; 74(1): 513. https://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11513
- Szyndler A., Adamski P., Kowalczyk K., Gąsecki D. Cerebrovascular disease in preeclampsia. In: Coca A., ed. Hypertension and brain damage. Updates in hypertension and cardiovascular protection. Cham: Springer; 2024: 253-72. https://dx.doi.org/10.1007/978-3-031-64928-8_17
- Bergman L., Hannsberger D., Schell S., Imberg H., Langenegger E., Moodley A. et al. Cerebral infarcts, edema, hypoperfusion, and vasospasm in preeclampsia and eclampsia. Am. J. Obstet. Gynecol. 2025; 232(6): 550.e1-14. https://dx.doi.org/10.1016/j.ajog.2024.10.034
- Gumusoglu S.B., Chilukuri A.S.S., Santillan D.A., Santillan M.K., Stevens H.E. Neurodevelopmental outcomes of prenatal preeclampsia exposure. Trends Neurosci. 2020; 43(4): 253-68. https://dx.doi.org/10.1016/j.tins.2020.02.003
- González-Rojas A., Valencia-Narbona M. Neurodevelopmental disruptions in children of preeclamptic mothers: pathophysiological mechanisms and consequences. Int. J. Mol. Sci. 2024; 25(7): 3632. https://dx.doi.org/10.3390/ijms25073632
- Staud F., Karahoda R. Trophoblast: the central unit of fetal growth, protection and programming. Int. J. Biochem. Cell. Biol. 2018; 105: 3540. https://dx.doi.org/10.1016/j.biocel.2018.09.016
- Kratimenos P., Penn A.A. Placental programming of neuropsychiatric disease. Pediatr. Res. 2019; 86(2): 15764. https://dx.doi.org/10.1038/ s4139001904059
- Creeth H.D.J., John R.M. The placental programming hypothesis: Placental endocrine insufficiency and the cooccurrence of low birth weight and maternal mood disorders. Placenta. 2020; 98: 529. https://dx.doi.org/10.1016/j.placenta.2020.03.011
- Ortega M.A., Fraile-Martínez O., García-Montero C., Sáez M.A., Álvarez-Mon M.A., Torres-Carranza D. et al. The pivotal role of the placenta in normal and pathological pregnancies: a focus on preeclampsia, fetal growth restriction, and maternal chronic venous disease. Cells. 2022; 11(3): 568. https://dx.doi.org/10.3390/cells11030568
- Scott H., Phillips T.J., Stuart G.C., Rogers M.F., Steinkraus B.R., Grant S. et al. Preeclamptic placentae release factors that damage neurons: implications for foetal programming of disease. Neuronal Signal. 2018; 2(4): NS20180139. https://dx.doi.org/10.1042/NS20180139
- Gumusoglu S.B. The role of the placenta-brain axis in psychoneuroimmune programming. Brain Behav. Immun. Health. 2024; 36: 100735. https://dx.doi.org/10.1016/j.bbih.2024.100735
- Liu D., Gao Q., Wang Y., Xiong T. Placental dysfunction: The core mechanism for poor neurodevelopmental outcomes in the offspring of preeclampsia pregnancies. Placenta. 2022; 126(3): 224-32. https://dx.doi.org/10.1016/j.placenta.2022.07.014
- Shallie P.D., Naicker T. The placenta as a window to the brain: A review on the role of placental markers in prenatal programming of neurodevelopment. Int. J. Dev. Neurosci. 2019; 73(1): 41-9. https://dx.doi.org/10.1016/j.ijdevneu.2019.01.003
- Rosenfeld C.S. The placenta-brain-axis. J. Neurosci. Res. 2021; 99(1): 271-83. https://dx.doi.org/10.1002/jnr.24603
- Gardella B., Dominoni M., Scatigno A.L., Cesari S., Fiandrino G., Orcesi S. et al. What is known about neuroplacentology in fetal growth restriction and in preterm infants: a narrative review of literature. Front. Endocrinol. (Lausanne). 2022; 13: 936171. https://dx.doi.org/10.3389/fendo.2022.936171
- Сидорова И.С., Манагадзе И.Д. Сущность преэклампсии и возможности ее прекращения. Акушерство и гинекология. 2026; 1: 5-11. https://dx.doi.org/10.18565/aig.2025.223 [Sidorova I.S., Managadze I.J. The essence of preeclampsia and the possibility of its termination. Obstetrics and Gynecology. 2026; (1): 5-11 (in Russian). https://dx.doi.org/10.18565/aig.2025.223].
- Vinci L. Immunohistochemical markers of stem/progenitor cells in the developing human cerebral cortex. 2017.
- Nogueira-Vale E. Brain development. In: Oxytocin, well-being and affect regulation. Springer, Cham; 2024: 64-74. https://dx.doi.org/10.1007/978-3-031-59038-2_6
- Цехмистренко Т.А., Васильева В.А., Обухов Д.К., Шумейко Н.С. Строение и развитие коры большого мозга. М.: Спутник+; 2019. 538 с. [Tsekhmistrenko T.A., Vasilyeva V.A., Obukhov D.K., Shumeiko N.S. Structure and development of the cerebral cortex. Moscow: Sputnik+; 2019. 538 p. (in Russian)].
- Циркин В.И., Трухина С.И., Трухин А.Н. Нейрофизиология: основы нейрофизиологии. Учебник для вузов. 2-е изд., испр. и доп. М.: Юрайт; 2023. 504 c. [Tsirkin V.I., Trukhina S.I., Trukhin A.N. Neurophysiology: basis of neurophysiology. Textbook for universities. 2nd ed., rev. exp. Moscow: Yurayt; 2023. 504 p. (in Russian)].
- Salihagić A., Kurjak A. Cognitive functions of the fetus. Kognitive funktionen beim feten. Ultraschall in der Medizin. 2018; 39(2), 181-9. https://dx.doi.org/10.1055/s-0043-123469
- Fagard J., Esseily R., Jacquey L., O'Regan K., Somogyi E. Fetal origin of sensorimotor behavior. Front. Neurorobot. 2018; 12: 23. https://dx.doi.org/10.3389/fnbot.2018.00023
- Mariani B., Nicoletti G., Barzon G., Ortiz Barajas M.C., Shukla M., Guevara R. et al. Prenatal experience with language shapes the brain. Sci. Adv. 2023; 9(47): eadj3524. https://dx.doi.org/10.1126/sciadv.adj3524
- Moser J., Schleger F., Weiss M., Sippel K., Semeia L., Preissl H. Magnetoencephalographic signatures of conscious processing before birth. Dev. Cogn. Neurosci. 2021; 49: 100964. https://dx.doi.org/10.1016/j.dcn.2021.100964
- Falsaperla R., Collotta A.D., Spatuzza M., Familiari M., Vitaliti G., Ruggieri M. Evidences of emerging pain consciousness during prenatal development: a narrative review. Neurol. Sci. 2022; 43(6): 3523-32. https://dx.doi.org/10.1007/s10072-022-05968-2
- Chorna O., Filippa M., De Almeida J.S., Lordier L., Monaci M.G., Hüppi P. et al. Neuroprocessing mechanisms of music during fetal and neonatal development: a role in neuroplasticity and neurodevelopment. Neural Plast. 2019; 2019: 3972918. https://dx.doi.org/10.1155/2019/3972918
- Bayne T., Frohlich J., Cusack R., Moser J., Naci L. Consciousness in the cradle: on the emergence of infant experience. Trends Cogn. Sci. 2023; 27(12): 1135-49. https://dx.doi.org/10.1016/j.tics.2023.08.018
- Kumar N., Kamath S., Kumar G., Kh V., Kumar Sinha M., Amin R. et al. Prenatal learning and memory: review on the impact of exposure. Curr. Pediatr. Rev. 2023; 19(2): 108-20. https://dx.doi.org/10.2174/1573396318666220601160537
- Yuan X., Li W., Yan Q., Ou Y., Long Q., Zhang P. Biomarkers of mature neuronal differentiation and related diseases. Future Sci. OA. 2024; 10(1): 2410146. https://dx.doi.org/10.1080/20565623.2024.2410146
- Bergman L., Zetterberg H., Kaihola H., Hagberg H., Blennow K., Åkerud H. Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study. PLoS One. 2018; 13(5): e0196025. https://dx.doi.org/10.1371/journal.pone.0196025
- Bergman L., Hastie R., Bokström-Rees E., Zetterberg H., Blennow K., Schell S. et al. Cerebral biomarkers in neurologic complications of preeclampsia. Am. J. Obstet. Gynecol. 2022; 227(2): 298.e1-10. https://dx.doi.org/10.1016/j.ajog.2022.02.036
- Liao J., Zhang Z., Huang W., Huang Q., Bi G. Neonatal neuron specific enolase, a sensitive biochemical marker of neuronal damage, is increased in preeclampsia: A retrospective cohort study. Brain Dev. 2020; 42(8): 564-71. https://dx.doi.org/10.1016/j.braindev.2020.04.011
- Busse M., Scharm M., Oettel A., Redlich A., Costa S.D., Zenclussen A.C. Enhanced S100B expression in T and B lymphocytes in spontaneous preterm birth and preeclampsia. J. Perinat. Med. 2021; 50(2): 157-66. https://dx.doi.org/10.1515/jpm-2021-0326
- Karampas G., Tzelepis A., Koulouraki S., Lykou D., Metallinou D., Erlandsson L. et al. The utility of maternal blood S100B in women with suspected or established preeclampsia – a systematic review. Biomolecules. 2025; 15(6): 840. https://dx.doi.org/10.3390/biom15060840
- Wu J., Sheng X., Zhou S., Fang C., Song Y., Wang H. et al. Clinical significance of S100B protein in pregnant woman with early- onset severe preeclampsia. Ginekol. Pol. 2024; 95(9): 711-7. https://dx.doi.org/10.5603/GP.a2021.0126
- Lederer W., Dominguez C.A., Popovscaia M., Putz G., Humpel C. Cerebrospinal fluid levels of tau and phospho-tau-181 proteins during pregnancy. Pregnancy Hypertens. 2016; 6(4): 384-7. https://dx.doi.org/10.1016/j.preghy.2016.08.243
- Wang Y., Guo B., Zhao K., Yang L., Chen T. Correlation between cognitive impairment and serum phosphorylated tau181 protein in patients with preeclampsia. Front. Aging Neurosci. 2023; 15: 1148518. https://dx.doi.org/10.3389/fnagi.2023.1148518
- Jash S., Banerjee S., Cheng S., Wang B., Qiu C., Kondo A. et al. Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia. Nat. Commun. 2023; 14(1): 5414. https://dx.doi.org/10.1038/s41467-023-41144-6
- Andersson M., Oras J., Thörn S.E., Karlsson O., Kälebo P., Zetterberg H. et al. Signs of neuroaxonal injury in preeclampsia – a case control study. PLoS One. 2021; 16(2): e0246786. https://dx.doi.org/10.1371/journal.pone.0246786
- Gu X., Rana S., Ngo L., Mueller A., Dillon S., Salahuddin et al. Plasma markers of neurological injury are elevated in preeclampsia. Pregnancy Hypertension. 2025; 42: 101265. https://dx.doi.org/10.1016/j.preghy.2025.101265
- Goasdoué K., Miller S.M., Colditz P.B., Björkman S.T. Review: the blood-brain barrier; protecting the developing fetal brain. Placenta. 2016; 54: 111-6. https://dx.doi.org/10.1016/j.placenta.2016.12.005
- Сидорова И.С., Никитина Н.А. Обоснование современной концепции развития преэклампсии. Акушерство и гинекология. 2019; 4: 26-33. https://dx.doi.org/10.18565/aig.2019.4.26-33 [Sidorova I.S., Nikitina N.A. Validation of the modern concept of the development of preeclampsia. Obstetrics and Gynecology. 2019; (4): 26-33 (in Russian). https://dx.doi.org/10.18565/aig.2019.4.26-33].
- Сидорова И.С., Никитина Н.А. Течение и ведение беременности по триместрам ее развития. Руководство. М.: ГЭОТАР-Медиа; 2021. 584 с. [Sidorova I.S., Nikitina N.A. Course and management of pregnancy by trimesters of its development. Guide. Moscow: GEOTAR-Media; 2021. 584 p. (in Russian)].
- Kadry H., Noorani B., Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020; 17(1): 69. https://dx.doi.org/10.1186/s12987-020-00230-3
- Wang J., Xu F., Zhu X., Li X., Li Y., Li J. Targeting microRNAs to Regulate the Integrity of the Blood-Brain Barrier. Front. Bioeng. Biotechnol. 2021; 9: 673415. https://dx.doi.org/10.3389/fbioe.2021.673415
- Toyama K., Spin J.M., Deng A.C., Huang T.T., Wei K., Wagenhäuser M.U. et al. MicroRNA-mediated therapy modulating blood-brain barrier disruption improves vascular cognitive impairment. Arterioscler. Thromb. Vasc. Biol. 2018; 38(6): 1392-406. https://dx.doi.org/10.1161/ATVBAHA.118.310822
- Congdon E.E., Ji C., Tetlow A.M., Jiang Y., Sigurdsson E.M. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nat. Rev. Neurol. 2023; 19(12): 715-36. https://dx.doi.org/10.1038/s41582-023-00883-2
- Sarkar S., Porel P., Kosey S., Aran K.R. Diverse role of S100 calcium-binding protein B in alzheimer's disease: pathological mechanisms and therapeutic implications. Inflammopharmacology. 2025; 33(4): 1803-16. https://dx.doi.org/10.1007/s10787-025-01697-y
- Kocurova G., Ricny J., Ovsepian S.V. Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases. Theranostics. 2022; 12(7): 3045-56. https://dx.doi.org/10.7150/thno.72126
- Torres-Vergara P., Troncoso F., Acurio J., Kupka E., Bergman L., Wikström A.K. et al. Dysregulation of vascular endothelial growth factor receptor 2 phosphorylation is associated with disruption of the blood-brain barrier and brain endothelial cell apoptosis induced by plasma from women with preeclampsia. Biochim. Biophys. Acta Mol. Basis Dis. 2022; 1868(9): 166451. https://dx.doi.org/10.1016/j.bbadis.2022.166451
- Mukherjee I., Singh S., Karmakar A., Kashyap N., Mridha A.R., Sharma J.B. et al. New immune horizons in therapeutics and diagnostic approaches to Preeclampsia. Am. J. Reprod. Immunol. 2023; 89(2): e13670. https://dx.doi.org/10.1111/aji.13670
Received 24.11.2025
Accepted 02.06.2026
About the Authors
Iraida S. Sidorova, Dr. Med. Sci., Professor, Academician of the RAS, Merited Scholar of the Russian Federation, Merited Doctor of the Russian Federation, Professor at the Department of Obstetrics and Gynecology No. 1, Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia(Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(499)248-67-29, sidorovais@yandex.ru, https://orcid.org/0000-0003-2209-8662
Ioanna D. Managadze, Resident and PhD student at the Department of Obstetrics and Gynecology No. 1, Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(499)248-67-29, ktb1966@mail.ru,
https://orcid.org/0000-0001-8745-9372
Corresponding author: Ioanna D. Managadze, ktb1966@mail.ru



