Pregnancy after liver transplantation: Four-year follow-up of the first case in mainland China

Abstract

The safety and feasibility of pregnancy following liver transplantation (LT) have been accredited in a series of LT center. The first case in mainland China is reported. The follow-up data of a 22-year-old pregnant patient with end-stage liver disease undergone orthotopic liver transplantation were analyzed retrospectively. After surgery, the patient was uneventfully recovered and became pregnant 33 mo after LT. The patient was closely monitored and treated with a standard and individualized triple-drug immunosuppressive therapy throughout her pregnancy. Caesarean section was performed in March 18, 2004, and a health live-born infant was delivered. After the delivery, a 4-year follow-up period indicated that the patient was satisfactory with her condition and her baby was healthy. Our case shows that a successful pregnancy following LT is possible and safe in women with end-stage liver diseases under close monitoring. Three factors including mother, baby, and transplanted liver function must be considered for the safety of high-risk pregnancies.

Key Words: Pregnancy, Liver transplantation, Follow-up

INTRODUCTION

Liver transplantation (LT) is now an acceptable therapy for patients with end-stage liver disease. Among patients undergoing LT, approximately 11% are women at the reproductive age[1]. Within one year after a successful LT, 97% of female patients at the childbearing age recover menstrual function owing to the restored hepatic estrogen metabolism, and the likelihood of conception and successful pregnancy is high[2]. The first known post-transplantation pregnancy in a LT recipient was reported in 1978. Since then, a series of cases have been reported worldwide[3,4]. We report the first case in mainland China.

CASE REPORT

A 22-year-old nulliparous woman, with a 4-year-history of persistent right upper quadrant pain, intermittent jaundice, and fever, was admitted to our hospital in September 2000. She had no particular family or genetic history, and underwent a cholecystostomy for acute cholangitis four months ago. The serum levels of total bilirubin (TB), direct bilirubin (DB), γ-glutamyl transferase (γ-GT) and alkaline phosphatase (ALP), and white blood cell (WBC) count were markedly increased. Microbiologic culture of blood demonstrated that Escherichia coli were the responsible bacteria in the patient. Alpha-fetoprotein (AFP) and viral markers for hepatitis A, B, and C were negative. B-type ultrasonography and computerized tomography (CT) showed a diffuse abscess and cirrhotic nodules in the shrunken liver. Therefore, she was diagnosed having primary biliary cirrhosis, sclerosing cholangitis, bacteremia, and bacterial liver abscess.

On September 28, 2000, after having been treated effectively, she underwent a successful orthotopic LT using conventional techniques with a veno-venous bypass. The donor was a 19-year-old brain-dead healthy female caused by head trauma and her family consented to her organ donation. The overall length of the OLT procedure was 530 min. The duration of anhepatic phase and venous bypass was 97 min and 73 min, respectively. The anastomosis time for suprahepatic vena cava, infrahepatic vena cava, and portal vein was 23, 13, and 15 min, respectively. Standard proximal end-to-end anastomosis between donor’s common hepatic artery and recipient’s proper hepatic artery was performed under magnification, which lasted 22 min. Choledochojejunostomy was carried out with a 40-cm-long Roux-en-Y jejunal limb. A total of 3600 mL blood was transfused and the volume of blood loss was 1400 mL. Intraoperative findings correlated well with CT and B ultrasound findings. The postoperative pathological diagnoses were biliary cirrhosis, sclerosing cholangitis, and liver abscess.

The recipient had an uneventful recovery in the postoperative period. She gained complete consciousness 1 h after LT, received extubation 10 h later, and was discharged on post-LT day 22. Normal menstrual cycles were observed (restored) 3 mo later. After operation, the patient received a standard triple-drug immunosuppressive therapy, including cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone. The dose of each agent was individualized according to the plasma drug concentration. Three months after operation, MMF was discontinued, and prednisone and CsA were maintained. One year later, prednisone was discontinued, and CsA was maintained alone. Twenty-six months later, she had a pregnancy and also an unstable graft. By agreement between the patient and physicians, pregnancy was terminated at 22 wk of gestation. Thirty months after LT, she became pregnant for the second time. During the first trimester of this pregnancy, she presumed to discontinue CsA because of serious pregnancy reaction without physicians’ permission. The sharply increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TB, DB, and ALP were suggestive of rejection. She was hospitalized then and treated with a daily regimen of 1 g of MMF, in addition to 450 mg of CsA. Despite the argument for MMF use during pregnancy, the patient and physicians decided to continue the pregnancy with regular ultrasound examinations. Two months later, she recovered with normal liver function and the fetus developed well. Her serum level of CsA remained within the normal limit (100-150 mg/L).

On March 18, 2004, the mother patient at 37 weeks’ gestation gave birth by Cesarean section to a boy weighing 2000 g and measuring 42 cm in length. The patient’s postpartum course was uneventful with normal liver and renal functions and she was discharged on the 12th d after Caesarean section. However, the newborn’s 1- and 5-min agar scores were 5 and 7, respectively. Although without any congenital malformation, he was diagnosed having hypoxic ischemic encephalopathy and neonatal pneumonia. His immune functions were examined on the first and seventh days after birth, showing that the baby was in a severe immunosuppressive state. After proper and careful treatment, the newborn was discharged in good health on the 22nd d after birth. The child demonstrated normal growth and development during the 4-year follow-up period.

Once a major surgery like LT is performed, a lifelong follow-up is required. After the postpartum course, a series of investigations were followed for the mother patient and her male baby routinely according to the tentative protocol of West China LT center. Subsequent visits were scheduled at each month (the first six months after LT), every 2 mo (6-12 mo after LT), every 3 mo (the 2nd year) and every 3-6 mo (the 3rd year and thereafter). During these visits, routine blood, liver and kidney function, blood concentration of immunosuppressant, hepatitis B or C, and ultrasound scans and X-rays would be regularly undertaken. As an outpatient, she was recommended for a series of notices including self-examination of appetite, abdomen, stool, urine, skin, strength, energy, etc, self-protection from infection, house environment, working environment, keeping fine spirit and proper exercise, relation with the family members, sexual intercourse with her husband and use of contraception, self-examination of her baby’s growth and development, necessary communications with doctors, and regular follow-up. The major content of follow-up at the late-stage post-LT included the monitoring of immunosuppressant concentration, new graft function, discovery of biliary and vascular complications, primary disease recurrency, rejection, and side effects of drugs. Currently, at 49 mo follow-up, the recipient and her son lived well with normal liver allograft function during the follow-up at 49 mo.

DISCUSSION

LT is considered an ultimate life-saving measure for patients with severe liver dysfunction and may provide patients with the best chance for long-term disease-free survival. Successful grafting offers the patient gross improvement in life quality, maximized rehabilitation, and restores the chance for parenthood to most recipients at their reproductive age. Reproductive function and sexuality, which are important components of quality of life, are commonly affected by end-stage liver disease. Shortly after successful LT, most female recipients at childbearing age normalize their menstrual function, thus leading to pregnancy[5].

The number of pregnancies following LT is increasing due to the greater survivals associated with constantly improved management and immunosuppressive regimens. Although pregnancy after LT does not seem to have obviously deleterious effects on allograft function or survival, complications can occur both in mothers and infants. Pregnancies in transplant recipients appear to be associated with increased health risks, including ectopic pregnancy, hypertension and pre-eclampsia, infection, and need for delivery by Cesarean section. The incidence of prematurity, intrauterine growth retardation and malformation is relatively high in newborns at the gestationalage age (SGA), irrespective of the type of immunosuppressive therapy used. The severe risks are mainly related to the fact that transplant recipients must continue immunosuppressive therapy throughout their pregnancy[6].

Most immunosuppressive agents (e.g. azathioprine, cyclosporine, and MMF) have been found to be teratogenic in animals. However, the frequency of birth defects in infants born to women receiving immunosu-ppressive agents is not statistically different from that in the general population[7]. Long-term or late-onset medical complications of immunosuppressive therapy for diseases (e.g. autoimmune disease, cancer, and infertility) are as yet unknown. Immunosuppressive agents can cross the placenta and result in a severe immunosuppressive state in the newborn. Right on the day of delivery, the concentration of CsA in the umbilical blood is 14.1 μg/L (75 -175 μg/L in adults). Cyclosporine is known to cause endothelial cell dysfunction and reduced nitric oxide production, which may be associated with cell dysfunction and hypertension. Tacrolimus-based immunosuppressive regimens are associated with a much lower incidence of new onset of hypertension and toxemia of pregnancy. Report from the National Transplantation Pregnancy Registry (NTPR) demonstrated that there was not any congenital malformation observed in the 5 off springs born to women receiving MMF[2]. So, during pregnancy, female recipients may continue their immunosuppressive medications to stabilize the allograft function. On the other hand, during pregnancy, increased plasma volume and adipose tissue and higher hormone concentrations lead to great changes in drug metabolism. Thus, the levels of immunosuppressive agents must be carefully monitored to individually establish therapeutic doses[3]. Our results are consistent with these findings.

Few data are available on breast-feeding by mothers taking immunosuppressive drugs. Whether the risks of exposure to immunosuppression through breast milk outweigh, the benefits of breast-feeding remain unknown. Our patient did not breast feed her baby because she was on CsA at a dose of 150 mg one day.

Pregnancy does not appear to increase the risk of graft rejection or impairment. In this case, a rejection episode occurred once at 8 wk gestation, and was believed to be related to the patient’s willful disconti-nuation of immunosuppressive therapy. Reduction of immunosuppressive medications during pregnancy, based on the premise of natural nonspecific maternal immuno-suppression, may lead to rejection of transplanted organs, which can be successfully managed with adjustment of immunosuppressive medications.

It was reported that the rate of Cesarean deliveries among LT recipients is higher than that of the general population[8]. In this case, Cesarean section was performed just for obstetric reasons, because we had not any experience with the management of such a patient.

All pregnancies in solid-organ-transplant recipients should be considered at high risk associated with hypertension, preeclampsia, intrauterine growth retardation and prematurity, and managed by a multidi-sciplinary team. The expectant mother should be closely monitored (at least every 2 wk) by her transplantation physicians and her prenatal care should preferentially be managed by a specialist in high-risk obstetrics (maternal-fetal medicine). Nagy et al[2] reported that the interval from transplantation to pregnancy was shorter in the group that had abortions and terminations (24.4 ± 24.3 mo) than in the group that had live births (47.8 ± 28.7 mo). NTPR has advised female organ transplant recipients to wait 1 or 2 years after transplantation before attempting to conceive to insure that the transplanted organ is functioning adequately and to allow for stabilization of the immunosuppressive regimen[7,9]. We strongly advocate delaying conception for at least 24 mo after LT. In reproductive-age women, who have undergone a liver transplant, physicians need to be proactive in discussing fertility issues and should counsel their patients regarding the timing of pregnancy, as well as the risks and alternatives. Moreover, physicians should respect the decision that each recipient makes about the risks and benefits. In this case, till now, the excellent maternal and neonatal outcome was a result of perfect communication and cooperation between the patient and the multidisci-plinary team of our LT center. To the present, two hundred and two pregnancies and 205 outcomes have been reported in 121 LT recipients in NTPR[4]. To our knowledge, this present case is the first successful pregnancy of woman after LT in mainland China.

In conclusion, pregnancies among liver-transplanted female recipients are generally regarded at high risk, but do not seem to have a deleterious effect on graft function or survival. Mother, baby, and transplanted liver function must be considered for the safety of these high-risk pregnancies.