Pregnancy After Kidney

Transplantation

Lisa A. Coscia, Dawn Armenti, Serban Constantinescu, and

Michael J. Moritz

In Memoriam
This manuscript is dedicated to Vincent T. Armenti, MD, PhD (1952–2014), the founding
principal investigator of the NTPR. His guidance and leadership allowed the NTPR to
flourish and provide countless transplant recipients with scientific information on which
to base their family planning decisions.

Abstract regarding post-transplant pregnancy is derived

Successful pregnancy after kidney transplanta-
tion has been reported worldwide since the
1960s and much of the clinical guidance
L.A. Coscia (*) • D. Armenti
National Transplantation Pregnancy Registry (NTPR), Gift
of Life Institute, Philadelphia, PA, USA
e-mail: lcoscia@giftoflifeinstitute.org;
ntpr@giftoflifeinstitute.org; darmenti@giftoflifeinstitute.
org; ntpr@giftoflifeinstitute.org
S. Constantinescu
National Transplantation Pregnancy Registry (NTPR), Gift
of Life Institute, Philadelphia, PA, USA
Kidney Transplant Program, Section of Nephrology,
Hypertension and Kidney Transplantation, Lewis Katz
School of Medicine, Temple University, Philadelphia, PA,
USA
e-mail: Serban.Constantinescu@tuhs.temple.edu;
ntpr@giftoflifeinstitute.org
M.J. Moritz
National Transplantation Pregnancy Registry (NTPR), Gift
of Life Institute, Philadelphia, PA, USA
Transplant Services, Lehigh Valley Health Network,
Allentown, PA, USA
University of South Florida Morsani College of Medicine,
Tampa, FL, USA
e-mail: michael.moritz@lvhn.org; ntpr@giftoflifeinstitute.org
from the experience in kidney recipients. This
chapter includes a review of the relevant liter-
ature plus data from the National Transplanta-
tion Pregnancy Registry (NTPR) regarding
pregnancy, maternal and newborn outcomes
in this population and clinical management
guidelines for the care of kidney transplant
recipients before, during, and after pregnancy.
Fertility is often restored soon after successful
kidney transplantation; therefore, appropriate
contraception and pregnancy counselling
should be key components of pre- and post-
transplant care. Conception planning is
strongly recommended. If the recipient’s
immunosuppressive regimen includes a
mycophenolic acid (MPA) product, modifying
the medication regimen prior to conception
should be seriously considered as exposure
confers substantial risks to the fetus. Close
monitoring of the recipient, the transplant func-
tion, and her medications should continue
throughout the pregnancy and postpartum.

# Springer International Publishing AG 2017 1

C.G.B. Ramirez, J. McCauley (eds.), Contemporary Kidney Transplantation, Organ and Tissue
Transplantation, DOI 10.1007/978-3-319-14779-6_29-1
2 L.A. Coscia et al.

Post-transplant pregnancies are high-risk and Introduction

warrant close collaboration among multiple
disciplines to provide the best possible out- The first pregnancy after kidney transplant
come for mother, her graft, and child. occurred in 1958 resulting in the delivery of a
healthy infant with no adverse effects on the recip-
Keywords ient’s kidney function (Murray et al. 1963). The
Kidney transplantation • Pregnancy • Immuno- recipient went on to have a second pregnancy and
suppression • Mycophenolate • High-risk • maintained her kidney graft function until she
Fetus • Prenatal • Birth defects • Breastfeeding • died from complications of dementia at the age
Contraception of 76. She was the first woman in the identical
twin series from the Brigham Hospital and was
not immunosuppressed. The first recipient with a
Contents pregnancy exposed to immunosuppression (aza-
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 thioprine and prednisone) was reported in 1967
and delivered a healthy infant with no
Biomechanical Instrumentation and Measurement 2
malformations. At the time of the report, the
Biomechanical Analysis of the Hip Joint . . . . . . . . . . . 3 mother’s graft function at 1.5 months postpartum
Osteokinematics, Arthrokinematics, and Muscle and the infant’s health at 5 months were favorable
Actions of the Hip Joint . . . . . . . . . . . . . . . . . . . . . . . . . 5 (Board et al. 1967).
Sagittal Plane Osteokinematics . . . . . . . . . . . . . . . . . . . . . 6 For years, pregnancy in transplant recipients
was discouraged due to concerns about the effect
Sagittal Plane Arthrokinematics . . . . . . . . . . . . . . . . . . . . 6
of pregnancy on transplant kidney function and
Sagittal Plane Muscle Actions . . . . . . . . . . . . . . . . . . . . . . 6 survival and potential teratogenic or long-term
Frontal Plane Osteokinematics . . . . . . . . . . . . . . . . . . . . . 7 effects of immunosuppressive drugs on the off-
Frontal Plane Arthrokinematics . . . . . . . . . . . . . . . . . . . . 8
spring. As experience in this population accrued,
many of these concerns have been allayed and
Frontal Plane Muscle Actions . . . . . . . . . . . . . . . . . . . . . . . 8
others have been clarified to the point that
Transverse Plane Osteokinematics . . . . . . . . . . . . . . . . . 8 healthcare providers ought to no longer automat-
Transverse Plane Arthrokinematics . . . . . . . . . . . . . . . . 9 ically dissuade kidney recipients who meet certain
criteria from considering pregnancy. These guide-
Transverse Plane Muscle Actions . . . . . . . . . . . . . . . . . . . 9
lines are based upon the many case and series plus
The Biomechanics of the Hip During Gait . . . . . . . . . 9 database reports regarding the outcomes of preg-
Temporal and Spatial Parameters of Gait . . . . . . . . . 10 nancies in kidney transplant recipients and other
Gait Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 issues of special interest in this population
(Kashanizadeh et al. 2007; Sibanda et al. 2007;
Sagittal Plane Gait Biomechanics . . . . . . . . . . . . . . . . . . 10
Al Duraihimh et al. 2008; Wyld et al. 2013). The
Frontal Plane Gait Biomechanics . . . . . . . . . . . . . . . . . . . 11 National Transplantation Pregnancy Registry
Transverse Plane Gait Biomechanics . . . . . . . . . . . . . . . 12 (NTPR), which is one of the largest repositories
of data regarding pregnancy after transplantation,
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
analyzes pregnancy outcomes in solid organ
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 transplant recipients and in pregnancies fathered
by male transplant recipients (NTPR Annual
Report 2015). This chapter is a condensed over-
view of over 50 years of experience regarding
pregnancy after kidney transplantation with a dis-
Pregnancy After Kidney Transplantation
cussion of recommendations for counselling the
kidney transplant recipient of child-bearing poten-
tial and her partner, as well as guidelines for
antenatal care.
Overview of Immunosuppressive
Agents
Virtually all kidney transplant recipients take
immunosuppressive medications to prevent
organ rejection, including during pregnancies.
Most take two or three immunosuppressives, and
the most potent one is termed the “primary”
immunosuppressant. Pregnancy outcomes
reported to the NTPR are listed in Table 1 by
primary immunosuppressant.
When weighing the need for a medication dur-
ing pregnancy against the potential effects the
medication may have on the developing fetus,
the scale unequivocally tilts toward kidney recip-
ients remaining on their immunosuppressive med-
ication(s) during their pregnancy. It is, however,
possible that recipients may be able to switch to
different medications that are safer in pregnancy.
A description of common maintenance immu-
nosuppressive agents with their potential for tera-
togenicity follows.
Prednisone
Prednisone at conventional transplant mainte-
nance dosages poses minimal risk to the develop-
ing fetus and is generally considered safe for use
during pregnancy. A meta-analysis of non-trans-
planted women who took oral corticosteroids dur-
ing the first trimester did not show a higher rate of
major anomalies. The 3.4-fold increase in oral
clefts was not confirmed by later analyses (Park-
Wyllie et al. 2000; Hviid and Mølgaard-Nielson
2011).
3
Azathioprine
Azathioprine in combination with steroids has
been used for the prevention of rejection since
1962. In early animal studies, when administered
at doses similar to the human primary immuno-
suppressant dose of >2 mg/kg/day, azathioprine
was associated with embryonic resorption and/or
fetal anomalies and thus was listed as an FDA
Category D agent (i.e., positive evidence of
human fetal risk based on adverse reaction data
from investigational or marketing experience or
studies in humans, but the potential benefits from
the use of the drug in pregnant women may be
acceptable despite its potential risks). Results
from these animal studies have not been supported
by clinical outcome data. Since the introduction of
calcineurin inhibitors (CNI), azathioprine is most
often used as adjunctive therapy at doses of 1 mg/
kg/day. At this level, azathioprine is considered a
safe option for use during pregnancy. Preterm
delivery and fetal growth restriction have been
noted, but without any predominant structural
malformation pattern (Cleary and Kallen 2009).
Data from the NTPR and other large cohorts
shows no increase in the incidence of
malformations or any obvious pattern of
malformations among offspring exposed to aza-
thioprine (Davison et al. 1985; Armenti et al.
1994; Langagergaard et al. 2007).
Cyclosporine
Cyclosporine, a CNI introduced in the 1980s,
supplanted azathioprine as the primary immuno-
suppressant of choice due to lower rejection rate
and increased graft survival. The teratogenic risk
of cyclosporine is minimal, although there is a
potential risk of fetal growth restriction (Paziana
et al. 2013). In animal studies, fetal abnormalities
and toxicities were noted at higher dosages than
those used clinically (Mason et al. 1985). Early
reports raised concerns about the safety of cyclo-
sporine use during pregnancy (Pickrell et al.
4 L.A. Coscia et al.

Table 1 NTPR: pregnancy outcomes in female kidney transplant recipients

Azathioprine and/or Cyclosporine- Tacrolimus-
prednisonea basedb,c basedb,c
Recipients 243 482 254
Maternal factors (n = pregnancies) (448) (822) (427)
Mean transplant-to-conception 6.8  4.9 4.7  3.5 4.8  3.3
interval (years)
Hypertension during pregnancy (%) 25 60 53
Diabetes during pregnancy (%) 5 9 9
Infection during pregnancy (%) 16 21 20
Preeclampsia (%) 22 32 35
Rejection episode during pregnancyd (%) 1 1 2
Mean serum creatinine (mg/dL)
Before pregnancy 1.1  0.4 1.4  0.4 1.2  0.3
During pregnancy 1.2  0.5 1.4  0.6 1.3  0.9
After pregnancy 1.2  0.6 1.5  0.8 1.3  0.5
Graft loss within 2 years of delivery (%) 4 7 9
Outcomes (n)e (463) (852) (439)
Terminations (%) 4 5 2.3
Miscarriages (%) 12 16 24.4
Ectopic (%) 1 1 0.5
Stillborn (%) 2 2 1.4
Live births (%) 81 76 71.5
Live births (n) (374) (645) (314)
Mean gestational age (weeks) 36.4  3.3 35.8  3.4 35.4  3.6
Premature (<37 weeks) (%) 47 52 52
Mean birthweight (g) 2734  718 2507  749 2522  821
Low birthweight (<2500 g) (%) 35 44 42
Cesarean section (%) 51 51 58
Newborn complications (%) 37 42 52
Birth defects (%) 2.2 4 8b
Neonatal deaths, n (%) (within 30 days of 6 (1.3%) 11 (1.7%)f 5 (1.6%)
birth)
a
No calcineurin inhibitor
b
MPA exposure during pregnancy: cyclosporine (4%); tacrolimus (23%)
c
Cyclosporine-based regimens (brand name or generic formulations of cyclosporine and cyclosporine-USP modified) and
tacrolimus-based regimens (brand name and generic formulations of tacrolimus and brand name tacrolimus extended
release); regimens may include azathioprine or MPA and/or prednisone
d
Biopsy-proven acute rejection only
e
Includes multiple births
f
Includes 24-week quadruplet pregnancy; all newborn died

1989), but clinical data have not demonstrated an Tacrolimus

increased incidence or pattern of birth defects with
exposure to cyclosporine (NTPR Annual Report
2015).
In the 1990s, tacrolimus, another CNI, was intro-
duced and is currently the most common primary
immunosuppressive prescribed to kidney trans-
plant recipients. Data from the NTPR and other
large reports have not revealed an increase in the
incidence of malformations or a specific pattern of
malformations among offspring exposed to
Pregnancy After Kidney Transplantation 5

tacrolimus in utero (NTPR Annual Report 2015; healthcare provider to plan a pregnancy, strategies
Kainz et al. 2000). In animal studies, fetal resorp- such as temporary replacement of MPA with aza-
tions occurred at doses higher than those in clin- thioprine along with adding or increasing predni-
ical use. In a lower dosage group (0.16 mg/kg/ sone should be considered in an attempt to
day) commonly used in clinical practice, surviv- balance the risks to the transplanted kidney and
ing fetuses appeared no different than controls the risks to the fetus (Coscia et al. 2015b). In a
(Farley et al. 1991). recent NTPR study, there was no increase in acute
rejections during pregnancy or postpartum in kid-
ney transplant recipients who discontinued and/or
Mycophenolic Acid Products switched MPA preconception (Constantinescu
et al. 2016a).
Two oral mycophenolic acid (MPA) products are Animal studies revealed developmental toxic-
available, the mofetil ester (MMF) and enteric ity, malformations, intrauterine death, and intra-
coated mycophenolate sodium (EC-MPS). MPA uterine growth restriction at MPA doses within the
products have widely replaced azathioprine as an recommended clinical range based on body sur-
adjunctive immunosuppressive and are most often face area. NTPR data demonstrated that exposure
used in conjunction with a CNI, with or without to MPA during pregnancy is associated with an
prednisone. increased incidence of miscarriage and a specific
MPA products are not considered safe for use pattern and increased incidence of malformations
during pregnancy. It is recommended that females (Sifontis et al. 2006). In a 2015 review article, the
of child-bearing potential use two forms of effec- MPA phenotype was described to include the
tive contraception while taking MPA and when- embryopathies listed in Table 2 (Coscia et al.
ever possible it should be discontinued prior to 2015b).
conceiving. When a patient approaches her These risks have not been noted in pregnancies
fathered by transplant recipients taking MPA
Table 2 Frequency of mycophenolate embryopathies (Jones et al. 2013; Constantinescu et al. 2016b).
Listed in Table 3 is a comparison of fathered
Fetuses with defect
Embryopathies (n = 35) % pregnancies with and without MPA exposure.
Microtia/external auditory 20 57 There was no difference in live birth, fetal loss,
canal defect or birth defect rates.
Cardiac anomalies 11 31
Clefts 11 31
Eye anomalies 9 26 Sirolimus and Everolimus
Skeletal anomalies 8 23
Hypertelorism 7 20 Sirolimus and everolimus are used in both pri-
Kidney abnormalities 7 20 mary and adjunctive immunosuppressive roles.
Micrognathia 7 15 In animal studies, in utero sirolimus exposure
Brain anomalies 5 14 resulted in decreased fetal weights and delayed
Trachea/esophageal 5 14
ossification of skeletal structures, but no teratoge-
anomalies
nicity was noted. When administered in

Table 3 NTPR fathered pregnancies: MPA exposed versus unexposed

Exposed (n) Unexposed (n) p-value
Pregnancies 268 251
Outcomes 278 263
Live births 250 89.9% 244 92.8% 0.29
Fetal losses 28 10% 18 6.8% 0.22
Birth defects 7 2.8% 6 2.5% 1
6 L.A. Coscia et al.
combination with cyclosporine to pregnant ani-
mals, there was increased fetal mortality,
increased numbers of resorptions, and decreased
numbers of live fetuses, suggesting increased tox-
icity in conjunction with a CNI. To date, limited
NTPR data and reports in the literature have not
demonstrated a specific pattern of birth defects in
offspring exposed to sirolimus (Framarino dei
Malatesta et al. 2011; NTPR Annual Report
2015).
Sirolimus taken by male transplant recipients
may reduce fertility (Kaczmarek et al. 2004;
Zuber et al. 2008). However, there are pregnan-
cies fathered by male transplant recipients taking
sirolimus. Based on the 16 pregnancies reported
to the NTPR (18 live births; no reported birth
defects), there does not appear to be increased
risks for pregnancies fathered while taking
sirolimus.
Similarly, everolimus administration to preg-
nant rats at 0.1 mg/kg/day before mating through
organogenesis resulted in increased preimplanta-
tion loss and early fetal resorptions. The area
under the curve (AUC) in rats at this dose was
approximately one-third that of the starting
human clinical dose. Everolimus administered to
pregnant rabbits resulted in increased late fetal
resorptions. No malformations were noted in the
case reports of pregnancy exposure to everolimus
to date (Carta et al. 2014; Margoles et al. 2014).
Whether everolimus has the same effect on male
fertility as sirolimus is an open question.
Belatacept
Belatacept, introduced in 2011, is given intrave-
nously monthly as maintenance immunosuppres-
sion in combination with MPA and prednisone.
As data regarding human pregnancy exposure are
limited, use during pregnancy is not
recommended. In animal studies, when adminis-
tered to female rats during pregnancy (and
throughout the lactation period) at doses four
times the human dose, belatacept was associated
with maternal toxicity (infections) in a small per-
centage of rats, resulting in increased pup mortal-
ity. At doses >20 times than the human dose,
surviving pups displayed no abnormalities or
malformations. The NTPR has reported on one
recipient who received belatacept throughout two
unplanned pregnancies. During her first post-
transplant pregnancy, she was on tacrolimus and
MPA and miscarried. Prior to her next pregnancy,
tacrolimus was switched to belatacept. She
remained on MPA through the first 3 weeks of
this pregnancy and miscarried at 11 weeks. Dur-
ing her third post-transplant pregnancy, she was
also maintained on belatacept and MPA was con-
tinued until the pregnancy was discovered in the
second trimester. She delivered a healthy 38-week
3090 g infant with no reported birth defects
(NTPR Annual Report 2015). To date, no other
reports of pregnancies exposed to belatacept have
appeared.
Fertility and Contraception After
Kidney Transplantation
• Fertility returns soon after successful
transplant.
• Appropriate birth control and pregnancy
counselling should occur before and early
after transplant.
The return of fertility post-transplantation is an
important discussion point during transplant
counselling, as nearly half of the women who
suffer from chronic kidney disease have menstrual
abnormalities or amenorrhea with reduced fertil-
ity (Pietrzak et al. 2007). In a survey of 209 solid
organ transplant recipients (including 73 kidney
recipients), 44% were not aware pre-transplanta-
tion that they could become pregnant after their
transplant (French et al. 2013).
The likely rapid return of fertility after kidney
transplantation makes it essential to have adequate
contraception in place, especially in the first post-
transplant year (McKay et al. 2005;
Constantinescu et al. 2014a). One survey found
that when compared to the general population
more post-transplant pregnancies were planned,
ascribed to the recipients’ health concerns. How-
ever, only 50% of the transplanted respondents of
Pregnancy After Kidney Transplantation
child-bearing age were using contraception
(French et al. 2013). The safety and efficacy of
contraceptive methods for solid organ transplant
recipients are rated in the 2010 Centers for Dis-
ease Control Prevention Report based on infer-
ences from their use in the general population and
published case and series reports in the transplant
population (Curtis 2010).
The most common methods of contraception
reportedly used by kidney transplant recipients
are tubal ligation and barrier methods (Guazzelli
et al. 2008; Xu et al. 2011; Rafie et al. 2014);
however, long-acting effective and reversible con-
traceptives, such as IUDs and the progesterone
implant, may be the best choice for female trans-
plant recipients (Krajewski et al. 2013). Proges-
terone-only hormonal contraceptives are
considered safe for transplant recipients (Curtis
2010).
It is reasonable to consider estrogen-containing
contraceptives for kidney transplant recipients
with well-controlled hypertension and stable
graft function, who do not have other contraindi-
cations, such as thromboembolic risks (Krajewski
and Sucato 2014). In one study, 36 kidney recip-
ients used either oral or transdermal low-dose
hormonal contraception. Two recipients
discontinued the contraceptive, one due to throm-
boembolic event and the other due to liver test
abnormalities. Overall, contraception was 100%
effective with no pregnancies occurring and
despite the risks, i.e., hypertension and altered
liver function, hormonal contraception should be
considered (Pietrzak et al. 2007). An American
Society of Transplantation (AST) consensus con-
ference found no evidence that combined oral
contraceptives were associated with adverse con-
sequences among transplant patients whose
hypertension was well controlled (McKay et al.
2005). Similarly, the theoretical concern that
estrogen-containing contraceptives could affect
immunosuppressant drug levels has not been
shown to be clinically significant, thus it has
been concluded that combined oral contraceptives
are suitable for solid organ transplant recipients
when appropriately monitored (Estes and
Westhoff 2007). Combined oral contraceptives
are contraindicated for recipients with a more
7
complicated course. No restrictions have been
placed on the use of emergency contraception
for solid organ transplant recipients (Curtis 2010).
Much of the published data regarding IUD use
in solid organ transplant recipients is derived from
kidney recipients. The theoretical risks of IUD use
in all transplant recipients are the potential for
infection and the possible reduction in efficacy
due to interactions with immunosuppressives
(Zerner et al. 1981; McKay et al. 2005; Estes
and Westhoff 2007). At least two studies have
shown no reduction in efficacy of IUDs due to
immunosuppression (Xu et al. 2011; Bahamondes
et al. 2011). It has been proposed that IUDs be
recommended for transplant recipients with
uncomplicated courses or for those who are
maintaining IUDs that were inserted pre-trans-
plantation; the restriction applies only for the ini-
tiating of IUDs in those recipients with a
complicated course (Curtis 2010).
In transplant recipients desiring a pregnancy
where fertility is compromised, there is guidance
from limited reports on the use of assisted repro-
ductive techniques (ART) in kidney transplant
recipients (Termini et al. 2011; Wyld et al. 2013;
Kennedy et al. 2012; Norrman et al. 2015). An
NTPR study (Termini et al. 2011) assessed in vitro
fertilization (IVF) in transplant recipients includ-
ing data from 11 kidney recipients who had 12
pregnancies after IVF, with 14 pregnancy out-
comes (86% live births). The mean gestational
age of the 12 infants was 36 weeks; their mean
birthweight was 1984 g. At last follow-up, one
child had been diagnosed as autistic and had a
seizure disorder and the remaining children were
reported healthy and developing well. There had
been no graft losses in the mothers. Norrman et al.
from Sweden, conducted follow-up of seven chil-
dren of kidney recipients who conceived by IVF,
comparing this group to children of transplant
recipients conceived naturally and to children of
non-transplanted mothers conceived by IVF
(Norrman et al. 2015). As noted in previous stud-
ies, the outcomes of pregnancies conceived by
IVF in this small group of kidney transplant recip-
ients were similar to those infants conceived nat-
urally. These limited reports are encouraging for
recipients eligible to consider the use of ART
8 L.A. Coscia et al.
following transplantation. Practitioners should be
aware that healthy offspring conceived by ART in
any woman might later display systemic and pul-
monary vascular dysfunction (as evidenced by
endothelial dysfunction) which does not appear
to be related to parental factors but to the ART
procedure itself (Scherrer et al. 2012; Rexhaj et al.
2014).
Transplant to Conception Interval (TCI)
• It is recommended that kidney recipients wait
at least a year after transplantation before con-
ceiving if they meet criteria in clinical
guidelines.
In the first guidelines for pregnancy after kidney
transplantation published in 1976, based on a
literature review and their own case report,
Davison et al. recommended that kidney trans-
plant recipients be in good general health for at
least 2 years post-transplant before conceiving.
Over time, the AST and others have considered
1 year as a reasonable TCI (Kim et al. 2008;
McKay et al. 2005). Analyses by Kim et al. com-
paring pregnancies with a TCI <1 year to those
with a TCI >1 year revealed that there was no
difference in pregnancy outcomes between the
two groups. The authors also noted that if a kidney
recipient has stable graft function and conceives
within the first year after transplant, the pregnancy
may be maintained with acceptable results for
mother, her transplant, and the fetus. An NTPR
study of different TCIs among CsA treated kidney
recipients revealed that there were more termina-
tions and fewer live births in a group with TCI
<6 months compared to those with longer TCIs
(Gaughan et al. 2001). Rose et al. suggest that a
TCI >2 years is associated with more favorable
graft survival in kidney recipients based on an
observational study of administrative data (Rose
et al. 2016).
The NTPR also analyzed pregnancy outcomes
in kidney transplant recipients with TCIs greater
than the recommended 2-year wait period (NTPR
2015). Kidney recipients’ first pregnancies were
grouped into three categories: TCI between 2 and
5 years, 5 and 10 years, or >10 years post-trans-
plant. The TCI >10 group was transplanted at a
significantly younger age, conceived at an older
age, and had less treated hypertension during
pregnancy. Graft function during pregnancy and
postpartum was similar among the groups, as
were pregnancy outcomes (Table 4). The analysis
did not reveal significant differences in outcomes
of pregnancies among the three groups. It was
concluded that kidney recipients should not be
discouraged from conceiving based on longer
TCI.
Pregnancy Outcomes
• The majority of post-kidney transplant preg-
nancies have successful maternal and newborn
outcomes.
• These are high-risk pregnancies and close col-
laboration among specialists is necessary.
• Comorbid conditions should be monitored and
treated appropriately.
• Higher incidences of hypertension and pre-
eclampsia are noted compared to the general
population.
• The newborn have higher incidences of prema-
turity and low birthweight.
Since the first report of pregnancy after kidney
transplant, thousands of pregnancies have been
reported. Some larger series are summarized in
Table 5. Overall, pregnancy is well tolerated
with 75% resulting in a live birth delivery.
Although there are high incidences of preeclamp-
sia, hypertension, preterm delivery, and cesarean
section, pregnancy does not appear to affect long-
term kidney function (Fischer et al. 2005;
Rahamimov et al. 2006), which is discussed fur-
ther in the next section of this chapter.
As of December 2015, 1005 kidney transplant
recipients participate in the NTPR and have
reported 1874 pregnancy outcomes. These out-
comes are listed in Table 6 (Coscia et al. 2016).
Deshpande et al. (2011) in a meta-analysis
compared pregnancy outcomes in kidney
Pregnancy After Kidney Transplantation 9

Table 4 NTPR comparison of kidney transplant recipients with different transplant to conception intervals
Transplant to conception interval 2–<5 years 5–<10 years >10 years p-
(range (mean  SD)) (3.3  0.9 years) (6.9  1.4 years) (13.3  3 years) valuea
Recipients/pregnancies 320/320 168/168 84/84
Maternal factors
Pre-transplant pregnancy 32%b 14%b 5%b <0.001
Age at first transplant (years) 24.6  5.9 21.9  5.2 17.4  5.6b <0.001
Age at post-transplant conception 28.8  5.4 29.2  5.2 30.9  5.6b 0.003
Planned pregnancy 62% 71% 64% NS
Pregnancy after two or more 15% 11% 6% 0.048
transplants
Living donor 57% 52% 72%b 0.012
Diabetes during pregnancy 8% 10% 9% NS
Hypertension during pregnancy 57% 54% 40%b 0.028
Preeclampsia 33% 33% 40% NS
Creatinine before pregnancy (mg/dL) 1.28  0.4 1.23  0.4 1.28  0.4 NS
Creatinine during pregnancy (mg/dL) 1.38  0.7 1.32  0.7 1.39  0.5 NS
Creatinine postpartum (mg/dL) 1.47  0.8 1.34  0.6 1.4  0.7 NS
Acute rejection during pregnancy 1% 1% 0% NS
Graft loss within 2 years of pregnancy 7% 6% 5% NS
Pregnancy outcomesc n = 330 n = 173 n = 88
Miscarriages 10% 12% 8% NS
Termination of pregnancy 2% 2% 2% NS
Ectopic 1% 1% 0% NS
Stillbirths 2% 2% 2% NS
Live births (n) 85% (280) 83% (143) 88% (77) NS
Mean gestational age (weeks) 35.4  4.0 36.2  2.9 35.9  3.6 NS
Premature (<37 weeks) 54% 53% 48% NS
Mean birthweight (g) 2475  817 2659  723b 2429  811 0.03
Low birthweight (<2500 g) 44% 39% 51% NS
Neonatal deaths n=5 n=0 n=0 NS
Birth defects 3.6% 8.4% 3.9% NS
a
Chi or ANOVA
b
p < 0.05 compared to each other group
c
Includes multiple births

transplant recipients to that of the general US
population. Data from the NTPR comprised the
majority of the outcomes in this meta-analysis.
The overall live birth rate of 73.5% was higher
than the general US population. Overall preg-
nancy complication rates, preeclampsia, cesarean
section, preterm birth, and low birthweight infants
were higher than the general US population. The
pooled acute rejection (4.2%) and 2-year graft loss
rates (8.1%) were similar across the analysis. The
authors caution that these pregnancies should be
considered high-risk and be cared for by a multi-
disciplinary team.
Two studies were performed using data from
the United States Renal Data System (USRDS)
(Arab et al. 2015; Gill et al. 2009). Gill et al.
looked at 530 pregnancies occurring between
1990 and 2003 and noted that the pregnancy rate
among kidney recipients declined from 5.9% in
1990 to 2% in 2000. The overall live birth rate was
55.4%; however, the study had several limitations
as it included only Medicare-insured recipients
during their first 3 years post-transplant. Conclu-
sions regarding immunosuppression were not
possible because the only known medications
were from the time of transplant and not during
10 L.A. Coscia et al.

Table 5 Comparison of pregnancy outcomes in kidney transplant recipients

Mean
Pregnancies Live gestational Mean Acute
Recipients (n) (multiples) births (%) age (weeks) birthweight (g) Preeclampsia (%) rejection (%)
USA
NTPR (2015)a 1005 1874 75 35.9 2567 30 0.8
Australiab
Wyld et 447 692 76 35 2485 29 NR
al. (2013)
UKb,c
Sibanda et al. 176 193 79 35.6 2316 NR NR
(2007)
Bramham et al. 101 105 91 36 (median) NR 24 2
(2013b)
Middle Eastd
Al Duraihimh et 140 234 74.4 33.2 2458 26.1 NR
al. (2008)
Mexico
Cruz Lemini et 60 75 84 37.1 2439 8 5.3
al. (2007)e
Poland
Dębska-Ślizień 17 22 77 35 2552 6 0
et al. (2014)e
Germany
Blume et 34 53 62 35 (median) 2290 (median) 26.4 NR
al. (2013)e
Japan
Abe et 20 29 72 35.4 2229 38.1 NR
al. (2008)e
Iran
Kashanizadeh et 86 NR 72 NR NR 10 NR
al. (2007)
Ghafari and 53 61 NR NR NR 26.4 NR
Sanadgol (2008)
a
North America
b
Country’s data
c
Potential overlap of cases
d
Data pooled from five different countries
e
Single center report
NR not reported

pregnancy. There was also no information avail-
able regarding the incidence of birth defects. Sim-
ilarly, Arab et al. obtained data from the
Healthcare Cost and Utilization Project-Nation-
wide Inpatient Sample (HCUP-NIS) for the period
2003–2010, to study obstetrical and neonatal out-
comes in kidney transplant recipients. They iden-
tified pregnancies in 375 renal transplant
recipients and compared outcomes to 7,094,025
patients without transplant. Kidney recipients in
this analysis were at an increased risk for pre-
eclampsia, preterm labor, and postpartum hemor-
rhage compared to those without a transplant.
Prematurity, intrauterine fetal death, congenital
anomalies, and intrauterine growth restriction
(IUGR) were common complications in the
Pregnancy After Kidney Transplantation 11

Table 6 NTPR: pregnancy after kidney transplant

Kidney
Recipients 1005
Mean age at first transplant (years) 24  6
Pre-transplant pregnancy (%) 31
Pregnancies 1810
Mean transplant-conception interval (years) 5.3  4
During pregnancy
Primary immunosuppressanta Aza CsA Tac Others
26% 47% 27% <1%
MPA exposure (%) 8
Hypertension treated (%) 49
Diabetes treated (%) 8
Preeclampsia (%) 30
Rejectionb (%) 0.8
After pregnancy
Postpartum rejectionb (%) 1.8
Graft loss within 2 years of delivery (%) 5.8
Outcomesc 1874
Live births (%) 75
Neonatal deaths (%) 1.6
Miscarriages (%) 18
MPA exposure (%) 21
Stillbirths (%) 2
Ectopic pregnancies (%) 1
Terminations (%) 4
Live births 1414
Mean gestational age (weeks) 35.9  3.4
Premature (<37 weeks) (%) 51
Early preterm (<34 weeks) (%) 21
Mean birthweight (g) 2567  766
Low (<2500 g) (%) 42
Very low (<1500 g) (%) 11
Cesarean section (%) 54
Birth defects (%) 4.3
Child follow-up (years) 13.7  9.3
Adult follow-up (years) 14.3  9.5
Maternal deaths (%) 18.2
Average age of child at maternal death (years) 16  7.9
214 children
Adequate graft function at last follow-up (%) 63
a
Azathioprine and/or prednisone (Aza); cyclosporine or its modified form (CsA); tacrolimus (Tac); sirolimus, everolimus,
mycophenolic acid products, or belatacept (other); mycophenolic acid products (MPA)
b
Biopsy-proven treated acute rejection
c
Includes multiple births

newborn of the transplant recipients. The authors of such a study however, recommended counsel-
noted a strong correlation between preexisting ling these women regarding the high-risk nature
maternal hypertension and the risk of IUGR. of these pregnancies.
Again, the authors acknowledged the limitations
12
Long-Term Transplant Outcomes After offspring of those recipients who lost their graft
Pregnancy within 5 years postpartum. The study found that
• When recipients enter pregnancy with stable
graft function, the pregnancy is unlikely to
affect transplant function.
Well-designed, case–control studies in kidney
transplant recipients have demonstrated that preg-
nancy does not cause deterioration of graft func-
tion when prepregnancy graft function is adequate
and stable. Long-term graft function also does not
appear to be affected by pregnancy (Fischer et al.
2005; Rahamimov et al. 2006; Kashanizadeh et al.
2007). In the study by Rahamimov et al., there
was no difference in graft (61.6%) and recipient
(84.8%) survival between those who had a preg-
nancy versus matched controls (68.7% and 78.8%
respectively). In another case–control study,
Fischer et al. demonstrated no difference in 10-
year postdelivery graft survival (pregnancy 62.5%
vs. control 67%) or recipient survival (pregnancy
93.4% vs. controls 88.7%) (Fischer et al. 2005).
An NTPR analysis of recipients with and with-
out graft loss after a pregnancy concluded that a
high serum creatinine at any time surrounding
pregnancy was associated with an increase in
postpartum graft loss (Armenti et al. 1998). This
study compared 40 recipients with graft loss ver-
sus 81 with no graft loss. Additionally, rejection
during and postpartum along with low birthweight
newborn were also associated with graft loss post-
partum. A serum creatinine before pregnancy
greater than 2.5 mg/dL was associated with a
three times higher likelihood of postpartum graft
loss compared to recipient with serum creatinine
below 1.5 mg/dL. Recipients must be advised of
the potential for increased postpartum graft loss
when the serum creatinine is higher before
pregnancy.
The NTPR studied the predictors of graft loss
within 5 years postpartum (Constantinescu et al.
2011). Recipient race, donor source, cesarean sec-
tion, and live birth percentage were similar
between recipients with graft loss and those with-
out graft loss within 5 years postpartum. Gesta-
tional age and birthweight were lower in the
L.A. Coscia et al.
graft loss within 5 years postpartum was signifi-
cantly associated increased serum creatinine
before pregnancy as well as with rejection during
and/or within 3 months after pregnancy.
Pregnancy After Living Donor Kidney
Transplantation
• Pregnancy outcome does not differ between
recipients of living versus deceased donors.
An NTPR analysis compared post-transplant
pregnancy outcomes in 259 females who received
either live donor or deceased donor kidney trans-
plants (Table 7)(Constantinescu et al. 2010). All
recipients were maintained on a calcineurin inhib-
itor based regimen during pregnancy. There were
no significant differences in maternal complica-
tion and rejection rates during pregnancy, graft
loss within 2 years after delivery, live birth rate
or neonatal outcomes between pregnancies in liv-
ing or deceased donor kidney transplant
recipients.
Pregnancy After Pediatric Kidney
Transplantation
• Successful pregnancies have been reported in
recipients transplanted as children.
Wyld et al. from Australia performed an observa-
tional cohort study of kidney transplant recipients
who received their transplant under the age of 18
(Wyld et al. 2015). There were a total of 66 recip-
ients with 101 pregnancies. The authors compared
this cohort to a group of 401 women who received
their transplants as adults and had 626 pregnan-
cies. They concluded that there were no differ-
ences in the pregnancy outcomes of the two
groups and that complication rates were similar
no matter how long the recipients had their
transplant.
Pregnancy After Kidney Transplantation 13

Table 7 NTPR: comparison of pregnancy outcomes in kidney recipients by donor source

Live donor Deceased donor P value
Recipients 148 111
Pregnancies 240 165
Pregnancy outcomesa 251 170
Maternal conditions
Transplant to conception interval (years) 5.2  3.5 5.2  3.7 NS
Hypertension during pregnancy 56% 63% NS
Preeclampsia 28% 35% NS
Infections during pregnancy 21% 22% NS
Rejection during pregnancy 2% 2% NS
Serum creatinine before pregnancy (mg/dL) 1.3  0.41 1.2  0.4 <0.01
Serum creatinine during pregnancy (mg/dL) 1.4  0.5 1.2  0.95 0.03
Serum creatinine after pregnancy (mg/dL) 1.5  0.62 1.3  0.8 <0.01
Graft loss within 2 years of delivery 8% 7% NS
Neonatal outcomes
Live births 77% 74% NS
Gestational age (weeks) 35.5  3.7 35.8  3.2 NS
Birthweight (g) 2470  809 2501  765 NS
a
Includes twins
1 versus 2, p < 0.01; NS not significant

The NTPR analyzed the 50 pregnancy out-
comes of 41 pediatric kidney transplant recipients
who conceived 49 pregnancies before the age of
20 (Coscia et al. 2015a). Outcomes included 34
(69%) live births, 9 miscarriages, 5 terminations,
and 2 stillbirths. There were 72% unplanned preg-
nancies; 43% were conceived within 2 years of
transplant. Fifteen percent of those who conceived
within 2 years of transplant experienced biopsy-
acute rejection within 3 months postpartum; two
of the four recipients who lost their graft within
2 years of delivery also conceived within 2 years
of transplant. Although recommended for all
transplant recipients with child-bearing potential,
adolescent recipients especially should receive
appropriate counselling regarding fertility, contra-
ception, and the risks of conceiving too soon after
transplant.
The literature on successful pregnancies in
kidney transplant recipients transplanted as chil-
dren is reassuring. When discussing pregnancy
with these women, the potential risks for mother
and newborn, inheritable disease conditions, and
long-term maternal survival need to be stressed
with the recipient and/or the parents of the recip-
ient after pediatric kidney transplantation. Studies
regarding fertility in this population are
warranted.
Successive Pregnancies After Kidney
Transplantation
Several case reports describe kidney transplant
recipients who have had more than one pregnancy
after their kidney transplant (Sibanda et al. 2007;
Al Duraihimh et al. 2008; Wyld et al. 2013).
In an NTPR review of 478 renal recipients who
had a first pregnancy, 189 had between one and
four subsequent pregnancies (Table 8). The pro-
portion of live births was not statistically different
among the groups. With successive pregnancies,
there was a trend toward increased gestational
age, leading to a significant decrease in the pre-
maturity rate. As a result, there was a significant
decrease in the proportion of infants with low and
very low birthweights. Female kidney recipients
with successive pregnancies had similar rejection
rates during each pregnancy and no difference in
graft loss within 2 years after delivery. Successive
pregnancies in kidney transplant recipients are not
associated with adverse fetal outcomes and/or
14 L.A. Coscia et al.

Table 8 NTPR outcomes of subsequent pregnancies after kidney transplant

First Second Third Fourth Fifth p
pregnancy pregnancy pregnancy pregnancy pregnancy valuea
No. of recipients 478 189 68 19 6
Age at conception (years) 29  5 30.2  5.1 31.3  4.8 32.8  4.4 31.2  4.5
Pregnancy outcomesb 495 191 70 20 6
Live births 78% 72% 83% 65% 67% NS
Miscarriages 13% 19% 13% 20% 17% NS
Stillbirths 3% 3% 1% 10% 0 NS
Therapeutic abortions 6% 6% 3% 5% 0 NS
Neonatal deaths 1.3% 0.5% 0 0 0 NS
Mean gestational 35.6  3.4 36  3.4 36.6  3 36.8  2.5 37.6  1.3 0.01
age (weeks)
Prematurity (<37 weeks) 54.7% 48.5% 46.4% 41.7% 25% 0.01
Mean birthweight (g) 2426  772 2578  749 2613  752 2646  816 3076  831 0.002
Low birthweight (<2500 g) 49.7% 40.2% 39.7% 30.8% 25% 0.001
Very low 14.8% 9.5% 5.2% 15.4% 0% 0.04
birthweight (<1500 g)
Rejection during pregnancy 1.5% 1.6% 4.5% 0% 0% NS
Graft loss within 2 years 8% 7.5% 7.4% 5.3% 0% NS
after delivery
a
Linear trends
b
Includes twins, triplets

80%

70%
Live Births Breastfeed (%)

60%

50%

40%

30%

20%

10%

0%

Fig. 1 NTPR trend in breastfeeding practices among transplant recipients

increased maternal graft loss. Transplant recipi-

ents with adequate allograft function who wish to
have more than one pregnancy should not be
discouraged to conceive (Constantinescu et al.
2007).
Breastfeeding
Although breastfeeding while taking immunosup-
pressive medications is not recommended on
product labelling, transplant recipients have cho-
sen to breastfeed at a steadily increasing rate (Fig.
1).
Pregnancy After Kidney Transplantation
Short-term follow-up of the development and
health of children of transplant recipients who
have been breastfed while their mothers were
taking immunosuppressive medications did not
reveal any adverse effects due to breastfeeding
(Constantinescu et al. 2014b). Over the years,
several studies, which measured levels of predni-
sone, azathioprine, and cyclosporine in maternal
or infant serum and in breast milk samples,
showed that the amount ingested via breast milk
was much less than that to which the fetus had
been exposed in utero. Subsequent studies have
found that the level of tacrolimus in infant blood
drops quickly after birth and at equivalent rates,
whether the baby is breastfed or bottle-fed, a
finding that led authors to conclude that transplant
recipients should not be discouraged from
breastfeeding while on tacrolimus, particularly if
monitoring of immunosuppressive content in
infant blood and breast milk is available
(Bramham et al. 2013a). Due to the lack of infor-
mation regarding breastfeeding on MPA,
sirolimus, everolimus, and belatacept,
breastfeeding should be avoided while taking
these agents. Although long-term studies are
warranted, researchers are cautiously optimistic
that breastfeeding can be considered safe while
taking prednisone, azathioprine, cyclosporine,
and tacrolimus (Bramham et al. 2013a;
Constantinescu et al. 2014b).
Management Guidelines
Although pregnancy is well tolerated by many
kidney transplant recipients with the majority
resulting in a healthy newborn, these women
must be considered a high-risk pregnancy group
requiring specialized multidisciplinary team care
in a tertiary center, with the facilities necessary to
ensure the best outcomes for mother, her graft, and
her child (Rao et al. 2016; Deshpande et al. 2013).
The initial clinical guidelines for pregnancy after
kidney transplantation were developed by
Davison et al. (1976); these guidelines have been
expanded and refined based on data accumulated
over the last 40 years (Rao et al. 2016). As with all
transplant recipients, it is recommended that any
15
transplant recipients use adequate contraception
to defer pregnancy for at least 1–2 years after
transplantation and that such “active preparation
for pregnancy” should be individualized to each
woman’s needs and should involve her partner.
There should be prepregnancy assessment of
kidney function, comorbid conditions, latent viral
infections, vaccination history, as well as a con-
sideration of the etiology of the original renal
failure and the potential for any genetic predispo-
sition in the offspring. Medications should be
reviewed and adjusted as necessary both before
and during pregnancy, including avoidance of
fetal MPA exposure whenever possible. The
risks of IUGR, prematurity, and a low birthweight
infant should be discussed.
Once pregnancy is discovered, monitoring of
kidney function and immunosuppressive drug
levels is recommended at 4-week intervals until
32 weeks gestation, then more frequently until
delivery (Rao et al. 2016). Monitoring of immu-
nosuppressive drug levels during pregnancy is
essential due to the physiologic changes of preg-
nancy, including an increase in plasma volume,
and changes in drug distribution and drug metab-
olism. Comorbidities, including bacterial and
viral infections, hypertension, proteinuria, diabe-
tes, and graft dysfunction, should be diagnosed
appropriately and treated promptly. Hypertension
and the potential onset of preeclampsia must be
closely managed because of the threat to the
health of the mother and compromise of fetal
development (Bramham et al. 2013b).
Vital postpartum concerns include maternal
medication adherence, measurement of drug
levels and dose adjustments, vigilance for post-
partum depression, discussion regarding the
safety of breastfeeding, and appropriate counsel-
ling regarding contraception (Rao et al. 2016;
Krajewski and Sucato 2014). For those mothers
who had preeclampsia, continued attention to nor-
malizing blood pressure is important, in light of
the long-term cardiovascular risks which include a
1.8–3.7 increase in the relative risk of cardiovas-
cular disease (hypertension, ischemic heart dis-
ease, stroke, venous thromboembolism)
(McDonald et al. 2008; Yinon et al. 2010).
16
Conclusion
Successful pregnancy after kidney transplantation
is possible; however, these are high-risk pregnan-
cies that require close coordination among the
various disciplines that care for these complex
patients. Continued reports to registries and to
the literature are encouraged. Further information
can be obtained from the NTPR by contacting
their office by email at NTPR@giftoflifeinsitute.
org.
Acknowledgments The NTPR acknowledges the coop-
eration of transplant recipients and the healthcare profes-
sionals of over 250 transplant centers in North America
who have contributed their time and information to the
NTPR. The NTPR is supported by grants from Astellas
Pharma US, Inc., Pfizer Inc., and Bristol-Myers Squibb
Company.
Cross-References
▶ Ethics of Transplantation
▶ History of Kidney Transplantation
▶ Medical Complications After Kidney Trans-
plantation: Late
▶ Pediatric Transplantation
▶ Psychosocial and Financial Aspects of
Transplantation
▶ Transplant Immunosuppression
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