Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent and associated with an increased risk of adverse pregnancy and birth outcomes,1,2 but the risk of adverse clinical outcomes beyond the perinatal period are under investigated. Recent studies suggest an overlap in clinical and immunological features between MASLD and autoimmune diseases,3,4 but whether fetal exposure to MASLD is associated with a higher risk of offspring autoimmune diseases remains unclear.
Aims & Methods
In this nationwide cohort study, we included all singleton live born offspring with fetal exposure to maternal biopsy-proven MASLD diagnosed in Sweden between 1992 and 2017. We stratified maternal MASLD in simple steatosis versus severe MASLD (defined as either steatohepatitis, any stage of liver fibrosis, or cirrhosis). We matched the 239 identified MASLD offspring with ≤5 reference offspring (n=1,131) of mothers without known MASLD. Matching factors were maternal age at delivery, calendar year of delivery, and parity. We used multivariable Cox proportional hazard models to estimate adjusted hazard ratios (aHRs). The endpoint was any incident autoimmune disease up until December 31, 2023. We performed a sibling-controlled analysis comparing the risk of autoimmune disease in offspring of sisters of women with biopsy-proven MASLD to investigate if early environmental and intrafamilial factors play a role.
Results
During a median of 18.4 years of follow-up (interquartile range [IQR] 13.2-23.8), 15 exposed offspring (incidence rate [IR] 3.4/1000 person-years) vs. 40 reference offspring (IR 1.9/1000 person-years) were diagnosed with autoimmune disease. This corresponded to an aHR of 1.20 (95% CI 0.57-2.53). The median age at incident autoimmune disease was higher among offspring of mothers with MASLD (14.7 years, IQR 5.5-17.5) compared to reference offspring (8.1 years, IQR 4.1-14.1). The sibling analysis yielded a similar risk magnitude (aHR 1.14, 95% CI 0.28-4.63), indicating that early environmental and intrafamilial factors likely do not substantially contribute to the risk of early-onset autoimmune disease. Among MASLD offspring, inflammatory bowel disease was the most frequent autoimmune disease during follow-up (26.7% [n=4] vs. 7.5% [n=3] among reference offspring), followed by type 1 diabetes (20%, n=3), and celiac disease (13.3%, n=2). Among reference offspring, celiac disease was the most common autoimmune disease (32.5%, n=13), followed by type 1 diabetes (27.5%, n=11) and psoriasis (15%, n=6). The risk of autoimmune disease remained unchanged among 175 offspring born to mothers with simple steatosis alone (aHR 0.84, 95% CI 0.29-2.45). However, we saw a positive association in 64 offspring of mothers with severe MASLD, but the risk estimate failed to attain statistical significance possibly due to small sample size (aHR 1.98, 95% CI 0.67-5.84).
Conclusion
Fetal exposure to maternal MASLD does not seem to be associated with increased risk of autoimmune disease in the offspring up until early adulthood. Further, studies with longer follow-up are needed to investigate the long-term risk of autoimmune disease after fetal exposure to MASLD.
References
[1] Hagström H, Höijer J, Ludvigsson JF, Bottai M, Ekbom A, Hultcrantz R, Stephansson O, Stokkeland K. Adverse outcomes of pregnancy in women with non-alcoholic fatty liver disease. Liver Int. 2016 Feb;36(2):268-74. doi: 10.1111/liv.12902. Epub 2015 Sep 9. PMID: 26114995.
[2] El Jamaly H, Eslick GD, Weltman M. Systematic review with meta-analysis: Non-alcoholic fatty liver disease and the association with pregnancy outcomes. Clin Mol Hepatol. 2022;28(1):52-66. doi:10.3350/CMH.2021.0205
[3] Zhu YJ, Zhang Y, Rao Y, Jiang Y, Liu YG, Li JZ, Yuan JQ, Zhao Y, Zheng WW, Ma L, Wang CY, Li J. Evaluation of autoimmune phenomena in patients with nonalcoholic fatty liver disease on the basis of liver pathology. World J Hepatol. 2024 Dec 27;16(12):1407-1416. doi: 10.4254/wjh.v16.i12.1407. PMID: 39744192; PMCID: PMC11686539.
[4] Xu M, Wu T, Li Z, Xin G. Influence of genetically predicted autoimmune diseases on NAFLD. Front Immunol. 2023 Sep 11;14:1229570. doi: 10.3389/fimmu.2023.1229570. PMID: 37767101; PMCID: PMC10520707.
Disclosure
Conflict of interests
C.A.M. has no conflict of interest
F.E. has served as an advisory board member for Boehringer Ingelheim.
D.B.: has no conflict of interest
J.S.: has no conflict of interest
H.H.: HH:s institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. H.H. has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers-Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Arrowhead, Boehringer Ingelheim, KOWA and GW Pharma.
M.T.: has no conflict of interest
O.S.: has no conflict of interest
J.F.L.: Dr Ludvigsson has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen corporation. Dr Ludvigsson has also received financial support from Merck developing a paper reviewing national healthcare registers in China. Dr Ludvigsson has an ongoing research collaboration on celiac disease with Takeda; and additional collaboration within IBD with Merck.
