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33926 Combined Heart and Other Organ Transplants
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Pregnancy in Heart Transplant Recipients
Michelle M. Kittleson
27
Abstract
With improved outcomes after heart transplantation (HTx), there is a growing pool
of individuals of childbearing age who may
wish to consider pregnancy. Pregnancy after
HTx requires anticipatory planning and guidance, careful patient risk assessment with
a discussion of individualized risk, close
monitoring of graft function and immunosuppression, and vigilance for optimization
of comorbid conditions. With a multidisciplinary approach and team, pregnancy after
HTx is feasible in selected patients. In the
future, multicenter registries may provide
much-needed experience to craft future
guidelines and recommendations concerning
pregnancy after HTx.
Keywords
Heart failure · Heart transplantation ·
Pregnancy
M. M. Kittleson (*)
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: michelle.kittleson@cshs.org
Clinical Pearls
• The keys to successful post-transplant preg-
nancy are preconception and contraceptive
planning, appropriate patient risk assessment
with comprehensive risk stratification, and
optimization of maternal comorbidities and
fetal health through careful monitoring.
• Counseling and shared decision-making
should be facilitated in an experienced transplant center with a multidisciplinary expert
team and should ideally include both the
patient and the partner.
• Due to the teratogenicity of mycophenolate
mofetil, this drug should be discontinued
6 weeks prior to conception. A transplant
recipient who has been weaned off prednisone and requires lower tacrolimus target
trough levels due to side effects may warrant
azathioprine at 50–100 mg.
• Diabetic control improves both maternal
and fetal outcomes, and the cornerstones
of pharmacological measures are insulin or
metformin.
• Meticulous blood pressure control is advis-
able; nifedipine, amlodipine, labetalol,
hydralazine, and methyldopa can generally
be used safely in pregnancy.
• Infections, especially those of the urinary
tract and respiratory tract, can be more common in pregnancy and should be actively
screened for and treated.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_27
341
342 M. M. Kittleson
• Given the increased risk of cardiovascular events in the immediate postpartum
period, postpartum care in an intensive care
unit setting is recommended, and early discharge from the hospital (<72 h) should be
discouraged.
Introduction
With surgical and immunosuppressive advances
in thoracic organ transplantation over the past
three decades and attendant improved longterm outcomes, post-transplant pregnancy is
an achievable goal for many heart transplant
(HTx) recipients [1]. The keys to successful
post-transplant pregnancy are preconception and
contraceptive planning, appropriate patient risk
assessment with comprehensive risk stratification, and optimization of maternal comorbidities and fetal health through careful monitoring
[2]. This chapter will summarize the current evidence and provide guidance surrounding these
issues.
Preconception Counseling
Preconception counseling for all individuals
of childbearing age encompasses pregnancy
intention, contraception, timing of conception after transplant, maternal risks, including
those unique to transplant recipients, fetal risks,
and psychosocial support for optimal shared
decision-making [3, 4]. Whenever possible,
counseling and shared decision-making should
be facilitated in an experienced transplant
center with a multidisciplinary expert team.
Unfortunately, about half of pregnancies in HTx
recipients are unplanned [5, 6], demonstrating a
significant opportunity for education both preand post-transplantation regarding contraception and transition to medications that are safe
during pregnancy. Because of the potential risks
involved with pregnancy after HTx, these discussions should ideally include both the patient
and partner and begin during the pre-transplant evaluation. Revisiting these discussions
annually throughout the post-transplant period
allows recipients opportunities to reassess their
decisions. Pre-pregnancy planning allows for
the adjustment of medications to those with a
safety profile compatible with pregnancy, time
to optimize comorbidities, and the opportunity
to consider genetic counseling for potentially
heritable pre-transplant diagnoses. Figure 27.1
summarizes the key components of preconception counseling. Figure 27.2 provides a patient-
focused summary of important concepts for
patients to discuss with their treating clinicians.
A major component of preconception counseling is a frank discussion of how transplant
status influences maternal and fetal risks during
pregnancy.
Contraception
As any disruption to the hypothalamic-gonadal
axis is usually restored within 2–6 months following transplant, effective contraception
should be recommended immediately; options
are summarized in Table 27.1 [7]. Intrauterine
devices (copper-containing IUD and levonorgestrel-releasing IUD) offer long-term, highly
effective, reversible contraception [4, 8, 9].
Immunosuppression is not a contraindication
to IUD use [10, 11]. IUDs are the contraceptive method of choice [2] and are considered
the only acceptable sole method of contraception in transplant recipients taking mycophenolate mofetil. IUDs are considered preferable to
other forms of birth control in transplant recipients because of their low failure rate, ability to remain in place for several years, lack
of required daily adherence for effectiveness,
lack of drug-drug interactions, and straightforward removal to reverse contraception.
Depo-medroxyprogesterone acetate administered every three months is another highly
effective form of contraception, but it is associated with delayed return to fertility after cessation and decreased bone mineral density and
weight gain [12], which may be significant in
transplant recipients who are also exposed to
long-term corticosteroid therapy [13]. Thus,
27 Pregnancy in Heart Transplant Recipients
343
Fig. 27.1 Approach to preconception counseling in
lung and heart transplant recipients. CAV = cardiac allo-
graft vasculopathy, CHD = congenital heart disease,
DSA = donor-specific antibodies, HT = heart transplant,
PPCM = peripartum cardiomyopathy. Reprinted from
The Journal of Heart and Lung Transplantation, 42(3),
Kittleson, Michelle M., Ersilia M. DeFilippis, Catriona
J. Bhagra, Jillian P. Casale, Matthew Cauldwell, Lisa A.
Coscia, Rohan D’Souza et al., Reproductive health after
thoracic transplantation: an ISHLT expert consensus
statement, e1–e42, Copyright (2023), with permission
from Elsevier.
Fig. 27.2 Educating patients on post-transplant
pregnancy. HT = heart transplant, LT; Lung trans-
plant. Reprinted from The Journal of Heart and Lung
Transplantation, 42(3), Kittleson, Michelle M., Ersilia
M. DeFilippis, Catriona J. Bhagra, Jillian P. Casale,
Matthew Cauldwell, Lisa A. Coscia, Rohan D’Souza
et al., Reproductive health after thoracic transplantation:
an ISHLT expert consensus statement, e1–e42, Copyright
(2023), with permission from Elsevier.
344 M. M. Kittleson
• Delayed return to fertility after cessation
• Decreased bone mineral density
• Weight gain
• Rapid return of fertility once removed
• Screen for hypercoagulable states prior to the initi-
ation of combination hormonal contraception
• Avoid in patient with transplant-related coronary
artery disease or hypertension
• Contraindicated in patients with a history of stroke,
increased risk of thrombosis, liver disease, and estro-
gen-sensitive malignancies
• Subject to drug interactions that may reduce contra-
ception efficacy
• Due to the inhibition of the cytochrome P450 3A4
pathway seen with these drugs, monitoring blood
levels of immunosuppressive medications is required
after initiation
• Avoid early postpartum due to risk of thrombosis
Notes
• Immunosuppression is not a contraindication
• Lack of drug-drug interactions
• Straightforward removal for reversal
administration due to short half-life
monal methods for prevention of pregnancy
• Should be used in combination with any another
form of contraception for protection against sexually
transmitted diseases
Safe in breastfee-
ding
Yes • Long-term, highly effective
taking mycophenolate pro-
ducts
Acceptable as sole method of
contraception
Preferred method for long-term
contraception
Use with barrier method Ye s • Highly effective
>2 years) contraception due to risk of
Use with barrier method Ye s • Long-term, highly effective
decreased bone mineral density
production
Use with barrier method May reduce milk
contraception
Not recommended as sole method of
contraception given contraindications
and drug interactions
Use with barrier method Ye s • Efficacy strongly dependent on consistent timing of
effectiveness diminishes with nonad-
Use with another method Yes • Should be used in combination with non-IUD hor-
herence
Not recommended as sole contra-
Souza et al., Reproductive health after thoracic transplantation: an ISHLT expert consensus statement,
ception
Type of contraception Consensus recommendations Use in transplant recipients
Table 27.1 Summary of contraceptive options in transplant recipients
Intrauterine devices (hormonal and
non-hormonal)
Progesterone depot injection Not recommended for long-term (i.e.,
Progesterone subdermal implant Acceptable method of long-term
Combined hormonal contraceptives
(pills, vaginal ring, transdermal patch)
Progestin-only pills Not routinely recommended given
Barrier methods (condoms, sponge,
diaphragm, cervical cap with or
without spermicide)
Barrier methods are recommended for use with progesterone implant or depot injection based on the Mycophenolate Risk Evaluation and Mitigation Strategies (REMS) pro-
gram (https://www.mycophenolaterems.com). Reprinted from The Journal of Heart and Lung Transplantation, 42(3), Kittleson, Michelle M., Ersilia M. DeFilippis, Catriona J.
Bhagra, Jillian P. Casale, Matthew Cauldwell, Lisa A. Coscia, Rohan D’
e1–e42, Copyright (2023), with permission from Elsevier.
34527 Pregnancy in Heart Transplant Recipients
depo-medroxyprogesterone acetate is not routinely recommended as a long-term contraceptive option [2, 14]. The use of combined
hormonal contraceptives should be considered
carefully in patients with cardiac allograft vasculopathy (CAV) or hypertension, and their use
is contraindicated in patients with an increased
risk of thrombosis, liver disease, or estrogensensitive malignancies [4]. Combined hormonal
contraceptives portend increased risk in patients
with prior myocardial infarction, stroke or deep
venous thrombosis, hypertension, migraine
with aura, and liver disease [13]. Transplant
recipients should be screened for hypercoagulable states prior to the initiation of combination
hormonal contraception [14]. Furthermore, due
to the inhibition of the cytochrome P450 3A4
pathway with these drugs, additional monitoring
of immunosuppression blood levels is required
after initiation. Progestin-only pills are not routinely recommended as their efficacy is strongly
dependent on consistent timing of administration due to the short half-life, and thus, the
effectiveness will diminish with non-adherence.
Barrier methods are not sufficient as a sole
method of contraception, given their relatively
high failure rates. They should be used, in combination with another reliable form of birth control, for protection against sexually transmitted
infection when indicated.
Assisted Reproductive Technology (ART)
A survey of 1090 solid organ transplant recipients in the Transplant Pregnancy Registry
International (TPRI) revealed that 22% of
women experienced difficulty achieving pregnancy [5]. For such patients and for those transplant recipients for whom pregnancy portends
prohibitive risk and is not recommended, the
options of surrogacy, adoption, and oocyte preservation may be considered. For other patients,
ART may be an option. The decision to proceed
with ART requires consultation between the
transplant physician and the reproductive endocrinologist, considering the transplant recipient’s
graft function, any comorbid conditions, and the
potential for success with ART. Of note, the risk
of thromboembolism is low with ART, 0.6% in
a large registry [15], which is reassuring when
considering ART for HTx recipients without risk
factors for or prior history of thromboembolism.
One risk of fertility treatments is an increased
incidence of multiple gestations, a known risk
factor for hypertension and preeclampsia, for
which transplant recipients are already at
increased risk [6, 16–21]. To avoid multiple gestations, guidelines from the American Society
of Reproductive Medicine recommend single
embryo transfer at the blastocyst stage, allowing for high implantation rates with a lower risk
of multiple pregnancies [22]. Controlled ovarian stimulation may cause increased vascular
fluid shifts [23], which should be tolerated in
transplant recipients with normal graft function.
However, a potentially life-threatening complication of controlled ovarian stimulation is ovarian hyperstimulation syndrome (OHSS). OHSS
is characterized by third-spacing fluid accumulation with increased vascular permeability
and may result in ascites, hypercoagulability,
and electrolyte imbalances [24]. In some cases,
OHSS can lead to arrhythmias, pericardial effusion, and adult respiratory distress syndrome.
It is not established that the risk of OHSS is
higher in transplant recipients than in the general population undergoing controlled ovarian
stimulation, and, thus, if felt to be an important
component of ART, controlled ovarian stimulation may be used with close monitoring for
potential complications.
Shared Decision-Making
A critical component of transplant care is shared
decision-making, a model of patient-clinician
communication that promotes the integration of
patient values and preferences with discussion
of potential risks, benefits, and harms to inform
treatment decisions [25, 26]. Shared decisionmaking is especially important given the unique
physical and psychological complexities faced
by transplant recipients and their families
346 M. M. Kittleson
[27–33]. Key components of communication in
shared decision-making are trust, understanding patient values, goals, and preferences, and
continued discussion of evolving choices as new
situations arise [34]. Ideally, shared decisionmaking about contraception and risks associated
with pregnancy after HTx will occur pre-transplant, regularly during post-transplant followup, and prior to conception. If pregnancy is
unplanned or undesired, counseling on maternal
and fetal risks associated with pregnancy continuation is necessary, particularly if pregnancy
is medically contraindicated. Shared decisionmaking is a central feature of care for transplant
recipients in general and specifically for individuals of reproductive age. Clinicians and patients
should work toward patient-centered care that
factors in individual and family values, goals,
and preferences [34].
Fatherhood After Transplantation
The reproductive health of the non-gestational
parent should also be considered. Some issues
are common to both the pregnant individual and
the non-gestational parent, including the impact
of post-transplant life expectancy on parenthood and the role of potentially inheritable conditions. A specific issue for the non-gestational
parent would be the potential teratogenicity
of immunosuppression. Fortunately, offspring
fathered by kidney, kidney-pancreas, liver, and
HTx recipients on mycophenolate at the time
of conception do not have a higher incidence of
adverse outcomes of pregnancy, congenital malformations, or other adverse neonatal outcomes,
and thus mycophenolate avoidance is not necessary for the non-gestational parent [35–37].
Similar reassuring findings have been noted
with corticosteroids, calcineurin inhibitors, and
azathioprine, though sirolimus may cause lower
sperm counts, dysmotility, and reduced spontaneous pregnancy rates [38].
Risk Assessment, Management, and Outcomes of Pregnancy After Heart Transplantation
Timing of Pregnancy
The risk of allograft rejection is highest, and the
immunosuppression regimen most aggressive,
in the first 6–12 months after transplantation;
hence the 2023 ISHLT Consensus Statement on
Reproductive Health in Thoracic Transplantation
advises that pregnancy should not be attempted
within the first year and recommends that HTx
recipients have stable graft function with no
rejection in the past 12 months, no active infection, and a stable immunosuppression regimen to
maximize the chance of a favorable outcome [2].
Patient Risk Assessment
Figure 27.3 illustrates some of the factors
requiring consideration when assessing the
risk of pregnancy in HTx recipients. The estimation of the risk of pregnancy for any given
individual post-transplantation is complex. Due
to the lack of data and unique patient factors
to be considered, no risk calculator specific to
transplantation currently exists. There are some
conditions under which pregnancy in a HTx
recipient is considered very high risk or contraindicated; these include poor graft function
(LVEF < 30%), which falls into the modified
World Health Organization (WHO) classification IV of maternal risk as prohibitive (LVEF
30–45% is WHO classification II-III as intermediate risk) [39], non-adherence with immunosuppression or other important medical therapy,
significant CAV, active infection, and poorly
controlled hypertension, diabetes or renal dysfunction (eGFR < 30 ml/min/1.73 m2) [1, 14,
40]. Prior rejection is a concern. While treated
acute cellular rejection more than one year prior
to pregnancy may be a relative contraindication,
27 Pregnancy in Heart Transplant Recipients
347
Fig. 27.3 Factors to be considered in risk assessment
for pregnancy after heart transplantation. Reprinted from
The Journal of Heart and Lung Transplantation, 42(3),
Kittleson, Michelle M., Ersilia M. DeFilippis, Catriona
J. Bhagra, Jillian P. Casale, Matthew Cauldwell, Lisa A.
Coscia, Rohan D’Souza et al., Reproductive health after
any history of antibody-mediated rejection
(AMR) or donor-specific antibodies (DSA)
should also be considered a contraindication
to pregnancy, given the risk of a heightened
humoral response from fetal exposure. When
adverse consequences to the cardiac allograft,
such as left ventricular dysfunction, valvular
disease, or arrhythmias, are present, the risk of
long-term cardiovascular complications may be
identified by using risk prediction tools such as
the CARPREG II (Canadian Cardiac Disease
thoracic transplantation: an ISHLT expert consensus
statement, e1–e42, Copyright (2023), with permission
from Elsevier. ACE = angiotensin-converting enzyme,
CHD = congenital heart disease, CM = cardiomyopathy,
PPCM = peripartum cardiomyopathy
in Pregnancy) risk score [3, 41–43]. In addition
to these risks, the importance of co-morbidities must be emphasized. In an ISHLT registry
analysis of women of childbearing age, the presence of DM and/or severe kidney dysfunction
(sCKD) strongly impacted survival: DM versus
No-DM: median survival 8.9 versus 14.7 years
(p < 0.0001); sCKD versus no-sCKD: median
survival 10.8 versus 14.5 years (p < 0.0001); and
DM plus CKD versus none: median survival
2.5 years versus 14.9 years (p < 0.0001) [44].
348 M. M. Kittleson
The impact of these comorbidities on maternal survival and on the decision to proceed or
not with pregnancy should be discussed with
patients. Additional maternal comorbidities
that may increase the risk of pregnancy from
a general cardiovascular perspective include
advanced maternal age, obesity, and significant
prior pregnancy-related cardiac or obstetric
complications. The presence of CAV negatively
affects survival. Hence, even early-stage CAV
requires aggressive treatment with statins and
mammalian target of rapamycin (mTOR) inhibitors. However, the safety of these agents has not
been established during pregnancy, and discontinuation may potentially expose the patient to
the risk of further CAV progression as another
possible risk of pregnancy [45]. While significant CAV (Grade 2 or higher) may be considered a contraindication to pregnancy, those
with milder CAV may consider pregnancy and,
in this situation, warrant ongoing therapy for
CAV. In patients with known CAV, the fetal
risks of potential exposure to statins and mTOR
inhibitors during pregnancy should be weighed
against the risks of worsening graft function. If
statin and mTOR inhibitor use is continued during pregnancy, the lowest effective dose should
be used to minimize fetal exposure. Finally, a
discussion regarding post-transplant life expectancy may impact decisions surrounding pregnancy planning. The median survival for HTx
recipients is 12.5 years, extending to 14.8 years
in those surviving the first year [46]. Median
survival for women is higher than for men
(12.2 years vs. 11.4 respectively), and leading causes of death are graft failure (mainly
related to CAV), Cytomegalovirus infection,
and multi-system organ failure [46]. These considerations emphasize the complexity of preconception counseling, and a comprehensive
approach is advised. Parenthood, however, is a
deeply personal choice, and some may choose
to try to conceive despite an individualized risk
assessment.
Surveillance
Baseline Evaluation of Graft Function and Risk Assessment
If not completed as part of usual post-transplant
surveillance within the previous six months,
an echocardiogram should be performed for a
diagnostic assessment of graft function with a
more detailed assessment for rejection and CAV
depending on the patient’s history and clinical
status [14, 47]. Laboratory assessment should
include immunosuppression levels, complete
blood count, assessment of liver and renal function, urinalysis to assess for proteinuria, and
screening for infection (urinary, CMV) [47]. The
list of recommended exams, with rationale and
impact of results, is shown in Table 27.2 [2].
Surveillance of Rejection
Pregnancy can proceed successfully in many HTx
recipients, provided timely preconception risk
assessment and management (Table 27.2) and
close monitoring of graft function and comorbidities during and after pregnancy (Table 27.3).
Echocardiography is recommended at least every
trimester and ideally every 1–2 months until
24 weeks of gestation and then monthly until
delivery. Non-invasive screening for rejection,
through gene expression profiling (GEP) and
donor-derived cell-free DNA (dd-cfDNA) testing,
are useful tools in monitoring for acute rejection
[48, 49]. However, dd-cfDNA testing will detect
fetal DNA and thus, cannot be reliably used in
pregnancy.
Diagnosis and Treatment of Acute Rejection
Endomyocardial biopsy for cause should be
performed when acute rejection is suspected
based on findings of the clinical assessment,
echocardiography, and genetic testing. An
echocardiographic-guided procedure is preferred. Otherwise, fluoroscopy should be