Skip to main content

Advertisement

SpringerLink
Log in

Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort

  • Preeclampsia (V Garovic, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To provide insight into the mechanisms underlying cerebral pathophysiology and to highlight possible methods for evaluation, screening, and surveillance of cerebral complications in preeclampsia.

Recent Findings

The pathophysiology of eclampsia remains enigmatic. Animal studies show that the cerebral circulation in pregnancy and preeclampsia might be affected with increased permeability over the blood-brain barrier and altered cerebral blood flow due to impaired cerebral autoregulation. The increased blood pressure cannot be the only underlying cause of eclampsia and cerebral edema, since some cases of eclampsia arise without simultaneous hypertension. Findings from animal studies need to be confirmed in human tissues. Evaluation of brain alterations in preeclampsia and eclampsia is challenging and demands a multidisciplinary collaboration, since no single method can accurately and fully describe how preeclampsia affects the brain.

Summary

Cerebral complications of preeclampsia are significant factors in maternal morbidity and mortality worldwide. No single method can accurately describe the full picture of how preeclampsia affects the brain vasculature and parenchyma. We recommend an international and multidisciplinary effort not only to overcome the issue of limited sample availability but also to optimize the quality of research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BBB:

Blood-brain barrier

BP:

Blood pressure

CBF:

Cerebral blood flow

CVR:

Cerebral vascular resistance

CSF:

Cerebrospinal fluid

GABA:

Gamma amino butyric acid

hPSCs:

Human pluripotent stem cells

JAMs:

Junctional adhesion molecules

LPS:

Lipopolysaccharide

MgSO4 :

Magnesium sulfate

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

H-MRS:

Magnetic resonance spectroscopy focused on hydrogen metabolites

P-MRS:

Magnetic resonance spectroscopy focused on phosphorus metabolites

NfL:

Neurofilament light chain

NSE:

Neuron-specific enolase

PTZ:

Pentylenetetrazole

PRES:

Posterior reversible encephalopathy syndrome

RUPP:

Reduced uteroplacental perfusion pressure

RUPP+HC:

Reduced uteroplacental perfusion pressure plus high cholesterol diet

S100B:

S100 calcium-binding protein B

TEER:

Transendothelial electrical resistance

WML:

White matter lesions

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Brown MA, Lindheimer MD, de Swiet M, Assche AV, Moutquin J-M. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy. 2001;20:ix–xiv. https://doi.org/10.3109/10641950109152635.

    Article  CAS  PubMed  Google Scholar 

  2. ACOG TFoHiP. Hypertension in pregnancy. Washington: 2013.

  3. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2018;13:291–310. https://doi.org/10.1016/j.preghy.2018.05.004.

    Article  CAS  PubMed  Google Scholar 

  4. Campbell OM, Graham WJ. Strategies for reducing maternal mortality: getting on with what works. Lancet. 2006;368:1284–99. https://doi.org/10.1016/S0140-6736(06)69381-1.

    Article  PubMed  Google Scholar 

  5. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323–33. https://doi.org/10.1016/S2214-109X(14)70227-X.

    Article  PubMed  Google Scholar 

  6. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387:999–1011. https://doi.org/10.1016/S0140-6736(15)00070-7.

    Article  PubMed  Google Scholar 

  7. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. Am J Obstet Gynecol. 2004;190:1520–6. https://doi.org/10.1016/j.ajog.2003.12.057.

    Article  CAS  PubMed  Google Scholar 

  8. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–99. https://doi.org/10.1016/S0140-6736(05)17987-2.

    Article  PubMed  Google Scholar 

  9. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130–7. https://doi.org/10.1053/j.semperi.2009.02.010.

    Article  PubMed  Google Scholar 

  10. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402–10.

    Article  PubMed  Google Scholar 

  11. Basit S, Wohlfahrt J, Boyd HA. Pre-eclampsia and risk of dementia later in life: nationwide cohort study. Bmj. 2018:k4109. https://doi.org/10.1136/bmj.k4109.

  12. Brussé I, Duvekot J, Jongerling J, Steegers E, De Koning I. Impaired maternal cognitive functioning after pregnancies complicated by severe pre-eclampsia: a pilot case-control study. Acta Obstet Gynecol Scand. 2008;87:408–12. https://doi.org/10.1080/00016340801915127.

    Article  PubMed  Google Scholar 

  13. Duley L. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The magpie trial: a randomised placebo-controlled trial. Lancet. 2002;359:1877–90. https://doi.org/10.1016/S0140-6736(02)08778-0.

    Article  CAS  PubMed  Google Scholar 

  14. •• Johnson AC, Tremble SM, Chan SL, Moseley J, LaMarca B, Nagle KJ, et al. Magnesium sulfate treatment reverses seizure susceptibility and decreases neuroinflammation in a rat model of severe preeclampsia. PLoS One. 2014;9(11):e113670. https://doi.org/10.1371/journal.pone.0113670 One of the few animal models for cerebral injury and blood brain barrier alteration in preeclampsia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Andolf EG, Sydsjo GC, Bladh MK, Berg G, Sharma S. Hypertensive disorders in pregnancy and later dementia: a Swedish National Register Study. Acta Obstet Gynecol Scand. 2017;96(4):464–71. https://doi.org/10.1111/aogs.13096.

    Article  PubMed  Google Scholar 

  16. Nerenberg KA, Park AL, Vigod SN, Saposnik G, Berger H, Hladunewich MA, et al. Long-term risk of a seizure disorder after eclampsia. Obstet Gynecol. 2017;130(6):1327–33. https://doi.org/10.1097/AOG.0000000000002364.

    Article  PubMed  Google Scholar 

  17. Aukes AM, De Groot JC, Wiegman MJ, Aarnoudse JG, Sanwikarja GS, Zeeman GG. Long-term cerebral imaging after pre-eclampsia. BJOG. 2012;119(9):1117–22. https://doi.org/10.1111/j.1471-0528.2012.03406.x.

    Article  CAS  PubMed  Google Scholar 

  18. Aukes AM, de Groot JC, Aarnoudse JG, Zeeman GG. Brain lesions several years after eclampsia. Am J Obstet Gynecol. 2009;200(5):504 e1–5. https://doi.org/10.1016/j.ajog.2008.12.033S0002-9378(08)02439-3.

  19. Enzinger C, Fazekas F, Ropele S, Schmidt R. Progression of cerebral white matter lesions - clinical and radiological considerations. J Neurol Sci. 2007;257:5–10. https://doi.org/10.1016/j.jns.2007.01.018.

    Article  PubMed  Google Scholar 

  20. Prins ND vDE, den Heijer T, et al. Cerebral white matter lesions and the risk of dementia. Arch Neurol. 2004;61:1531–4.

    Article  PubMed  Google Scholar 

  21. Wiegman MJ, Zeeman GG, Aukes AM, Bolte AC, Faas MM, Aarnoudse JG, et al. Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia. Obstet Gynecol. 2014;123(4):790–5. https://doi.org/10.1097/AOG.0000000000000162.

    Article  PubMed  Google Scholar 

  22. Raman MR, Tosakulwong N, Zuk SM, Senjem ML, White WM, Fields JA, et al. Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy. J Hypertens. 2017;35:2479–85. https://doi.org/10.1097/HJH.0000000000001492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. • Brewer J, Owens MY, Wallace K, Reeves AA, Morris R, Khan M, et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol. 2013;208(6):468 e1-6. https://doi.org/10.1016/j.ajog.2013.02.015 One of the largest studies characterizing cerebral edema in eclampsia.

    Article  PubMed  Google Scholar 

  24. Mielke MM, Milic NM, Weissgerber TL, White WM, Kantarci K, Mosley TH, et al. Impaired cognition and brain atrophy decades after hypertensive pregnancy disorders. Circ Cardiovasc Qual Outcomes. 2016;9:S70–S6. https://doi.org/10.1161/CIRCOUTCOMES.115.002461.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Siepmann T, Boardman H, Bilderbeck A, Griffanti L, Kenworthy Y, Zwager C, et al. Long-term cerebral white and gray matter changes after preeclampsia. Neurology. 2017;88:1256–64. https://doi.org/10.1212/WNL.0000000000003765.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Elharram M, Dayan N, Kaur A, Landry T, Pilote L. Long-term cognitive impairment after preeclampsia: a systematic review and meta-analysis. Obstet Gynecol. 2018;132(2):355–64. https://doi.org/10.1097/AOG.0000000000002686.

    Article  PubMed  Google Scholar 

  27. Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia. Hypertension. 2007;50:14–24. https://doi.org/10.1161/HYPERTENSIONAHA.106.079442.

    Article  CAS  PubMed  Google Scholar 

  28. Johnson AC, Nagle KJ, Tremble SM, Cipolla MJ. The contribution of normal pregnancy to eclampsia. PLoS One. 2015;10(7):e0133953. https://doi.org/10.1371/journal.pone.0133953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cipolla MJ, Kraig RP. Seizures in women with preeclampsia: mechanisms and management. Fetal Matern Med Rev. 2011;22(2):91–108. https://doi.org/10.1017/S0965539511000040.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Coughlin WF, McMurdo SK, Reeves T. MR imaging of postpartum cortical blindness. J Comput Assist Tomogr. 1989;13(4):572–6.

    Article  CAS  PubMed  Google Scholar 

  31. Trommer BL, Homer D, Mikhael MA. Cerebral vasospasm and eclampsia. Stroke. 1988;19(3):326–9.

    Article  CAS  PubMed  Google Scholar 

  32. Busija DW, Heistad DD. Factors involved in the physiological regulation of the cerebral circulation. Rev Physiol Biochem Pharmacol. 1984;101:161–211.

    Article  CAS  PubMed  Google Scholar 

  33. Donaldson JO. Eclamptic hypertensive encephalopathy. Semin Neurol. 1988;8:230–3. https://doi.org/10.1055/s-2008-1041383.

    Article  CAS  PubMed  Google Scholar 

  34. Zeeman GG, Cipolla MJ, Cunningham FG. Cerebrovascular (patho)physiology in preeclampsia/eclampsia. Chesley’s Hypertensive Disorders in Pregnancy. 2009:227–47. https://doi.org/10.1016/B978-0-12-374213-1.00013-6.

    Chapter  Google Scholar 

  35. Aagaard-Tillery KM, Belfort MA. Eclampsia: morbidity, mortality, and management. Clin Obstet Gynecol. 2005;48:12–23. https://doi.org/10.1097/01.grf.0000153882.58132.ba.

    Article  PubMed  Google Scholar 

  36. •• van Veen TR, Panerai RB, Haeri S, Griffioen AC, Zeeman GG, Belfort MA. Cerebral autoregulation in normal pregnancy and preeclampsia. Obstet Gynecol. 2013;122:1064–9. https://doi.org/10.1097/AOG.0b013e3182a93fb5 The first study to describe the dynamic cerebral autoregulation in preeclampsia.

    Article  PubMed  Google Scholar 

  37. Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J, et al. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23(2):233–46.

    Article  CAS  PubMed  Google Scholar 

  38. Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol. 1998;16(1):5–15. https://doi.org/10.1055/s-2007-1016248.

    Article  CAS  PubMed  Google Scholar 

  39. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int. 2004;45:545–52. https://doi.org/10.1016/j.neuint.2003.11.006.

    Article  CAS  PubMed  Google Scholar 

  40. Haseloff RF, Dithmer S, Winkler L, Wolburg H, Blasig IE. Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects. Semin Cell Dev Biol. 2015;38:16–25. https://doi.org/10.1016/j.semcdb.2014.11.004.

    Article  CAS  PubMed  Google Scholar 

  41. Keaney J, Campbell M. The dynamic blood-brain barrier. FEBS J. 2015;282:4067–79. https://doi.org/10.1111/febs.13412.

    Article  CAS  PubMed  Google Scholar 

  42. Daneman R, Prat A. The blood - brain barrier. Dev Med Child Neurol. 2015;3:311–4. https://doi.org/10.1111/j.1469-8749.1961.tb15323.x.

    Article  Google Scholar 

  43. Decleves X, Jacob A, Yousif S, Shawahna R, Potin S, Scherrmann J-M. Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier. Curr Drug Metab. 2011;12:732–41. https://doi.org/10.2174/138920011798357024.

    Article  CAS  PubMed  Google Scholar 

  44. Liao MZ, Gao C, Shireman LM, Phillips B, Risler LJ, Neradugomma NK, et al. P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine. Pharmacol Res. 2017;119:61–71. https://doi.org/10.1016/j.phrs.2017.01.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. •• Warrington JP, Fan F, Murphy SR, Roman RJ, Drummond HA, Granger JP, et al. Placental ischemia in pregnant rats impairs cerebral blood flow autoregulation and increases blood-brain barrier permeability. Physiol Rep. 2014;2(8). https://doi.org/10.14814/phy2.12134 This manuscript shown evidences of placental-derived moleculas that impairs brain circulation.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Clayton AM, Shao Q, Paauw ND, Giambrone AB, Granger JP, Warrington JP. Postpartum increases in cerebral edema and inflammation in response to placental ischemia during pregnancy. Brain Behav Immun. 2018;70:376–89. https://doi.org/10.1016/j.bbi.2018.03.028.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Black KD, Horowitz JA. Inflammatory markers and preeclampsia: a systematic review. Nurs Res. 2018;67:242–51. https://doi.org/10.1097/NNR.0000000000000285.

    Article  PubMed  Google Scholar 

  48. LaMarca BD, Ryan MJ, Gilbert JS, Murphy SR, Granger JP. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep. 2007;9:480–5. https://doi.org/10.1007/s11906-007-0088-1.

    Article  CAS  PubMed  Google Scholar 

  49. Warrington JP, Drummond HA, Granger JP, Ryan MJ. Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNFα. Am J Physiol Regul Integr Comp Physiol. 2015:ajpregu.00372.2015. https://doi.org/10.1152/ajpregu.00372.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. •• Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ. Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension. 2010;56(5):1003–8. https://doi.org/10.1161/HYPERTENSIONAHA.110.158931 This manuscript shown evidences of involvment of VEGFR2 in the blood brain barrier alterations induced by plasma from preeclampsia.

    Article  CAS  PubMed  Google Scholar 

  51. Li X, Han X, Bao J, Liu Y, Ye A, Thakur M, et al. Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the alpha7 nicotinic acetylcholine receptor. Brain Res. 1642;2016:487–96. https://doi.org/10.1016/j.brainres.2016.04.043.

    Article  CAS  Google Scholar 

  52. Huang Q, Liu L, Hu B, Di X, Brennecke SP, Liu H. Decreased seizure threshold in an eclampsia-like model induced in pregnant rats with lipopolysaccharide and pentylenetetrazol treatments. PLoS One. 2014;9(2):e89333. https://doi.org/10.1371/journal.pone.0089333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Eigenmann DE, Xue G, Kim KS, Moses AV, Hamburger M, Oufir M. Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood–brain barrier model for drug permeability studies. Fluids Barriers CNS. 2013:1–17.

  54. Rahman NA, ANaHM R, Meyding-Lamade U, Craemer EM, Diah S, Tuah AA, et al. Immortalized endothelial cell lines for in vitro blood–brain barrier models: a systematic review. Brain Res. 1642;2016:532–45. https://doi.org/10.1016/j.brainres.2016.04.024.

    Article  CAS  Google Scholar 

  55. Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem. 2008;107(6):1518–28. https://doi.org/10.1111/j.1471-4159.2008.05720.x.

    Article  CAS  PubMed  Google Scholar 

  56. Dutheil F, Jacob A, Dauchy S, Beaune P, Scherrmann JM, Decleves X, et al. ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol. 2010;6(10):1161–74. https://doi.org/10.1517/17425255.2010.510832.

    Article  CAS  PubMed  Google Scholar 

  57. Ohtsuki S, Ikeda C, Uchida Y, Sakamoto Y, Miller F, Glacial F, et al. Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model. Mol Pharm. 2013;10(1):289–96. https://doi.org/10.1021/mp3004308.

    Article  CAS  PubMed  Google Scholar 

  58. Bosworth AM, Faley SL, Bellan LM, Lippmann ES. Modeling neurovascular disorders and therapeutic outcomes with human-induced pluripotent stem cells. Front Bioeng Biotechnol. 2017;5:87. https://doi.org/10.3389/fbioe.2017.00087.

    Article  PubMed  Google Scholar 

  59. • Nielsen SSE, Siupka P, Georgian A, Preston JE, Tóth AE, Yusof SR, et al. Improved method for the establishment of an in vitro blood-brain barrier model based on porcine brain endothelial cells. J Vis Exp. 2017. https://doi.org/10.3791/56277 Key paper for understanding characteristics of in vitro model of brain blood barrier based in porcine endothelial cells.

  60. Smith M, Omidi Y, Gumbleton M. Primary porcine brain microvascular endothelial cells: biochemical and functional characterisation as a model for drug transport and targeting. J Drug Target. 2007;15:253–68. https://doi.org/10.1080/10611860701288539.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang Y, Li CSW, Ye Y, Johnson K, Poe J, Johnson S, et al. Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability. Drug Metab Dispos. 2006;34:1–15. https://doi.org/10.1124/dmd.105.006437.which.

    Article  Google Scholar 

  62. Culot M, Lundquist S, Vanuxeem D, Nion S, Landry C, Delplace Y, et al. An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicol in Vitro. 2008;22(3):799–811. https://doi.org/10.1016/j.tiv.2007.12.016.

    Article  CAS  PubMed  Google Scholar 

  63. Helms HC, Hersom M, Kuhlmann LB, Badolo L, Nielsen CU, Brodin B. An electrically tight in vitro blood-brain barrier model displays net brain-to-blood efflux of substrates for the ABC transporters, P-gp, Bcrp and Mrp-1. AAPS J. 2014;16(5):1046–55. https://doi.org/10.1208/s12248-014-9628-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Thomsen LB, Burkhart A, Moos T. A triple culture model of the blood-brain barrier using porcine brain endothelial cells, Astrocytes and Pericytes. PLOS ONE. 2015;10:e0134765. https://doi.org/10.1371/journal.pone.0134765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Helms HC, Waagepetersen HS, Nielsen CU, Brodin B. Paracellular tightness and claudin-5 expression is increased in the BCEC/astrocyte blood-brain barrier model by increasing media buffer capacity during growth. AAPS J. 2010;12(4):759–70. https://doi.org/10.1208/s12248-010-9237-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Torres-Vergara P, Penny J. Pro-inflammatory and anti-inflammatory compounds exert similar effects on P-glycoprotein in blood-brain barrier endothelial cells. J Pharm Pharmacol. 2018;70(6):713–22. https://doi.org/10.1111/jphp.12893.

    Article  CAS  PubMed  Google Scholar 

  67. Salmeri M, Motta C, Anfuso CD, Amodeo A, Scalia M, Toscano MA, et al. VEGF receptor-1 involvement in pericyte loss induced by Escherichia coli in an in vitro model of blood brain barrier. Cell Microbiol. 2013;15(8):1367–84. https://doi.org/10.1111/cmi.12121.

    Article  CAS  PubMed  Google Scholar 

  68. Perriere N, Yousif S, Cazaubon S, Chaverot N, Bourasset F, Cisternino S, et al. A functional in vitro model of rat blood-brain barrier for molecular analysis of efflux transporters. Brain Res. 2007;1150:1–13. https://doi.org/10.1016/j.brainres.2007.02.091.

    Article  CAS  PubMed  Google Scholar 

  69. Forster C, Silwedel C, Golenhofen N, Burek M, Kietz S, Mankertz J, et al. Occludin as direct target for glucocorticoid-induced improvement of blood-brain barrier properties in a murine in vitro system. J Physiol. 2005;565(Pt 2):475–86. https://doi.org/10.1113/jphysiol.2005.084038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Alms D, Fedrowitz M, Romermann K, Noack A, Loscher W. Marked differences in the effect of antiepileptic and cytostatic drugs on the functionality of p-glycoprotein in human and rat brain capillary endothelial cell lines. Pharm Res. 2014;31(6):1588–604. https://doi.org/10.1007/s11095-013-1264-4.

    Article  CAS  PubMed  Google Scholar 

  71. Neuhaus W, Stessl M, Strizsik E, Bennani-Baiti B, Wirth M, Toegel S, et al. Blood-brain barrier cell line PBMEC/C1-2 possesses functionally active P-glycoprotein. Neurosci Lett. 2010;469(2):224–8. https://doi.org/10.1016/j.neulet.2009.11.079.

    Article  CAS  PubMed  Google Scholar 

  72. Neuhaus W, Plattner VE, Wirth M, Germann B, Lachmann B, Gabor F, et al. Validation of in vitro cell culture models of the blood-brain barrier: tightness characterization of two promising cell lines. J Pharm Sci. 2008;97(12):5158–75. https://doi.org/10.1002/jps.21371.

    Article  CAS  PubMed  Google Scholar 

  73. Belfort MA, Saade GR, Yared M, Grunewald C, Herd JA, Varner MA, et al. Change in estimated cerebral perfusion pressure after treatment with nimodipine or magnesium sulfate in patients with preeclampsia. Am J Obstet Gynecol. 1999;181:402–7. https://doi.org/10.1016/S0002-9378(99)70569-7.

    Article  CAS  PubMed  Google Scholar 

  74. Belfort MA, Tooke-Miller C, Allen JC, Dizon-Townson D, Varner MA. Labetalol decreases cerebral perfusion pressure without negatively affecting cerebral blood flow in hypertensive gravidas. Hypertens Pregnancy. 2002;21:185–97. https://doi.org/10.1081/PRG-120015845.

    Article  CAS  PubMed  Google Scholar 

  75. Belfort MA, Varner MW, Dizon-Townson DS, Grunewald C, Nisell H. Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis. Am J Obstet Gynecol. 2002;187:626–34. https://doi.org/10.1067/mob.2002.125241.

    Article  PubMed  Google Scholar 

  76. Van Veen TR, Panerai RB, Haeri S, Singh J, Adusumalli JA, Zeeman GG, et al. Cerebral autoregulation in different hypertensive disorders of pregnancy. Am J Obstet Gynecol. 2015;212:513.e1-.e7. https://doi.org/10.1016/j.ajog.2014.11.003.

    Article  CAS  Google Scholar 

  77. Valdueza JM, Balzer JO, Villringer A, Vogl TJ, Kutter R, Einhaupl KM. Changes in blood flow velocity and diameter of the middle cerebral artery during hyperventilation: assessment with MR and transcranial Doppler sonography. AJNR Am J Neuroradiol. 1997;18(10):1929–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Williams DS, Detre JA, Leigh JS, Koretsky AP. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A. 1992;89(1):212–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Le Bihan D. Intravoxel incoherent motion imaging using steady-state free precession. Magn Reson Med. 1988;7(3):346–51.

    Article  PubMed  Google Scholar 

  80. Nelander M, Hannsberger D, Sundstrom-Poromaa I, Bergman L, Weis J, Akerud H, et al. Assessment of cerebral perfusion and edema in preeclampsia with intravoxel incoherent motion MRI. Acta Obstet Gynecol Scand. 2018;97(10):1212–8. https://doi.org/10.1111/aogs.13383.

    Article  CAS  PubMed  Google Scholar 

  81. Jansen JF, Backes WH, Nicolay K, Kooi ME. 1H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240(2):318–32. https://doi.org/10.1148/radiol.2402050314.

    Article  PubMed  Google Scholar 

  82. Oberhaensli RD, Galloway GJ, Hilton-Jones D, Bore PJ, Styles P, Rajagopalan B, et al. The study of human organs by phosphorus-31 topical magnetic resonance spectroscopy. Br J Radiol. 1987;60(712):367–73. https://doi.org/10.1259/0007-1285-60-712-367.

    Article  CAS  PubMed  Google Scholar 

  83. Nelander M, Weis J, Bergman L, Larsson A, Wikstrom AK, Wikstrom J. Cerebral magnesium levels in preeclampsia; a phosphorus magnetic resonance spectroscopy study. Am J Hypertens. 2017;30(7):667–72. https://doi.org/10.1093/ajh/hpx022.

    Article  CAS  PubMed  Google Scholar 

  84. Nelander M, Wikstrom AK, Weis J, Bergman L, Larsson A, Sundstrom-Poromaa I, et al. Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study. Am J Hypertens. 2018;31(7):847–53. https://doi.org/10.1093/ajh/hpy019.

    Article  PubMed  Google Scholar 

  85. Rutherford JM, Moody A, Crawshaw S, Rubin PC. Magnetic resonance spectroscopy in pre-eclampsia: evidence of cerebral ischaemia. BJOG. 2003;110(4):416–23.

    Article  PubMed  Google Scholar 

  86. Sengar AR, Gupta RK, Dhanuka AK, Roy R, Das K. MR imaging, MR angiography, and MR spectroscopy of the brain in eclampsia. AJNR Am J Neuroradiol. 1997;18(8):1485–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D. Peripheral markers of blood-brain barrier damage. Clin Chim Acta. 2004;342(1–2):1–12. https://doi.org/10.1016/j.cccn.2003.12.008.

    Article  CAS  PubMed  Google Scholar 

  88. Kanner AA, Marchi N, Fazio V, Mayberg MR, Koltz MT, Siomin V, et al. Serum S100β: a noninvasive marker of blood-brain barrier function and brain lesions. Cancer. 2003;97:2806–13. https://doi.org/10.1002/cncr.11409.

    Article  CAS  PubMed  Google Scholar 

  89. Schmidt A, Tort A, Amaral O, Schmidt A, Walz R, Vettorazzi-Stuckzynski J, et al. Serum S100B in pregnancy-related hypertensive dis- orders: a case–control study. Clin Chem. 2004;50:435–8. https://doi.org/10.1373/clinchem.2003.027391.

    Article  CAS  PubMed  Google Scholar 

  90. Vettorazzi J, Torres FV, de Avila TT, Martins-Costa SH, Souza DO, Portela LV, et al. Serum S100B in pregnancy complicated by preeclampsia: a case-control study. Pregnancy Hypertens. 2012;2(2):101–5. https://doi.org/10.1016/j.preghy.2011.11.004.

    Article  CAS  PubMed  Google Scholar 

  91. Bergman L, Akhter T, Wikstrom AK, Wikstrom J, Naessen T, Akerud H. Plasma levels of S100B in preeclampsia and association with possible central nervous system effects. Am J Hypertens. 2014;27(8):1105–11. https://doi.org/10.1093/ajh/hpu020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Artunc-Ulkumen B, Guvenc Y, Goker A, Gozukara C. Maternal serum S100-B, PAPP-A and IL-6 levels in severe preeclampsia. Arch Gynecol Obstet. 2015;292:97–102. https://doi.org/10.1007/s00404-014-3610-0.

    Article  CAS  PubMed  Google Scholar 

  93. Chou SHY, Robertson CS. Monitoring biomarkers of cellular injury and death in acute brain injury. Neurocrit Care. 2014;21:187–214. https://doi.org/10.1007/s12028-014-0039-z.

    Article  CAS  Google Scholar 

  94. Bergman L, Akerud H. Plasma levels of the cerebral biomarker, neuron-specific enolase, are elevated during pregnancy in women developing preeclampsia. Reprod Sci. 2016;23(3):395–400. https://doi.org/10.1177/1933719115604732.

    Article  CAS  PubMed  Google Scholar 

  95. Bergman L, Akerud H, Wikström AK, Larsson M, Naessen T, Akhter T. Cerebral biomarkers in women with preeclampsia are still elevated 1 year postpartum. Am J Hypertens. 2016;29:1374–9. https://doi.org/10.1093/ajh/hpw097.

    Article  PubMed  Google Scholar 

  96. Bogoslovsky T, Gill J, Jeromin A, Davis C, Diaz-Arrastia R. Fluid biomarkers of traumatic brain injury and intended context of use. Diagnostics. 2016;6:1–22. https://doi.org/10.3390/diagnostics6040037.

    Article  CAS  Google Scholar 

  97. Randall J, Mörtberg E, Provuncher GK, Fournier DR, Duffy DC, Rubertsson S, et al. Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation. 2013;84:351–6. https://doi.org/10.1016/j.resuscitation.2012.07.027.

    Article  CAS  PubMed  Google Scholar 

  98. Evers KS, Atkinson A, Barro C, Fisch U, Pfister M, Huhn EA, et al. Neurofilament as neuronal injury blood marker in preeclampsia. Hypertension. 2018;71(6):1178–84. https://doi.org/10.1161/HYPERTENSIONAHA.117.10314.

    Article  CAS  PubMed  Google Scholar 

  99. • Bergman L, Zetterberg H, Kaihola H, Hagberg H, Blennow K, Akerud 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://doi.org/10.1371/journal.pone.0196025 Cerebral biomarkers are increased in preeclampsia, reinforcing cerebral involvement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Emily Gatu for her editorial assistance and the researchers belonging to GRIVAS health for their valuable input.

Funding Disclose

This manuscript was supported by Conicyt grant REDI170373. CE is supported by DIUBB 184309 4/R.

Authors’ Roles

CE and LB: designed and wrote the manuscript. All co-authors included their respective sections according to expertise. JMR, AKW, and JP contributed to the writing of the manuscript and provided a critical revision of its contents. All co-authors approved the final version of this manuscript.

Author information

Authors and Affiliations

  1. Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

    Lina Bergman, Maria Nelander, Mary Tolcher & Anna-Karin Wikström

  2. Center for Clinical Research Dalarna, Falun, Uppsala, Sweden

    Lina Bergman

  3. Pharmacy Department, Faculty of Pharmacy, Universidad de Concepción, Concepción, Chile

    Pablo Torres-Vergara

  4. Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillán, Chile

    Pablo Torres-Vergara, Jose Leon & Carlos Escudero

  5. Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Jeffrey Penny

  6. Department of Radiology, Uppsala University, Uppsala, Sweden

    Johan Wikström

  7. Vascular Physiology Laboratory, Group of Investigation in Tumor Angiogenesis, (LFV-GIANT), Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán, Chile

    Jose Leon & Carlos Escudero

  8. Magee Womens Research Institute, Dept of Obstetrics Gynecology and Reproductive Sciences, Epidemiology and Clinical and Translational Research, University of Pittsburgh, Pittsburgh, PA, USA

    James M. Roberts

Authors
  1. Lina Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pablo Torres-Vergara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey Penny
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johan Wikström
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Nelander
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose Leon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary Tolcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James M. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna-Karin Wikström
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carlos Escudero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lina Bergman or Carlos Escudero.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Preeclampsia

Electronic Supplementary Material

ESM 1

(DOCX 28 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bergman, L., Torres-Vergara, P., Penny, J. et al. Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort. Curr Hypertens Rep 21, 72 (2019). https://doi.org/10.1007/s11906-019-0977-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-019-0977-0

Keywords

Search

Navigation