Sex-specific associations between birth weight and adult primary liver cancer in a large cohort of Danish children

Whether the prenatal period is critical for the development of adult primary liver cancer (PLC) is sparsely investigated. Recently, attention has been drawn to potential sex-differences in the early origins of adult disease. We investigated the association between birth weight and adult PLC separately in men and women, using a large cohort of 217,227 children (51% boys), born from 1936 to 1980, from the Copenhagen School Health Records Register, and followed them until 2010 in national registers. Hazard ratios (95% confidence intervals) of PLC (30 years or older) were estimated by Cox regression models stratified by birth cohort. During 5.1 million person-years of follow-up, 185 men and 65 women developed PLC. Sex modified the association between birth weight and adult PLC (p-value for interaction=0.0005). Compared with a sex-specific reference group of birth weights between 3.25-3.75 kg, men with birth weights between 2.00-3.25 kg and 3.75-5.50 kg, had HRs of 1.48 (1.06 to 2.05) and 0.85 (0.56 to 1.28), respectively. Among women the corresponding HRs were 1.71 (0.90 to 3.29) and 3.43 (1.73 to 6.82). Associations were similar for hepatocellular carcinoma only, across year of birth, and after accounting for diagnoses of alcohol-related disorders, viral hepatitis, and biliary cirrhosis. Prenatal exposures influence the risk of adult PLC, and the effects at the high birth weight levels appear to be sex-specific. Our findings underscore the importance of considering sex-specific mechanisms in the early origins of adult PLC.