Pregnancy after Kidney Transplantation

Dianne B. McKay* and Michelle A. Josephson†

*Department of Immunology, The Scripps Research Institute, La Jolla, California; and †Section of Nephrology,
Department of Medicine, University of Chicago, Chicago, Illinois
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Reproductive success is a common, expected outcome for male and female recipients of solid-organ transplants. Men can
father children, and women can become pregnant and carry the fetus to delivery. There are, however, important maternal and
fetal complications that need to be considered to provide optimal care to the mother and her infant. Although pregnancy is
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common after the transplantation of all solid organs, guidelines for optimal counseling and clinical management are limited.
This review discusses information to help the physician counsel the kidney transplant recipient about risks of pregnancy for
the mother and the fetus and provides information to help guide treatment of the pregnant transplant recipient.
Clin J Am Soc Nephrol 3: S117–S125, 2008. doi: 10.2215/CJN.02980707

Prevalence of Pregnancy in Transplant data on outcomes of approximately 200 transplant recipients.

Recipients
End-stage organ disease disrupts normal gonadal function;
consequently, pregnancies in patients with end-stage disease
are still relatively uncommon (1). Fertility is improved within
months after the successful replacement of an infirmed organ
(2); therefore, it is not surprising that increasing numbers of
pregnancies are reported in patients with transplanted kidneys,
liver, heart, lungs, and small bowel and even in those with
multiple organ transplants. The numbers of pregnancies that
have actually occurred in maternal or paternal transplant re-
cipients have not been quantified. In an attempt to estimate
numbers of pregnancies that have occurred in transplant recip-
ients, Davison and Baylis (3) tabulated all pregnancies reported
within the worldwide literature up to the year 2001. Reports of
14,000 pregnancies were acquired through review of case, cen-
ter, and registry reports. Certainly this number is an underes-
timation, because reporting of all pregnancies in transplant
recipients is no longer widespread practice.
Several pregnancy registries exist and have published infor-
mation on maternal, paternal, and infant outcomes. Three of
these registries have reported the largest numbers to date and
include in United States the National Transplantation Registry
(NTPR), a voluntary registry initiated in 1991 that relies on
transplant center or patient self-reporting (4); the United King-
dom Registry, which has collected information on the majority
of transplantation units in the United Kingdom from 1997 to
2002 (5,6), and the European Dialysis and Transplant Associa-
tion Registry, which collected information on outcomes from
European countries (7). The NTPR registry has reported ap-
proximately 1500 outcomes in female and 1000 outcomes in
male transplant recipients (4), the European Dialysis and Trans-
plant Association has reported approximately 400 pregnancies
in renal transplant recipients, and the UK Registry has reported
Correspondence: Dr. Dianne B. McKay, Department of Immunology, IMM-1, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
Phone: 858-784-9716; Fax: 858-784-8069; E-mail: dmckay@scripps.edu
Although these registries provide essential information, a com-
parison of the total number of pregnancies tabulated in the
three registries with the total number of patients reported in the
literature by the year 2001 shows that the three registries have
captured only a minority of the pregnancies in transplant re-
cipients. Because many more have occurred than have been
reported, the registries have captured information on far fewer
pregnancies than can be estimated by tabulations of reported
pregnancies. Unfortunately, registry data are limited by small
patient numbers and by unavoidable reporting bias. It is im-
portant to realize these limitations because the registry data
provide the primary source of data that guide patient treat-
ment. The limited published information is a wake-up call to
the need for enhanced registry reporting as well as large-scale
prospective studies that allow the design of evidence-based
care of the pregnant transplant recipient, information that is
essential to providing accurate advice for preconception coun-
seling.
Fertility, Contraception, and Optimal Timing
of Pregnancy
Male and female patients with end-stage kidney disease com-
monly experience sexual dysfunction and infertility as a result
of endocrine aberrations, vasomotor dysfunction, prescribed
medications, and psychological factors (8,9). Sexual function in
both men and women improves after transplantation (8,10 –12),
although one report suggested that one quarter of patients
remained sexually dysfunctional 3 yr after transplantation (12).
Female infertility results from altered hypothalamic function
and is associated with high follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and prolactin levels (8). The hor-
mone aberrations are usually reversed after transplantation,
resulting in normal ovulatory cycles and regular menstruation
(8,13,14). Many women with chronic kidney disease (CKD)
experience premature menopause, on an average of 4.5 yr
earlier than in the general population (15); therefore, chrono-
logical age and risk for early menopause should be considered
in the optimal timing of pregnancy after transplantation.

Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/302–0117

 S118 Clinical Journal of the American Society of Nephrology
Male infertility during ESRD is associated with low testos-
terone; high FSH, LH, and prolactin levels; and high estrogen
levels, resulting in impotence as well as spermatogenic abnor-
malities (8,16). The testis is marked by several signs of histo-
logic injury, including germinal aplasia and seminiferous tu-
bule destruction, the extent of which determines the
reversibility after transplantation (8,16). Transplantation re-
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stores the balance in the hypothalamic-pituitary axis and con-
sequently is associated with improvements in sperm motility
but not in sperm counts or morphology (17). The true incidence
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and prevalence of infertility are difficult to determine, and it is
unknown whether immunosuppressive medications have an
independent effect on fertility of the recipient, although cal-
cineurin inhibitors (CNI) and azathioprine do not seem to alter
male fertility after transplantation (18). There have been several
reports of male infertility associated with sirolimus, marked by
low free testosterone and significantly elevated levels of LH
and FSH (19). Sirolimus seems to cause a block in testosterone
synthesis at either the receptor or the postreceptor level, where
the cascade of transformation of cholesterol into testosterone
might be inhibited (18).
One potential way to gauge prevalence of infertility in the
posttransplantation population is to tabulate usage of assisted
reproduction by transplant recipients. Indeed, several cases of
female renal transplant patients who have undergone success-
ful in vitro fertilization treatments have been reported (20 –23).
As a word of caution, these treatments might result in preg-
nancies that are more complicated than natural pregnancies,
particularly because of the risk for multiple births (24,25). Al-
though there are no reports yet tabulating the incidence or
prevalence of assisted reproduction usage by transplant recip-
ients, this might be a useful exercise that could help yield
information about infertility in transplant recipients. The pre-
dominance of reports on pregnancies after transplantation sug-
gest restoration of fertility to an extent that at least should
inspire the practicing transplant physician to advise the patient
with a new transplant to use effective contraception.
Optimal contraception is important to initiate before trans-
plantation in women of childbearing age. Contraception should
be used before transplantation, because there have been several
reports of women who were pregnant in the peritransplanta-
tion period (26 –29). The peritransplantation period is not the
optimal time for pregnancy because this is a time of highest use
of potentially fetotoxic or teratogenic medications and a time
when optimization of immunosuppression is essential. The best
contraception has historically been considered to be barrier
methods, but because of potential for contraception failure, the
American Society of Transplantation Consensus Conference
report recommended that transplant recipients be advised that
barrier methods and intrauterine devices are not optimal forms
of contraception (30). Intrauterine devices are not optimal be-
cause they require an intact immune system for efficacy (31).
Progestin-only oral contraceptives as well as estrogen/proges-
tin are probably acceptable for use in this patient population as
long as hypertension is well controlled (32–34). The best con-
traceptive agent to use after transplantation depends on con-
siderations, made between the patient and her physician, of the
Clin J Am Soc Nephrol 3: S117–S125, 2008
desirability of pregnancy and considerations of the risks and
benefits of each contraceptive method (30).
The optimal timing of pregnancy depends somewhat on
individual circumstances of the transplant recipient. Histori-
cally, the recommendation was to wait 2 yr after successful
transplantation (33). This recommendation has been replaced
by the American Society of Transplantation Consensus Opinion
that as long as graft function is optimal, defined as a serum
creatinine ⬍1.5 mg/dl, with ⬍500 mg/24 h protein excretion,
and no concurrent fetotoxic infections or use of teratogenic or
fetotoxic medications, and immunosuppressive dosing is stable
at maintenance levels, the patient can safely proceed with the
pregnancy (30). Given the increasing age of the transplant
population, these recommendations might even be liberalized
to waiting 6 mo after transplantation in specific situations
(30,35). There have been no specific recommendations for male
transplant recipients with regard to posttransplantation inter-
vals and fathering a child.
A common concern during the peritransplantation period is
the optimal choice of immunosuppressive agents for women
who wish to become pregnant. The transplant physician is
often confronted with a dilemma: To continue mycophenolate
or rapamycin in a stable pregnant transplant recipient and risk
fetal abnormalities or to switch the immunosuppressive regi-
men (e.g., to azathioprine). Fetal risks associated with immuno-
suppressive medications are discussed in the Risks of Preg-
nancy to the Fetus section, but it should be mentioned that
current recommendations are to avoid mycophenolate mofetil
(MMF) and rapamycin for 6 wk before pregnancy (30,35,36). A
switch of immunosuppressive agents is particularly concerning
in the stable patient prescribed a steroid-free, two-immunosup-
pressive drug regimen. Unfortunately, there are few data on
which to base firm recommendations at this time.
Risks of Pregnancy to the Mother
Outcomes of pregnancy for the maternal transplant recipient
must focus on the affect of the pregnancy on maternal graft
function and on whether the pregnancy induces graft-indepen-
dent comorbidities. Preexisting kidney disease is an indepen-
dent risk factor for preeclampsia, prematurity, low birth
weight, and neonatal death (37,38). In the transplant setting, the
impact of kidney disease on these outcomes is influenced by the
degree of renal dysfunction, preexisting hypertension, and the
extent of proteinuria (38). A general guide for pre- and post-
transplantation medical management of pregnancy is provided
in Table 1.
An important concern for the potential mother is the effect of
the pregnancy on long-term allograft function. Several studies
have compared serum creatinine as an index of graft function
before and after pregnancy (5,39 – 43). Observations from preg-
nant patients with CKD have shown that mild kidney disease
(creatinine ⬍1.3 mg/dl) does not seem to risk worsening of
kidney function (38,44). Patients with moderate kidney disease
(defined as serum creatinine of 1.3 to 1.9 mg/dl) or severe
kidney disease (creatinine ⬎1.9 mg/dl) often experience a de-
cline in kidney function that can proceed to ESRD (38). Gener-
ally, the observations in patients with CKD support those in
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Table 1. Transplant physician monitoring schemea

Test/Visit When/Minimal Interval Rationale

Prepregnancy evaluation
rubella
RH compatibility of patient and
transplant
hepatitis B and C, HSV, CMV, HIV,
toxoplasmosis, and rubella
Before transplantation A live virus vaccine; do not administer after
transplantation
Before pregnancy If the patient is RH negative and the kidney is
RH positive, then theoretically the patient may
become sensitized to RH, which may pose a
problem only if the baby is RH positive
Before pregnancy Counsel regarding risks before pregnancy and
risk for transmission; hepatitis B vaccine can be
Clin J Am Soc Nephrol 3: S117–S125, 2008

given; reduce HIV transmission; check cervical

cultures if HSV positive
Pregnancy evaluation
BP Daily Patient can monitor and report
clinic visits Every 2 to 3 wk up to 20 wk; every 2 High-risk pregnancy with likelihood of preterm
wk until 28 wk; every week thereafter delivery
Routine laboratory testing
pyuria and urine culture Each visit Risk for ascending asymptomatic bacteriuria and
pyelonephritis
CBC Every 2 to 6 wk Decreased WBC count may predict neutropenia
and thrombocytopenia in the newborn; if
anemia is present, then an ESA may be useful if
not iron deficient or other reversible causes of
anemia are ruled out
serum BUN, creatinine, calculated Every 2 to 4 wk Rejection and pre-eclampsia are difficult to
clearance, and proteinuria diagnose
calcium and phosphorous Monitor at start and as needed Transplant patients may have tertiary
hyperparathyroidism or have had subtotal
parathyroidectomy
CNI Every 2 to 4 wk Levels may vary throughout gestation
liver function tests Every 6 wk Gravid liver may be more sensitive to
azathioprine hepatotoxicity
glucose tolerance test Each trimester Many patients are taking steroids or CNI
Testing specific to pregnancy
IgM to toxoplasmosis Each trimester if seronegative Risk for congenital infection
IgM to CMV Each trimester if seronegative Risk for congenital infection
More invasive testing
kidney biopsy Unexplained decrease in allograft Hard to appreciate graft dysfunction and to
function distinguish acute rejection from CNI toxicity,
Pregnancy and Kidney Transplantation

preeclampsia, and pyelonephritis

a
Adapted from reference (35). BUN, blood urea nitrogen; CBC, complete blood count; CMV, cytomegalovirus; CNI, calcineurin inhibitor; ESA, erythropoiesis-
stimulating agent; HSV, herpes simplex virus; WBC, white blood cell.
S119
 S120 Clinical Journal of the American Society of Nephrology
kidney transplant recipients, in who a serum creatinine ⱕ1.3
mg/dl, independent of immunosuppressive drug use, confers
little risk for short-term graft loss. Davison et al. (45) reported
that a serum creatinine ⬎1.5 mg/dl and proteinuria ⬎500
mg/24 h significantly increase the risk for irreversible graft loss
as a result of the pregnancy, consistent with expert consensus
opinion (30).
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Another significant risk to consider for the mother is graft
rejection. As a result of changes in blood volume, maintenance
of immunosuppressive medication dosing can be difficult, and
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vigilance of serum immunosuppressive levels is recommended
(36,46,47). Data from the NTPR suggested that higher dosages
of immunosuppressive medications are required to maintain
graft function (48). By contrast, others have not modified im-
munosuppressive dosing and found no resulting graft dysfunc-
tion (49); however, the lack of negative consequences should
not be interpreted to mean that it is without risk. The recom-
mendation by the American Society of Transplantation Con-
sensus Conference is that to avoid graft rejection, immunosup-
pressive dosing should be maintained at prepregnancy levels
through frequent monitoring of serum drug levels (36,30,47,50).
Pregnancy induces hyperfiltration in transplanted kidneys, as it
does in normal kidneys during pregnancy (51); therefore, de-
tection of rejection can be very difficult when monitoring for
changes in serum creatinine. If rejection is suspected, then the
kidney can be safely biopsied under ultrasound guidance (52).
If rejection occurs, then it can be treated with corticosteroids
(52,53). There are very few data on which to base recommen-
dations for treatment of rejection with other agents, such as
OKT3 or anti-thymocyte globulin (47).
Another maternal concern is hypertension during pregnancy,
as a result of either preexisting chronic hypertension or the
development of hypertension during gestation. Data from reg-
istry reports suggest a high prevalence of hypertension in preg-
nant renal transplant patients (up to 73% in the NTPR) (6,54,55).
During normal pregnancy, BP is lowest in the first trimester but
slowly returns to prepregnancy levels in late gestation. The
transplant recipient often experiences a similar but blunted
pattern of BP variation (52). Therapeutic targets for mild to
moderate hypertension in the CKD population are not known,
although recommendations have been made for treatment at
BP levels ⱖ150/90 mmHg (56). Treatment recommendations in
the gravid renal transplant recipient have been more aggres-
sive, with advice now to achieve a normotensive state (30,52).
The optimal choice of antihypertensive therapy depends on the
severity of hypertension. For mild hypertension, methyldopa
was recommended by several consensus studies, because it is
well tolerated and does not alter uteroplacental or fetal hemo-
dynamics (57). Other antihypertensive agents that are consid-
ered acceptable include labetolol, nifedipine, and thiazide di-
uretics (57). For urgent BP control, hydralazine, labetolol, and
nifedipine have been considered the drugs of choice (57). An-
giotensin-converting enzyme inhibitors and angiotensin recep-
tor blockers are contraindicated in pregnancy because of ad-
verse fetal effects, and atenolol should be avoided because of
concerns about fetal growth (56,57).
Maternal renal transplant patients with hypertension are at
Clin J Am Soc Nephrol 3: S117–S125, 2008
increased risk for development of superimposed preeclampsia,
with an incidence of 15 to 25% compared with 5% of normo-
tensive pregnancies (56). Preeclampsia is a syndrome charac-
terized by the development of hypertension in association with
new-onset proteinuria during the second half of pregnancy.
The incidence of preeclampsia is up to 32% in kidney/pancreas
recipients in the NTPR registry data (4); higher rates were
reported in recent center reports (58,59). Preeclampsia causes
severe maternal and fetal complications, such as renal failure,
HELLP syndrome (hemolysis, elevated liver enzymes, and
thrombocytopenia), seizures, liver failure, stroke, or death for
the mother. For the fetus, preeclampsia can result in being small
for gestational age, preterm delivery, hypoxic neurologic in-
jury, or death (60). Diagnosis of preeclampsia is difficult in the
gravid renal transplant recipient because BP commonly rises
late in pregnancy and many patients have preexisting protein-
uria (61). In addition, associated features of hyperuricemia and
edema are often coexistent in renal transplant patients (62). It is
interesting that histologic and molecular information show that
preeclampsia is a disorder of placental hypoxia and endothelial
dysfunction, although many mechanisms are yet unknown
(60,63). Whether markers of preeclampsia such as angiogenic or
antiangiogenc proteins will provide specific markers for pre-
eclampsia is unknown but could provide a very important area
for future study.
Other comorbidities to be considered in the maternal trans-
plant recipient include gestational diabetes, anemia, and infec-
tions such as urinary tract infections (58,59,64 – 66). Because
allograft recipients have increased risk for gestational diabetes,
they should be screened every trimester with a 50-g oral glu-
cose load (52). Urinary tract infections occur in up to 42% of
pregnant renal transplant patients (64), although pyelonephritis
is rare (52).
The maternal transplant recipient is placed at increased risk
for infection as a result of the use of immunosuppressive med-
ications; therefore, maternal–fetal transmission of infectious
agents needs to be considered as a potential risk not only to the
mother but also to the fetus. Cytomegalovirus infection is par-
ticularly serious because it is associated with hearing/vision
loss and mental retardation and can be transmitted from the
mother to the fetus through a transplacental route, as well as
during delivery or breastfeeding (52,67). Unfortunately, the
presence of maternal immunity does not absolutely protect the
fetus, although it does reduce the likelihood of transmission
(68,69). Antiviral medication prophylaxis has not generally
been recommended during pregnancy (70). Other infections
that may pose additional risks in the immunosuppressed
mother include toxoplasmosis, primary herpes simplex infec-
tion, primary varicella infection, HIV infection, and infection
with either hepatitis B or C virus (71,72). Prenatal screening can
detect each of these infections, although in many cases the
mother presents before prenatal screening when maternal pro-
phylaxis can no longer be considered.
It is interesting that most infants are delivered by cesarean
section (6), although the presence of the transplanted kidney in
the false pelvis does not in itself indicate the need for cesarean
delivery (52,73). Expert consensus opinion has been that unless
 Clin J Am Soc Nephrol 3: S117–S125, 2008
there is an obstetric reason to indicate cesarean delivery, vagi-
nal delivery is preferred (30).
Risks of Pregnancy to the Fetus
Determining risks of pregnancy from the fetus’s perspective
requires consideration of length of gestation, maternal health,
transmission of infections, and risks associated with in utero
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immunosuppressive exposure on organogenesis and matura-
tion. Published registry reports, as well as case and center
reports, consistently point to a high risk for preterm delivery
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(⬍37 wk) and low birth weight (⬍2500 g). The rates of preterm
delivery have been reported to be approximately 50% in the US
and European and UK registries (47) and even higher (64%) in
recent center reports (65). Most deliveries occur early because
of maternal and/or fetal compromise, rather than spontaneous
preterm labor (52). Transplant recipients are at high risk for
premature rupture of membranes, which also contributes to the
increased risk for preterm labor, as does pyelonephritis and
acute allograft rejection (52).
The mean gestational age at delivery in kidney transplant
recipients is 34 wk (52), and approximately 50% of infants are
delivered with low birth weight (47). Approximately 22% of the
infants in the UK registry had very low birth weight (⬍1500 g)
(6). Sibanda et al. (6) reported that when adjusted for gestational
age, there was no significant association between birth weight
and any other factor, except perhaps drug-treated hyperten-
sion, suggesting that fetal growth was not compromised. Be-
cause of likelihood of preterm delivery, recommendations are
to give steroids late in pregnancy (between 28 and 34 wk) to
promote lung maturity, if there is any sign of fetal compromise
(52,74). This recommendation is applicable to the fetus with
intrauterine growth restriction (IUGR), because there is a high
rate of associated perinatal mortality (52). The definition for
IUGR includes being ⱕ10th percentile of weight for gestational
age, suggesting a pathologic alteration in the placenta. The
incidence of IUGR is as high as 30 to 50% in kidney transplant
patients, believed to be secondary to the existing hypertension
and kidney disease and the propensity of these women to
develop preeclampsia (52,61,75). Serial sonographic assess-
ments of fetal growth are recommended in pregnant transplant
recipients to help assess for evidence of fetal growth compro-
mise (52).
The consequences of low and very low birth weight for the
fetus are substantial and include varied neurologic, endocrine,
cardiac, and renal abnormalities (76 – 83). Prospective evalua-
tions of childhood development have not been conducted in
infants who were born to transplant recipients. Data from the
NTPR are limited but suggest that developmental delays have
been seen in up to 26% of children after the age of 5 yr (84). The
significance of this finding, though, is not known, because
prospective neurocognitive testing has not routinely been per-
formed on children who were born to maternal transplant
recipients.
A major concern for the fetus is the potential effects of in utero
exposure to medications during organogenesis and develop-
ment. In the transplant setting, there is no choice but to expose
the fetus to immunosuppressive agents, because all immuno-
Pregnancy and Kidney Transplantation S121
suppressive medications pass through the maternal–fetal circu-
lation to varying degrees (47). There is much still to be learned
about the pharmacokinetics and pharmacodynamics of medi-
cations that routinely are given to maternal transplant recipi-
ents, making assertions about medication exposures difficult.
There is no reliable information that can be derived from the
Food and Drug Administration labeling because of limited
clinical data on which to determine the safety of many medi-
cations during pregnancy (57). None of the medications is
labeled A; in other words, there are no prospective, random-
ized trials indicating safety (Table 2). Further complicating the
situation is that there are unknown alterations in drug bioavail-
ability, drug elimination, and activity and distribution of drug
transporters within the placenta and fetus during pregnancy
(85). All immunosuppressive medications have been detected
to varying degrees in either the placental or the fetal circulation.
Table 2. FDA categories for Immunosuppressive
Medicationsa
FDA
Immunosuppressive Medication
Category
CNI
cyclosporine (Neoral, Sandimmune, C
Gengraf)
tacrolimus, FK506 (Prograf) C
Antiproliferative agents
mycophenolate mofetil (CellCept, D
Myfortic)
azathioprine (Imuran) D
rapamycin, sirolimus (Rapamune) C
leflunomide (Arava) X
Corticosteroids
prednisone (Deltazone) B
Antirejection agents
methylprednisolone C
muromonab-CD3 (Orthoclone OKT3) C
anti-thymocyte globulins C
(Thymoglobulin, ATGAM)
a
FDA pregnancy categories definitions: A, controlled
studies in pregnant women have not demonstrated a risk to
the fetus in the first trimester with no evidence of risk in
later trimesters; B, either animal-reproduction studies have
failed to demonstrate fetal risk but there are no controlled
studies in pregnant women, or animal-reproduction studies
have shown an adverse effect that was not confirmed in
controlled studies in women in the first trimester; C, either
studies in animals have revealed adverse effects on the fetus
(teratogenic or embryocidal effects or other) and there are no
controlled studies in women, or studies in women and
animals are not available; D, there is positive evidence of
human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the risk; X, studies in
animals or humans have demonstrated fetal abnormalities, or
there is evidence of fetal risk on the basis of human
experience, or both, and the risk of the use of the drug in
pregnant women clearly outweighs any possible benefit; the
drug is contraindicated in women who are or may become
pregnant.
 S122 Clinical Journal of the American Society of Nephrology
The placenta metabolizes prednisone; therefore, only low levels
have been detected in the fetal circulation. Azathioprine is a
prodrug that is rapidly metabolized to 6-mercaptopurine. This
moiety does pass into the fetus; however, a relative fetal lack of
the enzyme inosine pyrophosphorylase prevents it from being
transformed into its active form thioinosinic acid (86). CNI
readily cross the placenta and enter the fetal circulation. In fact,
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in one study, it was found that cyclosporine in fetal blood was
able to inhibit T cell function to the same degree as that found
in maternal serum (87). Much less is known about the mater-
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nal–fetal transport of MMF and sirolimus.
Immunosuppressive medication exposure may continue af-
ter birth if the mother opts to breastfeed. Most physicians
advise against breastfeeding (30), although this has not per-
suaded all new mothers with kidney transplants. The American
Academy of Pediatrics supports breastfeeding for mothers who
are taking prednisone and advises against it for those who are
taking cyclosporine (88). There are no specific American Acad-
emy of Pediatrics recommendations for mothers who are taking
azathioprine or tacrolimus (88). Prednisone and azathioprine
are detected in breast milk (in small amounts) (89), but there are
no human data for MMF or sirolimus. Studies are needed on
pharmacokinetics and transfer of immunosuppressive medica-
tions to breast milk. Until these studies are available, expert
consensus is that breastfeeding need not be seen as absolutely
contraindicated (30).
The impact of immunosuppressive exposure on the develop-
ing fetus is often measured by the presence of major structural
malformations at birth. Data from the NTPR registry as well as
many case and center reports suggest that the incidence of
major malformations is not much higher than that in the gen-
eral population. A concern, though, has been raised for in utero
exposure to MMF, which may be associated with severe struc-
tural malformations in case reports and in NTPR registry data
(90 –92). Information regarding sirolimus is still too limited to
make recommendations. It should be mentioned that it is often
difficult to discern which agent is responsible for birth defects
because patients are often taking more than one immunosup-
pressive agent.
It is not known whether infants who are born to maternal
transplant recipients have an increased risk for more subtle
defects. Subtle defects that may not be apparent at birth are
difficult to measure and require greater evaluations than can be
obtained by observational studies. CNI have been known for
many years to target a critical phase in T cell development
within the fetal thymus. By blocking normal T cell develop-
ment, CNI have been shown to block the normal process by
which self-reactive T cells are eliminated during thymic devel-
opment, leading to autoimmunity in animal models (93–95).
Whether exposure to CNI increases the likelihood of autoim-
munity in offspring of transplant recipients is not yet known,
although one case report suggested that there might be an
association (96). Concerns have also been raised about neuro-
cognitive deficits. It is has been known for some time that
calcineurin and FKBP12 (FK506-binding protein) are enriched
in the fetal brain and stimulation with FK506 causes functional
changes in the fetal brain (97,98). There are may other factors,
Clin J Am Soc Nephrol 3: S117–S125, 2008
though, that might also contribute to alterations in fetal neuro-
logic development in the gravid transplant recipient (99 –102).
Whether subtle defects are induced during pregnancies of ma-
ternal transplant recipients is not known; therefore, this is an
area that requires more study, optimally by prospective analy-
sis of children who are born to transplant recipients. While
these and other appropriate studies are designed, it is critically
important that all pregnancies be reported to existing trans-
plantation registries so that information continues to accumu-
late on the outcomes of maternal and paternal transplant recip-
ients and their offspring.
Risks of Pregnancy to Female Kidney
Donors
The issue of kidney donation and subsequent pregnancy has
been mostly ignored, but it has been part of the transplant
pregnancy story from the very beginning. The first woman with
a kidney transplant to deliver a child received her kidney from
an identical twin (103). Not only did this individual go on to
become pregnant after the transplant operation, but so did her
sister (103). Several small self-reporting surveys of women who
became pregnant after donation indicated little cause for con-
cern (104,105). A recent abstract presented at the 2006 meeting
of the American Society of Nephrology brought out the possi-
bility that donation may increase the risk for preeclampsia in
postdonation pregnancies (106). Further data, though, are
needed before any firm conclusions are drawn. This potentially
important observation finding serves as a call for additional
investigation in this area, particularly when living donation is
increasing and woman constitute nearly 60% of live donors
(107).
Conclusions
There are many questions to be answered about the safety of
pregnancy in the transplant setting. Transplant recipients and
their donors have been conceiving for more than 50 yr, yet only
limited, retrospective data are available about the short- and
long-term outcomes for the mother and her infant. Concerns
linger for both the mother and the fetus as a result of a paucity
of data on which to base treatment recommendations and on
which to offer advice to prospective parents.
Disclosures
None.
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