Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 236–238

236

Blackwell Publishing Ltd. Case SeriesLiver transplantation and pregnancy

Liver transplantation and pregnancy

Adam MORTONMater Misericordiae Hospital, South Brisbane, Queensland, Australia

Introduction

By June 2001, 1193 liver transplants had been carried out inAustralia on local residents. Approximately 350 of these werein women aged less than 50 years. Fertility returns withinmonths of successful liver transplantation. In the presentcase report the course of six pregnancies in three liver trans-plant recipients are described. Three of the pregnancies intwo mothers were complicated by intrahepatic cholestasis ofpregnancy, a possible association previously reported.1 Onepregnancy with significant preconception renal dysfunctionwas complicated by acute chronic renal failure requiringhaemodialysis.

Case 1

A 28-year-old gravida 1, para 0 (patient 1) had a livertransplant for autoimmune hepatitis, 9 months prior toconception. She also had a past history of hypothyroidismand hepatitis C. Immunosuppression was with cyclosporinand prednisone. Preconception serum creatinine (Cr) was0.1 mmol/L. At 29 weeks’ gestation she developed macro-cytic anaemia (haemoglobin, 80 g/L; mean corpusclar volume,102 fL) with normal serum vitamin B12 and red blood cellfolate levels, adequate replacement with thyroxine, and normalreticulocyte count. At 33 weeks’ gestation the patient wasadmitted to hospital with increasing hypertension andproteinuria. Serum Cr had risen to 0.18 mmol/L and thecyclosporine level was 160 µg/L. The patient complained ofprogressive pruritus, and elevated hepatic transaminases,consistent with intrahepatic cholestasis of pregnancy, werenoted. A Caesarean section was carried out at 34 weeks’gestation because of a flat cardiotocogram, as well as persist-ing hypertension and renal dysfunction. A girl weighing2592 g was delivered in good condition. Post-partum thiswoman’s itch resolved and the elevated transaminasesnormalised.

Case 2

Nine years post-transplantation patient 1, now a 36-year-oldgravida 4, para 1, conceived again. Cyclosporine had beenceased 12 months previously because of nephrotoxicity.Immunosuppression was with azathioprine and prednisone.Preconception Cr was 0.1 mmol/L. At 23 weeks’ gestation

the patient complained of generalised itch. The patient’shepatic transaminases were elevated and serum bile acidswere 335 µmol/L (normal <20). Ursodeoxycholic acid wascommenced and the dose gradually increased to 1500 mgper day. The patient’s liver function tests and bile acidsimproved, however, her pruritus worsened. There was norelief with antihistamines, dexamethasone or topical therapies.Because of the uncontrolled pruritus, the patient deliveredher baby at 33 weeks’ gestation. A healthy male baby weigh-ing 2090 g was delivered in good condition. Her itch andabnormal liver function tests gradually settled post-partum,azathioprine was continued.

Case 3

Patient 2, an 18-year-old-gravida 1, para 0, had a livertransplant for biliary atresia 16 years prior to conception.Immunosuppression was with cyclosporine alone. She alsohad hypertension previously treated with lisinopril. This waschanged to methyldopa at 12 weeks’ gestation. Preconcep-tion Cr was measured at 0.1 mmol/L. At 22 weeks’ gestationshe developed normocytic anaemia with normal haematinicsand inappropriately low erythropoietin levels. Her pregnancywas otherwise uneventful and at 38 weeks’ gestation shegave birth vaginally to boy weighing 2645 g.

Case 4

Patient 2, now a 19-year-old gravida 2, para 1, presented withruptured membranes at 19 weeks’ gestation. She proceededto miscarriage.

Case 5

Patient 3, a 26-year-old gravida 1, para 0, had two livertransplants for sclerosing cholangitis, the last being carriedout 2 years prior to conception. She also had a past historyof ulcerative colitis requiring an ileostomy and total colectomy

Correspondence: Dr Adam Morton, Mater Misericordiae Hospital, Raymond Tce, South Brisbane, Queensland 4101, Australia. Email: amorton@mater.org.au

Received 8 January 2003; accepted 31 January 2003.

Liver transplantation and pregnancy

Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 236–238 237

at the age 10 years. Immunosuppression was with cyclosporin,azathioprine and prednisone. Preconception Cr was0.14 mmol/L, and 24-h urine protein was 1.18 g/day. Thecourse of her pregnancy was uneventful until 31 weeks,when she developed hypertension, worsening proteinuria to2.6 g/day, and a rise in serum Cr to 0.18 mmol/L. Thepatient was admitted to hospital, commenced on antihyper-tensives and remained stable until delivery at 35 weeks of ahealthy boy weighing 2277 g.

Case 6

Patient 3, now a 30-year-old gravida 2, para 1, conceivedagain 6 years after her second liver transplant. Cyclosporinehad been changed to tacrolimus because of deteriorationin renal function. She was also taking azathioprine andprednisone. Preconception Cr was 0.19 mmol/L, 24-h urineprotein was 1.5 g/day. Despite detailed counselling regardingthe risks of permanent loss of renal function she elected tocontinue the pregnancy. Ultrasound scan revealed a pairof monochorionic diamniotic twins. Hypertension was wellcontrolled with aldomet 250 mg t.d.s. Tacrolimus was ceasedby her transplant team at 11 weeks’ gestation. Normocyticanaemia (hemoglobin, 86 g/dL) was noted at 18 weeks’gestation. Iron studies were consistent with iron deficiency.Anaemia persisted despite iron given orally and intrave-nously, and erythropoietin 4000 units twice a week. Between18 and 22 weeks’ gestation there was a progressive rise in Crfrom 0.22 to 0.34 mmol/L. Haemofiltration was commencedfour times a week. At 32 weeks’ gestation the patient complainedof itch, and was noted to have elevated transaminases, bilirubinand bile acids consistent with intrahepatic cholestasis ofpregnancy. The ultrasound revealed increasing umbilicalartery resistance in the second twin, and Caesarian sectionwas carried out at 32 weeks. Two male babies, weighing 1555g and 1434 g, respectively, were delivered in good condition.This patient has not required dialysis since delivery, with herCr remaining stable at 0.23 mmol/L 2 months post-partum.

Discussion

Since the first pregnancy to a liver transplant recipient in1978 there have been approximately 380 cases described inthe published data. The largest series of outcomes in 136pregnancies was reported by the National TransplantationPregnancy Registry (NTPR).2 They found a 72% live birthrate, with mean birthweight of 2739 g, at a mean gestationof 36.9 weeks, with 36% of births occurring before37 weeks’ gestation. Drug treated hypertension and pre-eclampsia were seen in 44 and 26% of cyclosporine treatedrecipients, with lower rates of 26 and 9% for those ontacrolimus. Rejection was seen in 8% of pregnancies, and theconclusion drawn was that pregnancy did not alter the prog-nosis of the graft.

No specific patterns of malformations were reported inthe newborn. There were no neonatal deaths, and complications

seen in 25% of newborns were predominantly related toprematurity.

Obstetric complications are increased in solid-organtransplant recipients with prepregnancy renal dysfunction.The NTPR noted adverse events with regard to smallerbabies or maternal complications in almost all of the 10% oftransplant recipients who reported elevations of serum Crin the peripartum period. Two transplant recipients oncyclosporine-based therapy required long-term dialysispost-partum.

In a study of the outcome of pregnancy in women withmoderate or severe renal insufficiency (defined as a precon-ception or first trimester serum Cr >0.12 mmol/L) due toany cause, 43% had a pregnancy-related loss of renal func-tion, with the decline persisting at 6 months post-partum in31%.3 Twenty-three percent of this subgroup had a rapidprogression to end-stage renal failure within 6 months afterdelivery – the risk of this was highest when the serum Cr wasabove 0.18 mmol/L at the beginning of pregnancy. Whereacute renal failure occurs during pregnancy in the absenceof a reversible cause, it is recommended that dialysis isinitiated once the serum Cr is greater than 0.35 mmol/L, orwhere the blood urea is in excess of 20 mmol/L.4 Polyhy-dramnios is common in mothers on dialysis, and may bereduced by increasing the frequency of dialysis to a dailybasis. This also allows for smaller fluid shifts lowering the riskof hypovolaemia, and allows for a more liberal diet. Compar-isons of pregnancy outcomes with peritoneal and haemodi-alysis favour the former, although numbers are too small tobe statistically significant.

A possible association between intrahepatic cholestasisaffecting three women in a series of seven successful preg-nancies to five liver transplant recipients has been reported;however, cholestasis was defined based upon elevation ofalkaline phosphatase, and only two women complained ofpruritus.1 Pruritus and jaundice have also been reported intwo cardiac transplant recipients receiving azathioprine andmethyldopa, with rapid resolution in the second case follow-ing withdrawal of these medications.5

In conclusion, a possible association between intra-hepatic cholestasis of pregnancy and liver transplantationis reported. Pregnancies in liver transplant recipients areassociated with increased risk of maternal and neonatalcomplications, especially where there is renal dysfunctionpreconception.

Acknowledgement

I would like to thank Professor Fung Yee Chan and Dr DavidMcIntyre for their help in preparing the paper.

References

1 Pruvot FR, Declerck N, Valat-Rigot AS et al. Pregnancy afterliver transplantation: focusing on risks to the mother. Trans-plantproc. 1997; 29: 2470–2471.

A. Morton

238 Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 236–238

2 Armenti VT, Herrine SK, Radomski JS, Moritz MJ. Pregnancyafter liver transplantation. Liver Transpl. 2000; 6: 671–685.

3 Jones DC, Hayslett JP. Outcome of pregnancy in women withmoderate or severe renal insufficiency. N Engl J Med. 1996;335: 226–232.

4 Jungers P, Chaveau D. Pregnancy in renal disease. Kidney Int.1997; 52: 871–885.

5 Scott JR, Wagoner LE, Olsen SL, Taylor DO, Renlund DG.Pregnancy in heart transplant recipients: management andoutcome. Obstet Gynecol. 1993; 82: 324–327.