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Successful pregnancy after combined pancreas-kidney transplantation
European Journal of Obstetrics & Gynecology and Reproductive Biology 52 (1993) 143-145
Successful pregnancy after combined pancreas-kidney transplantation F. Carmona* a, V. Cararacha, J.L. Bedinib, E. MAsb, P. Deulofeu”, M.J. RicartC, L. Fernbdez-Cruzd ‘Department of Obstetrics and Gynecology, bBiochemistry Laboratory, ‘Renal Transplant Unit, dDepartment of Surgery, Hospital Clinic i Provincial-Far&ad de Medicina, Universidad de Barcelona, C/ Villarroel, 170, 08036 Barcelona, Spain
(Accepted 4 August 1993)
Abstract In this paper we report a successful pregnancy after combined pancreas-kidney transplantation. During pregnancy the patient was treated with prednisone and cyclosporin. Pancreatic and renal function remained normal during pregnancy, but moderate hypertension was detected in the 28th week. A healthy baby of 1900 g (below the tenth percentile) was born at 36 weeks. In this case, urine pregnancy tests were negative throughout the pregnancy, probably due to the exocrine secretion of the pancreas, which had been diverted to the urinary bladder. This possibility has not been previously reported. Key words: Combined pancreas-kidney transplantation;
Pregnancy; Cyclosporin
1. Introduction Uremia alters the ovarian function and fertility is decreased in patients with chronic renal failure [l]. In women with end-stage nephropathy secondary to diabetes, combined kidney-pancreas transplantation restores not only the renal function and fertility but also, by improving metabolic abnormalities caused by diabetes, seems to increase the likelihood of a successful pregnancy. However, the pregnancy itself imposes a formidable challenge to the endocrine capacity of the pancreas graft and clinical experience concerning pregnancies after kidney-pancreas transplantation is scant and not altogether favorable [2]. In this paper we report
* Corresponding author
the fifth published case of a pregnancy after a combined kidney-pancreas transplantation, and the first in which the exocrine pancreatic secretion was diverted to the urinary bladder. 2. Case report The patient presented here was a 38-year-old woman who suffered insulin-dependent diabetes mellitus (IDDM) from the age of 19. At the age of 35 she developed diabetic nephropathy, resulting in progressive renal insufficiency. Haemodialysis was started in November 1989 at the age of 37. Normal menses disappeared one month later. She underwent a combined pancreas-kidney transplantation in January 1991. The kidney graft was placed extraperitoneally in the left iliac fossa by anastomosing the renai vessels to the primitive
0028-2243/93/$06.00 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. SSDI 0028-2243(93)01678-M
144
F. Carmona et al. /Eur.
iliac vessels and by performing an ureteroneocystostomy. The pancreas graft was placed intraperitoneally in the major pelvis and a pancreaticocystostomy was accomplished by anastomosing the duodenum to the bladder. Postoperative immunosuppression consisted of azathioprine (2 mg/kg/day), cyclosporin (5 mg/kg/day) and prednisone (1 mg/kg/day). Menses returned 45 days after transplantation and cycles were normal until 6 months after transplantation when the patient developed amenorrhea and pregnancy was suspected. However, three urine pregnancy tests (Clearview; Unipath, Bedford, UK) performed in the Transplant Unit were negative. The patient was then referred to the Department of Gynecology. Pelvic examination showed a clinically obvious pregnancy and echography dated the pregnancy at 12 weeks of gestational age. Despite the normal plasmatic levels of hCG, the urine pregnancy tests were negative throughout gestation. During pregnancy the dose of cyclosporin was raised slightly in order to maintain plasmatic levels. Azathioprine was discontinued. Initial laboratory values showed normal blood levels of glucose, creatinine, urea, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, bilirrubine, alkaline phosphatase, total serum protein, sodium and potassium. Amylase was 454 I.U./l (normal value, 60-400 I.U./l) and lipase was 373 I.U./l (normal value, lo-200 I.U./l). concentration was 9.7 g/dL and Haemoglobin haematocrit was 28%. Creatinine clearance, secretion of insulin and haemoglobin A, and blood levels were also within normal limits. Urine analysis showed no protein or renal blood cells. All of these determinations were repeated monthly and showed normal renal function during pregnancy. The 50-g oral glucose load test, as proposed by O’Sullivan et al. [3], was normal at 20, 28 and 34 weeks. Beginning at 13 weeks, 325 mg of oral ferrous sulphate were given three times/day, but haematocrit rose only to 31% and remained low throughout pregnancy. The patient was counseled but declined amniocentesis. Mild hypertension was detected in the 28th week and labetalol and hydralacine were started. Moderate fetal growth retardation was diagnosed in the 32nd week. In the 35th week Doppler assessment of the fetal circulation showed absence of end-diastolic flow in the umbilical artery with normal fetal cerebral circulation. Delivery was by cesarean section at 36 weeks after assessment of fetal maturity. The fetus weighed 1900 g and was small for dates (5th-10th percentile). No congenital abnormality was observed. The newborn postnatal course was normal. Mother’s renal and pancreatic function were normal 1 year after delivery. The baby was well at this time.
J. Ohstet. @neroI.
Reprod. Biol. 52 (1993)
143-145
In order to demonstrate that negativity of the urine pregnancy tests was due to the activity of pancreas proteolytic enzymes toward hCG, we performed the following experiments. First we demonstrated the proteolytic activity of our patient’s urine by performing the X-ray film test, which is based on the ability of trypsin to digest gelatin [4]. A piece of unexposed X-ray film was spotted with a drop of our patient’s urine and with a drop of urine of a non-transplantated pregnant woman (which was used as control). After 30 min incubation at 37”C, gelatine digestion was only observed with our patient’s urine sample. Immediately afterwards we performed l/100 dilutions of urine from a normal pregnant woman with urine of our patient and with urine of a non-pregnant woman. After 60 min at 37”C, the pregnancy test was still positive in the sample diluted with the urine of a non-pregnant woman; however, when dilution was made with urine of our patient, the pregnancy test became negative and gelatin digestion was present in the X-ray film test. 3. Discussion Patients with end-stage nephropathy secondary to IDDM improve their metabolic abnormalities after combined pancreas-kidney transplantation, facilitating normal conception and pregnancy. However, pregnancy represents a challenge for these patients. Indeed, patients who became pregnant after kidney transplantation may develop permanent impairment of their renal function as frequently as 15% [5] and, in addition, preterm birth and fetal growth retardation are much more frequent after renal transplantation than in normal patients [5,6]. In healthy women, physiological alterations during pregnancy, such as secretion of placental lactogen, impair peripheral insulin action and the second half of pregnancy is characterized by increased insulin resistance. As a result, gestational diabetes has been reported to be in the range of 0.15- 12.3% depending on the diagnostic criteria used [7]. Thus, in patients with pancreas transplantation, in which not only the pregnancy but also the use of steroids or cyclosporin may exert a diabetogenic effect [8,9], the risk of developing gestational diabetes is probably greater than in normal patients. However, the finding of normal metabolic control in our patient, as in the four patients reported by TydCn et al., [2], is very encouraging and suggests that pancreas graft adaptation to pregnancy may be as satisfactory as it is in non-diabetic women. In the case presented here the diagnosis of pregnancy was delayed because the urine pregnancy tests were falsely negative. In our patient all tests were performed by expert laboratory staff and the more commonly cited
F. Carmona et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 52 (19931
/43- 145
causes of false negative tests [lo] could be excluded. In this case the cause of the delayed diagnosis may have been the proteolityc activity of trypsin, which was present in the urine of our patient, a possibility not described elsewhere. Trypsin may denaturalize the hCG, as occurs with other peptides [ 1 I] and as demonstrated in our experiment, probably making the urine pregnancy tests falsely negative. Therefore, in cases with urinary diversion of the exocrine pancreatic secretion, plasmatic determinations of hCG should be performed promptly when pregnancy is suspected. Hypertension was detected in our patient during the third trimester of her pregnancy. In non-diabetic kidney graft recipients, the risk of developing hypertension has been evaluated to be 30% [5]. There is not enough information about the obstetrical course of the four previously reported pregnancies after combined kidneypancreas transplantation and only in the first case was
4. Acknowledgement
hypertension reported [ 121. Thus, the real incidence of hypertension in cases of combined kidney-pancreas transplantation cannot be determined, although it is probably high. Although in this case proteinuria was not found, detection of proteinuria could have also been impaired by the pancreatic proteolytic enzymes present in the bladder, thus making the diagnosis of preeclampsia difficult. However, determination of albuminuria was performed by a calorimetric method, which is probably not affected by denaturalization of albumin. Unfortunately, we did not evaluate this possibility. At present, lack of experience with pregnancy after combined pancreas-kidney transplantation does not allow us to determine the potential risks to either mother or fetus, but the outcome of this case and those reported by Tyden et al. [2] are encouraging. However, an acute pancreas graft rejection was seen in one of the patients studied by Tydtn et al. 121. Four out five cases reported were preterm and three fetuses were growth retarded. Thus. until valid conclusions are reached, all cases should be reported and the potential risks should be discussed with patients when pregnancy is being considered.
145
We thank Mr Robin Rycroft, from the Servei d’Assessorament Linguistic of the University of Barcelona, for language correction. 5. References I
Penn I. Makowski EL. Parenthood in kidney and liver transplant recipients. Transplant Proc 1981: 13: 36-39.
2
TydCn G. Brattstriim C, Bjarkman U et al. Pregnancy after combined pancreas-kidney transplantation. Diabetes 1989; 38 (Sl): 43-45. O’Sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening criteria for high risk gestational diabetic patients. Am J Obstet Gynecol 1973; 116: 895-900. Tietz N. Textbook of clinical chemistry. 1st edn. Philadelphia: WB Saunders Company, 1986. Davison JM. Dialysis, transplantation. and pregnancy. Am J Kidney Dis 1991; 17: 127-132. Cararach V. Carmona F, Monle6n FJ, Andreu J. Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol 1993; 100: 122-125. Cunningham FG, MacDonald PC. Cant NF. Williams obstetrics. 18th edn. Connecticut: Prentice-Hall, 1989. Briggs CC. Freeman RK, Yaffe SJ. A reference guide to
3
4 5 6
fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd edn. Baltimore: Williams & Wilkins, 1990. TydCn G, BrattstrGm C, &man J et al: Metabolic control at 2 months to 4.5 years after pancreatic transplantation with special reference to the role of cyclosporin. Transplant Proc 1987: 19: 2294-2296. Smith DB, Rustin GJS, Bagshawe KD. Don’t ignore a positive pregnancy test. Br Med J 1988: 297: I 119-l 120. Esmatjes E, Calvet JM, Ricart MJ et al. Urinary Cpeptide: unsuitable parameter of P-cell secretion in pancreas transplantation. Diabetes Care 1987; IO: 384-385. Castro LA. Baltzer J. Hillebrand G. Landgraf R. Kuhlmann H. Land W. Pregnancy in juvenile diabetes mellitus under cyclosporin treatment after combined kidney and pancreas transplantation. Transplant Proc 1986: 18: 1780-1781.
Successful pregnancy after combined pancreas-kidney transplantation F. Carmona* a, V. Cararacha, J.L. Bedinib, E. MAsb, P. Deulofeu”, M.J. RicartC, L. Fernbdez-Cruzd ‘Department of Obstetrics and Gynecology, bBiochemistry Laboratory, ‘Renal Transplant Unit, dDepartment of Surgery, Hospital Clinic i Provincial-Far&ad de Medicina, Universidad de Barcelona, C/ Villarroel, 170, 08036 Barcelona, Spain
(Accepted 4 August 1993)
Abstract In this paper we report a successful pregnancy after combined pancreas-kidney transplantation. During pregnancy the patient was treated with prednisone and cyclosporin. Pancreatic and renal function remained normal during pregnancy, but moderate hypertension was detected in the 28th week. A healthy baby of 1900 g (below the tenth percentile) was born at 36 weeks. In this case, urine pregnancy tests were negative throughout the pregnancy, probably due to the exocrine secretion of the pancreas, which had been diverted to the urinary bladder. This possibility has not been previously reported. Key words: Combined pancreas-kidney transplantation;
Pregnancy; Cyclosporin
1. Introduction Uremia alters the ovarian function and fertility is decreased in patients with chronic renal failure [l]. In women with end-stage nephropathy secondary to diabetes, combined kidney-pancreas transplantation restores not only the renal function and fertility but also, by improving metabolic abnormalities caused by diabetes, seems to increase the likelihood of a successful pregnancy. However, the pregnancy itself imposes a formidable challenge to the endocrine capacity of the pancreas graft and clinical experience concerning pregnancies after kidney-pancreas transplantation is scant and not altogether favorable [2]. In this paper we report
* Corresponding author
the fifth published case of a pregnancy after a combined kidney-pancreas transplantation, and the first in which the exocrine pancreatic secretion was diverted to the urinary bladder. 2. Case report The patient presented here was a 38-year-old woman who suffered insulin-dependent diabetes mellitus (IDDM) from the age of 19. At the age of 35 she developed diabetic nephropathy, resulting in progressive renal insufficiency. Haemodialysis was started in November 1989 at the age of 37. Normal menses disappeared one month later. She underwent a combined pancreas-kidney transplantation in January 1991. The kidney graft was placed extraperitoneally in the left iliac fossa by anastomosing the renai vessels to the primitive
0028-2243/93/$06.00 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. SSDI 0028-2243(93)01678-M
144
F. Carmona et al. /Eur.
iliac vessels and by performing an ureteroneocystostomy. The pancreas graft was placed intraperitoneally in the major pelvis and a pancreaticocystostomy was accomplished by anastomosing the duodenum to the bladder. Postoperative immunosuppression consisted of azathioprine (2 mg/kg/day), cyclosporin (5 mg/kg/day) and prednisone (1 mg/kg/day). Menses returned 45 days after transplantation and cycles were normal until 6 months after transplantation when the patient developed amenorrhea and pregnancy was suspected. However, three urine pregnancy tests (Clearview; Unipath, Bedford, UK) performed in the Transplant Unit were negative. The patient was then referred to the Department of Gynecology. Pelvic examination showed a clinically obvious pregnancy and echography dated the pregnancy at 12 weeks of gestational age. Despite the normal plasmatic levels of hCG, the urine pregnancy tests were negative throughout gestation. During pregnancy the dose of cyclosporin was raised slightly in order to maintain plasmatic levels. Azathioprine was discontinued. Initial laboratory values showed normal blood levels of glucose, creatinine, urea, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, bilirrubine, alkaline phosphatase, total serum protein, sodium and potassium. Amylase was 454 I.U./l (normal value, 60-400 I.U./l) and lipase was 373 I.U./l (normal value, lo-200 I.U./l). concentration was 9.7 g/dL and Haemoglobin haematocrit was 28%. Creatinine clearance, secretion of insulin and haemoglobin A, and blood levels were also within normal limits. Urine analysis showed no protein or renal blood cells. All of these determinations were repeated monthly and showed normal renal function during pregnancy. The 50-g oral glucose load test, as proposed by O’Sullivan et al. [3], was normal at 20, 28 and 34 weeks. Beginning at 13 weeks, 325 mg of oral ferrous sulphate were given three times/day, but haematocrit rose only to 31% and remained low throughout pregnancy. The patient was counseled but declined amniocentesis. Mild hypertension was detected in the 28th week and labetalol and hydralacine were started. Moderate fetal growth retardation was diagnosed in the 32nd week. In the 35th week Doppler assessment of the fetal circulation showed absence of end-diastolic flow in the umbilical artery with normal fetal cerebral circulation. Delivery was by cesarean section at 36 weeks after assessment of fetal maturity. The fetus weighed 1900 g and was small for dates (5th-10th percentile). No congenital abnormality was observed. The newborn postnatal course was normal. Mother’s renal and pancreatic function were normal 1 year after delivery. The baby was well at this time.
J. Ohstet. @neroI.
Reprod. Biol. 52 (1993)
143-145
In order to demonstrate that negativity of the urine pregnancy tests was due to the activity of pancreas proteolytic enzymes toward hCG, we performed the following experiments. First we demonstrated the proteolytic activity of our patient’s urine by performing the X-ray film test, which is based on the ability of trypsin to digest gelatin [4]. A piece of unexposed X-ray film was spotted with a drop of our patient’s urine and with a drop of urine of a non-transplantated pregnant woman (which was used as control). After 30 min incubation at 37”C, gelatine digestion was only observed with our patient’s urine sample. Immediately afterwards we performed l/100 dilutions of urine from a normal pregnant woman with urine of our patient and with urine of a non-pregnant woman. After 60 min at 37”C, the pregnancy test was still positive in the sample diluted with the urine of a non-pregnant woman; however, when dilution was made with urine of our patient, the pregnancy test became negative and gelatin digestion was present in the X-ray film test. 3. Discussion Patients with end-stage nephropathy secondary to IDDM improve their metabolic abnormalities after combined pancreas-kidney transplantation, facilitating normal conception and pregnancy. However, pregnancy represents a challenge for these patients. Indeed, patients who became pregnant after kidney transplantation may develop permanent impairment of their renal function as frequently as 15% [5] and, in addition, preterm birth and fetal growth retardation are much more frequent after renal transplantation than in normal patients [5,6]. In healthy women, physiological alterations during pregnancy, such as secretion of placental lactogen, impair peripheral insulin action and the second half of pregnancy is characterized by increased insulin resistance. As a result, gestational diabetes has been reported to be in the range of 0.15- 12.3% depending on the diagnostic criteria used [7]. Thus, in patients with pancreas transplantation, in which not only the pregnancy but also the use of steroids or cyclosporin may exert a diabetogenic effect [8,9], the risk of developing gestational diabetes is probably greater than in normal patients. However, the finding of normal metabolic control in our patient, as in the four patients reported by TydCn et al., [2], is very encouraging and suggests that pancreas graft adaptation to pregnancy may be as satisfactory as it is in non-diabetic women. In the case presented here the diagnosis of pregnancy was delayed because the urine pregnancy tests were falsely negative. In our patient all tests were performed by expert laboratory staff and the more commonly cited
F. Carmona et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 52 (19931
/43- 145
causes of false negative tests [lo] could be excluded. In this case the cause of the delayed diagnosis may have been the proteolityc activity of trypsin, which was present in the urine of our patient, a possibility not described elsewhere. Trypsin may denaturalize the hCG, as occurs with other peptides [ 1 I] and as demonstrated in our experiment, probably making the urine pregnancy tests falsely negative. Therefore, in cases with urinary diversion of the exocrine pancreatic secretion, plasmatic determinations of hCG should be performed promptly when pregnancy is suspected. Hypertension was detected in our patient during the third trimester of her pregnancy. In non-diabetic kidney graft recipients, the risk of developing hypertension has been evaluated to be 30% [5]. There is not enough information about the obstetrical course of the four previously reported pregnancies after combined kidneypancreas transplantation and only in the first case was
4. Acknowledgement
hypertension reported [ 121. Thus, the real incidence of hypertension in cases of combined kidney-pancreas transplantation cannot be determined, although it is probably high. Although in this case proteinuria was not found, detection of proteinuria could have also been impaired by the pancreatic proteolytic enzymes present in the bladder, thus making the diagnosis of preeclampsia difficult. However, determination of albuminuria was performed by a calorimetric method, which is probably not affected by denaturalization of albumin. Unfortunately, we did not evaluate this possibility. At present, lack of experience with pregnancy after combined pancreas-kidney transplantation does not allow us to determine the potential risks to either mother or fetus, but the outcome of this case and those reported by Tyden et al. [2] are encouraging. However, an acute pancreas graft rejection was seen in one of the patients studied by Tydtn et al. 121. Four out five cases reported were preterm and three fetuses were growth retarded. Thus. until valid conclusions are reached, all cases should be reported and the potential risks should be discussed with patients when pregnancy is being considered.
145
We thank Mr Robin Rycroft, from the Servei d’Assessorament Linguistic of the University of Barcelona, for language correction. 5. References I
Penn I. Makowski EL. Parenthood in kidney and liver transplant recipients. Transplant Proc 1981: 13: 36-39.
2
TydCn G. Brattstriim C, Bjarkman U et al. Pregnancy after combined pancreas-kidney transplantation. Diabetes 1989; 38 (Sl): 43-45. O’Sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening criteria for high risk gestational diabetic patients. Am J Obstet Gynecol 1973; 116: 895-900. Tietz N. Textbook of clinical chemistry. 1st edn. Philadelphia: WB Saunders Company, 1986. Davison JM. Dialysis, transplantation. and pregnancy. Am J Kidney Dis 1991; 17: 127-132. Cararach V. Carmona F, Monle6n FJ, Andreu J. Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol 1993; 100: 122-125. Cunningham FG, MacDonald PC. Cant NF. Williams obstetrics. 18th edn. Connecticut: Prentice-Hall, 1989. Briggs CC. Freeman RK, Yaffe SJ. A reference guide to
3
4 5 6
fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd edn. Baltimore: Williams & Wilkins, 1990. TydCn G, BrattstrGm C, &man J et al: Metabolic control at 2 months to 4.5 years after pancreatic transplantation with special reference to the role of cyclosporin. Transplant Proc 1987: 19: 2294-2296. Smith DB, Rustin GJS, Bagshawe KD. Don’t ignore a positive pregnancy test. Br Med J 1988: 297: I 119-l 120. Esmatjes E, Calvet JM, Ricart MJ et al. Urinary Cpeptide: unsuitable parameter of P-cell secretion in pancreas transplantation. Diabetes Care 1987; IO: 384-385. Castro LA. Baltzer J. Hillebrand G. Landgraf R. Kuhlmann H. Land W. Pregnancy in juvenile diabetes mellitus under cyclosporin treatment after combined kidney and pancreas transplantation. Transplant Proc 1986: 18: 1780-1781.