Introduction
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide and is being increasingly diagnosed at younger ages1. Pregnancy-related and early life factors have been shown to have a long-lasting influence on an individual’s future health. While low birthweight and preterm birth have been associated with future development of the metabolic syndrome2 3 and cardiovascular disease4, associations with NAFLD have been conflicting5 6.
Aims & Methods
This nationwide case-control study involving all Swedish children, adolescents, and young adults (≤25 years) who were diagnosed with biopsy-proven NAFLD between 1 January 1992 and 30 April 2017 (n=165) aimed to investigate the relationship between perinatal characteristics with later development of NAFLD. Individuals were matched to up to 5 matched general population comparators (n=717) on age, sex, calendar year, and county of residence. Data on maternal and perinatal characteristics were retrieved from the population-based Swedish Medical Birth Register. We used conditional multivariable-adjusted logistic regression, adjusted for several maternal health- and socioeconomic factors.
Results
Among individuals with biopsy-proven NAFLD, median age at time of diagnosis was 12.0 years (interquartile range 4.4-16.9) and the majority of cases were male (60.6%). There was a strong association between birth weight and future development of NAFLD: low birthweight (<2500g; aOR 4.24; 95% CI 1.03-17.53), normal birthweight (2500-4000g; reference, aOR 1.0), and high birthweight (>4000g; aOR 0.62; 0.27-1.40). A positve association with later NAFLD was also seen for individuals born small for gestational age (SGA, <10th percentile; aOR 3.12; 95% CI 1.84-5.29), when compared to adequate for gestational age (AGA, 10-90th percentile; reference aOR 1.0), and large for gestational age (LGA, >90th percentile; aOR 0.55; 95% CI 0.26-1.18). Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was significantly more common among individuals born with low birthweight (aOR 4.24; 95% CI 1.03-17.53) or SGA (aOR 4.33; 95% CI 1.85-10.10).
Table: Risk of NAFLD According to Perinatal Characteristics
| | NAFLD | Siblings | OR (95% CI)* | OR (95% CI)** | OR (95% CI)*** |
| Birth weight | | | | | |
| Very low or low birthweight (<2500g) | 8 (8.3%) | 9 (7.0%) | 1.26 (0.36-4.33) | 1.73 (0.46-6.55) | 1.60 (0.43-5.91) |
| Normal birthweight (2500-<4000g) | 76 (79.2%) | 95 (74.2%) | 1.00 | 1.00 | 1.00 |
| High or very high birthweight (≥4000) | 12 (12.5%) | 24 (18.8%) | 0.29 (0.10-0.84) | 0.25 (0.08-0.79) | 0.26 (0.08-0.85) |
| Birthweight for gestational age | | | | | |
| SGA (<10th percentile) | 16 (16.7%) | 16 (12.5%) | 2.10 (0.78-5.62) | 2.56 (0.90-7.30) | 2.45 (0.87-6.93) |
| AGA (10-90th percentile) (reference) | 73 (76.0%) | 102 (79.7%) | 1.00 | 1.00 | 1.00 |
| LGA (>90th percentile) | 7 (7.3%) | 10 (7.8%) | 1.08 (0.34-3.39) | 1.39 (0.41-4.75) | 1.39 (0.41-4.73) |
*Model I: Conditioned on family and further adjusted for age, sex, and birthyear.
**Model II: Model I and further adjusted for maternal age, maternal early-pregnancy BMI, maternal country of birth, parity, highest level of education in parents, and smoking in early pregnancy.
***Model III: Model II and further adjusted for pre-eclampsia and gestational diabetes.
Abbreviations: NAFLD, Non-alcoholic fatty liver disease; AGA, appropriate for gestational age; LGA, large for gestational age; OR, Odds ratio; SGA, small for gestational age.Conclusion
This nationwide study involving all children, adolescents, and young adults with biopsy-proven NAFLD compared to matched general population comparators shows a strong association between low birthweight, being born small for gestational age and future NAFLD as well as severe course of disease with development of NAFLD-associated fibrosis or cirrhosis. The findings were independent from maternal metabolic and socioeconomic factors.
References
1. Quek, J., et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 8, 20-30 (2023).
2. Sipola-Leppanen, M., et al. Cardiometabolic Risk Factors in Young Adults Who Were Born Preterm. American Journal of Epidemiology 181, 861-873 (2015).
3. Van Hulst, A., et al. Birth Weight, Postnatal Weight Gain, and Childhood Adiposity in Relation to Lipid Profile and Blood Pressure During Early Adolescence. J Am Heart Assoc 6, e006302 (2017).
4. Barker, D.J., Osmond, C., Forsen, T.J., Kajantie, E. & Eriksson, J.G. Trajectories of growth among children who have coronary events as adults. N Engl J Med 353, 1802-1809 (2005).
5. Querter, I., et al. Maternal and Perinatal Risk Factors for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review. Clinical Gastroenterology and Hepatology 20, 740-755 (2022).
6. Wesolowski, S.R., Kasmi, K.C., Jonscher, K.R. & Friedman, J.E. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 14, 81-96 (2017).
Disclosure
FE has served as advisory board member for Boehringer Ingelheim.
JS has no conflicts of interest.
JFL has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). This study received funding from Janssen corporation. He has also received financial support from MSD to develop a paper reviewing national healthcare registers in China and has ongoing discussions with Takeda about a celiac disease project.
