Introduction
The maternal safety of thiopurines (TP), including azathioprine (AZA) and mercaptopurine (6MP), in pregnancy for IBD management is well established. However, intrahepatic cholestasis of pregnancy (ICP) occurs more commonly in TP exposed IBD pregnancies1,2,. TP ‘shunting’ with a 6-methylmecrcaptopurine (MMP) to 6-thiogaunine (TGN) ratio of >11, is associated with hepatotoxicity, and increasingly occurs in later pregnancy3. We aimed to explore the mechanisms behind TP exposure and ICP, and identify risk minimisation strategies.
Aims & Methods
Pregnant or preconception participants with IBD receiving 6MP, AZA or biologic monotherapy (BM) were recruited to this prospective multi-centre cohort study. Demographic and disease activity data, as well as TP metabolites, biochemical and haemotologic parameters were obtained prior to conception (PC), in each trimester of pregnancy (T1, T2, T3), at delivery (D), and 6 weeks post-partum (PP). Bile acids (BA) were collected in T2 and T3 in TP exposed pregnancies. ICP was defined by BA >10 with clinical symptoms and LFT derangement. Obstetric outcomes were compared between TP and BM exposed controls. TP metabolites were assessed with high performance liquid chromatography and reported in pmol/8 x 108 RBCs.
Results
131 TP and 147 BM exposed pregnancies were included. 63% of TP pregnancy (82) received AZA and 60% (78) had CD. 12% receiving TP (13/109) had a pre-existing shunting phenotype. 59% (77) received concomitant biologics. 60% (75) had a prior pregnancy, with 5.3% (4) of those having had ICP. TP pregnancies were more likely to be exposed to aminosalycylates (39 vs 14%, p<0.01), and infliximab (32 vs 10, <0.01) and less likely exposed to ustekinumab (8 vs 44, <0.01) and vedolizumab (3 vs 29, <0.01). The median AZA dose was 100mg (IQR 75-150) and 6MP 50mg (IQR 50-75).
Rates of biochemically active disease were equivalent between TP and BM pregnancies. The median faecal calprotectin (FC) for TP exposed pregnancies was 42mg/ml (95% CI 11.9-126.5, n=72) PC, 45mg/ml (9.3-149, 89) in TI, 27mg/ml (12-74, 109) in T2, 21mg/ml (9.8-76, 86) in T3 and 19.7mg/ml (7.9-82.6, 72) PP. For BM pregnancies, the FC was 58mg/ml (95% CI 18.2-251, n=51) PC, 39mg/ml (18.6-150, 75) in T1, 38mg/ml (14.8-106, 80) in T2, 49.9mg/ml (17-189, 68) in T3 and 60mg/ml (13.9-156, 33) PP. FC did not change over the course of pregnancy in TP (p=0.63, Skilling’s Mack) and BM exposed (p=0.73) participants. In TP pregnancies, FC and TGN weakly negatively correlated prior to conception (-0.36, p=0.02, Spearman coefficient), but not at any other timepoint (first trimester; r=-0.07 p=0.59, second trimester; -0.09 p=0.39, third trimester; r=-0.09 p=0.44, postpartum; -0.14 p=0.29).
In those with no dose changes, MMP/TGN increased from PC to T3 (Skilling's Mack p<0.01) (Table 1).
| Timepoint | TGN (median, IQR) | MMP (median, IQR) | MMP/TGN (median, IQR) | MMP/TGN
over pregnancy (Skillings Mack) |
| Preconception (n=59) | 278 (152-368) | 808 (281-2373) | 3.9 (1.3-7.7) | Increased PC to T3 (p<0.01) & T1 to T3 (p 0.04) |
| Trimester 1 (n=78) | 238 (147-363) | 749 (249-2229) | 3.6 (1.2-9.2) |
| Trimester 2 (n=102) | 194 (135-283) | 833 (312-2390) | 4.5 (1.7-14) |
| Trimester 3 (n=91) | 186 (134-258) | 657 (255-1693) | 4.6 (1.4-11.6) |
| Delivery (n=69) | 214 (142-275) | 544 (214-1675) | 2.9 (1.1-7.8) |
| Postpartum (n=75) | 249 (163-400) | 410 (203-1031) | 2.2 (1.1-4.5) |
Table:
Thiopurine metabolites over the course of pregnancy (median, IQR)24% (18/76), 25% (26/103), 26% (24/92) and 17% (12/72) were shunting in T1, T2, T3 and at D respectively. 2.6% (3/116) were receiving split dose TP PC, and of these with bloods taken, 50% (3/6) were shunting in T1, 75% (2/8) in T2, 43% (3/7) in T3 & 20% (1/5) at D. Of PC shunters, 38.5% (5/13) had their dose split over pregnancy; 7.7% (1/13) PC, 23% (3/13) in T1 and 8% (1/13) in T2. Overall, 4% had their dose split (4/100) in T1, 7% in T2 (8/111) and 2% in T3 (2/105). In those who had their dose split in T2 for shunting management, the median MMP/TGN ratio decreased from 18 (IQR 6-57) in T2 to 7 (IQR 3-8) in T3 (p<0.01 Wilcoxon sign-rank) and 3 (IQR 2-3.5) at D (p=0.04).
Elevated ALT was observed in 8.1% (5/62) of TP pregnancies in T1, 5.7% (5/89) in T2, 18.3% (15/82) in T3 and 34.5% (20/38) at D. Increasing MMP was associated with an increasing ALT in T1 (0.001, 0.03), T3 (coeff. 0.002, p=0.001), PP (0.003, p=0.02) and at D (0.002, p<0.01). 60% (3/5), 50% (6/12) and 21.1% (4/19) with elevated ALT in T2, T3 and at D were diagnosed with ICP. The risk of ICP was increased in TP (6.7%, 7/105) vs BM (0%, 0/112) pregnancies (p<0.01). With multivariate binary linear regression, ICP risk was increased with shunting in T3 (RR 8.9, 95% CI 1.2-65.6 p=0.03) and at D (11.4,1.18-110.3, 0.04), TP dose increase antenatally (5.3, 1.4-23.5, <0.01) and prior ICP (21.1, 1.8-249.0, 0.02). Increasing MMP in T2 (0.011, 0.03), T3 (0.001, <0.01) and at D (0.006, <0.01) were associated with increasing bile acids. Of the 7 TP pregnancies with ICP, 1 had a history of shunting PC, and 1 had a prior history of ICP. All were shunting in pregnancy, with 2/7 having an MMP/TGN >75 in T3. 4 cases occurred following a TP dose increase. There was no increased risk of adverse obstetric outcomes, including preterm delivery (RR 0.40, 95% CI 0.05-2.79, p=0.3) and low birth weight (0.61, 0.14-2.62, 0.5) in TP vs BM pregnancies.
Conclusion
TP exposure was associated with an increased risk of ICP. In particular, TP shunting in late pregnancy, TP dose increases and prior ICP were associated with increased ICP risk. Shunting can be effectively managed with TP split dosing. TP dose increases should be avoided in pregnancy, and TP metabolites routinely monitored.
References
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Disclosure
Nil
