LAUSR

BACKGROUND AIMS Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP. APPROACH RESULTS This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6,722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first- (n=2,279), second- (n=1,373), and third-degree (n=1,758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. First-degree relatives of women who had recurrent ICP or first-trimester ICP appeared to be at higher risks (RRR, 4.30 [2.85-6.48], 3.04 [1.93-4.77], respectively). A minor increased risk was observed in non-biological relatives (RRR, 1.35 [1.05-1.73]; n=4,274, including women's full-brothers' partner and women's husbands' full-sisters). CONCLUSIONS Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second- and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family-clustering. Further investigation is needed to investigate the increased risk of ICP in non-biological relatives.