Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Novel insights into causal effects of maternal nonalcoholic fatty liver disease on adverse pregnancy outcomes: evidence from Human Genetics and Mendelian Randomization Study

European Journal of Clinical Nutrition volume 78, pages 1041–1050 (2024)Cite this article

Subjects

Abstract

Background

Observational studies have associated nonalcoholic fatty liver disease (NAFLD) with adverse pregnancy events, but findings show heterogeneity, leaving the causal direction and mediating pathways unclear. We aimed to investigate the causal relation between NAFLD and various pregnancy events, and to elucidate the underlying mediating pathways while determining the proportion of this correlation that is mediated through these pathways.

Methods

A genome-wide association study involving over 6 million participants employing Mendelian randomization (MR) and mediation analysis was performed. The study used genetically predicted NAFLD as exposures and cardiometabolic traits as mediators, with various adverse pregnancy events as outcomes. The main analysis was performed using the inverse variance weighted (IVW) approach, while sensitivity analyses included the weighted median, weighted mode, MR-Egger, and MR-PRESSO methods. Mediation analyses were performed using a two-step MR framework.

Results

In this MR cohort study, NAFLD was found to be strongly associated with elevated risks of GDM (P = 0.019 for the discovery dataset, P < 0.001 for the discovery dataset) and HDPs, including any HDP (P < 0.001 for the both datasets), gestational hypertension (P = 0.007 for the discovery dataset, P < 0.001 for the discovery dataset), and pre-eclampsia or eclampsia (P = 0.040 for the discovery dataset, P < 0.001 for the discovery dataset). However, no significant associations were found with hemorrhage in early pregnancy, postpartum hemorrhage, preterm birth, or offspring birthweight for both datasets. Cardiometabolic traits played a significant mediating role in these associations, rather than solely acting as confounding factors.

Conclusions

This study provided evidence supporting a correlation between NAFLD and a higher risk of adverse pregnancy events and introduces some new insights. These findings may inform preventions and interventions for remediating adverse pregnancy outcomes attributable to NAFLD.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic presentation for this study.
Fig. 2: Associations Between Genetically Estimated NAFLD and Adverse Pregnancy events.
Fig. 3: Associations between genetically estimated NAFLD and cardiometabolic risk factors.
Fig. 4: Associations between genetically estimated cardiometabolic risk factors and adverse pregnancy events.
Fig. 5: Mediation effects of cardiometabolic risk factors in the associations between genetically estimated NAFLD and adverse pregnancy events.

Similar content being viewed by others

Data availability

All the GWAS datasets in this study were from primary published articles and publicly accessible summary data online, including FinnGen and UK Biobank et al. Further details and other data that support the findings of this study are available from the corresponding author upon request.

Code availability

The codes are available from the corresponding author upon request.

References

  1. Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol. 2022;19:60–78.

    Article  CAS  PubMed  Google Scholar 

  2. Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61.

    Article  CAS  PubMed  Google Scholar 

  3. Lim GEH, Tang A, Ng CH, Chin YH, Lim WH, Tan DJH, et al. An observational data meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD. Clin Gastroenterol Hepatol. 2023;21:619–29.e7.

    Article  PubMed  Google Scholar 

  4. Le MH, Yeo YH, Zou B, Barnet S, Henry L, Cheung R, et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical Bayesian approach. Clin Mol Hepatol. 2022;28:841–50.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Arshad T, Golabi P, Paik J, Mishra A, Younossi ZM. Prevalence of nonalcoholic fatty liver disease in the female population. Hepatol Commun. 2019;3:74–83.

    Article  PubMed  Google Scholar 

  6. Sarkar M, Grab J, Dodge JL, Gunderson EP, Rubin J, Irani RA, et al. Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes. J Hepatol. 2020;73:516–22.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hagstrom H, Hoijer J, Ludvigsson JF, Bottai M, Ekbom A, Hultcrantz R, et al. Adverse outcomes of pregnancy in women with non-alcoholic fatty liver disease. Liver Int. 2016;36:268–74.

    Article  PubMed  Google Scholar 

  8. Qian Y, Zhang Y, Fan X, Yan H, Li X, Fan Y, et al. Nonalcoholic fatty liver disease and adverse pregnancy events in women with normal prepregnant weight. J Clin Endocrinol Metab. 2023;108:463–71.

    Article  PubMed  Google Scholar 

  9. Poston L, Caleyachetty R, Cnattingius S, Corvalan C, Uauy R, Herring S, et al. Preconceptional and maternal obesity: epidemiology and health consequences. Lancet Diabetes Endocrinol. 2016;4:1025–36.

    Article  PubMed  Google Scholar 

  10. Creanga AA, Catalano PM, Bateman BT. Obesity in pregnancy. N Engl J Med. 2022;387:248–59.

    Article  CAS  PubMed  Google Scholar 

  11. Park SH, Kim DJ, Plank LD. Association of grip strength with non-alcoholic fatty liver disease: investigation of the roles of insulin resistance and inflammation as mediators. Eur J Clin Nutr. 2020;74:1401–9.

    Article  CAS  PubMed  Google Scholar 

  12. Mnatzaganian G, Woodward M, McIntyre HD, Ma L, Yuen N, He F, et al. Trends in percentages of gestational diabetes mellitus attributable to overweight, obesity, and morbid obesity in regional Victoria: an eight-year population-based panel study. BMC Pregnancy Childbirth. 2022;22:95.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kim SY, England L, Wilson HG, Bish C, Satten GA, Dietz P. Percentage of gestational diabetes mellitus attributable to overweight and obesity. Am J Public Health. 2010;100:1047–52.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gross A, Lange M, Rosenbluth E, Carroll C, Sperling R, Juliano C, et al. Evaluation of 2-year outcomes in infants born to mothers with and without NAFLD in pregnancy. Eur J Pediatr. 2023;182:3765–74.

    Article  PubMed  Google Scholar 

  15. Chai TY, Byth K, George J, Pasupathy D, Cheung NW. Elevated hepatic steatosis index is associated with the development of adverse maternal, but not adverse neonatal, outcomes: a retrospective cohort study. Int J Women’s Health. 2023;15:589–98.

    Article  CAS  Google Scholar 

  16. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, et al. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet. 2022;54:761–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zeng L, Li Y, Hong C, Wang J, Zhu H, Li Q, et al. Association between fatty liver index and controlled attenuation parameters as markers of metabolic dysfunction-associated fatty liver disease and bone mineral density: observational and two-sample Mendelian randomization studies. Osteoporos Int. 2024;35:679–89.

    Article  CAS  PubMed  Google Scholar 

  19. Khan SS, Brewer LC, Canobbio MM, Cipolla MJ, Grobman WA, Lewey J, et al. Optimizing prepregnancy cardiovascular health to improve outcomes in pregnant and postpartum individuals and offspring: a scientific statement from the American Heart Association. Circulation. 2023;147:e76–91.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet. 2018;28:166–74.

    Article  PubMed Central  Google Scholar 

  21. Mbatchou J, Barnard L, Backman J, Marcketta A, Kosmicki JA, Ziyatdinov A, et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet. 2021;53:1097–103.

    Article  CAS  PubMed  Google Scholar 

  22. Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50:1505–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, et al. The power of genetic diversity in genome-wide association studies of lipids. Nature. 2021;600:675–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53:1415–24.

    Article  CAS  PubMed  Google Scholar 

  25. Wu Y, Zhong X, Lin Y, Zhao Z, Chen J, Zheng B, et al. Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies. Proc Natl Acad Sci USA 2021;118:e2023184118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613:508–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ye CJ, Kong LJ, Wang YY, Dou C, Zheng J, Xu M, et al. Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans. Nat Hum Behav. 2023;7:1357–70.

    Article  PubMed  Google Scholar 

  28. Verbanck M, Chen C-Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yavorska OO, Burgess S. MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017;46:1734–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lee SM, Kwak SH, Koo JN, Oh IH, Kwon JE, Kim BJ, et al. Non-alcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus. Diabetologia. 2019;62:238–48.

    Article  CAS  PubMed  Google Scholar 

  32. Lee SM, Jung YM, Choi ES, Kwak SH, Koo JN, Oh IH, et al. Metabolic dysfunction-associated fatty liver disease and subsequent development of adverse pregnancy events. Clin Gastroenterol Hepatol. 2022;20:2542–50.e8.

    Article  PubMed  Google Scholar 

  33. Hershman M, Mei R, Kushner T. Implications of Nonalcoholic Fatty Liver Disease on Pregnancy and Maternal and Child Outcomes. Gastroenterol Hepatol (N Y). 2019;15:221–8.

    PubMed  Google Scholar 

  34. Lavery J, Friedman A, Keyes K, Wright J, Ananth C. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG. 2017;124:804–13.

    Article  CAS  PubMed  Google Scholar 

  35. McCance DR, Cassidy L. Diabetes in pregnancy. In: Textbook of diabetes. John Wiley & Sons Ltd. 2024. pp. 1034–71.

  36. El Jamaly H, Eslick GD, Weltman M. Systematic review with meta-analysis: non-alcoholic fatty liver disease and the association with pregnancy events. Clin Mol Hepatol. 2022;28:52–66.

    Article  PubMed  Google Scholar 

  37. Hutcheon JA, Chiolero A, Hanley JA. Random measurement error and regression dilution bias. BMJ. 2010;340:c2289.

    Article  PubMed  Google Scholar 

  38. Eslam M, El-Serag HB, Francque S, Sarin SK, Wei L, Bugianesi E, et al. Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nat Rev Gastroenterol Hepatol. 2022;19:638–51.

    Article  PubMed  Google Scholar 

  39. Zhang Z, Li L, Hu Z, Zhou L, Zhang Z, Xiong Y, et al. The causal associations of non-alcoholic fatty liver disease with blood pressure and the mediating effects of cardiometabolic risk factors: a Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2023;33:2151–9.

    Article  CAS  PubMed  Google Scholar 

  40. Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol. 2020;73:263–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xie J, Huang H, Liu Z, Li Y, Yu C, Xu L, et al. The associations between modifiable risk factors and nonalcoholic fatty liver disease: a comprehensive Mendelian randomization study. Hepatology. 2023;77:949–64.

    Article  PubMed  Google Scholar 

  42. Song X, Wang C, Wang T, Zhang S, Qin J. Obesity and risk of gestational diabetes mellitus: a two-sample Mendelian randomization study. Diabetes Res Clin Pract. 2023;197:110561.

    Article  PubMed  Google Scholar 

  43. Rogne T, Gill D, Liew Z, Shi X, Stensrud VH, Nilsen TIL, et al. Mediating factors in the association of maternal educational level with pregnancy events: a Mendelian Randomization Study. JAMA Netw Open. 2024;7:e2351166.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ardissino M, Slob EAW, Millar O, Reddy RK, Lazzari L, Patel KHK, et al. Maternal hypertension increases risk of preeclampsia and low fetal birthweight: genetic evidence from a Mendelian Randomization Study. Hypertension. 2022;79:588–98.

    Article  CAS  PubMed  Google Scholar 

  45. Hosier H, Lipkind HS, Rasheed H, DeWan AT, Rogne T. Dyslipidemia and risk of preeclampsia: a multiancestry Mendelian Randomization Study. Hypertension. 2023;80:1067–76.

    Article  CAS  PubMed  Google Scholar 

  46. Chen Y, Mu L. Non-alcoholic fatty liver disease, pregnancy loss and preterm birth: a Mendelian Randomization study. Fertil Steril. 2023;120:e102.

    Article  Google Scholar 

  47. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371:1131–41.

    Article  PubMed  Google Scholar 

  48. DeFilippis AP, Blaha MJ, Martin SS, Reed RM, Jones SR, Nasir K, et al. Nonalcoholic fatty liver disease and serum lipoproteins: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2013;227:429–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang J, Meng X, Li J, Gong X, Wu T, Shi H, et al. Serum lipid reference values recommended during a twin pregnancy and evaluating its association with perinatal outcomes. BMC Pregnancy Childbirth. 2024;24:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hu J, Gillies CL, Lin S, Stewart ZA, Melford SE, Abrams KR, et al. Association of maternal lipid profile and gestational diabetes mellitus: a systematic review and meta-analysis of 292 studies and 97,880 women. EClinicalMedicine. 2021;34:100830.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Steinthorsdottir V, McGinnis R, Williams NO, Stefansdottir L, Thorleifsson G, Shooter S, et al. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women. Nat Commun. 2020;11:5976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Häring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol. 2016;12:721–37.

    Article  CAS  PubMed  Google Scholar 

  53. Kiiskinen T, Mars NJ, Palviainen T, Koskela J, Rämö JT, Ripatti P, et al. Genomic prediction of alcohol-related morbidity and mortality. Transl Psychiatry. 2020;10:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Nanning Maternity and Child Health Hospital, Nanning, PR China

    Qiuyan Luo, Guoting Liu, Qiulan Li, Jinghong Lu, Wenjing Zheng & Yukui Huang

  2. Department of Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, PR China

    Cun Li

Authors
  1. Qiuyan Luo
    View author publications

    Search author on:PubMed Google Scholar

  2. Guoting Liu
    View author publications

    Search author on:PubMed Google Scholar

  3. Qiulan Li
    View author publications

    Search author on:PubMed Google Scholar

  4. Jinghong Lu
    View author publications

    Search author on:PubMed Google Scholar

  5. Wenjing Zheng
    View author publications

    Search author on:PubMed Google Scholar

  6. Yukui Huang
    View author publications

    Search author on:PubMed Google Scholar

  7. Cun Li
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Cun Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Qiuyan Luo, Cun Li, and Yukui Huang conceived and designed the research methods. Qiuyan Luo, Guoting Liu, Qiulan Li, Jinghong Lu, and Wenjing Zheng collected and analyzed the data. Qiuyan Luo and Cun Li wrote the original draft. Yukui Huang reviewed and edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yukui Huang or Cun Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

All the GWAS datasets in this study were from publicly accessible summary data online, including FinnGen and UK Biobank et al. The approval for utilizing FinnGen data was granted by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District under reference number HUS/990/2017. Additionally, the ethical approvals for individual studies included in the analysis were detailed elsewhere [53]. For the UK Biobank data, ethical approval was obtained from the North West Multi-centre Research Ethics Committee (MREC). The study’s procedures were conducted in accordance with publicly accessible summary data.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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

Luo, Q., Liu, G., Li, Q. et al. Novel insights into causal effects of maternal nonalcoholic fatty liver disease on adverse pregnancy outcomes: evidence from Human Genetics and Mendelian Randomization Study. Eur J Clin Nutr 78, 1041–1050 (2024). https://doi.org/10.1038/s41430-024-01489-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41430-024-01489-7

This article is cited by

Search

Advanced search

Quick links