Download 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
• Pregnancy in patients with chronic kidney
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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
• Permanent decline in renal function in 0-10% of
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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
• Proteinuria increases in ~ ½ of the patients
• Hypertension develops or worsens in ~ ¼ of the
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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
• If blood pressure is controlled, rate of live births
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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
• Conception occurs in 0.3-1.5% of women of childbearing
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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
• Fertility returns!
• > 90% success after 1st trimester; slight increase in
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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: outcomes
• Increased risk of graft loss if Cr > 1.5 mg/dl
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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: outcomes
• One of the best studies we have: case-control study from 1
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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, Transplantation 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
Pregnancy in renal transplant patients: outcomes
McKay, DB et al, NEJM 2006 (review)
McKay, DB et al, NEJM 2006
McKay, DB et al, NEJM 2006
McKay, DB et al, Transplantation 2006
Transplant medications: steroids
• Associations noted between prednisone & a
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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
• 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:
cyclosporine
• 115 renal transplant recipients (154
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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…
Bar Oz, B et al, Transplantation 2001
Articles used for meta-analysis
Bar Oz, B et al, Transplantation 2001
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
• Again, limited data
• 84 women (100 pregnancies – 27% of them in
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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
Kainz, A et al, Transplantation 2000
Kainz, A et al, Transplantation 2000
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
Sifontis, NM et al, Transplantation 2006
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 mofetil
• Same case series from 2006: 18 renal transplant
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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
Sifontis, NM et al 2006
Sifontis, NM et al, Transplantation 2006
Transplant medications:
mycophenolate mofetil
• 2 forms of contraception should be used a few
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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
• AZA is metabolized to thiouric acid (inactive) by
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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:
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
McKay, DB et al, Transplantation 2006
Recommendations… & our
patient
AST Consensus Conference on Reproductive
Issues & Transplantation 2005
AST Consensus Conference on Reproductive
Issues & Transplantation 2005
McKay, DB et al, CJASN 2008
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
• 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
Recommendations
• In case cesarian section is necessary,
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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
• Rejection is difficult to diagnose since Cr falls somewhat
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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??
• Data for native kidneys
• Can be done safely in women with wellcontrolled blood pressure
• Biopsy after 32 weeks is not
recommended (? if applies to transplant
patients?)
Issues for donor & male recipient
• Little data re. hyperfiltration in donor who
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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
• Bar Oz, B et al. Pregnancy outcome after cyclosporine therapy during
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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.
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