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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


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 outcomes

  • 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 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 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 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 outcomes

  • 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


Pregnancy in renal transplant patients outcomes mckay db et al nejm 2006 review
Pregnancy in renal transplant patients: outcomes outcomesMcKay, DB et al, NEJM 2006 (review)





Transplant medications steroids
Transplant medications: steroids outcomes

  • 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 outcomes

  • 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 outcomes

  • 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 meta-analysis

  • 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 meta-analysis

  • 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: meta-analysissirolimus

  • 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: meta-analysismycophenolate 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 meta-analysis

  • 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 meta-analysis

  • 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 meta-analysis

  • 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 meta-analysis

  • 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






Mckay db et al cjasn 2008
McKay, DB et al, CJASN 2008 Transplantation 2005


Recommendations key points
Recommendations: key points Transplantation 2005

  • 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 Transplantation 2005

  • 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 Transplantation 2005

  • 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 Transplantation 2005

  • 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?? Transplantation 2005

  • 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 Transplantation 2005

  • 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 Transplantation 2005

  • 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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