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De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, ItalyDept of Cardiology, Cliniques Universitaires de Bruxelles - Hôpital Erasme, Brussels, Belgium
Peter Munk Cardiac Centre of the University Health Network, Toronto, Ontario, CanadaTed Rogers Centre for Heart Research, Toronto, Ontario, CanadaUniversity of Toronto, Toronto, Ontario, Canada
Pregnancy after thoracic organ transplantation is feasible for select individuals but requires multidisciplinary subspecialty care. Key components for a successful pregnancy after lung or heart transplantation include preconception and contraceptive planning, thorough risk stratification, optimization of maternal comorbidities and fetal health through careful monitoring, and open communication with shared decision-making. The goal of this consensus statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations.
With surgical and immunosuppressive advances in thoracic organ transplantation over the past 3 decades and attendant improved long-term outcomes, post-transplant pregnancy is an achievable goal for many lung transplant (LT) and heart transplant (HT) recipients.
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.
The goal to optimize outcomes in pregnant LT and HT recipients aligns well with the increasing contemporary emphasis on strategies to reduce maternal mortality worldwide.
The purpose of this statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, and medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations. This consensus statement represents the current state of knowledge and expertise in the field of pregnancy after thoracic organ transplantation.
Methods
This consensus document was developed in accordance with the International Society of Heart and Lung Transplantation (ISHLT) Standards and Guidelines committee document development policies. The consensus committee members were selected to represent the diversity and multidisciplinary nature of the society and were approved by the ISHLT Standards and Guidelines committee. Each member contributed to the literature searches, developed content, reviewed the final consensus statements, and approved the final manuscript.
Literature searches performed in mid-2021 reviewed all pertinent articles, focusing on newer peer-reviewed research. The guidance reflects expert synthesis of the current literature. In the absence of a strong evidentiary base regarding best practices for the reproductive health in thoracic transplantation, this document was written as a summation of the current literature with accompanying expert opinion, rather than guidelines written with specific levels of evidence. Recommendations were iteratively discussed by the full writing group in a series of virtual consensus meetings and correspondence until a majority of group members agreed on the text and qualifying remarks, akin to the process of similar ISHLT consensus statements.
ISHLT consensus statement for the selection and management of pediatric and congenital heart disease patients on ventricular assist devices endorsed by the American Heart Association.
The proposed statements herein represent consensus recommendations.
Preconception counseling
Achieving optimal pregnancy outcomes in LT and HT recipients requires a comprehensive and coordinated multidisciplinary team approach that begins before conception.
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.
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 HT recipients
are unplanned, demonstrating a significant opportunity for education both pre- and post-transplantation regarding contraception and transition to medications that are safe during pregnancy.
Because of the potential risks involved with pregnancy after LT or HT, 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 re-assess 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. The latter may be especially important in those with proven or suspected genetic cardiomyopathies or lung disease (e.g., cystic fibrosis [CF]).
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: donor and recipient size match.
Figure 1 summarizes the key components of preconception counseling. Figure 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.
Generally, pregnancy is considered relatively safe in transplant recipients if there is adequate and stable graft function, no episodes of allograft rejection in the prior year, no maternal infections that may impact upon the fetus, and stable dosing of maintenance non-teratogenic immunosuppression.
However, there are issues unique to LT and HT regarding contraindications to pregnancy and maternal and fetal risks. These considerations are described in detail in Sections IV and V, respectively. This section will focus on other aspects of preconception counseling including contraception, assisted reproductive technology (ART), psychosocial risks, and the importance of shared decision-making.
Contraception
As any disruption to the hypothalamic-gonadal axis is usually restored within 2-6 months following transplant, effective contraception should be recommended immediately.
are unplanned, with the risk of inadvertent fetal exposure to the teratogenic effects of immunosuppressive agents such as mycophenolate mofetil and other potential teratogens such as statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).
Thus, there is an opportunity for education both pre- and post-transplant regarding contraception. Table 1 provides a detailed summary of contraceptive options; the most commonly used options are discussed below.
Table 1Summary of Contraceptive Options in Transplant Recipients
Type of contraception
Consensus recommendations
Use in transplant recipients taking mycophenolate products
Safe in breastfeeding
Notes
Intrauterine devices (hormonal and non-hormonal)
Preferred method for long-term contraception
Acceptable as sole method of contraception
Yes
•
Long-term, highly effective
•
Immunosuppression is not a contraindication
•
Lack of drug-drug interactions
•
Straightforward removal for reversal
Progesterone depot injection
Not recommended for long-term (i.e., > 2 years) contraception due to risk of decreased bone mineral density
Not recommended as sole method of contraception given contraindications and drug interactions
Use with barrier method
May reduce milk production
•
Screen for hypercoagulable states before the initiation 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 estrogen-sensitive malignancies
•
Subject to drug interactions that may reduce contraception 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
Progestin-only pills
Not routinely recommended given effectiveness diminishes with nonadherence
Use with barrier method
Yes
•
Efficacy strongly dependent on consistent timing of administration due to short half-life
Barrier methods (condoms, sponge, diaphragm, cervical cap with or without spermicide)
Not recommended as sole contraception
Use with another method
Yes
•
Should be used in combination with non-IUD hormonal methods for prevention of pregnancy
•
Should be used in combination with any another form of contraception for protection against sexually transmitted diseases
Barrier methods are recommended for use with progesterone implant or depot injection based on the Mycophenolate Risk Evaluation and Mitigation Strategies (REMS) program (https://www.mycophenolaterems.com).
though the United States Centers for Disease Control (CDC) notes that the risks of IUD implantation may outweigh the benefits in those transplant recipients with graft failure, rejection, or cardiac allograft vasculopathy (CAV).
Similarly, the 2022 Guideline for the Care of the Heart Transplant Recipient notes that IUDs are not generally recommended for HT recipients with complications.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
However, IUDs are considered the only acceptable sole method of contraception in transplant recipients taking mycophenolate mofetil. The reasons why IUDs are considered preferable to other forms of birth control in transplant recipients are 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 3 months is a highly effective form of contraception, but it is associated with delayed return to fertility after cessation and decreased bone mineral density and weight gain,
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Use of combined hormonal contraceptives should be considered carefully in patients with CAV or hypertension, and their use is contraindicated in patients with an increased risk of thrombosis, liver disease, or estrogen-sensitive malignancies.
Combined hormonal contraceptives portend increased risk in patients with prior myocardial infarction, stroke or deep venous thrombosis, hypertension, migraine with aura, and liver disease.
In addition, the ISHLT guidelines recommend transplant recipients be screened for hypercoagulable states before the initiation of combination hormonal contraception.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
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 nonadherence.
Barrier methods are not recommended 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.
Sterilization of the recipient or partner may be considered for those who desire permanent forms of contraception. Failure rates are low, however, female sterilization such as tubal ligation does carry some surgical and anesthetic risk that should be accounted for depending on the individual risk profile. Male sterilization with vasectomy alternatively may be considered as a less invasive approach.
and couples should be advised that an analysis of a semen specimen after vasectomy is required to confirm success before the use of alternative contraception is abandoned.
It is important to note that endometrial ablation, which may be performed as a treatment for menorrhagia, is not a form of contraception. In fact, pregnancy post endometrial ablation may result in high rates of maternal and fetal complications.
Thus, individuals who desire pregnancy should not undergo this procedure and those who do should be counselled to use reliable contraception until menopause.
Assisted reproductive technology
A survey of 1090 solid organ transplant recipients in the Transplant Pregnancy Registry International (TPRI) revealed that 22% of women experienced difficulty achieving pregnancy.
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.
Although experience is limited, ART may be an option for select transplant recipients. However, the decision to proceed with ART should follow multidisciplinary discussions with the transplant physician and reproductive endocrinologist in the context of shared-decision making and account for graft function and comorbidities. Of note, the risk of thromboembolism is low with ART, 0.6% in a large registry,
Therefore, the American Society of Reproductive Medicine recommends single embryo transfer at the blastocyst stage, which allows for high implantation rates but with a lower risk of multiple pregnancies.
which should be tolerated in transplant recipients with normal graft function. However, patients should be closely monitored for ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication of controlled ovarian stimulation. OHSS may result in ascites, electrolyte imbalances and pro-thrombotic state as a result of third-spacing fluid accumulation and increased vascular permeability.
OHSS has been associated with arrhythmias, pericardial effusion and adult respiratory distress syndrome in certain cases.
Psychosocial risks and evaluation
Psychosocial risks
Psychological and social circumstances are important to consider across the transplant care continuum, as there is a high prevalence of anxiety and depression among transplant recipients.
In LT recipients, major depression is observed in 30%, panic disorder in 15%, post-traumatic stress disorder in 15%, and generalized anxiety disorder in 4% of recipients.
Similarly, in HT recipients, depression is observed in 21.6%, anxiety in 11.1%, adjustment disorder in 11%, and post-traumatic stress disorder in 13.5% of recipients.
In addition, both the antenatal and postpartum periods are vulnerable times for the onset or exacerbation of psychological morbidity in non-transplant recipients, with up to 15% and 20% of pregnant individuals reporting clinically significant symptoms of depression and anxiety, respectively.
Medical complications such as hypertensive disorders of pregnancy, gestational diabetes, and infection are among the most potent predictors of psychological conditions including postpartum depression, anxiety, and post-traumatic stress disorder.
The relationship between severe maternal morbidity and psychological health symptoms at 6–8 weeks postpartum: a prospective cohort study in one English maternity unit.
Thus, pregnant transplant recipients are an especially vulnerable group for several reasons: (1) both transplant status and pregnancy place these patients at high risk for anxiety and depression, (2) psychopathology post-transplant portends worse outcomes, and (3) the medical complications of pregnancy which are associated with adverse psychological outcomes are the most common encountered by transplant recipients.
As a result, pregnant transplant recipients warrant careful psychosocial evaluation.
Psychosocial evaluation
Psychosocial evaluation is recognized as an essential component of both transplant and pregnancy care. In 2018, the American College of Obstetricians and Gynecologists (ACOG) recommended screening for depression and anxiety at least once during pregnancy and again at the comprehensive 6-week postpartum visit with referral to a mental health professional for follow-up and treatment when necessary.
Also in 2018, the ISHLT published consensus recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support.
The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support.
These recommendations focus on the importance of evaluating treatment adherence and health behaviors, mental health history, substance use history, cognitive status, knowledge of current treatment options, coping with illness, and social support.
Within the context of preconception counseling, the psychosocial evaluation should cover the core components outlined in the 2018 ISHLT consensus recommendations,
The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support.
with additional assessment of circumstances unique to pregnancy such as a personal or family history of postpartum mood or anxiety disorders as well as other mental health conditions (e.g., bipolar disorder, schizophrenia, personality disorders). As summarized in Figure 3 and adapted for pregnancy post-transplantation, these domains can include: (1) factors specific to patients’ personal, social, and environmental resources and circumstances, (2) psychosocial risk factors for poor pregnancy outcomes, including treatment and medication adherence, health behaviors, mental health, and substance use history, (3)factors related to patient's knowledge, understanding, cognitive abilities, and capacity to engage in shared decision-making during preconception and pregnancy, and (4) factors specific to LT and HT recipients who may be contemplating pregnancy, including lifespan, candidacy for re-transplantation, and the impact of adverse outcomes (e.g., hospitalizations, rejection, graft failure, or death) on the life of an unborn child, or other offspring of a transplant recipient.
The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support.
Figure 3Components of a comprehensive psychosocial evaluation. Psychosocial evaluation is a key part of both transplant and pregnancy care. Important components of a comprehensive psychosocial evaluation include 1) factors specific to patients’ personal, social, and environmental resources and circumstances, 2) psychosocial risk factors for poor pregnancy outcomes, including treatment and medication adherence, health behaviors, mental health, and substance use history, 3) factors related to patient's knowledge, understanding, cognitive abilities, and capacity to engage in shared decision-making during preconception and pregnancy, and 4) factors specific to heart and lung transplant recipients who may be contemplating pregnancy, including lifespan, need for re-transplantation, and the impact of adverse outcomes.
should be integrated into psychosocial assessment and follow-up including evidence-based psychological interventions, when required, across the continuum of transplant care. Psychological follow-up can be complemented by consultation with psychiatry for additional assessment and psychotropic medication initiation and management depending on individual needs. Other healthcare professionals who offer more specialized services can be incorporated on a case-by case basis including social work, occupational therapy, physical therapy, chronic pain specialists, and specialists in the treatment of eating or substance use disorders. Community resources for patients, partners, and families can also be identified to enhance social support.
More research is needed on how to best assess and counsel LT and HT recipients regarding the unique psychological and social risks associated with pregnancy. Whether the integration of screening, comprehensive psychosocial assessments, and follow-up with psychological treatment and targeted functional support leads to more favorable patient, partner, family, or medical outcomes remains an opportunity for future research.
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.
Shared decision-making is especially important given the unique physical and psychological complexities faced by transplant recipients and their families.
What outcomes should researchers select, collect and report in pre-eclampsia research? A qualitative study exploring the views of women with lived experience of pre-eclampsia.
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.
Ideally, shared decision-making about contraception and risks associated with pregnancy after LT or HT will occur pre-transplant, regularly during post-transplant follow-up, and before 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 decision-making 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.
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, which are covered in detail in Sections IV and V.
A specific issue for the non-gestational parent would be the potential teratogenicity of immunosuppression. Fortunately, offspring fathered by kidney, kidney-pancreas, liver, and heart transplant 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.
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.
Consensus Statements on Preconception Counseling and Shared Decision-Making
•
Preconception counseling of individuals of childbearing age should: (1) ideally occur as part of the pretransplant evaluation process, (2) be repeated at least annually after transplant during childbearing years, and (3) include a discussion of optimal contraception, timing of pregnancy, contraindications to pregnancy, and maternal and fetal risks, including those unique to transplant recipients such psychosocial aspects of family planning in the context of a disorder with limited life-expectancy.
•
Intrauterine devices (IUD) are the preferred long-term contraception option for many patients after transplantation given their low failure rate, ability to be in place for several years, lack of required daily adherence for effectiveness, lack of drug-drug interactions, and straightforward removal to reverse contraception.
•
Experience with the use of assisted reproductive technology is limited in transplant recipients but may be considered on an individualized basis in collaboration with a reproductive endocrinologist, recognizing the risk of multiple gestations and ovarian hyperstimulation syndrome.
•
Pregnant transplant recipients are at high risk for anxiety and depression so psychosocial evaluation and support is an essential part of the preconception, antepartum, and postpartum process.
•
Issues surrounding pregnancy planning and contraception should be approached using a shared decision-making model.
Experience with pregnancy in other solid organ transplants
There is far more experience with pregnancy in recipients of abdominal organ transplants (kidney or liver), compared with thoracic organ transplant recipients. As kidney transplants are the most commonly performed, the largest cohort of pregnancy outcomes is from such recipients. The first reported pregnancy after solid organ transplantation occurred in 1958 in a woman who had received a kidney transplant from her identical twin sister 2 years prior.
The issues faced by clinicians during that pregnancy were considerably different to that of contemporary practice, since the recipient was not on immunosuppression and the treating clinicians were more concerned about the impact of the gravid uterus on the function of the transplanted kidney. Most of the subsequent experience regarding pregnancy after abdominal organ transplant comes from case reports, center studies, meta-analyses, and registry data.
These studies have laid the groundwork for guidelines and recommendations surrounding pregnancy after thoracic transplantation.
Guidelines for pregnancy in abdominal organ transplant recipients
The first guidelines regarding preconception counseling and peri-pregnancy management were written for kidney transplant recipients, updated over time, and extrapolated to solid-organ transplant recipients, more broadly.
Common themes of these pregnancy guidelines include the necessity of stable graft function, well-controlled comorbidities, absence of acute infection, and safety of immunosuppressive agents in pregnancy.
Other common themes derived from experience in kidney transplant recipients are delaying pregnancy until after the first transplant year and avoiding unplanned pregnancies. These recommendations stem from several studies which have demonstrated that transplant recipients who undergo pregnancy within 1 year of transplantation have a higher risk of rejection, graft loss, and non-viable fetal outcomes,
Outcomes of pregnancy in abdominal organ transplant recipients
The TPRI, formerly the National Transplantation Pregnancy Registry (NTPR), was established in 1991 by Dr. Vincent Armenti to study the outcomes of pregnancy after transplantation. The TPRI has continuously enrolled transplant recipients since that time and now has documentation of over 3,500 pregnancies. With international recipients added in 2016, it is the largest repository of pregnancy outcomes in transplant recipients.
Maternal outcomes
The most frequent complications reported during pregnancy after kidney transplant are hypertension and preeclampsia, reported at an incidence of 24% to 48% and 21% to 29%, respectively (Table 2).
In another meta-analysis, transplant recipients who had a pregnancy had no difference in kidney graft survival over time, though factors associated with graft loss were pre-pregnancy proteinuria, hypertension, and elevated serum creatinine.
Liver transplant recipients experience similar complications (Table 2). Liver recipients have an incidence of hypertension of 18% to 21% and preeclampsia of 13% to 21%.
respectively. There is also a high incidence of prematurity and low birthweight offspring in kidney transplant and liver transplant recipients. Preterm delivery occurred in 37% to 43.1% of kidney transplant
recipients. Despite this, however, overall long-term health and development of the offspring of kidney and liver recipients does not appear adversely affected.
Compared with kidney transplant recipients, liver transplant recipients appear to have a lower incidence of pregnancy-related hypertension and preeclampsia and lower rates of preterm birth and cesarean delivery. The reasons for these differences are not clear but may be related to the differences in immunosuppressive regimens and incidence of hypertension in liver vs kidney transplant recipients; further research is needed.
Summary
As a community, the experience with pregnancy after abdominal organ transplant has provided much of the framework for the general approach to pregnancy in thoracic transplant recipients. However, there are some important differences. The hemodynamic changes that occur during pregnancy may directly impact upon, or be influenced, by graft function in thoracic organ transplant recipients, which is not the case in abdominal transplantation.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: donor and recipient size match.
The International thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-eighth adult heart transplantation report - 2021. Focus on recipient characteristics.
As noted in Section I, preconception counseling should include individualized discussion of timing of conception, alternative pathways to parenthood, and maternal and fetal risks (see Figure 1). As outlined in Section II, this counseling should be introduced during pre-transplant evaluation and should be followed up throughout the post-transplant process. See Figure 2 for key factors that clinicians should discuss with their patients.
Timing of pregnancy
The relative infrequency of pregnancy following LT compared with other solid organ transplants makes establishing definite recommendations regarding the timing of pregnancy difficult. Generally, LT recipients should be advised to wait 1-2 years after transplant before becoming pregnant.
Although guidelines for recipients of other solid organ transplants recommend a wait of 12 months, the higher rates of allograft rejection and more aggressive immunosuppression utilized following lung transplantation
The registry of the International society for heart and lung transplantation: thirty-second official adult lung and heart-lung transplantation report–2015; focus theme: early graft failure.
support the need for a longer post-transplant period of stability before pregnancy.
Timing should allow opportunity for genetic counseling (in those with CF and other heritable conditions) if desired; appropriate consideration of risks (including those related to drugs and infections such as cytomegalovirus [CMV]); alterations to immunosuppression, and initiation of preconception vitamins.
Patient risk assessment
Figure 4 illustrates some of the factors to consider when assessing the risk of pregnancy in LT recipients. Pregnancy should not be recommended for those with evidence of progressive, chronic lung allograft dysfunction (CLAD) or for those who have not re-established lung function stability after an episode of acute rejection. Other important contraindications include medication nonadherence, uncontrolled comorbidities such as diabetes or hypertension, severe chronic kidney disease (eGFR < 30 ml/min/1.73 m2), or the presence of donor-specific antibodies (DSA) for which necessary adjustments in immunosuppression might increase the risk of rejection.
Figure 4Factors to be considered in risk assessment for pregnancy after lung transplant. CF, cystic fibrosis; ACE, angiotensin-converting enzyme.
Consideration must also be given to the risk of infection and its treatment. Primary CMV infection or reactivation in the transplant recipient can have potentially devastating consequences to both mother and fetus. Pregnancy should be delayed until viral prophylaxis is complete and alternate strategies of prophylaxis and treatment, including the use of CMV hyperimmune globulin, should be considered in those at risk.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: donor and recipient size match.
This presents specific challenges including an increased risk of diabetes, malabsorption of fat-soluble vitamins and gastric stasis, gastroesophageal reflux, and gastroparesis which are likely to be worsened during pregnancy. Those with CF should be continued on their nutritional supplements with special care taken to ensure that adequate nutritional intake occurs and no vitamin deficiencies develop. Folic acid supplementation (4-5 g daily) is recommended for all pregnant transplant recipients to prevent neural tube defects, with consideration of other fat-soluble vitamin replacement in those with CF. However, supplementation with vitamin A should not exceed 10,000 IU daily due to the risk of cranial neural crest defects.
Ideally, supplementation should begin before attempts to conceive or when pregnancy is confirmed.
It is important to recognize the limited survival of LT recipients, with a median 6.7 years, extending to 8.9 years in patients who survive the first year.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: donor and recipient size match.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: donor and recipient size match.
Counseling regarding life expectancy after LT may impact upon the shared decision-making process of pregnancy planning.
Graft function
Baseline assessment of graft function
Pre- and post-bronchodilator spirometry should be measured in anticipation of planned pregnancy to establish stability, capacity to carry a pregnancy to term, and to provide a baseline to allow monitoring for potential pregnancy-related deterioration. The list of recommended exams, with rationale and impact of results is shown in Table 3.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Routine imaging is not indicated; however, the availability of a contemporary baseline chest X-ray may be useful for comparison in the event of clinical decompensation.
Table 3Recommended Baseline Assessment of Clinical Status and Graft Function in Lung Transplant and Heart Transplant Recipients Desiring Pregnancy
Assessment
Impact on management or outcome
Contraindications to planned pregnancy
History
•
Genetic conditions may trigger the need for genetic counseling (Heart: ARVC, HCM, CHD, familial CM); special considerations for patients with pre-transplant diagnosis of PPCM
•
Lung: Patients with CF require special attention to nutrition status
•
Social history
•
Less than 1 year post-transplant (heart) or 1-2 years post-transplant (lung)
•
Nonadherence
Clinical examination
•
Arterial hypertension is associated with higher risk of preeclampsia
Pre-pregnancy DM, renal dysfunction and proteinuria are associated with higher risk of preeclampsia
•
DM requires close monitoring to lessen risk for macrosomia and shoulder dystocia
•
Poorly controlled diabetes
•
Severe renal dysfunction (creatinine >2.5 mg/dl, eGFR < 30 ml/min/1.73m2, or dialysis)
•
Significant proteinuria
Anti-HLA antibodies
•
Pregnancy could trigger alloimmunization
•
Sensitized patients have a worse long-term outcome
•
Donor-specific antibodies
Immunosuppressive levels
•
Trough levels of immunosuppression should be stable before pregnancy, to minimize the risk of rejection
•
Close monitoring of immunosuppression levels is recommended
•
Inability to maintain therapeutic levels of maintenance immunosuppression with CNI
•
Inability to stop mycophenolate products
Serology and PCR for CMV
•
Primary CMV infection and, to a lesser extent, CMV reactivation are associated with the risk of fetal CMV disease
•
CMV seronegative patients should be advised to take additional precautions
•
CMV infection within the past year
Standard assessment of graft function
•
Lung transplant: pre- and post-bronchodilator spirometry
•
Heart transplant: echocardiogram
•
Graft dysfunction is associated with high risk of complications during pregnancy and a worse long-term outcome
•
Lung transplant: spirometry to establish stability, capacity to carry a pregnancy to term, and to provide a baseline to allow monitoring for potential pregnancy-related deterioration
•
Lung transplant: Abnormal PFTs after an episode of acute rejection, evidence of CLAD
•
Heart transplant: Reduced EF (< 30%), severe valvular disease (stenotic lesions)
In-depth assessment of the graft function (if clinically indicated)
•
Lung transplant: bronchoscopy/biopsy
•
Heart transplant: RHC/biopsy, coronary angiogram
•
Rejection may recur during pregnancy or after delivery and portends increased risk
•
Lung transplant: microbiological surveillance with bronchoscopy in those unable to provide sputum specimens, especially if there is concern for recurrent infection with organisms; decline in spirometry should prompt bronchoscopy to evaluate for infection or rejection
•
Heart transplant: CAV portends increased risk
•
Lung transplant: rejection in the past year, history of AMR or CLAD
•
Heart transplant: cellular rejection in the past year, any history of AMR, CAV Grade 2 or greater
Microbiological surveillance with bronchoscopy in those unable to provide sputum specimens, especially in those with recurrent infection with organisms of concern, should be considered. Transbronchial biopsy need only be performed if specific concerns exist. Depending on the patient's risk, measurement of the DSA profile may be considered to enable accurate future comparison.
Surveillance of graft function
Spirometry remains the mainstay of screening of lung allograft function during pregnancy and should be undertaken monthly throughout pregnancy (Table 4). Physiological changes associated with pregnancy lead to a 20% decrease in functional residual capacity and associated increase in tidal volume and minute ventilation.
As evidence in LT recipients indicates that spirometric measures (FEV1 and FVC) remain stable, any changes (in particular, in FEV1) should be investigated as would be done in non-pregnant LT recipients, rather than being attributed to pregnancy itself.
Table 4Timetable of Periodic Assessment During Pregnancy in Lung Transplant and Heart Transplant Recipients
Exam
Timing
Notes
Graft function and rejection
•
Physical examination, vital parameters
Every 4 weeks
24h-monitoring of BP if hypertension is suspected
•
12-lead EKG
Every 4 weeks
EMB (preferably echo-guided) if rejection is suspected
•
Spirometry (Lung)
Every 4 weeks
Bronchoscopy if decline in lung function by spirometry
•
Echocardiography (Heart)
At least every trimester and ideally every 1-2 months until 24th week and then every 4 weeks until delivery.
EMB (preferably echo-guided) if rejection is suspected
Hypertensive disorders
•
Renal function, liver function, blood cells count
Every 4 weeks
Increase in eGFR is expected. Monitoring liver enzymes and platelet count if HELLP syndrome is suspected
•
Urinalysis
Every 4 weeks
Check for proteinuria
Diabetes mellitus
•
Fasting plasma glucose
Every 4 weeks
Additional therapy if increase in steroid dose is needed
•
Glucose challenge test
Between 24-28 weeks
May be performed earlier in patients at risk for diabetes
Immunosuppression
•
Circulating levels
Every 4 weeks until 32nd week; every 2 weeks until 36th week; weekly until delivery and the first month after delivery
Additional therapeutic drug monitoring in the first two trimesters may be suggested, following daily dose adaptation, as needed
•
HLA-specific antibodies
1-3 months after delivery
Earlier testing of HLA-specific Ab if acute rejection during pregnancy
Infections
•
Complete blood count, CRP
Every 4 weeks
•
PCR for CMV genome
Every 4 weeks
•
Urine culture
Every 4 weeks
•
Serology for Toxoplasma (in seronegative patients), HSV, hepatitis
Third trimester (36 0/7 - 37 6/7 weeks of gestation)
•
Vaginal swab culture for Streptococci B
Third trimester (36 0/7 - 37 6/7 weeks of gestation)
Fetal growth
•
Echo assessment of fetal well-being
Routine dating ultrasound between 8-9 weeks of gestation when available Nuchal translucency scan between 11-14 weeks gestation when available Early (transabdominal or transvaginal) anatomy scan between 11 -16 weeks of gestation when available Every 2 months until 24th week; every 4 weeks until delivery
In diabetic patients: - consider closer monitoring of fetal growth from 28th week - weekly monitoring from 32nd week
Evaluation of a decline in spirometry should include bronchoscopy to assess for infection and/or rejection. Bronchoscopies have been safely performed in pregnant LT recipients.
Procedural sedation during bronchoscopy is safe in this patient population, though may be best administered by physicians trained in obstetrical anesthesia.
and when acute rejection is diagnosed, timely and appropriate treatment is indicated.
Maternal and fetal outcomes
Maternal outcomes
Table 5 summarizes existing data, albeit limited, regarding outcomes in pregnant LT recipients. There is a risk of acute rejection and graft loss during pregnancy.
with CF recipients in 1 series demonstrating a higher incidence of acute rejection when compared to LT recipients with other underlying diseases (25% vs 11%).
The risk to allograft function continues into the postpartum period. In a large cohort of pregnant lung and heart-lung transplant recipients, 40% of the cohort had an absolute FEV1 decline of >5% and 29% with an absolute FEV1 decline of >10% at 12 months post pregnancy.
While the mechanisms leading to decline in allograft function and/or CLAD are unclear, the potential instability of immunosuppression levels due to the sudden disappearance of the placenta, decrease in circulating progesterone levels, and sudden modification of volume distribution may contribute.
Maternal mortality during pregnancy is rare in LT recipients and reported overall at 1.7%, though this is still magnitudes greater than the maternal mortality rate in nontransplant recipients.
Despite the theoretical risk of in utero exposure to immunosuppressants, no specific patterns of birth defects in offspring have been reported in LT recipients.
Breastfeeding while receiving immunosuppressive medication is discussed in more detail in Section VIII. Theoretically, there may be challenges with breastmilk production after LT as the bilateral thoracotomies associated with transplant surgery have the potential to disrupt the neurovascular supply of the breast tissue. As such, breastfeeding should be considered on a case-by-case basis and early lactation support from an experienced lactation consultant sought if the pregnant transplant recipient plans to breastfeed.
Consensus statements on risk assessment, management, and outcomes of pregnancy after lung transplantation
•
Lung transplant recipients should wait 1-2 years post lung transplant before pursuing pregnancy. Before planned conception, recipients should have stable lung function (without chronic allograft lung dysfunction or donor-specific antibodies), no evidence of rejection in the preceding 12 months, stable doses of maintenance immunosuppression safe in pregnancy, and no acute infection.
•
Non-adherence with medical therapy, poorly controlled hypertension, diabetes, and renal dysfunction (eGFR < 30 ml/min/1.73 m2) are considered contraindications to pregnancy.
•
Pregnant lung transplant recipients with cystic fibrosis require special attention to specific co-morbidities including gastroesophageal reflux and nutritional supplementation.
•
Clinical evaluation and spirometry should occur at least monthly during pregnancy in lung transplant recipients; any changes in spirometric measures, and in particular FEV1, should be investigated as would be done in a non-pregnant lung transplant recipient, rather than being attributed to pregnancy itself.
•
The risk of chronic lung allograft dysfunction remains high in the postpartum period.
Risk assessment, management, and outcomes of pregnancy after heart transplantation
The first pregnancy in a HT recipient was described in 1988.
The International thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-eighth adult heart transplantation report - 2021. Focus on recipient characteristics.
there have been increasing reports of successful pregnancies in this population. Worldwide, in the eras spanning 1992-2000, 2001-2009 and 2010-2018; 2509, 3142 and 3578 women of child-bearing age (15 - 45 years) have undergone HT, respectively, with a median survival of 15.2 years.
Impact of co-morbidities on survival after heart transplant in females of childbearing age: analysis of the International Society for Heart and Lung Transplantation (ISHLT) Registry.
The current median survival conditional to surviving the first year after HT is 14.8 years for women and 13.6 years for men, with 86% survival at 1 year.
The International thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match.
Given the significant number of young transplant recipients who may be considering pregnancy, an understanding of the appropriate timing and contraindications is essential.
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 2022 ISHLT guidelines for post-transplant care advise that pregnancy should not be attempted within the first year.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Similarly, the American Society of Transplantation recommends that transplant recipients considering pregnancy should 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.
Figure 5 illustrates some of the factors requiring consideration when assessing the risk of pregnancy in HT 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.
Figure 5Factors to be considered in risk assessment for pregnancy after heart transplantation. ACE, angiotensin-converting enzyme; CHD, congenital heart disease; DCM, dilated cardiomyopathy; PPCM, peripartum cardiomyopathy.
There are some conditions under which pregnancy in a HT recipient is considered very high risk or contraindicated; these include poor graft function (LVEF <30%) which falls into the modified World Health Organization (mWHO) classification IV of maternal risk as prohibitive (LVEF 30% to 45% is mWHO classification II to III as intermediate risk),
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).
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Prior rejection is a concern. While treated acute cellular rejection more than 1 year before pregnancy may be a relative contraindication, any history of AMR or DSA should be considered a stronger contraindication to pregnancy given risk of sensitization from the fetus. 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 in Pregnancy) risk score.
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 vs no-DM: median survival 8.9 vs 14.7 years (p < 0.0001); sCKD vs no-sCKD: median survival 10.8 vs 14.5 years (p < 0.0001); and DM plus CKD vs none: median survival 2.5 years vs 14.9 years (p < 0.0001).
Impact of co-morbidities on survival after heart transplant in females of childbearing age: analysis of the International Society for Heart and Lung Transplantation (ISHLT) Registry.
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 which 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 International thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-eighth adult heart transplantation report - 2021. Focus on recipient characteristics.
hence even early-stage CAV requires aggressive treatment with statins and mammalian target of rapamycin (mTOR) inhibitors. However, 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.
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 HT recipients is 12.5 years extending to 14.8 years in those surviving the first year.
The International Thoracic Organ Transplant Registry of the International society for heart and lung transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics.
Median survival for women is higher than men (12.2 years vs 11.4 respectively) and leading causes of death are graft failure (mainly related to CAV), CMV infection, and multi-system organ failure.
The International Thoracic Organ Transplant Registry of the International society for heart and lung transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics.
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.
Underlying maternal cardiac conditions
Peripartum cardiomyopathy
Peripartum cardiomyopathy (PPCM) remains a relatively rare, but potentially significant cause of heart failure in women of childbearing age. In the United Network for Organ Sharing (UNOS) database, PPCM is the fourth leading indication for heart transplantation in women
Evaluation of the clinical relevance of baseline left ventricular ejection fraction as a predictor of recovery or persistence of severe dysfunction in women in the United States with peripartum cardiomyopathy.
It is important to recognize that HT recipients with a pre-transplant diagnosis of PPCM are at higher risk for poor outcomes compared with those without PPCM. HT recipients with PPCM have higher rates of allograft rejection through the first 12 months, reduced graft half-life (8.2 years vs 10.2 years), and higher rates of re-transplantation (6.6% vs 2.1%).
These findings have been confirmed in an analysis of ISHLT registry data: in a group of 535 women aged 15-45 years transplanted for PPCM between 2000 and 2017, the median survival was 9.1 years, compared with a median survival of 15.2 years those with congenital heart disease and 15.5 years in the remaining female HT recipients with other indications for transplantation.
Impact of co-morbidities on survival after heart transplant in females of childbearing age: analysis of the International Society for Heart and Lung Transplantation (ISHLT) Registry.
It has been suggested that women with previous PPCM may have an increased risk of peripartum recurrence in a subsequent pregnancy although there are currently no published data to support this. Non-adherence was a significant contributor to cause of death in this group,
reinforcing the need for patients to be fully informed on risk and engaged in their long-term care.
Congenital heart disease
Offspring of patients transplanted for congenital heart disease (CHD) have a varying degree of inheritance risk dependent upon the underlying lesion. For CHD that arises de novo, the risk of recurrence in infants is approximately 3% to 7%
though varies significantly based on the specific lesion. The inheritance risk of Tetralogy of Fallot, for example, is around 2.5% while that of aortic stenosis may be as high as 13% to 18%.
Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.
For HT recipients with a suspected or known genetic cardiomyopathy, pre-pregnancy genetic counseling should be performed. For those with an established genetic basis for their cardiomyopathy, preimplantation genetic testing of embryos may be offered.
Preimplantation genetic testing may be particularly helpful in cases of inherited cardiac diseases associated with premature or sudden death. Use of preimplantation genetic testing has been reported in families with hereditary transthyretin-related amyloidosis, familial dilated cardiomyopathies, hypertrophic cardiomyopathy, and other genetic cardiomyopathies.
The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring.
Baseline evaluation of graft function and risk-assessment
If not completed as part of usual post-transplant surveillance within the previous 6 months, echocardiogram should be performed for a diagnostic assessment of graft function with more detailed assessment for rejection and CAV depending on the patient's history and clinical status.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
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).
For patients with documented DSA, human leukocyte antigen (HLA) testing of the potential father may give insight into the risk of rejection if both the donor and father have similar antigens, though this is not routinely performed.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Pregnancy can proceed successfully in many HT recipients, provided timely preconception risk-assessment and management (Table 3) and close monitoring of graft function and comorbidities during and after pregnancy (Table 4). 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.
thus possibly increasing the risk of AMR and CAV. Therefore, the immunologic status should be assessed before and early after pregnancy. Some reports suggest that the partners of HT patients may be typed for HLA-antigens before conception, due to the increased risk of AMR should they express the same HLA-antigens of the donor,
though this is not considered a standard practice.
Diagnosis and treatment of acute rejection
Endomyocardial biopsy for cause should be performed when acute rejection is suspected (clinical assessment, echocardiography, genetic testing). An echocardiographic-guided procedure is preferred, otherwise fluoroscopy should be done with lead draping of the abdomen.
Velleca A, Shullo MA, Dhital K, et al. The international society for heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1053249822021660?via%3Dihub. Accessed December 20, 2022.
Recommended regimens for the treatment of acute cellular rejection during pregnancy include high-dose corticosteroids; however, due to the relative insulin-resistance induced by pregnancy, closer glucose monitoring is recommended if steroids are used. The safety of other agents for treatment of rejection, such as anti-thymocyte globulin, in pregnancy has not been established and should be used with utmost caution.
Maternal and Fetal Outcomes
As noted in Section II, a key component of preconception counseling is an explanation of the maternal and fetal pregnancy outcomes. Table 6 provides a summary of the key maternal and fetal outcomes in HT recipients across a review of the largest series in the literature.
Table 6Summary of Maternal and Fetal Outcomes in Heart Transplant Recipients Across Contemporary Published Series, With > 10 Reported Pregnancies
Duodenal atresia, tetralogy of Fallot, laryngomalacia, facial deformities, vermian hypoplasia of the cerebellum, hypospadias, cystic hygroma, pectus excavatum, lip and tongue tie, and long QT syndrome.
a Duodenal atresia, tetralogy of Fallot, laryngomalacia, facial deformities, vermian hypoplasia of the cerebellum, hypospadias, cystic hygroma, pectus excavatum, lip and tongue tie, and long QT syndrome.
b Frontonasal dysplasia, bilateral radial ray anomalies with oligodactyly.
c Only fetal cardiac malformations noted; perimembranous ventricular septal defect.
HT rejection is uncommon during pregnancy but occurs more frequently after delivery. Rejection rates in the peripartum period range from 5% to 12% and episodes are most commonly low grade without significant hemodynamic compromise.
Episodes can often be treated with adjustments to baseline immunosuppression and may be related to both activation of maternal alloreactive T-cells and subtherapeutic exposure to immunosuppressive drugs, the latter being secondary to changes in circulating blood volume, intestinal motility, and renal function.
The cause for rejection may be due to variable immunosuppressant levels due to increased blood volume as well as HLA antigen-sharing between fetus and donor.
The association between pregnancy and the development of CAV is not clear. In 157 pregnancies in 97 HT recipients, 2 individuals developed CAV after pregnancy, leading to listing for re-transplantation, and 5 had CAV or myocardial infarction listed as the cause of death.
However, the longer-term survival of HT recipients after pregnancy warrants consideration. In 1 analysis, 33% of HT recipients who experienced pregnancy died with the median time after first pregnancy to death of 8.9 years with an average survival of 9.4 years.
These real-world data reinforce the importance of thorough preconception counseling for the recipient and partner, ensuring the couple contemplating a pregnancy are aware of longer-term outcomes.
Fetal outcomes
The rate of miscarriage in HT recipients ranges can be as high as 25%
However, several contemporary published series have shown that with careful intrapartum management, pregnancy in HT recipients can be successful with a reported live birth rate between 69% to 91%.
Nonetheless, about half of infants in published series were delivered preterm, before 37 weeks’ gestation, and 35% to 40% were low birth weight (<2500g).
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