Observational Study

. 2025 Jun:116:105742.

doi: 10.1016/j.ebiom.2025.105742. Epub 2025 May 8.

Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia

Valentina Bucher¹, Owen T Herrock², Sonja Schell³, Jacqui Visser³, Henrik Imberg⁴, Jonathan Burke⁵, Henrik Zetterberg⁶, Kaj Blennow⁷, Susan P Walker⁸, Stephen Tong⁸, Joakim Ek⁹, Catherine Cluver¹⁰, Lina Bergman¹¹

Affiliations

¹ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: valentina.bucher@gu.se.
² Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa.
⁴ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Statistiska Konsultgruppen Sweden, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Department of Anaesthesia and Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska, Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska, Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁸ Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
⁹ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.
¹¹ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa; Department of Obstetrics and Gynecology, Region Västra Götaland, Sahlgrenska, University Hospital, Goteborg, Sweden; Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

PMID: 40344719
PMCID: PMC12136835
DOI: 10.1016/j.ebiom.2025.105742

Observational Study

Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia

Valentina Bucher et al. EBioMedicine. 2025 Jun.

. 2025 Jun:116:105742.

doi: 10.1016/j.ebiom.2025.105742. Epub 2025 May 8.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: valentina.bucher@gu.se.
² Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa.
⁴ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Statistiska Konsultgruppen Sweden, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Department of Anaesthesia and Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska, Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska, Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁸ Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
⁹ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.
¹¹ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa; Department of Obstetrics and Gynecology, Region Västra Götaland, Sahlgrenska, University Hospital, Goteborg, Sweden; Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

PMID: 40344719
PMCID: PMC12136835
DOI: 10.1016/j.ebiom.2025.105742

Abstract

Background: Cerebral complications of pre-eclampsia are a leading cause of maternal mortality. Better understanding of the pathophysiology may enable the development of novel strategies to protect the maternal brain. We aimed to investigate blood-brain barrier injury and neuroinflammatory pathways in women with eclampsia and pre-eclampsia compared to normotensive pregnancies.

Methods: This observational cross-sectional study conducted between March 2021 and June 2023, included women with eclampsia, pre-eclampsia, and normotensive pregnancies admitted to Tygerberg Hospital, Cape Town, South Africa who underwent caesarean delivery. Cerebrospinal fluid and plasma samples were collected during caesarean delivery. Blood-brain barrier injury was assessed using immunonephelometry for albumin and ELISA assays for claudin-5 and matrix metalloproteinase-9 (MMP-9). Neuroinflammatory markers were analysed on the multiplex Bio-Plex Pro Human Cytokine-Screening assay. Data were analysed using parametric methods after log transformation and are presented as fold changes (geometric mean ratios) between groups.

Findings: The study included 129 women: Eleven had eclampsia, 17 had pre-eclampsia with end-organ complications, 88 had pre-eclampsia without end-organ complications, and 13 with normotensive pregnancies. Women with eclampsia had increased cerebrospinal fluid concentrations of claudin-5 (2.7-fold, 95% CI 1.4-5.1, p = 0.002 vs normotensive control) and MMP-9 (2.5-fold, 95% CI 1.1-5.3, p = 0.024 vs pre-eclampsia with end-organ complications). They also demonstrated increased cerebrospinal fluid cytokine levels compared to normotensive controls, reflecting inflammatory recruitment (Interleukin-8: 7.2-fold, 95% CI 2.7-18.5, p < 0.001), cytotoxicity (Interleukin-6: 20.7-fold, 95% CI 6.4-63.6, p < 0.001), and immune modulation (Interleukin-10: 2.0-fold, 95% CI 1.2-3.1, p = 0.004). Neuroprotective markers were reduced in eclampsia (stem cell factor: 0.5-fold, 95% CI 0.3-0.8, p = 0.005) compared to normotensive controls. There was no correlation between cytokine concentrations in the cerebrospinal fluid and plasma. Women with pre-eclampsia showed less pronounced changes indicative of blood-brain barrier injury and immune modulation.

Interpretation: Eclampsia is associated with blood-brain barrier injury and acute neuroinflammation originating from cerebral tissue, inducing cytotoxicity. This may be an underlying mechanism for seizures and cerebral injury in eclampsia and pre-eclampsia.

Funding: This study was supported by the Swedish Research Council, Herbert och Karin Jacobsson Stiftelse, Wilhelm and Martina Lundgren Foundations, and Swedish Society Of Medicine.

Keywords: Blood-brain barrier; Eclampsia; Maternal complications; Neuroinflammation; Pre-eclampsia.

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Conflict of interest statement

Declaration of interests HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is together with KB a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). HZ is chair of the Alzheimer's Association Global Biomarker Standardisation Consortium and chair of the IFCC WG-BND. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018; and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-128438-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen fӧr Gamla Tjӓnarinnor, Hjӓrnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL (UKDRI-1003), and an anonymous donor. KB has served at scientific advisory boards and/or as a consultant for Abbvie, AC Immune, ALZpath, Aribio, Beckman Coulter, BioArctic, Biogen, Eisai, Lilly, Neurimmune, Ono Pharma, Prothena, Roche Diagnostics, Sanofi, Siemens Healthineers, Novartis, and Julius Clinical. KB has received payments from Biogen, Eisai, and Roche Diagnostics for participation in educational programs. KB has received grants paid to the institute from Swedish Research Council (#2017-00915 and #2022-00732), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-965240 and #ALFGBG-1006418), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270, and #AF-994551), Hjärnfonden, Sweden (#ALZ2022-0006, #FO2024-0048-TK-130, and FO2024-0048-HK-24), the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer's Association 2022-2025 Special Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, Familjen Rӧnstrӧms Stiftelse, Stockholm, Sweden To the Institute. LB has collaborated with Roche, PerkinElmer, and Thermo Fischer as sponsors for PlGF and sFlt-1 reagents (IMPACT study). LB has obtained reimbursement for lecture by iLab Medical and Thermo Fisher, expert opinion from Homburg and Partner. LB has received trial drug and placebo from Merck.

Figures

**Fig. 1**
Flow chart of the study cohort illustrating the number of participants with normotensive pregnancies, pre-eclampsia without end-organ complications, pre-eclampsia with end-organ complications, and eclampsia. The number of analyses performed is also presented.

**Fig. 2**
Distribution of blood-brain barrier injury markers in cerebrospinal fluid (CSF) across participant groups. Claudin-5 (a), matrix metalloprotease-9 (MMP-9) (b), and CSF/plasma albumin ratio (c) are shown for normotensive women, women with pre-eclampsia (without and with end-organ complications), and women with eclampsia. Points represent observed values, and red lines indicate geometric means. [p-values were derived using Welch's analysis of covariance on log-transformed data].

**Fig. 3**
Distribution of inflammatory cytokines interleukin and growth factors in cerebrospinal fluid across participant groups. Shown are interleukin-8 (IL-8) (a), monocyte chemoattractant protein 1 (MCP-1) (b), interleukin-6 (IL-6) (c), interferon-γ (IFN-γ) (d), interleukin-10 (IL-10) (e), leukaemia inhibitory factor (LIF) (f), stem cell factor (SCF) (g), macrophage colony stimulating factor (M-CSF) (h), and tumour necrosis factor α (TNF-α) (i). Data are presented for normotensive women, women with pre-eclampsia (without and with end-organ complications), and women with eclampsia. Points represent observed values, and red lines indicate geometric means. [p-values were derived using log-normal Tobit regression for IL-6, TNF-α, IFN-γ, LIF, SCF, and IL-10, and Welch's analysis of covariance for IL-8, MCP-1, and M-CSF, all on log-transformed data].

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Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia

Affiliations

Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous