1. Pregnancy & Renal Transplantation Alicia Notkin May 20, 2008

2. Case A 30 year old female w/ ESRD, s/p LDRT from her mother 3 years prior, comes to clinic for f/u. She is fully compliant with her regimen of prednisone 5mg daily, tacro 3mg q12h, and MMF 1g q12h. Her renal function has been stable, with a Cr ~ 1.2 mg/dl and a negative UA. She wishes to become pregnant. How should she be advised & managed?

3. Outline Pregnancy in patients with chronic kidney disease Pregnancy in patients with chronic kidney disease Pregnancy in patients on dialysis Pregnancy in patients on dialysis Pregnancy in renal transplant patients Pregnancy in renal transplant patients Transplantation medications in pregnancy Transplantation medications in pregnancy Recommendations Recommendations Other issues: graft dysfunction in pregnancy, donor & pregnancy, male fertility Other issues: graft dysfunction in pregnancy, donor & pregnancy, male fertility

4. Pregnancy in patients with chronic kidney disease: patient considerations Permanent decline in renal function in 0-10% of women with normal to mildly reduced renal function Permanent decline in renal function in 0-10% of women with normal to mildly reduced renal function Patients w/ moderate renal insufficiency may initially have decline in Cr, but may rise above baseline over rest of pregnancy (in a small study, 40% of patients w/ a Cr from 1.4-1.9 mg/dl had rise in Cr) Patients w/ moderate renal insufficiency may initially have decline in Cr, but may rise above baseline over rest of pregnancy (in a small study, 40% of patients w/ a Cr from 1.4-1.9 mg/dl had rise in Cr) Women w/ Cr > 3.0 mg/dl have menstrual abnormalities & have much lower chance of conception & carrying fetus to term Women w/ Cr > 3.0 mg/dl have menstrual abnormalities & have much lower chance of conception & carrying fetus to term

5. Pregnancy in patients with chronic kidney disease: other patient considerations Proteinuria increases in ~ ½ of the patients Proteinuria increases in ~ ½ of the patients Hypertension develops or worsens in ~ ¼ of the patients Hypertension develops or worsens in ~ ¼ of the patients Significant worsening of edema can occur during pregnancy in women w/ nephrotic syndrome Significant worsening of edema can occur during pregnancy in women w/ nephrotic syndrome Β-HCG can be increased in patients w/ ESRD, so confirm pregnancy w/ an ultrasound Β-HCG can be increased in patients w/ ESRD, so confirm pregnancy w/ an ultrasound

6. Pregnancy in patients with chronic kidney disease: fetal outcomes If blood pressure is controlled, rate of live births is > 90% in women w/ normal renal function & is slightly lower in women w/ mild renal insufficiency If blood pressure is controlled, rate of live births is > 90% in women w/ normal renal function & is slightly lower in women w/ mild renal insufficiency Lower fetal survival if bp not controlled (10-fold increase if MAP > 105 at conception) Lower fetal survival if bp not controlled (10-fold increase if MAP > 105 at conception) Higher risk of prematurity if Cr > 1.4 (59% v. 10%) – increased risk of preeclampsia & IUGR Higher risk of prematurity if Cr > 1.4 (59% v. 10%) – increased risk of preeclampsia & IUGR

7. Pregnancy in patients on dialysis Conception occurs in 0.3-1.5% of women of childbearing age per year (disrupted gonadal function) Conception occurs in 0.3-1.5% of women of childbearing age per year (disrupted gonadal function) Live births occur in 40-50% Live births occur in 40-50% Prematurity occurs in most (average age at delivery is ~ 30.5 weeks) Prematurity occurs in most (average age at delivery is ~ 30.5 weeks) Increased risk for severe hypertension Increased risk for severe hypertension Similar outcomes in HD & PD patients Similar outcomes in HD & PD patients More intensive dialysis recommended (5-7x/wk to keep BUN under 45-50); more frequent, lower volume exchanges if on PD More intensive dialysis recommended (5-7x/wk to keep BUN under 45-50); more frequent, lower volume exchanges if on PD Avoid hemodynamic instability & monitor the fetus during treatment Avoid hemodynamic instability & monitor the fetus during treatment

8. Pregnancy in renal transplant patients: outcomes Fertility returns! Fertility returns! > 90% success after 1 st trimester; slight increase in spontaneous abortion > 90% success after 1 st trimester; slight increase in spontaneous abortion IUGR a/o premature delivery in up to 20% & 50%, respectively (some say as much as 1/2-2/3 cases) IUGR a/o premature delivery in up to 20% & 50%, respectively (some say as much as 1/2-2/3 cases) US & UK registries suggest ~ 14% spontaneous abortion, high prevalence of hypertension, increased preeclampsia (~ 1/3) US & UK registries suggest ~ 14% spontaneous abortion, high prevalence of hypertension, increased preeclampsia (~ 1/3) Developmental delays related to prematurity Developmental delays related to prematurity Fewer complications & birth abnormalities than dialysis patients Fewer complications & birth abnormalities than dialysis patients

9. Pregnancy in renal transplant patients: outcomes Increased risk of graft loss if Cr > 1.5 mg/dl before pregnancy Increased risk of graft loss if Cr > 1.5 mg/dl before pregnancy No large, long-term controlled studies looking at GFR & proteinuria in graft recipients who have become pregnant (varying results) No large, long-term controlled studies looking at GFR & proteinuria in graft recipients who have become pregnant (varying results) Birth weight & gestational age seem to be lower in pancreas-kidney transplants than in kidney alone Birth weight & gestational age seem to be lower in pancreas-kidney transplants than in kidney alone

10. Pregnancy in renal transplant patients: outcomes One of the best studies we have: case-control study from 1 center in Israel One of the best studies we have: case-control study from 1 center in Israel Included patients transplanted between ’83 & ’98 Included patients transplanted between ’83 & ’98 Looked at 39 women who became pregnant (44% received CRT, 43.6% had glomerular disease originally, average age 24, most at least 2 years out) Looked at 39 women who became pregnant (44% received CRT, 43.6% had glomerular disease originally, average age 24, most at least 2 years out) Each matched w/ 3 controls from the Collaborative Transplant Study database for 12 factors known to affect graft survival (donor type, ethnic origin, transplant #, year transplanted, donor & recipient ages, IS regimen, CIT, HLA mismatch, PRA, underlying disease, duration of functioning graft from transplant to pregnancy) Each matched w/ 3 controls from the Collaborative Transplant Study database for 12 factors known to affect graft survival (donor type, ethnic origin, transplant #, year transplanted, donor & recipient ages, IS regimen, CIT, HLA mismatch, PRA, underlying disease, duration of functioning graft from transplant to pregnancy) IS regimen: 26 on CsA/AZA/pred, 7 on AZA/pred, 4 on CsA/pred, 2 on CsA/AZA IS regimen: 26 on CsA/AZA/pred, 7 on AZA/pred, 4 on CsA/pred, 2 on CsA/AZA F/u of 15 years F/u of 15 years

11. Rahamimov, R et al, Transplantation 2006

12. Rahamimov, R et al 2006 Similar graft and patient survival (62 & 85% v. 69 & 79%) Similar graft and patient survival (62 & 85% v. 69 & 79%) Similar kidney function 1, 5, & 10 years post-transplant Similar kidney function 1, 5, & 10 years post-transplant Preterm delivery in 60% Preterm delivery in 60% Preeclampsia in 15.3% Preeclampsia in 15.3% IUGR in 52% IUGR in 52% No acute rejection No acute rejection

13. Pregnancy in renal transplant patients: outcomes McKay, DB et al, NEJM 2006 (review)

14. McKay, DB et al, NEJM 2006

16. McKay, DB et al, Transplantation 2006

17. Transplant medications: steroids Associations noted between prednisone & a variety of birth defects (but mainly @ doses > 20 mg/d) Associations noted between prednisone & a variety of birth defects (but mainly @ doses > 20 mg/d) Retrospective data suggest an increased risk of cleft palate w/ glucocorticoids Retrospective data suggest an increased risk of cleft palate w/ glucocorticoids Possible increased risk of PROM & IUGR w/ glucocorticoids Possible increased risk of PROM & IUGR w/ glucocorticoids Glucocorticoids are excreted in breast milk (small amounts), but considered ok if needed by mother Glucocorticoids are excreted in breast milk (small amounts), but considered ok if needed by mother

18. Transplant medications: cyclosporine Can induce/worsen hypertension Can induce/worsen hypertension Drug levels may fall during pregnancy Drug levels may fall during pregnancy Premature labor and infants that are small for gestational age have been reported (possible confounders) Premature labor and infants that are small for gestational age have been reported (possible confounders)

19. Transplant medications: cyclosporine 115 renal transplant recipients (154 pregnancies): CsA v. AZA/pred 115 renal transplant recipients (154 pregnancies): CsA v. AZA/pred CsA had lower birth weights, more maternal DM/htn/rejection, but complication rate in newborns was slightly lower & congenital malformations were not seen CsA had lower birth weights, more maternal DM/htn/rejection, but complication rate in newborns was slightly lower & congenital malformations were not seen Meta-analysis of 15 studies suggests that it is not a significant teratogen (4.1% of offspring w/ major malformations – similar to general population); limited by data available, study design, confounders… Meta-analysis of 15 studies suggests that it is not a significant teratogen (4.1% of offspring w/ major malformations – similar to general population); limited by data available, study design, confounders…

20. Bar Oz, B et al, Transplantation 2001 Articles used for meta-analysis

21. Bar Oz, B et al, Transplantation 2001

22. Transplant medications: cyclosporine Conflicting data re. passage across placenta (rodents show little or no transfer) Conflicting data re. passage across placenta (rodents show little or no transfer) Excreted in breast milk with even therapeutic levels found in infants Excreted in breast milk with even therapeutic levels found in infants Not recommended for lactating mothers Not recommended for lactating mothers

23. Transplant medications: tacrolimus Again, limited data Again, limited data 84 women (100 pregnancies – 27% of them in renal transplant recipients) 84 women (100 pregnancies – 27% of them in renal transplant recipients) Live birth in 68 Live birth in 68 60% of deliveries premature 60% of deliveries premature 4 babies w/ malformations (no pattern) 4 babies w/ malformations (no pattern) Dose remained reasonably stable Dose remained reasonably stable Levels in breast milk similar to that in maternal serum; not recommended during lactation Levels in breast milk similar to that in maternal serum; not recommended during lactation

24. Kainz, A et al, Transplantation 2000

26. Transplant medications: sirolimus Should be discontinued >/= 12 weeks before conception Should be discontinued >/= 12 weeks before conception Recommend switch to cyclosporine if planning to conceive Recommend switch to cyclosporine if planning to conceive Can switch back following delivery Can switch back following delivery Case series in 2006 – 7 pregnancies w/ exposure: 4 live births (1 w/ structural malformations), 3 spontaneous abortions Case series in 2006 – 7 pregnancies w/ exposure: 4 live births (1 w/ structural malformations), 3 spontaneous abortions

27. Sifontis, NM et al, Transplantation 2006

28. Transplant medications: mycophenolate mofetil Adverse effects seen in lab animals at lower doses than those used in humans Adverse effects seen in lab animals at lower doses than those used in humans Increases 1 st trimester pregnancy loss & congenital malformations (cleft lip/palate, anomalies of distal limbs, heart, esophagus, kidneys) Increases 1 st trimester pregnancy loss & congenital malformations (cleft lip/palate, anomalies of distal limbs, heart, esophagus, kidneys)

29. Transplant medications: mycophenolate mofetil Same case series from 2006: 18 renal transplant recipients (26 pregnancies) exposed to MMF Same case series from 2006: 18 renal transplant recipients (26 pregnancies) exposed to MMF 11 spontaneous abortions 11 spontaneous abortions 15 live births 15 live births 4/15 live births had structural malformations: hypoplastic nails, shortened 5 th finger, microtia w/ & w/o cleft lip & palate, neonatal death w/ multiple malformations 4/15 live births had structural malformations: hypoplastic nails, shortened 5 th finger, microtia w/ & w/o cleft lip & palate, neonatal death w/ multiple malformations

30. Sifontis, NM et al 2006

31. Sifontis, NM et al, Transplantation 2006

32. Transplant medications: mycophenolate mofetil 2 forms of contraception should be used a few weeks before & after therapy, as well as during therapy 2 forms of contraception should be used a few weeks before & after therapy, as well as during therapy If planning pregnancy, should switch to azathioprine If planning pregnancy, should switch to azathioprine Should be off of MMF >/= 6 weeks before conception Should be off of MMF >/= 6 weeks before conception Excreted into breast milk – lactating mothers should avoid Excreted into breast milk – lactating mothers should avoid

33. Transplant medications: azathioprine AZA is metabolized to thiouric acid (inactive) by the fetus (a large percent of AZA given to mothers appears as inactive metabolites in fetal blood) AZA is metabolized to thiouric acid (inactive) by the fetus (a large percent of AZA given to mothers appears as inactive metabolites in fetal blood) Suggests that fetus lacks inosinate pyrophosphorylase which converts AZA to 6-MP Suggests that fetus lacks inosinate pyrophosphorylase which converts AZA to 6-MP 146 renal transplant recipients: 90% given AZA/pred, 2% given AZA, 8% given pred 146 renal transplant recipients: 90% given AZA/pred, 2% given AZA, 8% given pred AZA groups showed more problems w/ low birthweight, prematurity, jaundice, respiratory distress syndrome, & aspiration AZA groups showed more problems w/ low birthweight, prematurity, jaundice, respiratory distress syndrome, & aspiration

34. Transplant medications: azathioprine Lactation: 31 breast milk samples – 29 had no 6-MP & 2 had minimal Lactation: 31 breast milk samples – 29 had no 6-MP & 2 had minimal 6-MP & 6-thioguanine were not detectable in neonatal blood 6-MP & 6-thioguanine were not detectable in neonatal blood Preferable to MMF Preferable to MMF

35. McKay, DB et al, Transplantation 2006

36. Recommendations… & our patient

37. AST Consensus Conference on Reproductive Issues & Transplantation 2005

39. McKay, DB et al, CJASN 2008

40. Recommendations: key points Preferable to wait >/= 1 year following LDRT & >/= 2 years following CRT to avoid rejection-related complications (drug doses are lower & doses are stable) Preferable to wait >/= 1 year following LDRT & >/= 2 years following CRT to avoid rejection-related complications (drug doses are lower & doses are stable) Graft should preferably be functioning well (stable Cr < 1.5 mg/dl, proteinuria < 500mg/d) Graft should preferably be functioning well (stable Cr < 1.5 mg/dl, proteinuria < 500mg/d) Frequent monitoring Frequent monitoring

41. Recommendations Aggressive treatment of hypertension (goal is normalization of bp) Aggressive treatment of hypertension (goal is normalization of bp) Close monitoring for preeclampsia Close monitoring for preeclampsia Evidence suggests that pregnancy is not an immunosuppressed state & transplant medications should not be reduced based on that notion Evidence suggests that pregnancy is not an immunosuppressed state & transplant medications should not be reduced based on that notion

42. Recommendations In case cesarian section is necessary, obstetrician should know graft and ureter location In case cesarian section is necessary, obstetrician should know graft and ureter location Careful wound closure & prophylactic antibiotics to avoid infection Careful wound closure & prophylactic antibiotics to avoid infection Contraception: theoretical problems with hormonal methods, IUDs less effective & increased risk of infection, barrier methods traditionally preferred Contraception: theoretical problems with hormonal methods, IUDs less effective & increased risk of infection, barrier methods traditionally preferred

43. Graft dysfunction in pregnancy Rejection is difficult to diagnose since Cr falls somewhat during pregnancy Rejection is difficult to diagnose since Cr falls somewhat during pregnancy Methylprednisolone is the recommended treatment of rejection Methylprednisolone is the recommended treatment of rejection IVIg has been used a fair amount without problems IVIg has been used a fair amount without problems Need to include causes specific to transplant as well as causes specific to pregnancy Need to include causes specific to transplant as well as causes specific to pregnancy Ureteral obstruction from a gravid uterus is not common, but has been reported Ureteral obstruction from a gravid uterus is not common, but has been reported TTP-HUS from AHR or from cyclosporine/tacro occur peri-transplant, so a TTP-HUS picture in a pregnant patient is likely pregnancy-related TTP-HUS from AHR or from cyclosporine/tacro occur peri-transplant, so a TTP-HUS picture in a pregnant patient is likely pregnancy-related

44. OK to biopsy?? Data for native kidneys Data for native kidneys Can be done safely in women with well- controlled blood pressure Can be done safely in women with well- controlled blood pressure Biopsy after 32 weeks is not recommended (? if applies to transplant patients?) Biopsy after 32 weeks is not recommended (? if applies to transplant patients?)

45. Issues for donor & male recipient Little data re. hyperfiltration in donor who becomes pregnant; fertility & complications do not seem to be affected Little data re. hyperfiltration in donor who becomes pregnant; fertility & complications do not seem to be affected Sexual function & sperm motility (but not sperm counts or morphology) improve after transplantation Sexual function & sperm motility (but not sperm counts or morphology) improve after transplantation Several reports of male infertility associated w/ sirolimus (CNIs & AZA seem ok) Several reports of male infertility associated w/ sirolimus (CNIs & AZA seem ok)

46. References Bar Oz, B et al. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001; 71:1051. Bar Oz, B et al. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001; 71:1051. Kainz, A et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70:1718. Kainz, A et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70:1718. McKay, DB et al. Pregnancy after kidney transplantation. CJASN 2008; 3:S117. McKay, DB et al. Pregnancy after kidney transplantation. CJASN 2008; 3:S117. McKay, DB et al. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med 2006; 354:1281. McKay, DB et al. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med 2006; 354:1281. McKay, DB et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005; 5:1592. McKay, DB et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005; 5:1592. Rahamimov, R et al. Pregnancy in renal transplant recipients: long-term effect on patient and graft survival. A single-center experience. Transplantation 2006; 81:660. Rahamimov, R et al. Pregnancy in renal transplant recipients: long-term effect on patient and graft survival. A single-center experience. Transplantation 2006; 81:660. Salmela, KT et al. Impaired renal function after pregnancy in renal transplant recipients. Transplantation 1993; 56:1372. Salmela, KT et al. Impaired renal function after pregnancy in renal transplant recipients. Transplantation 1993; 56:1372. Sifontis, NM et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82:1698. Sifontis, NM et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82:1698. Sturgiss, SN et al. Effect of pregnancy on long-term function in renal allografts: an update. Am J Kidney Dis 1995; 26:54. Sturgiss, SN et al. Effect of pregnancy on long-term function in renal allografts: an update. Am J Kidney Dis 1995; 26:54. www.uptodate.com www.uptodate.com