Pregnancy & Renal Pregnancy & Renal TransplantationTransplantation

Alicia NotkinAlicia Notkin

May 20, 2008May 20, 2008

CaseCase

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

OutlineOutline

• Pregnancy in patients with chronic kidney Pregnancy in patients with chronic kidney diseasedisease

• Pregnancy in patients on dialysisPregnancy in patients on dialysis

• Pregnancy in renal transplant patientsPregnancy in renal transplant patients

• Transplantation medications in pregnancyTransplantation medications in pregnancy

• RecommendationsRecommendations

• Other issues: graft dysfunction in Other issues: graft dysfunction in pregnancy, donor & pregnancy, male pregnancy, donor & pregnancy, male fertilityfertility

Pregnancy in patients with chronic Pregnancy in patients with chronic kidney disease: patient kidney disease: patient considerationsconsiderations• Permanent decline in renal function in 0-Permanent decline in renal function in 0-

10% of women with normal to mildly 10% of women with normal to mildly reduced renal functionreduced renal function

• Patients w/ moderate renal insufficiency Patients w/ moderate renal insufficiency may initially have decline in Cr, but may may initially have decline in Cr, but may rise above baseline over rest of pregnancy rise above baseline over rest of pregnancy (in a small study, 40% of patients w/ a Cr (in a small study, 40% of patients w/ a Cr from 1.4-1.9 mg/dl had rise in Cr)from 1.4-1.9 mg/dl had rise in Cr)

• Women w/ Cr > 3.0 mg/dl have menstrual Women w/ Cr > 3.0 mg/dl have menstrual abnormalities & have much lower chance abnormalities & have much lower chance of conception & carrying fetus to termof conception & carrying fetus to term

Pregnancy in patients with chronic Pregnancy in patients with chronic kidney disease: other patient kidney disease: other patient considerationsconsiderations• Proteinuria increases in ~ ½ of the patientsProteinuria increases in ~ ½ of the patients

• Hypertension develops or worsens in ~ ¼ of Hypertension develops or worsens in ~ ¼ of the patientsthe patients

• Significant worsening of edema can occur Significant worsening of edema can occur during pregnancy in women w/ nephrotic during pregnancy in women w/ nephrotic syndromesyndrome

• ΒΒ-HCG can be increased in patients w/ ESRD, -HCG can be increased in patients w/ ESRD, so confirm pregnancy w/ an ultrasoundso confirm pregnancy w/ an ultrasound

Pregnancy in patients with Pregnancy in patients with chronic kidney disease: fetal chronic kidney disease: fetal outcomesoutcomes• If blood pressure is controlled, rate of live If blood pressure is controlled, rate of live

births is > 90% in women w/ normal renal births is > 90% in women w/ normal renal function & is slightly lower in women w/ function & is slightly lower in women w/ mild renal insufficiencymild renal insufficiency

• Lower fetal survival if bp not controlled (10-Lower fetal survival if bp not controlled (10-fold increase if MAP > 105 at conception)fold increase if MAP > 105 at conception)

• Higher risk of prematurity if Cr > 1.4 (59% Higher risk of prematurity if Cr > 1.4 (59% v. 10%) – increased risk of preeclampsia & v. 10%) – increased risk of preeclampsia & IUGRIUGR

Pregnancy in patients on Pregnancy in patients on dialysisdialysis• Conception occurs in 0.3-1.5% of women of Conception occurs in 0.3-1.5% of women of

childbearing age per year (disrupted gonadal childbearing age per year (disrupted gonadal function)function)

• Live births occur in 40-50%Live births occur in 40-50%• Prematurity occurs in most (average age at Prematurity occurs in most (average age at

delivery is ~ 30.5 weeks)delivery is ~ 30.5 weeks)• Increased risk for severe hypertensionIncreased risk for severe hypertension• Similar outcomes in HD & PD patientsSimilar outcomes in HD & PD patients• More intensive dialysis recommended (5-7x/wk to More intensive dialysis recommended (5-7x/wk to

keep BUN under 45-50); more frequent, lower keep BUN under 45-50); more frequent, lower volume exchanges if on PDvolume exchanges if on PD

• Avoid hemodynamic instability & monitor the fetus Avoid hemodynamic instability & monitor the fetus during treatmentduring treatment

Pregnancy in renal transplant Pregnancy in renal transplant patients: outcomespatients: outcomes• Fertility returns!Fertility returns!• > 90% success after 1> 90% success after 1stst trimester; slight increase trimester; slight increase

in spontaneous abortionin spontaneous abortion• IUGR a/o premature delivery in up to 20% & 50%, IUGR a/o premature delivery in up to 20% & 50%,

respectively (some say as much as 1/2-2/3 cases)respectively (some say as much as 1/2-2/3 cases)• US & UK registries suggest ~ 14% spontaneous US & UK registries suggest ~ 14% spontaneous

abortion, high prevalence of hypertension, abortion, high prevalence of hypertension, increased preeclampsia (~ 1/3)increased preeclampsia (~ 1/3)

• Developmental delays related to prematurityDevelopmental delays related to prematurity• Fewer complications & birth abnormalities than Fewer complications & birth abnormalities than

dialysis patientsdialysis patients

Pregnancy in renal transplant Pregnancy in renal transplant patients: outcomespatients: outcomes

• Increased risk of graft loss if Cr > 1.5 Increased risk of graft loss if Cr > 1.5 mg/dl before pregnancymg/dl before pregnancy

• No large, long-term controlled studies No large, long-term controlled studies looking at GFR & proteinuria in graft looking at GFR & proteinuria in graft recipients who have become pregnant recipients who have become pregnant (varying results)(varying results)

• Birth weight & gestational age seem to be Birth weight & gestational age seem to be lower in pancreas-kidney transplants than lower in pancreas-kidney transplants than in kidney alonein kidney alone

Pregnancy in renal transplant Pregnancy in renal transplant patients: outcomespatients: outcomes• One of the best studies we have: case-control study from One of the best studies we have: case-control study from

1 center in Israel1 center in Israel• Included patients transplanted between ’83 & ’98 Included patients transplanted between ’83 & ’98 • Looked at 39 women who became pregnant (44% received Looked at 39 women who became pregnant (44% received

CRT, 43.6% had glomerular disease originally, average CRT, 43.6% had glomerular disease originally, average age 24, most at least 2 years out)age 24, most at least 2 years out)

• Each matched w/ 3 controls from the Collaborative Each matched w/ 3 controls from the Collaborative Transplant Study database for 12 factors known to affect Transplant Study database for 12 factors known to affect graft survival (donor type, ethnic origin, transplant #, year graft survival (donor type, ethnic origin, transplant #, year transplanted, donor & recipient ages, IS regimen, CIT, HLA transplanted, donor & recipient ages, IS regimen, CIT, HLA mismatch, PRA, underlying disease, duration of mismatch, PRA, underlying disease, duration of functioning graft from transplant to pregnancy)functioning graft from transplant to pregnancy)

• IS regimen: 26 on CsA/AZA/pred, 7 on AZA/pred, 4 on IS regimen: 26 on CsA/AZA/pred, 7 on AZA/pred, 4 on CsA/pred, 2 on CsA/AZACsA/pred, 2 on CsA/AZA

• F/u of 15 yearsF/u of 15 years

Rahamimov, R et al, Transplantation Rahamimov, R et al, Transplantation 20062006

Rahamimov, R et al 2006Rahamimov, R et al 2006

• Similar graft and patient survival (62 Similar graft and patient survival (62 & 85% v. 69 & 79%)& 85% v. 69 & 79%)

• Similar kidney function 1, 5, & 10 Similar kidney function 1, 5, & 10 years post-transplantyears 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 rejectionNo acute rejection

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

McKay, DB et al, NEJM 2006McKay, DB et al, NEJM 2006

McKay, DB et al, NEJM 2006McKay, DB et al, NEJM 2006

McKay, DB et al, Transplantation McKay, DB et al, Transplantation 20062006

Transplant medications: Transplant medications: steroidssteroids• Associations noted between prednisone & Associations noted between prednisone &

a variety of birth defects (but mainly @ a variety of birth defects (but mainly @ doses > 20 mg/d)doses > 20 mg/d)

• Retrospective data suggest an increased Retrospective data suggest an increased risk of cleft palate w/ glucocorticoidsrisk of cleft palate w/ glucocorticoids

• Possible increased risk of PROM & IUGR w/ Possible increased risk of PROM & IUGR w/ glucocorticoidsglucocorticoids

• Glucocorticoids are excreted in breast milk Glucocorticoids are excreted in breast milk (small amounts), but considered ok if (small amounts), but considered ok if needed by motherneeded by mother

Transplant medications: Transplant medications: cyclosporinecyclosporine

• Can induce/worsen hypertensionCan induce/worsen hypertension

• Drug levels may fall during Drug levels may fall during pregnancypregnancy

• Premature labor and infants that are Premature labor and infants that are small for gestational age have been small for gestational age have been reported (possible confounders)reported (possible confounders)

Transplant medications: Transplant medications: cyclosporinecyclosporine• 115 renal transplant recipients (154 115 renal transplant recipients (154

pregnancies): CsA v. AZA/pred pregnancies): CsA v. AZA/pred • CsA had lower birth weights, more maternal CsA had lower birth weights, more maternal

DM/htn/rejection, but complication rate in DM/htn/rejection, but complication rate in newborns was slightly lower & congenital newborns was slightly lower & congenital malformations were not seen malformations were not seen

• Meta-analysis of 15 studies suggests that it Meta-analysis of 15 studies suggests that it is not a significant teratogen (4.1% of is not a significant teratogen (4.1% of offspring w/ major malformations – similar offspring w/ major malformations – similar to general population); limited by data to general population); limited by data available, study design, confounders…available, study design, confounders…

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

analysisanalysis

Bar Oz, B et al, Transplantation Bar Oz, B et al, Transplantation 20012001

Transplant medications: Transplant medications: cyclosporinecyclosporine

• Conflicting data re. passage across Conflicting data re. passage across placenta (rodents show little or no placenta (rodents show little or no transfer)transfer)

• Excreted in breast milk with even Excreted in breast milk with even therapeutic levels found in infantstherapeutic levels found in infants

• Not recommended for lactating Not recommended for lactating mothersmothers

Transplant medications: Transplant medications: tacrolimustacrolimus

• Again, limited dataAgain, limited data• 84 women (100 pregnancies – 27% of them in 84 women (100 pregnancies – 27% of them in

renal transplant recipients)renal transplant recipients)• Live birth in 68Live birth in 68• 60% of deliveries premature60% of deliveries premature• 4 babies w/ malformations (no pattern)4 babies w/ malformations (no pattern)• Dose remained reasonably stableDose remained reasonably stable• Levels in breast milk similar to that in Levels in breast milk similar to that in

maternal serum; not recommended during maternal serum; not recommended during lactationlactation

Kainz, A et al, Transplantation Kainz, A et al, Transplantation 20002000

Kainz, A et al, Transplantation Kainz, A et al, Transplantation 20002000

Transplant medications:Transplant medications:sirolimussirolimus

• Should be discontinued >/= 12 weeks Should be discontinued >/= 12 weeks before conceptionbefore conception

• Recommend switch to cyclosporine if Recommend switch to cyclosporine if planning to conceiveplanning to conceive

• Can switch back following deliveryCan switch back following delivery• Case series in 2006 – 7 pregnancies w/ Case series in 2006 – 7 pregnancies w/

exposure: 4 live births (1 w/ structural exposure: 4 live births (1 w/ structural malformations), 3 spontaneous malformations), 3 spontaneous abortionsabortions

Sifontis, NM et al, Transplantation Sifontis, NM et al, Transplantation 20062006

Transplant medications:Transplant medications:mycophenolate mofetilmycophenolate mofetil

• Adverse effects seen in lab animals Adverse effects seen in lab animals at lower doses than those used in at lower doses than those used in humanshumans

• Increases 1Increases 1stst trimester pregnancy trimester pregnancy loss & congenital malformations loss & congenital malformations (cleft lip/palate, anomalies of distal (cleft lip/palate, anomalies of distal limbs, heart, esophagus, kidneys)limbs, heart, esophagus, kidneys)

Transplant medications: Transplant medications: mycophenolate mofetilmycophenolate mofetil

• Same case series from 2006: 18 renal Same case series from 2006: 18 renal transplant recipients (26 pregnancies) transplant recipients (26 pregnancies) exposed to MMFexposed to MMF

• 11 spontaneous abortions11 spontaneous abortions

• 15 live births15 live births

• 4/15 live births had structural malformations: 4/15 live births had structural malformations: hypoplastic nails, shortened 5hypoplastic nails, shortened 5thth finger, finger, microtia w/ & w/o cleft lip & palate, neonatal microtia w/ & w/o cleft lip & palate, neonatal death w/ multiple malformationsdeath w/ multiple malformations

Sifontis, NM et al 2006Sifontis, NM et al 2006

Sifontis, NM et al, Transplantation Sifontis, NM et al, Transplantation 20062006

Transplant medications: Transplant medications: mycophenolate mofetilmycophenolate mofetil

• 2 forms of contraception should be used a 2 forms of contraception should be used a few weeks before & after therapy, as well few weeks before & after therapy, as well as during therapyas during therapy

• If planning pregnancy, should switch to If planning pregnancy, should switch to azathioprineazathioprine

• Should be off of MMF >/= 6 weeks before Should be off of MMF >/= 6 weeks before conceptionconception

• Excreted into breast milk – lactating Excreted into breast milk – lactating mothers should avoidmothers should avoid

Transplant medications: Transplant medications: azathioprineazathioprine• AZA is metabolized to thiouric acid (inactive) AZA is metabolized to thiouric acid (inactive)

by the fetus (a large percent of AZA given to by the fetus (a large percent of AZA given to mothers appears as inactive metabolites in mothers appears as inactive metabolites in fetal blood)fetal blood)

• Suggests that fetus lacks inosinate Suggests that fetus lacks inosinate pyrophosphorylase which converts AZA to 6-pyrophosphorylase which converts AZA to 6-MPMP

• 146 renal transplant recipients: 90% given 146 renal transplant recipients: 90% given AZA/pred, 2% given AZA, 8% given predAZA/pred, 2% given AZA, 8% given pred

• AZA groups showed more problems w/ low AZA groups showed more problems w/ low birthweight, prematurity, jaundice, respiratory birthweight, prematurity, jaundice, respiratory distress syndrome, & aspirationdistress syndrome, & aspiration

Transplant medications: Transplant medications: azathioprineazathioprine

• Lactation: 31 breast milk samples – Lactation: 31 breast milk samples – 29 had no 6-MP & 2 had minimal29 had no 6-MP & 2 had minimal

• 6-MP & 6-thioguanine were not 6-MP & 6-thioguanine were not detectable in neonatal blooddetectable in neonatal blood

• Preferable to MMFPreferable to MMF

McKay, DB et al, Transplantation 2006McKay, DB et al, Transplantation 2006

Recommendations… & our Recommendations… & our patientpatient

AST Consensus Conference on AST Consensus Conference on Reproductive Issues & Transplantation Reproductive Issues & Transplantation

20052005

AST Consensus Conference on AST Consensus Conference on Reproductive Issues & Transplantation Reproductive Issues & Transplantation

20052005

McKay, DB et al, CJASN 2008McKay, DB et al, CJASN 2008

Recommendations: key Recommendations: key pointspoints• Preferable to wait >/= 1 year Preferable to wait >/= 1 year

following LDRT & >/= 2 years following LDRT & >/= 2 years following CRT to avoid rejection-following CRT to avoid rejection-related complications (drug doses related complications (drug doses are lower & doses are stable)are lower & doses are stable)

• Graft should preferably be Graft should preferably be functioning well (stable Cr < 1.5 functioning well (stable Cr < 1.5 mg/dl, proteinuria < 500mg/d)mg/dl, proteinuria < 500mg/d)

• Frequent monitoringFrequent monitoring

RecommendationsRecommendations

• Aggressive treatment of Aggressive treatment of hypertension (goal is normalization hypertension (goal is normalization of bp)of bp)

• Close monitoring for preeclampsiaClose monitoring for preeclampsia

• Evidence suggests that pregnancy is Evidence suggests that pregnancy is not an immunosuppressed state & not an immunosuppressed state & transplant medications should not be transplant medications should not be reduced based on that notionreduced based on that notion

RecommendationsRecommendations

• In case cesarian section is necessary, In case cesarian section is necessary, obstetrician should know graft and ureter obstetrician should know graft and ureter locationlocation

• Careful wound closure & prophylactic Careful wound closure & prophylactic antibiotics to avoid infectionantibiotics to avoid infection

• Contraception: theoretical problems with Contraception: theoretical problems with hormonal methods, IUDs less effective & hormonal methods, IUDs less effective & increased risk of infection, barrier methods increased risk of infection, barrier methods traditionally preferredtraditionally preferred

Graft dysfunction in Graft dysfunction in pregnancypregnancy• Rejection is difficult to diagnose since Cr falls Rejection is difficult to diagnose since Cr falls

somewhat during pregnancysomewhat during pregnancy• Methylprednisolone is the recommended Methylprednisolone is the recommended

treatment of rejectiontreatment of rejection• IVIg has been used a fair amount without IVIg has been used a fair amount without

problems problems • Need to include causes specific to transplant as Need to include causes specific to transplant as

well as causes specific to pregnancywell as causes specific to pregnancy• Ureteral obstruction from a gravid uterus is not Ureteral obstruction from a gravid uterus is not

common, but has been reportedcommon, but has been reported• TTP-HUS from AHR or from cyclosporine/tacro TTP-HUS from AHR or from cyclosporine/tacro

occur peri-transplant, so a TTP-HUS picture in a occur peri-transplant, so a TTP-HUS picture in a pregnant patient is likely pregnancy-relatedpregnant patient is likely pregnancy-related

OK to biopsy??OK to biopsy??

• Data for native kidneys Data for native kidneys

• Can be done safely in women with Can be done safely in women with well-controlled blood pressurewell-controlled blood pressure

• Biopsy after 32 weeks is not Biopsy after 32 weeks is not recommended (? if applies to recommended (? if applies to transplant patients?)transplant patients?)

Issues for donor & male Issues for donor & male recipientrecipient

• Little data re. hyperfiltration in donor who Little data re. hyperfiltration in donor who becomes pregnant; fertility & becomes pregnant; fertility & complications do not seem to be affectedcomplications do not seem to be affected

• Sexual function & sperm motility (but not Sexual function & sperm motility (but not sperm counts or morphology) improve sperm counts or morphology) improve after transplantationafter transplantation

• Several reports of male infertility Several reports of male infertility associated w/ sirolimus (CNIs & AZA seem associated w/ sirolimus (CNIs & AZA seem ok)ok)

ReferencesReferences• Bar Oz, B et al. Pregnancy outcome after cyclosporine therapy Bar Oz, B et al. Pregnancy outcome after cyclosporine therapy

during pregnancy: a meta-analysis. Transplantation 2001; 71:1051.during pregnancy: a meta-analysis. Transplantation 2001; 71:1051.• Kainz, A et al. Review of the course and outcome of 100 pregnancies Kainz, A et al. Review of the course and outcome of 100 pregnancies

in 84 women treated with tacrolimus. Transplantation 2000; in 84 women treated with tacrolimus. Transplantation 2000; 70:1718.70:1718.

• McKay, DB et al. Pregnancy after kidney transplantation. CJASN McKay, DB et al. Pregnancy after kidney transplantation. CJASN 2008; 3:S117.2008; 3:S117.

• McKay, DB et al. Pregnancy in recipients of solid organs – effects on McKay, DB et al. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med 2006; 354:1281.mother and child. N Engl J Med 2006; 354:1281.

• McKay, DB et al. Reproduction and transplantation: report on the McKay, DB et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005; 5:1592.Transplantation. Am J Transplant 2005; 5:1592.

• Rahamimov, R et al. Pregnancy in renal transplant recipients: long-Rahamimov, R et al. Pregnancy in renal transplant recipients: long-term effect on patient and graft survival. A single-center experience. term effect on patient and graft survival. A single-center experience. Transplantation 2006; 81:660. Transplantation 2006; 81:660.

• Salmela, KT et al. Impaired renal function after pregnancy in renal Salmela, KT et al. Impaired renal function after pregnancy in renal transplant recipients. Transplantation 1993; 56:1372.transplant recipients. Transplantation 1993; 56:1372.

• Sifontis, NM et al. Pregnancy outcomes in solid organ transplant Sifontis, NM et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82:1698.Transplantation 2006; 82:1698.

• Sturgiss, SN et al. Effect of pregnancy on long-term function in renal Sturgiss, SN et al. Effect of pregnancy on long-term function in renal allografts: an update. Am J Kidney Dis 1995; 26:54.allografts: an update. Am J Kidney Dis 1995; 26:54.

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