Poster Presentation - Cholestasis in Pregnancy Day Society of Obstetric Medicine of Australia and New Zealand ASM 2023

Thiopurine metabolites as a novel tool to guide azathioprine dosing in pregnancy: an interim analysis   (#75)

Paul Champion de Crespigny 1 2 3 4 , Anna Krelle 2 , Sarah Price 1 2 4 5 6 , Peter Hughes 1 3
  1. Department of Medicine, The University of Melbourne , Melbourne
  2. Department of Obstetric Medicine, The Royal Women's Hospital , Melbourne
  3. Department of Nephrology, The Royal Melbourne Hospital, Melbourne
  4. Department of Obstetric Medicine, Frances Perry House, Melbourne
  5. Department of Diabetes and Endocrinology, The Royal Melbourne Hospital , Melbourne
  6. Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne

Background:Mycophenolate-based immunosuppression regimes have complicated reproductive planning for women with kidney transplants. Most women are advised to transition from mycophenolate to azathioprine prior to conception1. Although azathioprine dosing is weight-based, the optimal level of immunosuppression for pregnant women has not been established. Established data suggests that thiopurine metabolite levels correlate with the risk of marrow suppression and hepatic toxicity. We aim to understand the role of thiopurine metabolites in pregnancy with respect to azathioprine dose and pregnancy outcomes.

Methods:We conducted a 3-year retrospective audit of pregnant women with a kidney transplant taking azathioprine at a tertiary maternity centre in Melbourne, Australia, between 1st January-2021 and 1st June-2023. The electronic medical record was screened for women meeting inclusion criteria and individual records were reviewed by two research staff to establish a consensus. Data on thiopurine metabolite levels collected at least once during pregnancy, pathology results of liver and bone marrow function, and pregnancy outcomes were collected.

Results:We identified 17 subjects who met inclusion criteria including two subjects with kidney-pancreas transplants. Mean maternal age at conception was 35years (29–42). The median 6-Methylmercaptopurine (6-MMP) and Thioguanine Nucleotide (6-TGN) level was 664pmol/8x10^8 RBC and 335pmol/8x10^8 RBC (113 – 697) respectively. The median MMP:6-TG Ratio was 1.54 (0.4–27).

The median pregnancy haemoglobin was 99g/L (85–133) and there was no evidence of acute bone marrow suppression at any time-point. The median change in alanine aminotransferase (ALT) throughout pregnancy was 4 U/L (0–52), with 2 patients having a 2-fold rise in their baseline ALT.  The median change in aspartate aminotransferase (AST) throughout the pregnancy was 5U/L (0–63), with only 1 patient having a 2-fold rise in their baseline AST. 

Three subjects developed severe intrahepatic cholestasis of pregnancy (ICP). One of these cases had a significantly elevated 6-MMP level (7440pmol/8x10^8 RBC) and the other a 6-MMP level above the median at 779pmol/8x10^8 RBC. Other significant pregnancy outcomes are reported in Table 1.  

Conclusions:Thiopurine metabolites were highly variable between patients. There were no significant episodes of bone marrow suppression or hepatic toxicity. However, three subjects (18%) developed severe ICP which may be associated with azathioprine use2,3. Ongoing research into thiopurine metabolites within this unique population may guide dosing and improve pregnancy outcomes. 

 

Table 1: Adverse pregnancy outcomes in kidney transplant recipients during pregnancy

Adverse pregnancy outcome

Number(n=17)

ICP 

3(18%)

AFLP

0(0%)

Preeclampsia

4(29%)

HELLP

1(6%)

Extreme pre-term delivery

1(6%)

Fetal death >20weeks gestation

2(12%)
  1. Gaston R. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001 Dec;38(6 Suppl 6):S25-35.doi: 10.1053/ajkd.2001.28923.
  2. Céruti H, Kayem G, Guilbaud L et al. Intrahepatic cholestasis of pregnancy associated with azathioprine: A case series..J Gynecol Obstet Hum Reprod. 2021 Apr;50(4):102083. doi: 10.1016/j.jogoh.2021.102083.
  3. Lauterbach R, Linder R, Vitner D et al. Azathioprine-induced cholestasis of pregnancy-A new insight on azathioprine safety in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2020 Jul;250:271-272. doi: 10.1016/j.ejogrb.2020.05.002.