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

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pregnancy renal transplantation

Pregnancy & Renal Transplantation

Alicia Notkin

May 20, 2008

slide2
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?

outline
Outline
  • Pregnancy in patients with chronic kidney disease
  • Pregnancy in patients on dialysis
  • Pregnancy in renal transplant patients
  • Transplantation medications in pregnancy
  • Recommendations
  • Other issues: graft dysfunction in pregnancy, donor & pregnancy, male fertility
pregnancy in patients with chronic kidney disease patient considerations
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
  • 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
pregnancy in patients with chronic kidney disease other patient considerations
Pregnancy in patients with chronic kidney disease: other patient considerations
  • Proteinuria increases in ~ ½ 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
  • Β-HCG can be increased in patients w/ ESRD, so confirm pregnancy w/ an ultrasound
pregnancy in patients with chronic kidney disease fetal outcomes
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
  • 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
pregnancy in patients on dialysis
Pregnancy in patients on dialysis
  • Conception occurs in 0.3-1.5% of women of childbearing age per year (disrupted gonadal function)
  • Live births occur in 40-50%
  • Prematurity occurs in most (average age at delivery is ~ 30.5 weeks)
  • Increased risk for severe hypertension
  • 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
  • Avoid hemodynamic instability & monitor the fetus during treatment
pregnancy in renal transplant patients outcomes
Pregnancy in renal transplant patients: outcomes
  • Fertility returns!
  • > 90% success after 1st 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)
  • US & UK registries suggest ~ 14% spontaneous abortion, high prevalence of hypertension, increased preeclampsia (~ 1/3)
  • Developmental delays related to prematurity
  • Fewer complications & birth abnormalities than dialysis patients
pregnancy in renal transplant patients outcomes1
Pregnancy in renal transplant patients: outcomes
  • 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)
  • Birth weight & gestational age seem to be lower in pancreas-kidney transplants than in kidney alone
pregnancy in renal transplant patients outcomes2
Pregnancy in renal transplant patients: outcomes
  • One of the best studies we have: case-control study from 1 center in Israel
  • 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)
  • 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
  • F/u of 15 years
rahamimov r et al 2006
Rahamimov, R et al 2006
  • Similar graft and patient survival (62 & 85% v. 69 & 79%)
  • Similar kidney function 1, 5, & 10 years post-transplant
  • Preterm delivery in 60%
  • Preeclampsia in 15.3%
  • IUGR in 52%
  • No acute rejection
transplant medications steroids
Transplant medications: steroids
  • 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
  • Possible increased risk of PROM & IUGR w/ glucocorticoids
  • Glucocorticoids are excreted in breast milk (small amounts), but considered ok if needed by mother
transplant medications cyclosporine
Transplant medications: cyclosporine
  • Can induce/worsen hypertension
  • Drug levels may fall during pregnancy
  • Premature labor and infants that are small for gestational age have been reported (possible confounders)
transplant medications cyclosporine1
Transplant medications: cyclosporine
  • 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
  • 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…
transplant medications cyclosporine2
Transplant medications: cyclosporine
  • Conflicting data re. passage across placenta (rodents show little or no transfer)
  • Excreted in breast milk with even therapeutic levels found in infants
  • Not recommended for lactating mothers
transplant medications tacrolimus
Transplant medications: tacrolimus
  • Again, limited data
  • 84 women (100 pregnancies – 27% of them in renal transplant recipients)
  • Live birth in 68
  • 60% of deliveries premature
  • 4 babies w/ malformations (no pattern)
  • Dose remained reasonably stable
  • Levels in breast milk similar to that in maternal serum; not recommended during lactation
transplant medications sirolimus
Transplant medications:sirolimus
  • Should be discontinued >/= 12 weeks before conception
  • Recommend switch to cyclosporine if planning to conceive
  • Can switch back following delivery
  • Case series in 2006 – 7 pregnancies w/ exposure: 4 live births (1 w/ structural malformations), 3 spontaneous abortions
transplant medications mycophenolate mofetil
Transplant medications:mycophenolate mofetil
  • Adverse effects seen in lab animals at lower doses than those used in humans
  • Increases 1st trimester pregnancy loss & congenital malformations (cleft lip/palate, anomalies of distal limbs, heart, esophagus, kidneys)
transplant medications mycophenolate mofetil1
Transplant medications: mycophenolate mofetil
  • Same case series from 2006: 18 renal transplant recipients (26 pregnancies) exposed to MMF
  • 11 spontaneous abortions
  • 15 live births
  • 4/15 live births had structural malformations: hypoplastic nails, shortened 5th finger, microtia w/ & w/o cleft lip & palate, neonatal death w/ multiple malformations
transplant medications mycophenolate mofetil2
Transplant medications: mycophenolate mofetil
  • 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
  • Should be off of MMF >/= 6 weeks before conception
  • Excreted into breast milk – lactating mothers should avoid
transplant medications azathioprine
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)
  • 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
  • AZA groups showed more problems w/ low birthweight, prematurity, jaundice, respiratory distress syndrome, & aspiration
transplant medications azathioprine1
Transplant medications: azathioprine
  • Lactation: 31 breast milk samples – 29 had no 6-MP & 2 had minimal
  • 6-MP & 6-thioguanine were not detectable in neonatal blood
  • Preferable to MMF
recommendations key points
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)
  • Graft should preferably be functioning well (stable Cr < 1.5 mg/dl, proteinuria < 500mg/d)
  • Frequent monitoring
recommendations
Recommendations
  • Aggressive treatment of hypertension (goal is normalization of bp)
  • Close monitoring for preeclampsia
  • Evidence suggests that pregnancy is not an immunosuppressed state & transplant medications should not be reduced based on that notion
recommendations1
Recommendations
  • In case cesarian section is necessary, obstetrician should know graft and ureter location
  • 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
graft dysfunction in pregnancy
Graft dysfunction in pregnancy
  • Rejection is difficult to diagnose since Cr falls somewhat during pregnancy
  • Methylprednisolone is the recommended treatment of rejection
  • IVIg has been used a fair amount without problems
  • 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
  • TTP-HUS from AHR or from cyclosporine/tacro occur peri-transplant, so a TTP-HUS picture in a pregnant patient is likely pregnancy-related
ok to biopsy
OK to biopsy??
  • Data for native kidneys
  • Can be done safely in women with well-controlled blood pressure
  • Biopsy after 32 weeks is not recommended (? if applies to transplant patients?)
issues for donor male recipient
Issues for donor & male recipient
  • 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
  • Several reports of male infertility associated w/ sirolimus (CNIs & AZA seem ok)
references
References
  • 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.
  • 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. 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.
  • 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.
  • 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
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