Skip to main content

Advertisement

SpringerLink
Log in

Pregnancy Loss and Cardiovascular Diseases in Women: Recent Findings and Potential Mechanisms

  • Women and Ischemic Heart Disease (J.M. Peña and F. Lin, Section Editors)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Pregnancy loss (PL) has been acknowledged by the American Heart Association as a risk factor for cardiovascular diseases (CVD) later in life. This review aims to sum up recent findings (< ~ 5 years), concerning the link between PL and CVD.

Recent Findings

The association between PL and risk of CVD increased with increasing number of PLs and is inversely correlated to maternal age, indicating that the association concerns euploid PLs. Likely mechanisms leading to PL and an increased risk of CVD include endothelial dysfunction, a pro-inflammatory state, antiphospholipid syndrome, autoimmunity, and genetic predisposition.

Summary

PL as an independent risk factor for CVD constitutes an obvious gateway for a more targeted approach to future research, prevention, and treatment. Future research should clarify the following questions to which the answers are still unknown: whether PL is (a) directly causing the increased risk of CVD or (b) sharing pathophysiological mechanisms also leading to CVD.

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

Similar content being viewed by others

References

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

  1. Cardiovascular diseases (CVDs) World Health Organization 2021 [cited 2022 25th of February].Available from: https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

  2. The facts about women and heart disease: American Heart Association; [cited 2022 9. of March].Available from: https://www.goredforwomen.org/en/about-heart-disease-in-women/facts.

  3. Dawber TR, Moore FE, Mann GV. Coronary heart disease in the Framingham study. Am J Public Health Nations Health. 1957;47(4 Pt 2):4–24.

    Article  CAS  Google Scholar 

  4. Dawber TR, Kannel WB, Revotskie N, Stokes J 3rd, Kagan A, Gordon T. Some factors associated with the development of coronary heart disease: six years’ follow-up experience in the Framingham study. Am J Public Health Nations Health. 1959;49(10):1349–56.

    Article  CAS  Google Scholar 

  5. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J 3rd. Factors of risk in the development of coronary heart disease–six year follow-up experience. Framingham Study Ann Intern Med. 1961;55:33–50.

    Article  CAS  Google Scholar 

  6. Arora S, Stouffer GA, Kucharska-Newton AM, Qamar A, Vaduganathan M, Pandey A, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation. 2019;139(8):1047–56.

    Article  Google Scholar 

  7. Bots SH, Peters SAE, Woodward M. Sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between 1980 and 2010. BMJ Glob Health. 2017;2(2):e000298.

    Article  Google Scholar 

  8. Maffei S, Guiducci L, Cugusi L, Cadeddu C, Deidda M, Gallina S, et al. Women-specific predictors of cardiovascular disease risk - new paradigms. Int J Cardiol. 2019;286:190–7.

    Article  Google Scholar 

  9. Vogel B, Acevedo M, Appelman Y, Bairey Merz CN, Chieffo A, Figtree GA, et al. The Lancet women and cardiovascular disease commission: reducing the global burden by 2030. Lancet. 2021;397(10292):2385–438.

    Article  Google Scholar 

  10. Young L, Cho L. Unique cardiovascular risk factors in women. Heart. 2019;105(21):1656–60.

    Article  CAS  Google Scholar 

  11. Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(5):1545–88.

    Article  Google Scholar 

  12. Parikh NI, Gonzalez JM, Anderson CAM, Judd SE, Rexrode KM, Hlatky MA, 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(18):e902–16.

    Article  CAS  Google Scholar 

  13. Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod. 2006;21(12):3217–27.

    Article  CAS  Google Scholar 

  14. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–43.

    Article  CAS  Google Scholar 

  15. ESHRE. Recurrent pregnancy loss: Early Pregnancy Guideline Development Group; 2017 [updated 1st of April 2019. Version 2:[cited 2022 18 of March].Available from: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.

  16. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000;73(2):300–4.

    Article  CAS  Google Scholar 

  17. What is down syndrome? : National Down Syndrome Society; 2022 [cited 2022 May 1st, 2022].Available from: https://www.ndss.org/about-down-syndrome/down-syndrome/.

  18. Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6(1):98.

    Article  Google Scholar 

  19. Wartosch L, Schindler K, Schuh M, Gruhn JR, Hoffmann ER, McCoy RC, et al. Origins and mechanisms leading to aneuploidy in human eggs. Prenat Diagn. 2021;41(5):620–30.

    Article  Google Scholar 

  20. Hardy K, Hardy PJ, Jacobs PA, Lewallen K, Hassold TJ. Temporal changes in chromosome abnormalities in human spontaneous abortions: results of 40 years of analysis. Am J Med Genet A. 2016;170(10):2671–80.

    Article  CAS  Google Scholar 

  21. Wang Y, Cheng Q, Meng L, Luo C, Hu H, Zhang J, et al. Clinical application of SNP array analysis in first-trimester pregnancy loss: a prospective study. Clin Genet. 2017;91(6):849–58.

    Article  CAS  Google Scholar 

  22. Lidegaard O, Mikkelsen AP, Egerup P, Kolte AM, Rasmussen SC, Nielsen HS. Pregnancy loss: a 40-year nationwide assessment. Acta Obstet Gynecol Scand. 2020;99(11):1492–6.

    Article  Google Scholar 

  23. Bashiri A, Harlev A, Agarwal A. Recurrent pregnancy loss: evidence-based evaluation, diagnosis and treatment. Cham: Springer International Publishing AG; 2016.

    Book  Google Scholar 

  24. Lund M, Kamper-Jorgensen M, Nielsen HS, Lidegaard O, Andersen AM, Christiansen OB. Prognosis for live birth in women with recurrent miscarriage: what is the best measure of success? Obstet Gynecol. 2012;119(1):37–43.

    Article  Google Scholar 

  25. Ranthe MF, Andersen EA, Wohlfahrt J, Bundgaard H, Melbye M, Boyd HA. Pregnancy loss and later risk of atherosclerotic disease. Circulation. 2013;127(17):1775–82.

    Article  Google Scholar 

  26. Maino A, Siegerink B, Algra A, Martinelli I, Peyvandi F, Rosendaal FR. Pregnancy loss and risk of ischaemic stroke and myocardial infarction. Br J Haematol. 2016;174(2):302–9.

    Article  CAS  Google Scholar 

  27. Peters SA, Woodward M. Women’s reproductive factors and incident cardiovascular disease in the UK Biobank. Heart. 2018;104(13):1069–75.

    Article  CAS  Google Scholar 

  28. Robinson MR, Kleinman A, Graff M, Vinkhuyzen AAE, Couper D, Miller MB, et al. Genetic evidence of assortative mating in humans. Nat Hum Behav. 2017;1(1):0016.

    Article  Google Scholar 

  29. McQueen DB, Zhang J, Robins JC. Sperm DNA fragmentation and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2019;112(1):54-60 e3.

    Article  Google Scholar 

  30. Brandt NB, Kristensen MLS, Catalini L, Fedder J. Effect of paternal health on pregnancy loss-a review of current evidence. Andrologia. 2022;54(1):e14259.

    Article  Google Scholar 

  31. •• Wang YX, Minguez-Alarcon L, Gaskins AJ, Wang L, Ding M, Missmer SA, et al. Pregnancy loss and risk of cardiovascular disease: the Nurses’ Health Study II. Eur Heart J. 2022;43(3):190–9. This article put forward a clear association between pregnancy loss and CVD; furthermore, they showed that the association was dependent on number of pregnancy losses as well as maternal age.

  32. Sarwar AH, Singh B, Kishore S, Priyanka F, Ali A, Pariya F, et al. History of pregnancy loss as a risk factor for myocardial infarction. Cureus. 2021;13(8):e17288.

    Google Scholar 

  33. Hall PS, Nah G, Vittinghoff E, Parker DR, Manson JE, Howard BV, et al. Relation of pregnancy loss to risk of cardiovascular disease in parous postmenopausal women (From the Women’s Health Initiative). Am J Cardiol. 2019;123(10):1620–5.

    Article  Google Scholar 

  34. Parikh NI, Jeppson RP, Berger JS, Eaton CB, Kroenke CH, LeBlanc ES, et al. Reproductive risk factors and coronary heart disease in the Women’s Health Initiative observational study. Circulation. 2016;133(22):2149–58.

    Article  Google Scholar 

  35. Peters SAE, Yang L, Guo Y, Chen Y, Bian Z, Tian X, et al. Pregnancy, pregnancy loss, and the risk of cardiovascular disease in Chinese women: findings from the China Kadoorie Biobank. BMC Med. 2017;15(1):148.

    Article  Google Scholar 

  36. •• Westergaard D, Nielsen AP, Mortensen LH, Nielsen HS, Brunak S. Phenome-wide analysis of short- and long-run disease incidence following recurrent pregnancy loss using data from a 39-year period. J Am Heart Assoc. 2020;9(8):e015069. The largest RPL study so far which showed primary RPL strongly associated to CVD later in life.

  37. •• Grandi SM, Hinkle SN, Mumford SL, Sjaarda LA, Grantz KL, Mendola P, et al. Long-term mortality in women with pregnancy loss and modification by race/ethnicity. American Journal of Epidemiology. 2022:kwac023. This study revealed increased CVD mortality rates in women with history of pregnancy loss compared to no history of pregnancy loss.

  38. Yamada K, Iso H, Cui R, Tamakoshi A. Recurrent pregnancy loss and cardiovascular disease mortality in Japanese women: a population-based, prospective cohort study. J Stroke Cerebrovasc Dis. 2017;26(5):1047–54.

    Article  Google Scholar 

  39. Pober JS, Min W, Bradley JR. Mechanisms of endothelial dysfunction, injury, and death. Annu Rev Pathol. 2009;4:71–95.

    Article  CAS  Google Scholar 

  40. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr. 2012;23(4):222–31.

    Article  Google Scholar 

  41. Hadi HA, Carr CS, Al SJ. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183–98.

    CAS  Google Scholar 

  42. Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension. 2007;49(1):90–5.

    Article  CAS  Google Scholar 

  43. Dassanayake M, Langen E, Davis MB. Pregnancy complications as a window to future cardiovascular disease. Cardiol Rev. 2020;28(1):14–9.

    Article  Google Scholar 

  44. Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Front Immunol. 2020;11:2025.

    Article  CAS  Google Scholar 

  45. Reinhard G, Noll A, Schlebusch H, Mallmann P, Ruecker AV. Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. Biochem Biophys Res Commun. 1998;245(3):933–8.

    Article  CAS  Google Scholar 

  46. La Farina F, Raparelli V, Napoleone L, Guadagni F, Basili S, Ferroni P. Inflammation and thrombophilia in pregnancy complications: implications for risk assessment and clinical management. Cardiovasc Hematol Disord Drug Targets. 2016;15(3):187–203.

    Article  Google Scholar 

  47. Wagner MM, Jukema JW, Hermes W, le Cessie S, de Groot CJM, Bakker JA, et al. Assessment of novel cardiovascular biomarkers in women with a history of recurrent miscarriage. Pregnancy Hypertens. 2018;11:129–35.

    Article  CAS  Google Scholar 

  48. Bruno Costa Teixeira ALL, Rodrigo Cauduro Oliveira Macedo, Cleiton Silva CorreaThiago Rozales Ramis, Jerri Luiz Ribeiro, Alvaro Reischak-Oliveira. Inflammatory markers, endothelial function and cardiovascular risk. Jornal Vascular Brasileiro. 2014;13(2).

  49. Hein TW, Singh U, Vasquez-Vivar J, Devaraj S, Kuo L, Jialal I. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009;206(1):61–8.

    Article  CAS  Google Scholar 

  50. Schreiber K, Sciascia S, de Groot PG, Devreese K, Jacobsen S, Ruiz-Irastorza G, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;4:17103.

    Article  Google Scholar 

  51. Svenungsson E, Antovic A. The antiphospholipid syndrome - often overlooked cause of vascular occlusions? J Intern Med. 2020;287(4):349–72.

    Article  CAS  Google Scholar 

  52. Dabit JY, Valenzuela-Almada MO, Vallejo-Ramos S, Duarte-García A. Epidemiology of antiphospholipid syndrome in the general population. Curr Rheumatol Rep. 2022;23(12):85.

    Article  Google Scholar 

  53. Di Prima FA, Valenti O, Hyseni E, Giorgio E, Faraci M, Renda E, et al. Antiphospholipid syndrome during pregnancy: the state of the art. J Prenat Med. 2011;5(2):41–53.

    Google Scholar 

  54. Pleguezuelo DE, Cabrera-Marante O, Abad M, Rodriguez-Frias EA, Naranjo L, Vazquez A, et al. Anti-phosphatidylserine/prothrombin antibodies in healthy women with unexplained recurrent pregnancy loss. J Clin Med. 2021;10(10).

  55. Kwak-Kim J, Agcaoili MS, Aleta L, Liao A, Ota K, Dambaeva S, et al. Management of women with recurrent pregnancy losses and antiphospholipid antibody syndrome. Am J Reprod Immunol. 2013;69(6):596–607.

    CAS  Google Scholar 

  56. Thomas L, Ortel DE, Michael D. Lockshin. Clinical Immunology. 5th ed. Robert R. Rich TAF, William T. Shearer, Harry W. Schroeder, Anthony J. Frew, Cornelia M. Weyand, editor: Elsevier; 2018.

  57. Matsuura E, Shen L, Matsunami Y, Quan N, Makarova M, Geske FJ, et al. Pathophysiology of beta2-glycoprotein I in antiphospholipid syndrome. Lupus. 2010;19(4):379–84.

    Article  CAS  Google Scholar 

  58. Abrahams VM, Chamley LW, Salmon JE. Emerging treatment models in rheumatology: antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheumatol. 2017;69(9):1710–21.

    Article  Google Scholar 

  59. Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol. 2009;62(2):96–111.

    Article  CAS  Google Scholar 

  60. Clark CA, Laskin CA, Spitzer KA. Anticardiolipin antibodies and recurrent early pregnancy loss: a century of equivocal evidence. Hum Reprod Update. 2012;18(5):474–84.

    Article  CAS  Google Scholar 

  61. Velasquez M, Rojas M, Abrahams VM, Escudero C, Cadavid AP. Mechanisms of endothelial dysfunction in antiphospholipid syndrome: Association With Clinical Manifestations. Front Physiol. 2018;9:1840.

    Article  Google Scholar 

  62. Nielsen HS, Witvliet MD, Steffensen R, Haasnoot GW, Goulmy E, Christiansen OB, et al. The presence of HLA-antibodies in recurrent miscarriage patients is associated with a reduced chance of a live birth. J Reprod Immunol. 2010;87(1–2):67–73.

    Article  CAS  Google Scholar 

  63. Cavalcante M, Cavalcante C, Sarno M, Belo da Silva AC, Barini R. Antinuclear antibodies and recurrent miscarriage: systematic review and meta-analysis. American Journal of Reproductive Immunology. 2019;83.

  64. Chen S, Yang G, Wu P, Sun Y, Dai F, He Y, et al. Antinuclear antibodies positivity is a risk factor of recurrent pregnancy loss: a meta-analysis. Semin Arthritis Rheum. 2020;50(4):534–43.

    Article  CAS  Google Scholar 

  65. Sharshiner R, Romero ST, Bardsley TR, Branch DW, Silver RM. Celiac disease serum markers and recurrent pregnancy loss. J Reprod Immunol. 2013;100(2):104–8.

    Article  CAS  Google Scholar 

  66. Cappola AR, Desai AS, Medici M, Cooper LS, Egan D, Sopko G, et al. Thyroid and cardiovascular disease. Circulation. 2019;139(25):2892–909.

    Article  Google Scholar 

  67. Hershberg U, Luning Prak ET. The analysis of clonal expansions in normal and autoimmune B cell repertoires. Philos Trans R Soc Lond B Biol Sci. 2015;370(1676).

  68. Rawlings DJ, Metzler G, Wray-Dutra M, Jackson SW. Altered B cell signalling in autoimmunity. Nat Rev Immunol. 2017;17(7):421–36.

    Article  CAS  Google Scholar 

  69. Khizroeva J, Nalli C, Bitsadze V, Lojacono A, Zatti S, Andreoli L, et al. Infertility in women with systemic autoimmune diseases. Best Pract Res Clin Endocrinol Metab. 2019;33(6):101369.

    Article  CAS  Google Scholar 

  70. Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, et al. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019;25(4):486–503.

    Article  Google Scholar 

  71. Shen M, O’Donnell E, Leon G, Kisovar A, Melo P, Zondervan K, et al. The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review. Hum Reprod Open. 2022;2022(1):hoab043.

    Article  Google Scholar 

  72. Garcia-Rivas G, Castillo EC, Gonzalez-Gil AM, Maravillas-Montero JL, Brunck M, Torres-Quintanilla A, et al. The role of B cells in heart failure and implications for future immunomodulatory treatment strategies. ESC Heart Fail. 2020;7(4):1387–99.

    Article  Google Scholar 

  73. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, Levy RA, Cervera R, editors. Autoimmunity: from bench to bedside. Bogota (Colombia): El Rosario University Press© 2013 Universidad del Rosario. 2013.

  74. Smith GC, Wood AM, Pell JP, Hattie J. Recurrent miscarriage is associated with a family history of ischaemic heart disease: a retrospective cohort study. BJOG. 2011;118(5):557–63.

    Article  CAS  Google Scholar 

  75. Su MT, Lin SH, Chen YC. Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update. 2011;17(6):803–12.

    Article  CAS  Google Scholar 

  76. • Laisk T, Soares ALG, Ferreira T, Painter JN, Censin JC, Laber S, et al. The genetic architecture of sporadic and multiple consecutive miscarriage. Nat Commun. 2020;11(1):5980. The first GWAS on RPL and sporadic PL, providing important genetic information.

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark

    Mette Marie Babiel Schmidt Petersen & Henriette Svarre Nielsen

  2. Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650, Hvidovre, Denmark

    Mette Marie Babiel Schmidt Petersen, Tanja Schlaikjær Hartwig & Henriette Svarre Nielsen

Authors
  1. Mette Marie Babiel Schmidt Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanja Schlaikjær Hartwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henriette Svarre Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mette Marie Babiel Schmidt Petersen.

Ethics declarations

Conflict of Interest

Dr. Henriette Svarre Nielsen reports grants or contracts paid to her institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordisk Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark. They also report payment or honoraria from Ferring Pharmaceuticals, Merck A/S, AstraZeneca, Cook Medical, and Ibsa Nordic.

The other authors declare that they have no conflict of interest.

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 Women and Ischemic Heart Disease

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Petersen, M.M.B.S., Hartwig, T.S. & Nielsen, H.S. Pregnancy Loss and Cardiovascular Diseases in Women: Recent Findings and Potential Mechanisms. Curr Atheroscler Rep 24, 889–899 (2022). https://doi.org/10.1007/s11883-022-01065-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-022-01065-z

Keywords

Search

Navigation