A State of the Art lecture titled "Impact of Adverse Pregnancy Outcomes on Brain Vascular Health and Cognition" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Adverse pregnancy outcomes, encompassing conditions such as gestational hypertension, eclampsia, preeclampsia, preterm birth, fetal growth restriction, stillbirth, and gestational diabetes, may form part of an underrecognized pathway from early adulthood reproductive health factors to later-life vascular cognitive impairment and dementia in women. Adverse pregnancy outcomes are caused by dysregulated vascular and metabolic adaptations during pregnancy, and these pathophysiological changes may persist after delivery. Adverse pregnancy outcomes may contribute to the increased risk of cognitive impairment and dementia directly through vascular and metabolic dysregulation and subsequent development of cardiovascular diseases, or other biological processes may be at play, such as shared maternal risk factors. Extensive epidemiologic evidence has shown that many cognitive impairment and dementia cases may be prevented or delayed by strategies targeting midlife cardiovascular health. Despite the recognized importance of adverse pregnancy outcomes for cardiovascular health, the literature on associated long-term health outcomes is limited. In this State of the Art review article, we summarize the current epidemiologic evidence on the relationship between adverse pregnancy outcomes and cognitive impairment and dementia and provide an overview of the potential pathophysiological mechanisms. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.

Department of Epidemiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Neurology Columbia University New York New York USA

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O’Brien J.T., Thomas A. Vascular dementia. Lancet. 2015;386:1698–1706. PubMed

Graff-Radford J. Vascular cognitive impairment. Continuum (Minneap Minn) 2019;25:147–164. PubMed PMC

Iadecola C., Duering M., Hachinski V., Joutel A., Pendlebury S.T., Schneider J.A., et al. Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;73:3326–3344. PubMed PMC

Parikh N.I., Gonzalez J.M., Anderson C.A.M., Judd S.E., Rexrode K.M., Hlatky M.A., et al. Adverse pregnancy outcomes and cardiovascular disease risk: unique opportunities for cardiovascular disease prevention in women: a scientific statement from the American Heart Association. Circulation. 2021;143:e902–e916. PubMed

Khedagi A.M., Bello N.A. Hypertensive disorders of pregnancy. Cardiol Clin. 2021;39:77–90. PubMed PMC

Hutcheon J.A., Lisonkova S., Joseph K.S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25:391–403. PubMed

WHO recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Modifications recommended by FIGO as amended October 14, 1976. Acta Obstet Gynecol Scand. 1977;56:247–253. PubMed

Fetal growth restriction: ACOG practice bulletin, number 227. Obstet Gynecol. 2021;137:e16–e28. PubMed

Tavares Da Silva F., Gonik B., McMillan M., Keech C., Dellicour S., Bhange S., et al. Stillbirth: case definition and guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2016;34:6057–6068. PubMed PMC

Plows J.F., Stanley J.L., Baker P.N., Reynolds C.M., Vickers M.H. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci. 2018;19:3342. doi: 10.3390/ijms19113342. PubMed DOI PMC

Freaney P.M., Harrington K., Molsberry R., Perak A.M., Wang M.C., Grobman W., et al. Temporal trends in adverse pregnancy outcomes in birthing individuals aged 15 to 44 years in the United States, 2007 to 2019. J Am Heart Assoc. 2022;11 doi: 10.1161/JAHA.121.025050. PubMed DOI PMC

Kennedy-Moulton K., Miller S., Persson P., Rossin-Slater M., Wherry L., Aldana G. National Bureau of Economic Research; Cambridge, MA: 2022. Maternal and infant health inequality: new evidence from linked administrative data.

Wu P., Park K., Gulati M. The fourth trimester: pregnancy as a predictor of cardiovascular disease. Eur Cardiol. 2021;16:e31. doi: 10.15420/ecr.2021.18. PubMed DOI PMC

Langley-Evans S.C., Pearce J., Ellis S. Overweight, obesity and excessive weight gain in pregnancy as risk factors for adverse pregnancy outcomes: a narrative review. J Hum Nutr Diet. 2022;35:250–264. PubMed PMC

Gascoigne E.L., Webster C.M., Honart A.W., Wang P., Smith-Ryan A., Manuck T.A. Physical activity and pregnancy outcomes: an expert review. Am J Obstet Gynecol MFM. 2023;5 doi: 10.1016/j.ajogmf.2022.100758. PubMed DOI PMC

Sweeney M.D., Kisler K., Montagne A., Toga A.W., Zlokovic B.V. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018;21:1318–1331. PubMed PMC

Attems J., Jellinger K.A. The overlap between vascular disease and Alzheimer’s disease--lessons from pathology. BMC Med. 2014;12:206. doi: 10.1186/s12916-014-0206-2. PubMed DOI PMC

Wang K., Guo K., Ji Z., Liu Y., Chen F., Wu S., et al. Association of preeclampsia with incident dementia and Alzheimer’s disease among women in the Framingham Offspring Study. J Prev Alzheimers Dis. 2022;9:725–730. PubMed

Basit S., Wohlfahrt J., Boyd H.A. Pre-eclampsia and risk of dementia later in life: nationwide cohort study. BMJ. 2018;363:k4109. doi: 10.1136/bmj.k4109. PubMed DOI PMC

Wallis A.B., Saftlas A.F., Hsia J., Atrash H.K. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens. 2008;21:521–526. PubMed

Gestational hypertension and preeclampsia: ACOG practice bulletin, number 222. Obstet Gynecol. 2020;135:e237–e260. PubMed

Zhou T., Du S., Sun D., Li X., Heianza Y., Hu G., et al. Prevalence and trends in gestational diabetes mellitus among women in the United States, 2006-2017: a population-based study. Front Endocrinol (Lausanne) 2022;13 doi: 10.3389/fendo.2022.868094. PubMed DOI PMC

Lavery J.A., Friedman A.M., Keyes K.M., Wright J.D., Ananth C.V. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG. 2017;124:804–813. PubMed PMC

Suhag A., Berghella V. Intrauterine growth restriction (iugr): etiology and diagnosis. Curr Obstet Gynecol Rep. 2013;2:102–111.

Osterman M.J.K., Hamilton B.E., Martin J.A., Driscoll A.K., Valenzuela C.P. Births: final data for 2021. Natl Vital Stat Rep. 2023;72:1–53. PubMed

Gregory E.C., Valenzuela C.P., Hoyert D.L. Fetal mortality: United States, 2020. Natl Vital Stat Rep. 2022;71:1–20. PubMed

Grandi S.M., Filion K.B., Yoon S., Ayele H.T., Doyle C.M., Hutcheon J.A., et al. Cardiovascular disease-related morbidity and mortality in women with a history of pregnancy complications. Circulation. 2019;139:1069–1079. PubMed

Canoy D., Cairns B.J., Balkwill A., Wright F.L., Khalil A., Beral V., et al. Hypertension in pregnancy and risk of coronary heart disease and stroke: a prospective study in a large UK cohort. Int J Cardiol. 2016;222:1012–1018. PubMed PMC

Theilen L.H., Meeks H., Fraser A., Esplin M.S., Smith K.R., Varner M.W. Long-term mortality risk and life expectancy following recurrent hypertensive disease of pregnancy. Am J Obstet Gynecol. 2018;219:107.e1. -6. PubMed PMC

Tanz L.J., Stuart J.J., Williams P.L., Missmer S.A., Rimm E.B., James-Todd T.M., et al. Preterm delivery and maternal cardiovascular disease risk factors: the Nurses’ Health Study II. J Womens Health (Larchmt) 2019;28:677–685. PubMed PMC

Wu P., Gulati M., Kwok C.S., Wong C.W., Narain A., O’Brien S., et al. Preterm delivery and future risk of maternal cardiovascular disease: a systematic review and meta-analysis. J Am Heart Assoc. 2018;7 doi: 10.1161/JAHA.117.007809. PubMed DOI PMC

Crump C., Sundquist J., Howell E.A., McLaughlin M.A., Stroustrup A., Sundquist K. Pre-term delivery and risk of ischemic heart disease in women. J Am Coll Cardiol. 2020;76:57–67. PubMed PMC

Melchiorre K., Sutherland G.R., Liberati M., Thilaganathan B. Maternal cardiovascular impairment in pregnancies complicated by severe fetal growth restriction. Hypertension. 2012;60:437–443. PubMed

Miller E.C., Kauko A., Tom S.E., Laivuori H., Niiranen T., Bello N.A., et al. Risk of midlife stroke after adverse pregnancy outcomes: the FinnGen Study. Stroke. 2023;54:1798–1805. PubMed PMC

Hung S.K., Lee M.S., Lin H.Y., Chen L.C., Chuang C.J., Chew C.H., et al. Impact of hypertensive disorders of pregnancy on the risk of stroke stratified by subtypes and follow-up time. Stroke. 2022;53:338–344. PubMed PMC

Crump C., Sundquist J., Sundquist K. Preterm delivery and long-term risk of stroke in women: a national cohort and cosibling study. Circulation. 2021;143:2032–2044. PubMed PMC

Liang C., Chung H.F., Dobson A.J., Hayashi K., van der Schouw Y.T., Kuh D., et al. Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women. BMJ. 2022;377 doi: 10.1136/bmj-2022-070603. PubMed DOI PMC

Liang C., Chung H.-F., Dobson A.J., Mishra G.D. Infertility, miscarriage, stillbirth, and the risk of stroke among women: a systematic review and meta-analysis. Stroke. 2022;53:328–337. PubMed

Schliep K.C., McLean H., Yan B., Qeadan F., Theilen L.H., de Havenon A., et al. Association between hypertensive disorders of pregnancy and dementia: a systematic review and meta-analysis. Hypertension. 2023;80:257–267. PubMed PMC

Samara A.A., Liampas I., Dadouli K., Siokas V., Zintzaras E., Stefanidis I., et al. Preeclampsia, gestational hypertension and incident dementia: a systematic review and meta-analysis of published evidence. Pregnancy Hypertens. 2022;30:192–197. PubMed

Basit S., Wohlfahrt J., Boyd H.A. Pregnancy loss and risk of later dementia: a nationwide cohort study, Denmark, 1977-2017. Alzheimers Dement (N Y) 2019;5:146–153. PubMed PMC

Adank M.C., Hussainali R.F., Oosterveer L.C., Ikram M.A., Steegers E.A.P., Miller E.C., et al. Hypertensive disorders of pregnancy and cognitive impairment: a prospective cohort study. Neurology. 2021;96:e709–e718. PubMed PMC

Andolf E., Bladh M., Möller L., Sydsjö G. Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort study. BJOG. 2020;127:1090–1099. PubMed

Andolf E.G., Sydsjö G.C., Bladh M.K., Berg G., Sharma S. Hypertensive disorders in pregnancy and later dementia: a Swedish National Register Study. Acta Obstet Gynecol Scand. 2017;96:464–471. PubMed

Nelander M., Cnattingius S., Åkerud H., Wikström J., Pedersen N.L., Wikström A.K. Pregnancy hypertensive disease and risk of dementia and cardiovascular disease in women aged 65 years or older: a cohort study. BMJ Open. 2016;6 doi: 10.1136/bmjopen-2015-009880. PubMed DOI PMC

Fields J.A., Garovic V.D., Mielke M.M., Kantarci K., Jayachandran M., White W.M., et al. Preeclampsia and cognitive impairment later in life. Am J Obstet Gynecol. 2017;217:74.e1. 11. PubMed PMC

Sheng J., Liu J., Chan K.H.K. Evaluating the causal effects of gestational diabetes mellitus, heart disease, and high body mass index on maternal Alzheimer's disease and dementia: multivariable Mendelian randomization. Front Genet. 2022;13 doi: 10.3389/fgene.2022.833734. PubMed DOI PMC

Livingston G., Huntley J., Sommerlad A., Ames D., Ballard C., Banerjee S., et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–446. PubMed PMC

Arvanitakis Z., Shah R.C., Bennett D.A. Diagnosis and management of dementia: review. JAMA. 2019;322:1589–1599. PubMed PMC

Amjad H., Roth D.L., Sheehan O.C., Lyketsos C.G., Wolff J.L., Samus Q.M. Underdiagnosis of dementia: an observational study of patterns in diagnosis and awareness in US older adults. J Gen Intern Med. 2018;33:1131–1138. PubMed PMC

Brosens I., Pijnenborg R., Vercruysse L., Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204:193–201. PubMed PMC

Albonici L., Benvenuto M., Focaccetti C., Cifaldi L., Miele M.T., Limana F., et al. PlGF Immunological Impact during pregnancy. Int J Mol Sci. 2020;21:8714. doi: 10.3390/ijms21228714. PubMed DOI PMC

Chau K., Hennessy A., Makris A. Placental growth factor and pre-eclampsia. J Hum Hypertens. 2017;31:782–786. PubMed PMC

Rana S., Burke S.D., Karumanchi S.A. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol. 2022;226:S1019–S1034. PubMed PMC

Agrawal S., Parks W.T., Zeng H.D., Ravichandran A., Ashwal E., Windrim R.C., et al. Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction. Am J Obstet Gynecol. 2022;227:618.e1. 16. PubMed

Kluivers A.C.M., Biesbroek A., Visser W., Saleh L., Russcher H., Danser A.H.J., et al. Angiogenic imbalance in pre-eclampsia and fetal growth restriction: enhanced soluble fms-like tyrosine kinase-1 binding or diminished production of placental growth factor? Ultrasound Obstet Gynecol. 2023;61:466–473. PubMed

Garcia-Manau P., Mendoza M., Bonacina E., Garrido-Gimenez C., Fernandez-Oliva A., Zanini J., et al. Soluble fms-like tyrosine kinase to placental growth factor ratio in different stages of early-onset fetal growth restriction and small for gestational age. Acta Obstet Gynecol Scand. 2021;100:119–128. PubMed

Goulopoulou S. Maternal vascular physiology in preeclampsia. Hypertension. 2017;70:1066–1073. PubMed

Winder Z., Lee T., Fardo D.W., Cheng Q., Goldstein L., Nelson P.T., et al. Evaluating vascular cognitive impairment and dementia due to small-vessel disease using plasma levels of PLGF and VEGF-A. Alzheimer's Dement. 2020;16 doi: 10.1002/alz.044576. DOI

Hinman J.D., Elahi F., Chong D., Radabaugh H., Ferguson A., Maillard P., et al. Placental growth factor as a sensitive biomarker for vascular cognitive impairment. Alzheimers Dement. 2023;19:3519–3527. PubMed PMC

Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer’s disease. J Neuroinflammation. 2011;8:26. doi: 10.1186/1742-2094-8-26. PubMed DOI PMC

Valero P., Cornejo M., Fuentes G., Wehinger S., Toledo F., van der Beek E.M., et al. Platelets and endothelial dysfunction in gestational diabetes mellitus. Acta Physiol (Oxf) 2023;237 doi: 10.1111/apha.13940. PubMed DOI

Pantham P., Aye I.L., Powell T.L. Inflammation in maternal obesity and gestational diabetes mellitus. Placenta. 2015;36:709–715. PubMed PMC

Preda A., Iliescu D.G., Comănescu A., Zorilă G.L., Vladu I.M., Forțofoiu M.C., et al. Gestational diabetes and preterm birth: what do we know? Our experience and mini-review of the literature. J Clin Med. 2023;12:4572. doi: 10.3390/jcm12144572. PubMed DOI PMC

Yang Y., Wu N. Gestational diabetes mellitus and preeclampsia: correlation and influencing factors. Front Cardiovasc Med. 2022;9 doi: 10.3389/fcvm.2022.831297. PubMed DOI PMC

Haas D.M., Parker C.B., Marsh D.J., Grobman W.A., Ehrenthal D.B., Greenland P., et al. Association of adverse pregnancy outcomes with hypertension 2 to 7 years postpartum. J Am Heart Assoc. 2019;8 doi: 10.1161/JAHA.119.013092. PubMed DOI PMC

Pabón M.A., Misra A., Honigberg M.C. Adverse pregnancy outcomes and future risk of heart failure. Curr Opin Cardiol. 2023;38:215–222. PubMed PMC

Park J.H., Hong J.H., Lee S.W., Ji H.D., Jung J.A., Yoon K.W., et al. The effect of chronic cerebral hypoperfusion on the pathology of Alzheimer’s disease: a positron emission tomography study in rats. Sci Rep. 2019;9 doi: 10.1038/s41598-019-50681-4. PubMed DOI PMC

Qiu L., Ng G., Tan E.K., Liao P., Kandiah N., Zeng L. Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice. Sci Rep. 2016;6 doi: 10.1038/srep23964. PubMed DOI PMC

van Dijk M., van Bezu J., Poutsma A., Veerhuis R., Rozemuller A.J., Scheper W., et al. The pre-eclampsia gene STOX1 controls a conserved pathway in placenta and brain upregulated in late-onset Alzheimer’s disease. J Alzheimers Dis. 2010;19:673–679. PubMed

Winder Z., Sudduth T.L., Anderson S., Patel E., Neltner J., Martin B.J., et al. Examining the association between blood-based biomarkers and human post mortem neuropathology in the University of Kentucky Alzheimer’s Disease Research Center autopsy cohort. Alzheimers Dement. 2023;19:67–78. PubMed PMC

Horn C., Bravo M., Orfeo T., Roberts L., McLean K., Bernstein I. The effect of a history of preeclampsia on hemostatic balance in the non-pregnant state [abstract] Res Pract Thromb Haemost. 2023;7(Suppl 2)

López A.R., Youssef L., Molina P., Guillen E., Martinez-Sanchez J., Moreno-Castaño A., et al. Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in pregnant women with preeclampsia [abstract] Res Pract Thromb Haemost. 2023;7(Suppl 2)

Kenny M., Shukla R., Weiss L., Fouhy E., Murphy C., Áinle F.N., et al. Deep learning extracts embedded signatures associated with pregnancy and preeclampsia from circulating vesicle profiles [abstract] Res Pract Thromb Haemost. 2023;7(Suppl 2)

Paulo M.S., Abdo N.M., Bettencourt-Silva R., Al-Rifai R.H. Gestational diabetes mellitus in Europe: a systematic review and meta-analysis of prevalence studies. Front Endocrinol (Lausanne) 2021;12 doi: 10.3389/fendo.2021.691033. PubMed DOI PMC

Zeitlin J., Mortensen L., Cuttini M., Lack N., Nijhuis J., Haidinger G., et al. Declines in stillbirth and neonatal mortality rates in Europe between 2004 and 2010: results from the Euro-Peristat project. J Epidemiol Community Health. 2016;70:609–615. PubMed PMC

Nebel R.A., Aggarwal N.T., Barnes L.L., Gallagher A., Goldstein J.M., Kantarci K., et al. Understanding the impact of sex and gender in Alzheimer’s disease: a call to action. Alzheimers Dement. 2018;14:1171–1183. PubMed PMC

Associations between adverse pregnancy outcomes and cognitive impairment and dementia: a systematic review and meta-analysis