Autoimmune diseases disproportionately impact women, and pregnancy-related events could play an underlying role. We summarized literature on the association between pregnancy complications and future risk of autoimmune disease.
Materials and Methods:
We systematically searched Medline, EMBASE, CINAHL Plus, and Web of Science from database inception to January 2024 for observational studies that reported on history of pregnancy complications (exposure), risk of newly diagnosed autoimmune disease (outcome), and included a comparison group of unaffected women. Two reviewers independently assessed study eligibility, extracted data, and rated risk of bias. We estimated pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) for pregnancy complications with ≥3 identified studies using DerSimonian and Laird random effects models and otherwise summarized findings following synthesis without meta-analysis (SWiM).
Results:
We screened 7,763 citations and included 25 studies (12 cohort, 13 case–control). Most studies were from Denmark (n = 10) or the United Kingdom (n = 5), with sample sizes ranging from 138 to >1.5 million women (median = 1,304 women). Risk of bias was moderate, serious, and critical in 10, 13, and 2 studies, respectively, with quality adversely impacted by potential unmeasured confounding. Meta-analyses indicated an elevated risk of autoimmune disease following preeclampsia (adjusted RR: 1.61, 95% CI: 0.98–2.65, I2 = 90.0%) and small fetal/infant size (adjusted OR: 2.02, 95% CI: 1.16–3.52, I2 = 28.4%), and possibly spontaneous pregnancy loss (adjusted RR: 1.58, 95% CI: 0.66–3.79, I2 = 99.4%) and stillbirth (adjusted RR: 2.18, 95% CI: 0.65–7.34, I2 = 99.2%), although estimates were often imprecise. SWiM findings generally supported a positive association between pregnancy complications and autoimmune disease; there were insufficient studies for gestational diabetes, placental disorders, and preterm birth.
Conclusions:
History of certain pregnancy complications may be a novel risk factor for autoimmune disease in women. Additional high-quality research with geographically diverse data sources would be valuable.
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References
1.
Rich-EdwardsJW, McElrathTF, KarumanchiSA, et al.Breathing life into the lifecourse approach: Pregnancy history and cardiovascular disease in women. Hypertension, 2010; 56(3):331–334; doi: 10.1161/HYPERTENSIONAHA.110.156810
2.
FraserA, NelsonSM, MacDonald-WallisC, et al.Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: The Avon longitudinal study of parents and children. Circ, 2012; 125(11):1367–1380; doi: 10.1161/CIRCULATIONAHA.111.044784
3.
Rich-EdwardsJW. Reproductive health as a sentinel of chronic disease in women. Womens Health (Lond), 2009; 5(2):101–105; doi: 10.2217/17455057.5.2.101
4.
TanEK, TanEL. Alterations in physiology and anatomy during pregnancy. Best Pract Res Clin Obstet Gynaecol, 2013; 27(6):791–802; doi: 10.1016/j.bpobgyn.2013.08.001
5.
GrandiSM, FilionKB, YoonS, et al.Cardiovascular disease-related morbidity and mortality in women with a history of pregnancy complications: Systematic review and meta-analysis. Circ, 2019; 139(8):1069–1079; doi: 10.1161/CIRCULATIONAHA.118.036748
6.
ACOG practice bulletin no. 212: Pregnancy and heart disease. Am J Obstet Gynecol, 2019; 133(5):320–356; doi: 10.1097/AOG.0000000000003243
7.
ParikhNI, GonzalezJM, AndersonCAM, et al.; American Heart Association Council on Epidemiology and Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and the Stroke Council. Adverse pregnancy outcomes and cardiovascular disease risk: Unique opportunities for cardiovascular disease prevention in women: A scientific statement from the American Heart Association. Circ, 2021; 143(18):E902–E916; doi: 10.1161/CIR.0000000000000961
8.
WalshSJ, RauLM. Autoimmune diseases: A leading cause of death among young and middle-aged women in the United States. Am J Public Health, 2000; 90(9):1463–1466; doi: 10.2105/AJPH.90.9.1463
9.
SebbagE, FeltenR, SagezF, et al.The world-wide burden of musculoskeletal diseases: A systematic analysis of the World Health Organization Burden of Diseases Database. Ann Rheum Dis, 2019; 78(6):844–848; doi: 10.1136/annrheumdis-2019-215142
10.
ThomasSL, GriffithsC, SmeethL, et al.Burden of mortality associated with autoimmune diseases among females in the United Kingdom. Am J Public Health, 2010; 100(11):2279–2287; doi: 10.2105/AJPH.2009.180273
11.
ConradN, MisraS, VerbakelJY, et al.Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: A population-based cohort study of 22 million individuals in the UK. Lancet, 2023; 401(10391):1878–1890; doi: 10.1016/S0140-6736(23)00457-9
12.
CooperGS, BynumMLK, SomersEC. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. J Autoimmun, 2009; 33(3–4):197–207; doi: 10.1016/j.jaut.2009.09.008
13.
ParksCG, MillerFW, PollardKM, et al.Expert panel workshop consensus statement on the role of the environment in the development of autoimmune disease. Int J Mol Sci, 2014; 15(8):14269–14297; doi: 10.3390/ijms150814269
14.
Nadeau-ValléeM, ObariD, PalaciosJ, et al.Sterile inflammation and pregnancy complications: A review. Reproduction, 2016; 152(6):R277–R292; doi: 10.1530/REP-16-0453
15.
BrosensI, PijnenborgR, VercruysseL, et al.The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol, 2011; 204(3):193–201; doi: 10.1016/j.ajog.2010.08.009
16.
CatovJM, ScifresCM, CaritisSN, et al.Neonatal outcomes following preterm birth classified according to placental features. Am J Obstet Gynecol, 2017; 216(4):411.e1–411.e14; doi: 10.1016/j.ajog.2016.12.022
17.
JørgensenKT, NielsenNM, PedersenBV, et al.Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish population-based cohort. J Autoimmun, 2012; 38(2–3):J120–J128; doi: 10.1016/j.jaut.2011.10.002
18.
LinLT, WangPH, TsuiKH, et al.Increased risk of systemic lupus erythematosus in pregnancy-induced hypertension: A nationwide population-based retrospective cohort study. Med (United States), 2016; 95(30):e4407–e7; doi: 10.1097/MD.0000000000004407
19.
CooperGS, DooleyMA, TreadwellEL, et al.Hormonal and reproductive risk factors for development of systemic lupus erythematosus: Results of a population-based, case-control study. Arthritis Rheum, 2002; 46(7):1830–1839; doi: 10.1002/art.10365
20.
DharJP, EssenmacherLM, AgerJW, et al.Pregnancy outcomes before and after a diagnosis of systemic lupus erythematosus. Am J Obstet Gynecol, 2005; 193(4):1444–1455; doi: 10.1016/j.ajog.2005.02.104
21.
KitherH, HeazellA, BruceIN, et al.Adverse pregnancy outcomes and subsequent development of connective tissue disease in the UK: An epidemiological study. BJOG, 2020; 127(8):941–949; doi: 10.1111/1471-0528.16191
22.
StroupDF, BerlinJA, MortonSC, et al.Meta-analysis of observational studies in epidemiology: A proposal for reporting. JAMA, 2000; 283(15):2008–2012; doi: 10.1001/jama.283.15.2008
Veritas Health Innovation. Covidence systematic review software. Available from: https://www.covidence.org
25.
VandenbrouckeJP, von ElmE, AltmanDG, et al.; STROBE Initiative. Strengthening the reporting of observational studies in epidemiology (STROBE): Explanation and elaboration. Int J Surg, 2014; 12(12):1500–1524; doi: 10.1016/j.ijsu.2014.07.014
26.
SterneJA, HernánMA, ReevesBC, et al.ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. Bmj, 2016; 355:i4919–i10; doi: 10.1136/bmj.i4919
27.
JørgensenKT, PedersenBV, NielsenNM, et al.Childbirths and risk of female predominant and other autoimmune diseases in a population-based Danish cohort. J Autoimmun, 2012; 38(2–3):J81–J87; doi: 10.1016/j.jaut.2011.06.004
28.
VersiniM, JeandelPY, RosenthalE, et al.Obesity in autoimmune diseases: Not a passive bystander. Autoimmun Rev, 2014; 13(9):981–1000; doi: 10.1016/j.autrev.2014.07.001
29.
LeddyM, PowerM, SchulkinJ. The impact of maternal obesity on maternal and fetal health. Rev Obstet Gynecol, 2008; 1(4):170–178.
30.
CostenbaderKH, KarlsonEW. Cigarette smoking and autoimmune disease: What can we learn from epidemiology? Lupus, 2006; 15(11):737–745; doi: 10.1177/0961203306069344
31.
SalihuHM, WilsonRE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev, 2007; 83(11):713–720; doi: 10.1016/j.earlhumdev.2007.08.002
32.
De GraafJP, SteegersEAP, BonselGJ. Inequalities in perinatal and maternal health. Curr Opin Obstet Gynecol, 2013; 25(2):98–108; doi: 10.1097/GCO.0b013e32835ec9b0
33.
HigginsJ, ThomasJ, ChandlerJ, et al. (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3. Cochrane; 2022. Available from: https://training.cochrane.org/handbook
34.
Huedo-MedinaTB, Sanchez-MecaJ, Marin-MartinezF, et al.Assessing heterogeneity in meta-analysis: I2 or Q statistic? Psychol Methods, 2006; 11(2):193–206.
35.
RileyRD, HigginsJPT, DeeksJJ. Interpretation of random effects meta-analyses. Bmj, 2011; 342(7804):d549–d967; doi: 10.1136/bmj.d549
36.
CampbellM, McKenzieJE, SowdenA, et al.Synthesis without meta-analysis (SWiM) in systematic reviews: Reporting guideline. Bmj, 2020; 368:l6890–l6; doi: 10.1136/bmj.l6890
37.
SchünemannH, BrożekJ, GuyattG. (eds). GRADE handbook for grading quality of evidence and strength of recommendations. 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html [Last accessed: October4, 2022].
38.
AtkinsD, BestD, BrissP, et al.; GRADE Working Group. Grading quality of evidence and strength of recommendations. Bmj, 2004; 328(7454):1490; doi: 10.1136/bmj.328.7454.1490
39.
NielsenNM, JørgensenKT, StenagerE, et al.Reproductive history and risk of multiple sclerosis. Epidemiology, 2011; 22(4):546–552; doi: 10.1097/EDE.0b013e31821c7adc
40.
Ulff-MøllerCJ, JørgensenKT, PedersenBV, et al.Reproductive factors and risk of systemic lupus erythematosus: Nationwide cohort study in Denmark. J Rheumatol, 2009; 36(9):1903–1909; doi: 10.3899/jrheum.090002
41.
AugerN, QuachC, Healy-ProfitósJ, et al.Early predictors of Guillain-Barré syndrome in the life course of women. Int J Epidemiol, 2018; 47(1):280–288; doi: 10.1093/ije/dyx181
42.
HarpsøeMC, JørgensenKT, FrischM, et al.Risk of inflammatory bowel disease according to self-rated health, pregnancy course, and pregnancy complications: A study within the Danish National Birth Cohort. PLoS One, 2013; 8(3):e59698–e6; doi: 10.1371/journal.pone.0059698
43.
JørgensenKT, PedersenBV, JacobsenS, et al.National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: A role for hyperemesis, gestational hypertension and preeclampsia? Ann Rheum Dis, 2010; 69(2):358–363; doi: 10.1136/ard.2008.099945
44.
JørgensenKT, HarpsøéMC, JacobsenS, et al.Increased risk of rheumatoid arthritis in women with pregnancy complications and poor self-rated health: A study within the Danish National Birth Cohort. Rheumatol (Oxford), 2014; 53(8):1513–1519; doi: 10.1093/rheumatology/keu150
45.
Kamper-JørgensenM, GammillHS, NelsonJL. Preeclampsia and scleroderma: A prospective nationwide analysis. Obstet Anesth Dig, 2018; 38(3):124–125; doi: 10.1097/01.aoa.0000542341.36267.7e
46.
MerlinoLA, CerhanJR, CriswellLA, et al.Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum, 2003; 33(2):72–82; doi: 10.1016/S0049-0172(03)00084-2
47.
MikkelsenAP, EgerupP, KolteAM, et al.Pregnancy loss and risk of multiple sclerosis and autoimmune neurological disorder: A nationwide cohort study. PLoS One, 2022; 17(3)March):e0266203–e13; doi: 10.1371/journal.pone.0266203
48.
CarléA, PedersenIB, KnudsenN, et al.Development of autoimmune overt hypothyroidism is highly associated with live births and induced abortions but only in premenopausal women. J Clin Endocrinol Metab, 2014; 99(6):2241–2249; doi: 10.1210/jc.2013-4474
49.
CarléA, KnudsenN, JørgensenT, et al.Previous live births and induced abortions may precede later development of graves’ hyperthyroidism. Eur Thyroid J, 2019; 8(2):70–78; doi: 10.1159/000494836
50.
SpectorTD, SilmanAJ. Is poor pregnancy outcome a risk factor in rheumatoid arthritis? Ann Rheum Dis, 1990; 49(1):12–14; doi: 10.1136/ard.49.1.12
51.
SymmonsDP, BankheadCR, HarrisonBJ, et al.Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: Results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum, 1997; 40(11):1955–1961; doi: 10.1002/art.1780401106
52.
van WykL, van der MarelJ, SchuerweghAJM, et al.Increased incidence of pregnancy complications in women who later develop scleroderma: A case control study. Arthritis Res Ther, 2011; 13(6):R183–R9; doi: 10.1186/ar3510
53.
ChungMP, KolstadKD, DontsiM, et al.Increased rates of obstetric complications prior to systemic sclerosis diagnosis. Arthritis Care Res (Hoboken), 2022; 74(6):912–917; doi: 10.1002/acr.24533
54.
EnglertH, BrennanP, McNeilD, et al.Reproductive function prior to disease onset in women with scleroderma. J Rheumatol, 1992; 19(10):1575–1579.
55.
MaK, NelsonJ, GuthrieK, et al.Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis. Arthritis Rheumatol, 2014; 66(3):508–512; doi: 10.1002/art.38247
56.
McHughN, ReillyP, McHughL. Pregnancy outcome and autoantibodies in connective tissue disease. J Rheumatol, 1989; 16(1):42–46.
57.
NelsonJL, VoigtLF, KoepsellTD, et al.Pregnancy outcome in women with rheumatoid arthritis before disease onset. J Rheumatol, 1992; 19(1):18–21.
58.
PrioriR, MeddaE, ContiF, et al.Risk factors for Sjögren’s syndrome: A case-control study. Clin Exp Rheumatol, 2007; 25(3):378–384.
59.
SilmanAJ, BlackC. Increased incidence of spontaneous abortion and infertility in women with scleroderma before disease onset: A controlled study. Ann Rheum Dis, 1988; 47(6):441–444; doi: 10.1136/ard.47.6.441
60.
MuñozCM, GouldenB, AhmedK, et al.Risk of adverse pregnancy outcomes prior to the onset of an autoimmune rheumatic disease: A systematic review. Rheumatology (Oxford), 2023; 62(2):497–511; doi: 10.1093/rheumatology/keac417
61.
DeaneKD, El-GabalawyH. Pathogenesis and prevention of rheumatic disease: Focus on preclinical RA and SLE. Nat Rev Rheumatol, 2014; 10(4):212–228; doi: 10.1038/nrrheum.2014.6
62.
KlareskogL, GregersenPK, HuizingaTWJ. Prevention of autoimmune rheumatic disease: State of the art and future perspectives. Ann Rheum Dis, 2010; 69(12):2062–2066; doi: 10.1136/ard.2010.142109
63.
ChoiMY, BarberMRW, BarberCEH, et al.Preventing the development of SLE: Identifying risk factors and proposing pathways for clinical care. Lupus, 2016; 25(8):838–849; doi: 10.1177/0961203316640367
64.
Mauvais-JarvisF, Bairey MerzN, BarnesPJ, et al.Sex and gender: Modifiers of health, disease, and medicine. Lancet, 2020; 396(10250):565–582; doi: 10.1016/S0140-6736(20)31561-0
65.
BernsteinIM, MongeonJA, BadgerGJ, et al.Maternal smoking and its association with birth weight. Obstet Gynecol, 2005; 106(5 Pt 1):986–991; doi: 10.1097/01.AOG.0000182580.78402.d2
66.
PinelesBL, ParkE, SametJM. Systematic review and meta-analysis of miscarriage and maternal exposure to tobacco smoke during pregnancy. Am J Epidemiol, 2014; 179(7):807–823; doi: 10.1093/aje/kwt334
67.
CriswellLA, PfeifferKA, LumRF, et al.Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: The PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet, 2005; 76(4):561–571; doi: 10.1086/429096
68.
NilssonE, RosHS, CnattingiusS, et al.The importance of genetic and environmental effects for pre-eclampsia and gestational hypertension: A family study. BJOG, 2004; 111(3):200–206; doi: 10.1111/j.1471-0528.2004.00042x.x
69.
PrabhuDasM, BonneyE, CaronK, et al.Immune mechanisms at the maternal-fetal interface: Perspectives and challenges. Nat Immunol, 2015; 16(4):328–334; doi: 10.1038/ni.3131
70.
BurtonGJ, JauniauxE. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol, 2018; 218(2S):S745–S761; doi: 10.1016/j.ajog.2017.11.577
71.
SpinilloA, BeneventiF, LocatelliE, et al.The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: A longitudinal cohort study. BMC Pregnancy Childbirth, 2016; 16(1):313–318; doi: 10.1186/s12884-016-1076-8
72.
XiaY, KellemsRE. Angiotensin receptor agonistic autoantibodies and hypertension: Preeclampsia and beyond. Circ Res, 2013; 113(1):78–87; doi: 10.1161/CIRCRESAHA.113.300752
73.
GleicherN. Why much of the pathophysiology of preeclampsia-eclampsia must be of an autoimmune nature. Am J Obstet Gynecol, 2007; 196(1):5.e1–5.e7; doi: 10.1016/j.ajog.2006.09.016
74.
National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, et al.Enhancing NIH research on autoimmune disease; 2022: Washington (DC): National Academies Press (US) doi: 10.1722/6/26554
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