Background
The strongest independent risk factor for developing inflammatory bowel disease (IBD) is a family history with IBD. The early life, including the intra-uterine period, is critical for immune system maturation and therefore, exposures during early life can influence IBD risk. We conducted this study to understand if the risk of IBD in the offspring of women with IBD is due to an inflammatory prenatal environment in addition to genetic predisposition.

Methods
Using cross-linked nationwide Danish health registers, we identified all individuals born in Denmark from 1997 to 2022 as well as their legal parents. Of these, we identified all individuals diagnosed with IBD and the date of diagnosis. The follow up period was from the date of birth until date of IBD diagnosis, death, emigration, or August 1, 2022, whichever occurred first. We performed Cox proportional hazards analyses adjusted for calendar period to assess the risk of IBD in individuals born of mothers diagnosed with IBD before childbirth, those diagnosed with IBD after childbirth, and those with no IBD diagnosis. Since paternal IBD status would be unlikely to influence the prenatal environment, we performed corresponding analyses of paternal IBD status as a negative control analysis.

Results
We identified 1,290,358 children born in Denmark between 1997 and 2022. Of these, 10,041 (0.8 %) had a mother with IBD before childbirth and 9,985 (0.8 %) had a mother with IBD onset after childbirth. Individuals were followed for a total of 18,370,420 person-years, with a median (IQR) follow up time of 14.4 (8.6, 19.9) years. A total of 3,537 individuals were diagnosed with IBD before the end of follow up. The hazard ratio of IBD in individuals born of mothers diagnosed with IBD before childbirth was 6.29 (95% CI 5.23, 7.56) compared to those whose mother did not have IBD. The corresponding hazard ratio for those diagnosed with IBD after childbirth was 3.88 (95% CI 3.27, 4.60) (p<0.001). In our negative control analysis assessing risk based on paternal IBD status, risk was increased in the same direction. Hazard ratios of IBD were 5.26 (95% CI 4.22,6.56) and 3.73 (95% CI 3.10, 4.50) (p<0.001), respectively (Figure 1).

Conclusion
In this population-based cohort study, the risk of IBD is highest among individuals with either parent diagnosed with IBD before childbirth. These findings suggest that the timing of parental IBD diagnosis, in addition to family history of IBD, influences IBD risk. Since these associations are consistent across maternal and paternal IBD status, genetic predisposition may play a weightier role than a prenatal inflammatory environment in the IBD risk of offspring to IBD patients.

Figure 1. The hazard ratio of IBD in offspring according to maternal and paternal IBD onset.

Linéa Bonfils

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