BACKGROUND: Individuals with adverse pregnancy outcomes have an increased risk of cerebrovascular disease, but the association between adverse pregnancy outcomes and cognitive impairment and dementia is less well established. We aimed to synthesise, combine, and assess the growing body of data examining the associations between adverse pregnancy outcomes and mild cognitive impairment and dementia in parous women. METHODS: In this systematic review and meta-analysis, we searched PubMed (MEDLINE), Web of Science, and Embase from database inception up to July 18, 2024, with no language restrictions, for observational studies or clinical trials that reported mild cognitive impairment or dementia as outcomes and included female individuals or women who had an adverse pregnancy outcome, including hypertensive disorders of pregnancy, gestational diabetes, stillbirth, fetal growth restriction, preterm birth, or placental abruption. We excluded studies of men, nulliparous women, women with pre-pregnancy conditions associated with impaired cognition, and studies examining cognitive impairment within 6 months of pregnancy. Database searches were supplemented by manual review of the reference lists of included studies. If studies met eligibility criteria but did not have sufficient data for meta-analysis (ie, did not report a summary statistic or a hazard ratio [HR] for outcome estimation), they were included in the systematic review and excluded from the meta-analysis. After removing duplicates, two investigators independently screened titles and abstracts using Covidence software, with potentially eligible studies undergoing full-text review by the same reviewers, with further review by a third reviewer and disagreements resolved by discussion and group consensus. Study quality was assessed and summary statistics extracted by two reviewers independently. The primary outcomes of our study were mild cognitive impairment, all-cause dementia, Alzheimer's disease, and vascular dementia. Heterogeneity was measured using the Q test and I2 statistic, and we used random-effects models with inverse-variance weighting to assess the association between adverse pregnancy outcome and primary outcomes with sufficient meta-analysable data via pooled adjusted HRs and 95% CIs. The study protocol was registered with PROSPERO, CRD42023453511. FINDINGS: Of 11 251 publications identified, 15 studies (including 7 347 202 participants) met inclusion criteria for the systematic review, and 11 studies (6 263 431 participants) had sufficient data for meta-analysis. A history of any adverse pregnancy outcome was associated with higher risk of all-cause dementia (adjusted HR 1·32 [95% CI 1·17-1·49]; I2= 80%), Alzheimer's disease (1·26 [1·04-1·53]; I2=63%), and vascular dementia (1·94 [1·70-2·21]; I2=0%). A history of any hypertensive disorder of pregnancy was significantly associated with all-cause dementia (1·32 [1·11-1·57]; I2=74%) and vascular dementia (1·78 [1·46-2·17]; I2=0%), but not Alzheimer's disease (1·24 [0·98-1·57]; I2=66%). Stillbirth was not significantly associated with higher risk of all-cause dementia (1·26 [95% CI 0·93-1·71]; I2=62%). In individual studies, similar effect directions were observed for preterm birth and fetal growth restriction, but data were insufficient for meta-analysis. INTERPRETATION: Given their increased risk of dementia, women with a history of adverse pregnancy outcomes should be evaluated for additional dementia risk factors and monitored closely for any signs of cognitive decline. Furthermore, to obtain more reliable findings, future studies should measure both exposures and outcomes prospectively and objectively. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, and National Heart, Lung and Blood Institute.

Department of Cardiology Smidt Heart Institute Cedars Sinai Medical Center Los Angeles CA USA

Department of Neurology Columbia University New York NY USA

Department of Neurology Columbia University New York NY USA; Department of Epidemiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Neurology Jona Goldrich Center for Alzheimer's and Memory Disorders Cedars Sinai Medical Center Los Angeles CA USA

Department of Neurology Tehran University of Medical Sciences Tehran Iran

Department of Obstetrics and Gynecology Northwestern University Chicago IL USA

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Parikh NI, Gonzalez JM, Anderson CAM, 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: e902–16. PubMed

Iadecola C, Duering M, Hachinski V, et al. Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J Am Coll Cardiol 2019; 73: 3326–44. PubMed PMC

Harville EW, Guralnik J, Romero M, Bazzano LA. Reproductive history and cognitive aging: the Bogalusa Heart Study. Am J Geriatr Psychiatry 2020; 28: 217–25. PubMed PMC

Testo AA, McBride C, Bernstein IM, Dumas JA. Preeclampsia and its relationship to pathological brain aging. Front Physiol 2022; 13: 979547. PubMed PMC

Miller KB, Miller VM, Barnes JN. Pregnancy history, hypertension, and cognitive impairment in postmenopausal women. Curr Hypertens Rep 2019; 21: 93. PubMed PMC

Cao Q, Tan CC, Xu W, et al. The prevalence of dementia: a systematic review and meta-analysis. J Alzheimers Dis 2020; 73: 1157–66. PubMed

GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 88–106. PubMed PMC

WHO. Dementia. World Health Organization, March 15, 2023. https://www.who.int/news-room/fact-sheets/detail/dementia (accessed Dec 28, 2023).

Vogel B, Acevedo M, Appelman Y, et al. The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet 2021; 397: 2385–438. PubMed

Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens 2008; 21: 521–26. PubMed

Wang W, Xie X, Yuan T, et al. Epidemiological trends of maternal hypertensive disorders of pregnancy at the global, regional, and national levels: a population-based study. BMC Pregnancy Childbirth 2021; 21: 364. PubMed PMC

Shah NS, Wang MC, Freaney PM, et al. Trends in gestational diabetes at first live birth by race and ethnicity in the US, 2011-2019. JAMA 2021; 326: 660–69. PubMed PMC

Zhou T, Du S, Sun D, 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: 868094. PubMed PMC

Lavery JA, Friedman AM, Keyes KM, Wright JD, Ananth CV. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG 2017; 124: 804–13. PubMed PMC

Ananth CV, Fields JC, Brandt JS, Graham HL, Keyes KM, Zeitlin J. Evolving stillbirth rates among Black and White women in the United States, 1980–2020: a population-based study. Lancet Reg Health Am 2022; 16: 100380. PubMed PMC

Ohuma EO, Moller AB, Bradley E, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet 2023; 402: 1261–71. PubMed

Baecke M, Spaanderman ME, van der Werf SP. Cognitive function after pre-eclampsia: an explorative study. J Psychosom Obstet Gynaecol 2009; 30: 58–64. PubMed

Postma IR, Bouma A, Ankersmit IF, Zeeman GG. Neurocognitive functioning following preeclampsia and eclampsia: a long-term follow-up study. Am J Obstet Gynecol 2014; 211: 37. PubMed

Postma IR, Wessel I, Aarnoudse JG, Zeeman GG. Neurocognitive functioning in women with a history of eclampsia: executive functioning and sustained attention. Am J Perinatol 2010; 27: 685–90. PubMed

Mielke MM, Milic NM, Weissgerber TL, et al. Impaired cognition and brain atrophy decades after hypertensive pregnancy disorders. Circ Cardiovasc Qual Outcomes 2016; 9 (suppl 1): S70–76. PubMed PMC

Shaaban CE, Rosano C, Cohen AD, et al. Cognition and cerebrovascular reactivity in midlife women with history of preeclampsia and placental evidence of maternal vascular malperfusion. Front Aging Neurosci 2021; 13: 637574. PubMed PMC

Miller KB, Fields JA, Harvey RE, et al. Aortic Hemodynamics and cognitive performance in postmenopausal women: impact of pregnancy history. Am J Hypertens 2020; 33: 756–64. PubMed PMC

Adank MC, Hussainali RF, Oosterveer LC, et al. Hypertensive disorders of pregnancy and cognitive impairment: a prospective cohort study. Neurology 2021; 96: e709–18. PubMed PMC

Schliep KC, Mclean H, Yan B, et al. Association between hypertensive disorders of pregnancy and dementia: a systematic review and meta-analysis. Hypertension 2023; 80: 257–67. PubMed PMC

Samara AA, Liampas I, Dadouli K, et al. Preeclampsia, gestational hypertension and incident dementia: a systematic review and meta-analysis of published evidence. Pregnancy Hypertens 2022; 30: 192–97. PubMed

Sukmanee J, Liabsuetrakul T. Risk of future cardiovascular diseases in different years postpartum after hypertensive disorders of pregnancy: a systematic review and meta-analysis. Medicine (Baltimore) 2022; 101: e29646. PubMed PMC

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: 355–64. PubMed

Carey C, Mulcahy E, McCarthy FP, et al. Hypertensive disorders of pregnancy and the risk of maternal dementia: a systematic review and meta-analysis. Am J Obstet Gynecol 2024; 231: 196–210. PubMed

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: 1090–99. PubMed

Basit S, Wohlfahrt J, Boyd HA. Pregnancy loss and risk of later dementia: a nationwide cohort study, Denmark, 1977–2017. Alzheimers Dement (N Y) 2019; 5: 146–53. PubMed PMC

Zhang Y, Gao D, Gao Y, et al. Gestational diabetes mellitus is associated with greater incidence of dementia during long-term post-partum follow-up. J Intern Med 2024; 295: 774–84. PubMed

Sheng J, Liu J, Chan KHK. 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: 833734. PubMed PMC

Li M, Qu K, Wang Y, Wang Y, Sun L. Associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure: a Mendelian randomization study. J Hypertens 2024; 42: 399–409. PubMed PMC

Abheiden CN, van Doornik R, Aukes AM, van der Flier WM, Scheltens P, de Groot CJ. Hypertensive disorders of pregnancy appear not to be associated with Alzheimer’s disease later in life. Dement Geriatr Cogn Disord Extra 2015; 5: 375–85. PubMed PMC

Nelander M, Cnattingius S, Åkerud H, Wikström J, Pedersen NL, Wikström AK. Pregnancy hypertensive disease and risk of dementia and cardiovascular disease in women aged 65 years or older: a cohort study. BMJ Open 2016; 6: e009880. PubMed PMC

Wang K, Guo K, Ji Z, 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: 725–30. PubMed

Liang C, Chung HF, Dobson AJ, Mishra GD. Infertility, miscarriage, stillbirth, and the risk of stroke among women: a systematic review and meta-analysis. Stroke 2022; 53: 328–37. PubMed

Basit S, Wohlfahrt J, Boyd HA. Pre-eclampsia and risk of dementia later in life: nationwide cohort study. BMJ 2018; 363: k4109. PubMed PMC

Schliep KC, Shaaban CE, Meeks H, et al. Hypertensive disorders of pregnancy and subsequent risk of Alzheimer’s disease and other dementias. Alzheimers Dement (Amst) 2023; 15: e12443. PubMed PMC

Theilen LH, Fraser A, Hollingshaus MS, et al. All-cause and cause-specific mortality after hypertensive disease of pregnancy. Obstet Gynecol 2016; 128: 238–44. PubMed PMC

Wolfova K, Miller EC. Impact of adverse pregnancy outcomes on brain vascular health and cognition. Res Pract Thromb Haemost 2024; 8: 102331. PubMed PMC

Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6: e1000100. PubMed PMC

Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 303–08. PubMed

Alzheimer’s Association. Criteria for Diagnosis and Staging of Alzheimer’s Disease. 2024. https://www.alz.org/research/for_researchers/diagnostic-criteria-guidelines (accessed Nov 15, 2024).

Higgins J, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions, version 6.5. August, 2024, Cochrane. https://training.cochrane.org/handbook (accessed Aug 20, 2024).

Olié V, Lailler G, Torres MJ, Regnault N, Carcaillon-Bentata L, Blacher J. Young-onset dementia among individuals with history of preeclampsia. JAMA Netw Open 2024; 7: e2412870. PubMed PMC

National Heart, Lung, and Blood Institute. Study quality assessment tools. July, 2021. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools (accessed Dec 11, 2023).

Fields JA, Garovic VD, Mielke MM,et al. Preeclampsia and cognitive impairment later in life. Am J Obstet Gynecol 2017; 217: 74. PubMed PMC

Garovic VD, White WM, Vaughan L, et al. Incidence and long-term outcomes of hypertensive disorders of pregnancy. J Am Coll Cardiol 2020; 75: 2323–34. PubMed PMC

Liang C, Dobson AJ, Chung H-F, et al. Association of infertility and recurrent pregnancy loss with the risk of dementia. Eur J Epidemiol 2024; 39: 785–93. PubMed PMC

Ananth CV, Patrick HS, Ananth S, Zhang Y, Kostis WJ, Schuster M. Maternal cardiovascular and cerebrovascular health after placental abruption: a systematic review and meta-analysis (CHAP-SR). Am J Epidemiol 2021; 190: 2718–29. PubMed PMC

Xie W, Wang Y, Xiao S, Qiu L, Yu Y, Zhang Z. Association of gestational diabetes mellitus with overall and type specific cardiovascular and cerebrovascular diseases: systematic review and meta-analysis. BMJ 2022; 378: e070244. PubMed PMC

Wu P, Gulati M, Kwok CS, et al. Preterm delivery and future risk of maternal cardiovascular disease: a systematic review and meta-analysis. J Am Heart Assoc 2018; 7: e007809. PubMed PMC

Rana S, Burke SD, Karumanchi SA. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol 2022; 226: S1019–34. PubMed PMC

Agrawal S, Parks WT, Zeng HD, 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. PubMed

Jaime Garcia D, Chagnot A, Wardlaw JM, Montagne A. A scoping review on biomarkers of endothelial dysfunction in small vessel disease: molecular insights from human studies. Int J Mol Sci 2023; 24: 13114. PubMed PMC

Hinman JD, Elahi F, Chong D, et al. Placental growth factor as a sensitive biomarker for vascular cognitive impairment. Alzheimers Dement 2023; 19: 3519–27. PubMed PMC

Alzheimer’s Association. Alzheimer’s disease facts and figures. 2024. https://www.alz.org/alzheimers-dementia/facts-figures (accessed Oct 23, 2024).

Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 2017; 134: 171–86. PubMed PMC

Dichgans M, Leys D. Vascular cognitive impairment. Circ Res 2017; 120: 573–91. PubMed

O’Brien JT, Thomas A. Vascular dementia. Lancet 2015; 386: 1698–706. PubMed

Miller EC, Kauko A, Tom SE, et al. Risk of midlife stroke after adverse pregnancy outcomes: the FinnGen study. Stroke 2023; 54: 1798–805. PubMed PMC

van Dijk M, van Bezu J, Poutsma A, 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: 673–79. PubMed

Buhimschi IA, Nayeri UA, Zhao G, et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Sci Transl Med 2014; 6: 245ra92. PubMed

Hoffman MK. The great obstetrical syndromes and the placenta. BJOG 2023; 130 (suppl 3): 8–15. PubMed PMC

Shen Z, Yang X, Lan Y, Chen G. The neuro-inflammatory microenvironment: an important regulator of stem cell survival in Alzheimer’s disease. J Alzheimers Dis 2024; 98: 741–54. PubMed

Lopez-Lee C, Torres ERS, Carling G, Gan L. Mechanisms of sex differences in Alzheimer’s disease. Neuron 2024; 112: 1208–21. PubMed PMC

Winder Z, Sudduth TL, Anderson S, 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

Cathey AL, Watkins DJ, Rosario ZY, et al. Gestational hormone concentrations are associated with timing of delivery in a fetal sex-dependent manner. Front Endocrinol (Lausanne) 2021; 12: 742145. PubMed PMC

Hansel MC, Murphy HR, Brunner J, et al. Associations between neighborhood stress and maternal sex steroid hormones in pregnancy. BMC Pregnancy Childbirth 2023; 23: 730. PubMed PMC

Parisi F, Fenizia C, Introini A, et al. The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester. Hum Reprod Update 2023; 29: 699–720. PubMed PMC

Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 2007; 72: 381–405. PubMed PMC

Lee JK, Raghavan S, Christenson LR, et al. Longitudinal associations of reproductive factors and exogeneous estrogens with neuroimaging biomarkers of Alzheimer’s disease and cerebrovascular disease. Alzheimers Dement 2024; 20: 4613–24. PubMed PMC

Cirillo PM, Cohn BA. Pregnancy complications and cardiovascular disease death: 50-year follow-up of the Child Health and Development Studies pregnancy cohort. Circulation 2015; 132: 1234–42. PubMed PMC

Carter EB, Stuart JJ, Farland LV, et al. Pregnancy complications as markers for subsequent maternal cardiovascular disease: validation of a maternal recall questionnaire. J Womens Health (Larchmt) 2015; 24: 702–12. PubMed PMC

Gunderson EP, Chiang V, Lewis CE, et al. Long-term blood pressure changes measured from before to after pregnancy relative to nonparous women. Obstet Gynecol 2008; 112: 1294–302. PubMed PMC

Gunderson EP, Lewis CE, Tsai AL, et al. A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetes 2007; 56: 2990–96. PubMed PMC

Solomon A, Ngandu T, Soininen H, Hallikainen MM, Kivipelto M, Laatikainen T. Validity of dementia and Alzheimer’s disease diagnoses in Finnish national registers. Alzheimers Dement 2014; 10: 303–09. PubMed

van de Vorst IE, Vaartjes I, Sinnecker LF, Beks LJ, Bots ML, Koek HL. The validity of national hospital discharge register data on dementia: a comparative analysis using clinical data from a university medical centre. Neth J Med 2015; 73: 69–75. PubMed

Widera EW, Brangman SA, Chin NA. Ushering in a new era of Alzheimer disease therapy. JAMA 2023; 330: 503–04. PubMed