AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2
March 1991
TWIN PREGNANCY AFTER ORTHOTOPIC LIVER TRANSPLANTATION, WITH EXACERBATION OF CHRONIC GRAFT REJECTION Daniel R. Grow, M.D., Nicolas V. Simon, M.D., Jonathan Liss, M.D., and William T. Delp, M.D.
We report the sixth pregnancy and the first occurrence of twins after liver transplantation, and the second time cyclosporine was used in pregnancy for that indication. The pregnancy was interrupted at 33 weeks, menstrual age, for exacerbation of chronic graft rejection and intrauterine growth retardation of both twins with possible fetal compromise. The neonatal outcomes were good without any detected anomalies except for some neurodevelopmental problems in one twin at the long-term follow-up. The mother underwent a second liver transplant shortly after delivery.
Orthotopic liver transplantation is a procedure increasingly performed throughout the world. With the advent of cyclosporin A and the experience with immunosuppression gained from renal transplantation, the 5-year survival rate of liver transplant recipients now approaches 50%.! In spite of the increasing number of survivors, there are onlyfivereported pregnancies following liver transplantation,2"7 with two occurrences in the same patient.4-5 Of these five pregnancies, one was electively terminated in the first trimester2 and four ended between 28 and 40 weeks, menstrual age, in live births but with fetal growth retardation.4-7 Only one of these four latter pregnancies included cyclosporine as a part of the immunosuppressive regimen.7 Because of the rarity of the event and the limited experience with cyclosporine in pregnancy,7-8 we present the fifth case of pregnancy resulting in live birth, which is also the first reported occurrence of twins and the second reported use of cyclosporine in a pregnant woman following liver transplantation.7 CASE REPORT
A 24-year-old primiparous woman underwent an orthotopic liver transplantation for fulminant cryptogenic liver failure in February 1986 at the University of Pittsburgh Transplant Center. Severe
acute rejection occurred following the transplant, requiring aggressive immunosuppressive therapy that included the administration of the monoclonal antibody OKT3. Pneumocystis carinii pneumonia and cytomegalovirus gastritis resulted but resolved after tapering the immunosuppressive therapy to simply cyclosporine. The patient was discharged on 400 mg cyclosporine and 10 mg prednisone daily, 2 months after the transplant. During the ensuing 20 months, she was rehospitalized twice for exacerbation of chronic rejection. Control was maintained with 300 mg cyclosporin, 50 mg azathioprine, and 15 mg prednisone daily. She also received atenolol 75 mg a day for post-transplant hypertension. While following this regimen, the patient had regular menses at intervals of 27 days. Twenty-three months after her liver transplantation, the patient conceived following a spontaneous ovulation. Eight weeks after her last menstrual period (LMP), an ultrasound revealed a twin gestation. Both crownrump lengths were compatible with her menstrual age by LMP. The patient was followed with biweekly complete blood counts, liver function tests, prothrombin times, electrolytes, and creatinine, uric acid, and cyclosporine serum levels. At 10 weeks' menstrual age, the patient developed fever and elevated liver enzymes (aspartate aminotransferase: 325 U/liter (normal 10 to 41 U/liter); alanine aminotransferase: 271 U/liter (normal, 8 to 40 U/liter).
Department of Obstetrics and Gynecology and Department of Pediatrics, Division of Newborn Medicine, York Hospital, York, Pennsylvania Reprint requests: Dr. Simon, Department of Obstetrics and Gynecology, York Hospital, 1001 South George Street, York, PA 17405 Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
135
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ABSTRACT
136
A liver biopsy showed focal bile duct loss and changes consistent with on-going rejection. Rejec-tion was controlled by two 1 gm injections of methylprednisone intravenously and by increasing the cyclosporine from 300 to 400 mg daily. At 28 weeks, menstrual age, the liver enzymes began to rise again and the patient received another injection of 1 gm methylprednisone. At that time, the total bilirubin was 2 mg/dl (normal 0.2 to 1.0 mg/dl) and reached 4.0 mg/dl at 33 weeks. Ultrasound scans were obtained at 16 and 22 weeks, menstrual age, to project individual fetal growth curve standards through the Rossavik-Deter growth model.9 From 26 weeks on, the patient was followed by biweekly fetal acceleration tests and weekly ultrasound scans for fetal biophysical profile and growth evaluation using both cross-sectional and individual growth curve standards. From 26 through 33 weeks, the head (HC) and abdominal (AC) circumferences and femur diaphysis length (FDL) of both twins were small for menstrual age with estimated fetal weights (EFW) (Hadlock weight estimating procedure based on HC, AC, and FDL) consistently below the 2.5th percentile of the EFW distribution for menstrual age, established for the normal singletons of our population.10 However, all measurements were increasing normally along their projected individual growth curves standards.911 At 32 weeks, the differences between the projected and the actual measurements of HC, AC, and EFW exceeded those compatible with normal growth for twins and singletons,1112 indicating that both twins were experiencing growth failure. The fetal acceleration tests had been consistently nonreactive, but the weekly biophysical profiles were normal. However, at 33 weeks, both twins showed absent breathing motion. In addition, twin B displayed decreased fetal movements. Throughout the pregnancy, serum uric acid levels ranged from 5.7 to 9.6 mg/dl (normal, 2.4 to 8.5 mg/dl), serum creatinine ranged from 1.1 to 1.5 mg/dl (normal, 0.8 to 1.2 mg/dl), and serum cyclosporine levels were between 434 and 1010 ng/ml by the fluorescent polarization immunoassay (FPI) procedure. The patient was somewhat anorexic and lost 5 pounds during the last 5 weeks of gestation. The total weight gain was 7 pounds (weight, 204 lb at 10 weeks and 211 lb at 33 weeks, menstrual age). Blood pressure measurements were elevated from the beginning of the pregnancy, with systolic blood pressures ranging from 126 to 160 mmHg and diastolic blood pressures ranging from 76 to 110 mmHg. There was no proteinuria. Considering the evidence of fetal growth failure with possible fetal compromise and the ongoing rejection of the liver transplant, it was decided to interrupt the pregnancy by cesarean section at 33 weeks, menstrual age. The twins were delivered in good condition, both having 1- and 5-minute Apgar scores of 8 and 9, respectively. Both infants had birthweights below the 2.5th percentile of our birth-
March 1991
weight curve for menstrual age for singletons.10 Their physical examination indicated asymmetrical growth retardation. Twin A (birthweight, 1003 gm) had hyperbilirubinemia, which resolved with phototherapy, and mild apnea of prematurity. Neutropenia (white blood count, 3.0), thrombocytopenia (platelet count, 76,000), and polycythemia (hematocrit, 68) were present at birth, but resolved spontaneously. There was no respiratory distress. No congenital anomalies were detected. Urine culture for cytomegalovirus was negative. Renal function, funduscopic examination, cranial ultrasound, and brainstem auditory evoked response (BAER) testing were all normal. Twin B (birthweight, 1340 gm) had hyperbilirubinemia, which resolved with phototherapy. Neutropenia (white blood count, 4.8) was present at birth but the hematocrit and platelet count were normal. Renal function, funduscopic examination, and BAER testing were normal. There were no congenital anomalies. The cranial ultrasound revealed a mild left lateral ventricular dilation with suggestion of a grade I choroid plexus hemorrhage. Follow-up ultrasound scans indicated normal head growth. Both twins were discharged 26 days after birth. Neurodevelopmental follow-up (25 months of observation) showed some abnormalities of neuromuscular tone and fine motor skills in twin A. However, language cognition and social skills were appropriate for age. The neurodevelopment of twin B has been normal so far. Serum cyclosporine levels were obtained from the mother at birth and from both twins at birth (cord blood) and 25 hours and 37 hours thereafter (peripheral blood). Cyclosporine concentrations were measured by high-pressure liquid chromatography (HPLC) and by the FPI procedure (Table 1). The latter method measures cyclosporine metabolites in addition to the parent compound. The cord blood cyclosporine concentrations were approximately half that of the maternal serum at birth. The calculated cyclosporine half-life was 39 hours in twin A and 60 hours in twin B. Deterioration of the mother's liver graft function occurred shortly after delivery, requiring transfer to the University of Pittsburgh Transplant Center 7 days after birth, where the patient received a second liver transplant 2 months thereafter. DISCUSSION
Our patient is not only the first twin pregnancy after liver transplantation, but also, to our knowledge, the first case in which pregnancy occurred concomitantly with exacerbation of chronic rejection of the liver transplant. A causality between the two events was unlikely, since pregnancy is considered an immunologically privileged state that should protect the homograft.13 Indeed, experience with pregnancies following renal transplant shows that patients with adequate graft function have little if any deteri-
Downloaded by: University of British Columbia. Copyrighted material.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2
TWIN PREGNANCY AFTER LIVER TRANSPLANTATION/Grow, et al. Table 1. Cyclosporine Concentrations in Maternal and Neonatal Sera Measured by High Pressure Liquid Chromatography (HPLC)1 and Fluorescent Polarization Immunoassay (EPI)2 in a Liver Transplant Recipient with Twin Pregnancy* Cyclosporine Mother Mother
Concentration
Twin A
Twin B
Time
Method
Serum Level (ng/ml)
Method
Serum Level (ng/ml)
Method
Serum Level (ng/ml)
Birth
HPLC FPI
226
1010
HPLC FPI HPLC FPI HPLC FPI
96 898 63 743
March 1991
TWIN PREGNANCY AFTER ORTHOTOPIC LIVER TRANSPLANTATION, WITH EXACERBATION OF CHRONIC GRAFT REJECTION Daniel R. Grow, M.D., Nicolas V. Simon, M.D., Jonathan Liss, M.D., and William T. Delp, M.D.
We report the sixth pregnancy and the first occurrence of twins after liver transplantation, and the second time cyclosporine was used in pregnancy for that indication. The pregnancy was interrupted at 33 weeks, menstrual age, for exacerbation of chronic graft rejection and intrauterine growth retardation of both twins with possible fetal compromise. The neonatal outcomes were good without any detected anomalies except for some neurodevelopmental problems in one twin at the long-term follow-up. The mother underwent a second liver transplant shortly after delivery.
Orthotopic liver transplantation is a procedure increasingly performed throughout the world. With the advent of cyclosporin A and the experience with immunosuppression gained from renal transplantation, the 5-year survival rate of liver transplant recipients now approaches 50%.! In spite of the increasing number of survivors, there are onlyfivereported pregnancies following liver transplantation,2"7 with two occurrences in the same patient.4-5 Of these five pregnancies, one was electively terminated in the first trimester2 and four ended between 28 and 40 weeks, menstrual age, in live births but with fetal growth retardation.4-7 Only one of these four latter pregnancies included cyclosporine as a part of the immunosuppressive regimen.7 Because of the rarity of the event and the limited experience with cyclosporine in pregnancy,7-8 we present the fifth case of pregnancy resulting in live birth, which is also the first reported occurrence of twins and the second reported use of cyclosporine in a pregnant woman following liver transplantation.7 CASE REPORT
A 24-year-old primiparous woman underwent an orthotopic liver transplantation for fulminant cryptogenic liver failure in February 1986 at the University of Pittsburgh Transplant Center. Severe
acute rejection occurred following the transplant, requiring aggressive immunosuppressive therapy that included the administration of the monoclonal antibody OKT3. Pneumocystis carinii pneumonia and cytomegalovirus gastritis resulted but resolved after tapering the immunosuppressive therapy to simply cyclosporine. The patient was discharged on 400 mg cyclosporine and 10 mg prednisone daily, 2 months after the transplant. During the ensuing 20 months, she was rehospitalized twice for exacerbation of chronic rejection. Control was maintained with 300 mg cyclosporin, 50 mg azathioprine, and 15 mg prednisone daily. She also received atenolol 75 mg a day for post-transplant hypertension. While following this regimen, the patient had regular menses at intervals of 27 days. Twenty-three months after her liver transplantation, the patient conceived following a spontaneous ovulation. Eight weeks after her last menstrual period (LMP), an ultrasound revealed a twin gestation. Both crownrump lengths were compatible with her menstrual age by LMP. The patient was followed with biweekly complete blood counts, liver function tests, prothrombin times, electrolytes, and creatinine, uric acid, and cyclosporine serum levels. At 10 weeks' menstrual age, the patient developed fever and elevated liver enzymes (aspartate aminotransferase: 325 U/liter (normal 10 to 41 U/liter); alanine aminotransferase: 271 U/liter (normal, 8 to 40 U/liter).
Department of Obstetrics and Gynecology and Department of Pediatrics, Division of Newborn Medicine, York Hospital, York, Pennsylvania Reprint requests: Dr. Simon, Department of Obstetrics and Gynecology, York Hospital, 1001 South George Street, York, PA 17405 Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
135
Downloaded by: University of British Columbia. Copyrighted material.
ABSTRACT
136
A liver biopsy showed focal bile duct loss and changes consistent with on-going rejection. Rejec-tion was controlled by two 1 gm injections of methylprednisone intravenously and by increasing the cyclosporine from 300 to 400 mg daily. At 28 weeks, menstrual age, the liver enzymes began to rise again and the patient received another injection of 1 gm methylprednisone. At that time, the total bilirubin was 2 mg/dl (normal 0.2 to 1.0 mg/dl) and reached 4.0 mg/dl at 33 weeks. Ultrasound scans were obtained at 16 and 22 weeks, menstrual age, to project individual fetal growth curve standards through the Rossavik-Deter growth model.9 From 26 weeks on, the patient was followed by biweekly fetal acceleration tests and weekly ultrasound scans for fetal biophysical profile and growth evaluation using both cross-sectional and individual growth curve standards. From 26 through 33 weeks, the head (HC) and abdominal (AC) circumferences and femur diaphysis length (FDL) of both twins were small for menstrual age with estimated fetal weights (EFW) (Hadlock weight estimating procedure based on HC, AC, and FDL) consistently below the 2.5th percentile of the EFW distribution for menstrual age, established for the normal singletons of our population.10 However, all measurements were increasing normally along their projected individual growth curves standards.911 At 32 weeks, the differences between the projected and the actual measurements of HC, AC, and EFW exceeded those compatible with normal growth for twins and singletons,1112 indicating that both twins were experiencing growth failure. The fetal acceleration tests had been consistently nonreactive, but the weekly biophysical profiles were normal. However, at 33 weeks, both twins showed absent breathing motion. In addition, twin B displayed decreased fetal movements. Throughout the pregnancy, serum uric acid levels ranged from 5.7 to 9.6 mg/dl (normal, 2.4 to 8.5 mg/dl), serum creatinine ranged from 1.1 to 1.5 mg/dl (normal, 0.8 to 1.2 mg/dl), and serum cyclosporine levels were between 434 and 1010 ng/ml by the fluorescent polarization immunoassay (FPI) procedure. The patient was somewhat anorexic and lost 5 pounds during the last 5 weeks of gestation. The total weight gain was 7 pounds (weight, 204 lb at 10 weeks and 211 lb at 33 weeks, menstrual age). Blood pressure measurements were elevated from the beginning of the pregnancy, with systolic blood pressures ranging from 126 to 160 mmHg and diastolic blood pressures ranging from 76 to 110 mmHg. There was no proteinuria. Considering the evidence of fetal growth failure with possible fetal compromise and the ongoing rejection of the liver transplant, it was decided to interrupt the pregnancy by cesarean section at 33 weeks, menstrual age. The twins were delivered in good condition, both having 1- and 5-minute Apgar scores of 8 and 9, respectively. Both infants had birthweights below the 2.5th percentile of our birth-
March 1991
weight curve for menstrual age for singletons.10 Their physical examination indicated asymmetrical growth retardation. Twin A (birthweight, 1003 gm) had hyperbilirubinemia, which resolved with phototherapy, and mild apnea of prematurity. Neutropenia (white blood count, 3.0), thrombocytopenia (platelet count, 76,000), and polycythemia (hematocrit, 68) were present at birth, but resolved spontaneously. There was no respiratory distress. No congenital anomalies were detected. Urine culture for cytomegalovirus was negative. Renal function, funduscopic examination, cranial ultrasound, and brainstem auditory evoked response (BAER) testing were all normal. Twin B (birthweight, 1340 gm) had hyperbilirubinemia, which resolved with phototherapy. Neutropenia (white blood count, 4.8) was present at birth but the hematocrit and platelet count were normal. Renal function, funduscopic examination, and BAER testing were normal. There were no congenital anomalies. The cranial ultrasound revealed a mild left lateral ventricular dilation with suggestion of a grade I choroid plexus hemorrhage. Follow-up ultrasound scans indicated normal head growth. Both twins were discharged 26 days after birth. Neurodevelopmental follow-up (25 months of observation) showed some abnormalities of neuromuscular tone and fine motor skills in twin A. However, language cognition and social skills were appropriate for age. The neurodevelopment of twin B has been normal so far. Serum cyclosporine levels were obtained from the mother at birth and from both twins at birth (cord blood) and 25 hours and 37 hours thereafter (peripheral blood). Cyclosporine concentrations were measured by high-pressure liquid chromatography (HPLC) and by the FPI procedure (Table 1). The latter method measures cyclosporine metabolites in addition to the parent compound. The cord blood cyclosporine concentrations were approximately half that of the maternal serum at birth. The calculated cyclosporine half-life was 39 hours in twin A and 60 hours in twin B. Deterioration of the mother's liver graft function occurred shortly after delivery, requiring transfer to the University of Pittsburgh Transplant Center 7 days after birth, where the patient received a second liver transplant 2 months thereafter. DISCUSSION
Our patient is not only the first twin pregnancy after liver transplantation, but also, to our knowledge, the first case in which pregnancy occurred concomitantly with exacerbation of chronic rejection of the liver transplant. A causality between the two events was unlikely, since pregnancy is considered an immunologically privileged state that should protect the homograft.13 Indeed, experience with pregnancies following renal transplant shows that patients with adequate graft function have little if any deteri-
Downloaded by: University of British Columbia. Copyrighted material.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2
TWIN PREGNANCY AFTER LIVER TRANSPLANTATION/Grow, et al. Table 1. Cyclosporine Concentrations in Maternal and Neonatal Sera Measured by High Pressure Liquid Chromatography (HPLC)1 and Fluorescent Polarization Immunoassay (EPI)2 in a Liver Transplant Recipient with Twin Pregnancy* Cyclosporine Mother Mother
Concentration
Twin A
Twin B
Time
Method
Serum Level (ng/ml)
Method
Serum Level (ng/ml)
Method
Serum Level (ng/ml)
Birth
HPLC FPI
226
1010
HPLC FPI HPLC FPI HPLC FPI
96 898 63 743
![[Twin pregnancy after liver transplantation].](/assets/img/hold.png)
