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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Reproductive Health after Thoracic Transplantation: An ISHLT Expert Consensus Statement

Published:October 25, 2022DOI:https://doi.org/10.1016/j.healun.2022.10.009

      Abstract

      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.

      Keywords

      Abbreviations

      ACE
      angiotensin-converting enzyme
      ACOG
      American College of Obstetricians and Gynecologists
      AMR
      antibody-mediated rejection
      ART
      assisted reproductive technology
      CAV
      cardiac allograft vasculopathy
      CF
      cystic fibrosis
      CHD
      congenital heart disease
      CLAD
      chronic lung allograft dysfunction
      CMV
      cytomegalovirus
      CNI
      calcineurin inhibitor
      DM
      diabetes mellitus
      DSA
      donor-specific antibodies
      ISHLT
      International Society for Heart and Lung Transplantation
      LT
      lung transplantation
      LVAD
      left ventricular assist device
      HT
      heart transplantation
      mTOR
      mammalian target of rapamycin
      PPCM
      peripartum cardiomyopathy
      TPRI
      Transplant Pregnancy Registry International
      UNOS
      United Network for Organ Sharing

      Introduction

      With surgical and immunosuppressive advances in thoracic organ transplantation over the past three decades and attendant improved long-term outcomes, post-transplant pregnancy is an achievable goal for many lung transplant (LT) and heart transplant (HT) recipients.
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      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.
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      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.
      • Chinn JJ
      • Eisenberg E
      • Artis Dickerson S
      • et al.
      Maternal mortality in the United States: research gaps, opportunities, and priorities.
      ,
      • Collier AY
      • Molina RL.
      Maternal Mortality in the United States: Updates on Trends, Causes, and Solutions.
      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.

      McGlothlin D, Granton J, Klepetko W, et al. ISHLT CONSENSUS STATEMENT: Peri-operative Management of Patients with Pulmonary Hypertension and Right Heart Failure Undergoing Surgery. The Journal of Heart and Lung Transplantation.

      • Lorts A
      • Conway J
      • Schweiger M
      • et al.
      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.
      • Leard LE
      • Holm AM
      • Valapour M
      • et al.
      Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.
      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 prior to conception.
      • Mehta LS
      • Warnes CA
      • Bradley E
      • et al.
      Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association.
      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.
      • Davis MB
      • Arendt K
      • Bello NA
      • et al.
      Team-Based Care of Women With Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 1/5.
      ,
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      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
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      and LT recipients
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      are unplanned, demonstrating a significant opportunity for education both pre- and post-transplantation regarding contraception and transition to medications that are safe during pregnancy.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      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)).
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      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 Journal of heart and lung transplantation : the official publication of the International Society for.
      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.
      Figure 1
      Figure 1Approach to Preconception Counseling in Lung and Heart Transplant Recipients. CAV = cardiac allograft vasculopathy, CHD = congenital heart disease, CLAD = chronic lung allograft dysfunction, DSA = donor-specific antibodies, HT = heart transplant, LT = lung transplant, PPCM = peripartum cardiomyopathy.
      Figure 2
      Figure 2Educating Patients on Post-Transplant Pregnancy. HT = heart transplant, LT = lung transplant.
      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.
      • McKay DB
      • Josephson MA
      • Armenti VT
      • et al.
      Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.
      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.
      • Vos R
      • Ruttens D
      • Verleden SE
      • et al.
      Pregnancy after heart and lung transplantation.
      This is particularly relevant as nearly half of pregnancies in HT recipients
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      and LT recipients
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      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).
      • Potena L
      • Moriconi V
      • Presta E.
      Pregnancy and Heart Transplantation: Giving Birth After a New Life.
      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 contraceptionConsensus recommendationsUse in transplant recipients taking mycophenolate productsSafe in breastfeedingNotes
      Intrauterine devices (hormonal and non-hormonal)Preferred method for long-term contraceptionAcceptable as sole method of contraceptionYes
      • Long-term, highly effective
      • Immunosuppression is not a contraindication
      • Lack of drug-drug interactions
      • Straightforward removal for reversal
      Progesterone depot injectionNot recommended for long-term (i.e., > 2 years) contraception due to risk of decreased bone mineral densityUse with barrier methodYes
      • Highly effective
      • Delayed return to fertility after cessation
      • Decreased bone mineral density
      • Weight gain
      Progesterone subdermal implantAcceptable method of long-term contraceptionUse with barrier methodYes
      • Long-term, highly effective
      • Rapid return of fertility once removed
      Combined hormonal contraceptives (pills, vaginal ring, transdermal patch)Not recommended as sole method of contraception given contraindications and drug interactionsUse with barrier methodMay reduce milk production
      • Screen for hypercoagulable states prior to 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 pillsNot routinely recommended given effectiveness diminishes with nonadherenceUse with barrier methodYes
      • 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 contraceptionUse with another methodYes
      • 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).
      Intrauterine devices (copper-containing IUD and levonorgestrel-releasing IUD) offer long term, highly effective, reversible contraception.
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      ,
      • Curtis KM
      • Jatlaoui TC
      • Tepper NK
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ,
      • Curtis KM
      • Tepper NK
      • Jatlaoui TC
      • et al.
      U.S. Medical Eligibility Criteria for Contraceptive Use, 2016.
      Immunosuppression is not a contraindication to IUD use,
      • Gordon C
      • Harken T.
      Controversies in family planning: intrauterine device placement in solid organ transplant patients.
      ,
      • Krajewski CM
      • Geetha D
      • Gomez-Lobo V.
      Contraceptive options for women with a history of solid-organ transplantation.
      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).

      CDC Contraceptive Guidance for Health Care Providers: Classification of Intrauterine Devices. at https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/appendixB.html#references.)

      Similarly, the 2022 Guideline for the Care of the Heart Transplant Recipient notes that IUDs are not generally recommended for HT recipients with complications.

      Placeholder reference for the unpublished Guideline for the Care of the Heart Transplant Recipient. 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
      • Sims J
      • Lutz E
      • Wallace K
      • Kassahun-Yimer W
      • Ngwudike C
      • Shwayder J.
      Depo-medroxyprogesterone acetate, weight gain and amenorrhea among obese adolescent and adult women.
      , which may be significant in transplant recipients who are also exposed to long-term corticosteroid therapy.
      • Estes CM
      • Westhoff C.
      Contraception for the transplant patient.
      Thus, depo-medroxyprogesterone acetate is not routinely recommended as a long-term contraceptive option.
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      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.
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      Combined hormonal contraceptives portend increased risk in patients with prior myocardial infarction, stroke or deep venous thrombosis, hypertension, migraine with aura, and liver disease.
      • Estes CM
      • Westhoff C.
      Contraception for the transplant patient.
      In addition, the ISHLT guidelines recommend transplant recipients be screened for hypercoagulable states prior to the initiation of combination hormonal contraception.
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      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.
      • Maroo A
      • Chahine J.
      Contraceptive Strategies in Women With Heart Failure or With Cardiac Transplantation.
      However, it is important to note that there is a failure rate of 1-2 per 1000 men,
      • Kaplan KA
      • Huether CA.
      A clinical study of vasectomy failure and recanalization.
      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.
      • Haldar N
      • Cranston D
      • Turner E
      • MacKenzie I
      • Guillebaud J.
      How reliable is a vasectomy? Long-term follow-up of vasectomised men.
      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.
      • Kohn J
      • Shamshirsaz A
      • Popek E
      • Guan X
      • Belfort M
      • Fox K.
      Pregnancy after endometrial ablation: a systematic review.
      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 22% of women experienced difficulty achieving pregnancy.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      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 is an option for transplant recipients on an individualized basis. 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,
      • Grandone E
      • Di Micco PP
      • Villani M
      • et al.
      Venous Thromboembolism in Women Undergoing Assisted Reproductive Technologies: Data from the RIETE Registry.
      which is reassuring when considering ART for HT and LT 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.
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      ,
      • Dagher O
      • Alami Laroussi N
      • Carrier M
      • et al.
      Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      • Daly TA
      • Coscia L
      • Nathan HM
      • Hasz RD
      • Constantinescu S
      • Moritz MJ.
      PREGNANCY OUTCOMES IN 36 LUNG TRANSPLANT RECIPIENTS.
      • Gadre S
      • Gadre SK.
      Pregnancy and Lung Transplantation.
       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.
      • Penzias A
      • Bendikson K
      • Butts S
      • et al.
      ASRM standard embryo transfer protocol template: a committee opinion.
      Controlled ovarian stimulation may cause increased vascular fluid shifts,
      • De Pinho JC
      • Sauer MV.
      Infertility and ART after transplantation.
      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.
      Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline.
      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.

      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.
      • Dew MA
      • Rosenberger EM
      • Myaskovsky L
      • et al.
      Depression and Anxiety as Risk Factors for Morbidity and Mortality After Organ Transplantation: A Systematic Review and Meta-Analysis.
      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%.
      • Dew MA
      • Dimartini AF
      • Devito Dabbs AJ
      • et al.
      Onset and risk factors for anxiety and depression during the first 2 years after lung transplantation.
      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%.
      • Loh AZH
      • Tan JSY
      • Tam JKC
      • Zhang MW
      • Ho CSH
      • Ho RC.
      Postoperative Psychological Disorders Among Heart Transplant Recipients: A Meta-Analysis and Meta-Regression.
      Compared with male HT recipients, depression is more common in women (50% vs 23.6%),
      • de la Rosa A
      • Singer-Englar T
      • Hamilton MA
      • IsHak WW
      • Kobashigawa JA
      • Kittleson MM.
      The impact of depression on heart transplant outcomes: A retrospective single-center cohort study.
      and tends to persist over time.
      • Loh AZH
      • Tan JSY
      • Tam JKC
      • Zhang MW
      • Ho CSH
      • Ho RC.
      Postoperative Psychological Disorders Among Heart Transplant Recipients: A Meta-Analysis and Meta-Regression.
      • de la Rosa A
      • Singer-Englar T
      • Hamilton MA
      • IsHak WW
      • Kobashigawa JA
      • Kittleson MM.
      The impact of depression on heart transplant outcomes: A retrospective single-center cohort study.
      • Havik OE
      • Sivertsen B
      • Relbo A
      • et al.
      Depressive symptoms and all-cause mortality after heart transplantation.
      • Evangelista LS
      • Doering L
      • Dracup K.
      Meaning and life purpose: the perspectives of post-transplant women.
      Pre- and post-transplant depression is associated with an increased risk of mortality after heart, lung, and other solid-organ transplantation.
      • Dew MA
      • Rosenberger EM
      • Myaskovsky L
      • et al.
      Depression and Anxiety as Risk Factors for Morbidity and Mortality After Organ Transplantation: A Systematic Review and Meta-Analysis.
      ,
      • Corbett C
      • Armstrong MJ
      • Parker R
      • Webb K
      • Neuberger JM.
      Mental Health Disorders and Solid-Organ Transplant Recipients.
      • Havik OE
      • Sivertsen B
      • Relbo A
      • et al.
      Depressive Symptoms and All-Cause Mortality After Heart Transplantation.
      • Rosenberger EM
      • Dew MA
      • Crone C
      • DiMartini AF.
      Psychiatric disorders as risk factors for adverse medical outcomes after solid organ transplantation.
      • Zipfel S
      • Schneider A
      • Wild B
      • et al.
      Effect of depressive symptoms on survival after heart transplantation.
      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.

      Fawcett EJ, Fairbrother N, Cox ML, White IR, Fawcett JM. The Prevalence of Anxiety Disorders During Pregnancy and the Postpartum Period. The Journal of Clinical Psychiatry: Physicians Postgraduate Press Inc.; 2019.

      ,
      • Tebeka S
      • Strat YL
      • Dubertret C.
      Developmental trajectories of pregnant and postpartum depression in an epidemiologic survey.
      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.
      • Furuta M
      • Sandall J
      • Bick D.
      A systematic review of the relationship between severe maternal morbidity and post-traumatic stress disorder.
      • Furuta M
      • Sandall J
      • Cooper D
      • Bick D.
      The relationship between severe maternal morbidity and psychological health symptoms at 6–8 weeks postpartum: a prospective cohort study in one English maternity unit.
      • Goyal N
      • Herrick JS
      • Son S
      • Metz TD
      • Shah RU.
      Maternal Cardiovascular Complications at the Time of Delivery and Subsequent Re-Hospitalization in the United States, 2010 to 2016.
      • Nazeema Zainura I
      • Michelle Glenda A
      A systematic review regarding women's emotional and psychological experiences of high-risk pregnancies.
      • Tsakiridis I
      • Bousi V
      • Dagklis T
      • Sardeli C
      • Nikolopoulou V
      • Papazisis G.
      Epidemiology of antenatal depression among women with high-risk pregnancies due to obstetric complications: a scoping review.
      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.
      • Kallapur A
      • Jang C
      • Yin O
      • Mei JY
      • Afshar Y.
      Pregnancy care in solid organ 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.
      ACOG Committee Opinion No. 757 Summary: Screening for Perinatal Depression.
      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.
      • Dew MA
      • DiMartini AF
      • Dobbels F
      • et al.
      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,
      • Dew MA
      • DiMartini AF
      • Dobbels F
      • et al.
      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.
      • Dew MA
      • DiMartini AF
      • Dobbels F
      • et al.
      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 3
      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.
      Routine psychological screening using validated tools (e.g., Edinburgh Postnatal Depression Scale
      • Cox JL
      • Holden JM
      • Sagovsky R.
      Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale.
      and Generalized Anxiety Disorder-7
      • Spitzer RL
      • Kroenke K
      • Williams JBW
      • Löwe B.
      A Brief Measure for Assessing Generalized Anxiety Disorder.
      ) 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.
      • Dy SM
      • Purnell TS.
      Key concepts relevant to quality of complex and shared decision-making in health care: a literature review.
      ,
      • Oshima Lee E
      • Emanuel EJ
      Shared decision making to improve care and reduce costs.
      Shared decision-making is especially important given the unique physical and psychological complexities faced by transplant recipients and their families.
      • Evangelista LS
      • Doering L
      • Dracup K.
      Meaning and life purpose: the perspectives of post-transplant women.
      ,
      • Duffy J
      • Thompson T
      • Hinton L
      • Salinas M
      • McManus R
      • Ziebland S.
      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.
      • Hinton L
      • Locock L
      • Knight M.
      Support for mothers and their families after life-threatening illness in pregnancy and childbirth:a qualitative study in primary care.
      • Hinton L
      • Locock L
      • Knight M.
      Maternal critical care: what can we learn from patient experience? A qualitative study.
      • Khan A
      • Pare E
      • Shah S.
      Peripartum Cardiomyopathy: a Review for the Clinician.
      • Hinton L
      • Locock L
      • Knight M.
      Partner experiences of "near-miss" events in pregnancy and childbirth in the UK: A qualitative study.
      • Conway A
      • Schadewaldt V
      • Clark R
      • et al.
      The effectiveness of non-pharmacological interventions in improving psychological outcomes for heart transplant recipients: a systematic review.
      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.
      • Allen LA
      • Stevenson LW
      • Grady KL
      • et al.
      Decision making in advanced heart failure: a scientific statement from the American Heart Association.
      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 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 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.
      • Allen LA
      • Stevenson LW
      • Grady KL
      • et al.
      Decision making in advanced heart failure: a scientific statement from the American Heart Association.

      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, 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.
      • Coscia L
      • Daly T
      • Nathan H
      • et al.
      Transplant pregnancy registry international.
      • Jones A
      • Clary MJ
      • McDermott E
      • et al.
      Outcomes of pregnancies fathered by solid-organ transplant recipients exposed to mycophenolic acid products.
      • Midtvedt K
      • Bergan S
      • Reisæter AV
      • Vikse BE
      • Åsberg A.
      Exposure to mycophenolate and fatherhood.
      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.
      • Zuber J
      • Anglicheau D
      • Elie C
      • et al.
      Sirolimus may reduce fertility in male renal transplant recipients.
      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 and 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 two years prior.
      • Murray JE
      • Reid DE
      • Harrison JH
      • Merrill JP.
      Successful pregnancies after human renal transplantation.
      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.
      • Shah S
      • Venkatesan RL
      • Gupta A
      • et al.
      Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.
      • Coscia LA
      • Constantinescu S
      • Moritz MJ
      • et al.
      Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.
      • van Buren MC
      • Schellekens A
      • Groenhof TKJ
      • et al.
      Long-term Graft Survival and Graft Function Following Pregnancy in Kidney Transplant Recipients: A Systematic Review and Meta-analysis.
      • Deshpande NA
      • James NT
      • Kucirka LM
      • et al.
      Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis.
      • Deshpande NA
      • James NT
      • Kucirka LM
      • et al.
      Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis.
      • Marson EJ
      • Kamarajah SK
      • Dyson JK
      • White SA.
      Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.
      • Kamarajah SK
      • Arntdz K
      • Bundred J
      • Gunson B
      • Haydon G
      • Thompson F.
      Outcomes of Pregnancy in Recipients of Liver Transplants.
      • Coffin CS
      • Shaheen AA
      • Burak KW
      • Myers RP.
      Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis.
      • Bramham K
      • Nelson-Piercy C
      • Gao H
      • et al.
      Pregnancy in renal transplant recipients: a UK national cohort study.
      • Thornton AT
      • Huang Y
      • Mourad MJ
      • Wright JD
      • D'Alton ME
      • Friedman AM
      Obstetric outcomes among women with a liver transplant.

      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.
      • McKay DB
      • Josephson MA
      • Armenti VT
      • et al.
      Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.
      ,
      • Davison JM
      • Lind T
      • Uldall PR.
      Planned pregnancy in a renal transplant recipient.
      ,
      • Sarkar M
      • Brady CW
      • Fleckenstein J
      • et al.
      Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases.
      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 one year of transplantation have a higher risk of rejection, graft loss, and non-viable fetal outcomes,
      • Kamarajah SK
      • Arntdz K
      • Bundred J
      • Gunson B
      • Haydon G
      • Thompson F.
      Outcomes of Pregnancy in Recipients of Liver Transplants.
      ,
      • Kim HW
      • Seok HJ
      • Kim TH
      • Han DJ
      • Yang WS
      • Park SK.
      The experience of pregnancy after renal transplantation: pregnancies even within postoperative 1 year may be tolerable.
      and that unplanned pregnancy results in more rejection and greater risk of graft loss within the subsequent 2 years.
      • Rao SC
      • L A.
      • Kliniewski D.
      • Constantinescu S.
      • Moritz M.J
      Comparison of Planned vs. Unplanned Pregnancies in Female Kidney Transplant Recipients [abstract].

      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 24-48% and 21-29%, respectively (Table 2).
      • Shah S
      • Venkatesan RL
      • Gupta A
      • et al.
      Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.
      Rejection occurred in 3-9.4% of recipients; yet, at a mean follow-up of 14 years, 67% report adequate graft function.
      • Shah S
      • Venkatesan RL
      • Gupta A
      • et al.
      Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.
      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.
      • van Buren MC
      • Schellekens A
      • Groenhof TKJ
      • et al.
      Long-term Graft Survival and Graft Function Following Pregnancy in Kidney Transplant Recipients: A Systematic Review and Meta-analysis.
      Table 2Pregnancy Outcomes in Abdominal Transplant Recipients
      Kidney Transplant RecipientsLiver Transplant RecipientsNon-transplant Pregnancies
      TPRI
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      Shah et al
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.


      (pooled data)
      TPRI
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      Marson et al
      • Chinn JJ
      • Eisenberg E
      • Artis Dickerson S
      • et al.
      Maternal mortality in the United States: research gaps, opportunities, and priorities.


      (pooled data)
      US National Vital Statistics
      • Collier AY
      • Molina RL.
      Maternal Mortality in the United States: Updates on Trends, Causes, and Solutions.
      Recipients125141743631073-
      Pregnancies223367127161496-
      Live births75%72.9%72%85.6%59%
      Miscarriage19%15.4%23%7.8%16%
      Hypertension48%

      (drug-treated)
      24.1%

      (pregnancy-induced)
      21%18.2%-
      Preeclampsia29%21.5%21%12.8%3.8%
      Gestational diabetes8%5.7%8%7.0%3.9%
      Rejection
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      3%9.4%5%NR-
      Mean gestational age at delivery, weeks35.834.936.737.1-
      Mean birth weight2555 g2470 g2772 g2783 g3400 g
      Preterm delivery37%43.1%26%27.8 %26%
      Cesarean delivery51%62.6%32%
      1-TPRI references not included in analyses; 2-TPRI included all types of rejection while Shah included acute only; NR = not reported; TPRI = Transplant Pregnancy Registry International
      Liver transplant recipients experience similar complications (Table 2). Liver recipients have an incidence of hypertension of 18-21% and preeclampsia of 13-21%.
      • Marson EJ
      • Kamarajah SK
      • Dyson JK
      • White SA.
      Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.
      Rejection is uncommon in pregnant liver transplant recipients, occurring in 5%.
      • Marson EJ
      • Kamarajah SK
      • Dyson JK
      • White SA.
      Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.
      Data are lacking regarding transplant outcomes in pregnant versus non-pregnant liver recipients.

      Fetal outcomes

      There is a high prevalence of reported cesarean deliveries for both kidney and liver recipients, at 51-62.6%
      • Shah S
      • Venkatesan RL
      • Gupta A
      • et al.
      Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.
      to 42.4-43%,
      • Marson EJ
      • Kamarajah SK
      • Dyson JK
      • White SA.
      Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.
      respectively. There is also a high incidence of prematurity and low birthweight offspring in kidney transplant and liver transplant recipients. Preterm delivery occurred in 37-43.1% of kidney transplant
      • Shah S
      • Venkatesan RL
      • Gupta A
      • et al.
      Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.
      and 26-27.8% of liver transplant
      • Marson EJ
      • Kamarajah SK
      • Dyson JK
      • White SA.
      Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.
      recipients. Despite this, however, overall long-term health and development of the offspring of kidney and liver recipients does not appear adversely affected.
      • Dinelli MIS
      • Ono E
      • Viana PO
      • Dos Santos AMN
      • De Moraes-Pinto MI
      Growth of children born to renal transplanted women.
      • Drozdowska-Szymczak A
      • Pietrzak B
      • Czaplińska N
      • et al.
      Immunological Status of Children Born to Female Liver Recipients.
      • Nulman I
      • Sgro M
      • Barrera M
      • Chitayat D
      • Cairney J
      • Koren G.
      Long-term neurodevelopment of children exposed in utero to ciclosporin after maternal renal transplant.

      Kidney versus liver transplant recipients

      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 versus 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.
      • DeFilippis EM
      • Haythe J
      • Farr MA
      • Kobashigawa J
      • Kittleson MM.
      Practice Patterns Surrounding Pregnancy After Heart Transplantation.
      Additionally, rates of rejection are higher in thoracic transplant recipients and hence, higher levels of immunosuppression are required.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      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 Journal of heart and lung transplantation : the official publication of the International Society for.
      ,
      • Khush KK
      • Hsich E
      • Potena L
      • et al.
      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.
      • Hart A
      • Lentine KL
      • Smith JM
      • et al.
      OPTN/SRTR 2019 Annual Data Report: Kidney.
      • Kwong AJ
      • Kim WR
      • Lake JR
      • et al.
      OPTN/SRTR 2019 Annual Data Report: Liver.
      Special considerations during pregnancy for LT and HT recipients will be discussed in the next two sections.

      Risk A, Management, and Outcomes of Pregnancy after Lung Transplantation

      In 1996, the first successful pregnancy in a LT recipient was reported.
      • Parry D
      • Hextall A
      • Robinson V
      • Banner N
      • Yacoub M.
      Pregnancy following a single lung transplant.
      Since then, an increasing number of pregnancies in this cohort have been described.
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      ,
      • Gyi KM
      • Hodson ME
      • Yacoub MY.
      Pregnancy in cystic fibrosis lung transplant recipients: Case series and review.
      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.
      • Vos R
      • Ruttens D
      • Verleden SE
      • et al.
      Pregnancy after heart and lung transplantation.
      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
      • Yusen RD
      • Edwards LB
      • Kucheryavaya AY
      • et al.
      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 prior to 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 4
      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.
      • Rawlinson WD
      • Boppana SB
      • Fowler KB
      • et al.
      Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy.
      ,
      • Rea F
      • Potena L
      • Yonan N
      • Wagner F
      • Calabrese F.
      Cytomegalovirus Hyper Immunoglobulin for CMV Prophylaxis in Thoracic Transplantation.
      Almost half of all LT recipients of reproductive age have CF as their underlying diagnosis.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      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 Journal of heart and lung transplantation : the official publication of the International Society for.
      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 grams 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.
      • Rothman KJ
      • Moore LL
      • Singer MR
      • Nguyen U-SDT
      • Mannino S
      • Milunsky A.
      Teratogenicity of High Vitamin A Intake.
      Ideally, supplementation should begin prior to 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.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      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 Journal of heart and lung transplantation : the official publication of the International Society for.
      Long-term causes of death include chronic lung allograft dysfunction (CLAD), infection, and graft failure.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      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 Journal of heart and lung transplantation : the official publication of the International Society for.
      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.
      • McKay DB
      • Josephson MA
      • Armenti VT
      • et al.
      Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.
      ,
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      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
      AssessmentImpact on management or outcomeContraindications to planned pregnancy
      History
      • Genetic condition may trigger 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.
      • Symptomatic graft dysfunction
      • Uncontrolled hypertension
      Laboratory assessment: comprehensive metabolic panel, Hgb A1c, urinalysis
      • 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
      • Active infection
      AMR = antibody-mediated rejection; ARVC = arrhythmogenic right ventricular cardiomyopathy; CAV = cardiac allograft vasculopathy; CHD = congenital heart disease; CF = cystic fibrosis; CLAD = chronic lung allograft dysfunction; CMV = cytomegalovirus; DM = diabetes mellitus; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; PFTs = pulmonary function tests; PPCM = peripartum cardiomyopathy; RHC = right heart catheterization.
      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 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.
      • Weinberger SE
      • Weiss ST
      • Cohen WR
      • Weiss JW
      • Johnson TS.
      Pregnancy and the lung.
      Respiratory rate, forced expiratory volume (FEV1) and forced vital capacity (FVC) however, remain unchanged.
      • Weinberger SE
      • Weiss ST
      • Cohen WR
      • Weiss JW
      • Johnson TS.
      Pregnancy and the lung.
      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.
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      Table 4Timetable of periodic assessment during pregnancy in lung transplant and heart transplant recipients
      ExamTimingNotes
      Graft function and rejection
      • Physical examination, vital parameters
      Every 4 weeks24h-monitoring of BP if hypertension is suspected.
      12-lead EKGEvery 4 weeksEMB (preferably echo-guided) if rejection is suspected.
      • Spirometry (Lung)
      Every 4 weeksBronchoscopy 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 deliveryEMB (preferably echo-guided) if rejection is suspected.
      • Hypertensive disorders
      • Renal function, liver function, blood cells count
      Every 4 weeksIncrease in eGFR is expected.

      Monitoring liver enzymes and platelet count if HELLP syndrome is suspected.
      • Urinalysis
      Every 4 weeksCheck for proteinuria.
      Diabetes mellitus
      • Fasting plasma glucose
      Every 4 weeksAdditional therapy if increase in steroid dose is needed.
      • Glucose challenge test
      Between 24-28 weeksMay 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 deliveryAdditional therapeutic drug monitoring in the first two trimesters may be suggested, following daily dose adaptation, as needed.
      • HLA-specific antibodies
      1-3 months after deliveryEarlier 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
      Abbreviations: BP = blood pression; CMV = cytomegalovirus; CNI = calcineurin-inhibitors; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; EMB = endomyocardial biopsy; HELLP = hemolysis, elevated liver enzymes, low platelets; HLA = human leukocyte antigen; HSV = herpes-simplex virus; PCR = polymerase chain reaction.
      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.
      • Divithotawela C
      • Chambers D
      • Hopkins P.
      Pregnancy after lung transplant: Case Report.
      Procedural sedation during bronchoscopy is safe in this patient population, though may be best administered by physicians trained in obstetrical anesthesia.
      • Neuman G
      • Koren G.
      Safety of procedural sedation in pregnancy.
      Antibody-mediated rejection (AMR) following pregnancy has been described in other solid organ transplant recipients
      • Cornella C
      • Riboni F
      • Praticò L
      • et al.
      Pregnancy and Renal Transplantation: A Case Report of the Risk of Antibody Induction Against Partner Antigens.
      ,
      • O'Boyle PJ
      • Smith JD
      • Danskine AJ
      • Lyster HS
      • Burke MM
      • Banner NR.
      De novo HLA sensitization and antibody mediated rejection following pregnancy in a heart transplant recipient.
      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.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      Rates of acute rejection have been reported as ranging from 0 to 33%,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      with CF recipients in one series demonstrating higher incidence of acute rejection when compared to those LT recipients with other underlying diseases (25% vs. 11%).
      • Shaner J
      • Coscia LA
      • Constantinescu S
      • et al.
      Pregnancy after Lung Transplant.
      Heart-lung transplant recipients may have similar to slightly higher rates of rejection during pregnancy than heart-alone recipients (11% vs 9.4%).
      • Durst JK
      • Rampersad RM.
      Pregnancy in Women With Solid-Organ Transplants: A Review.
      Table 5Summary of Maternal and Fetal Outcomes in Lung Transplant Recipients across contemporary published series, with > 10 reported pregnancies.
      Series (year)TPRI (2019)

      McGlothlin D, Granton J, Klepetko W, et al. ISHLT CONSENSUS STATEMENT: Peri-operative Management of Patients with Pulmonary Hypertension and Right Heart Failure Undergoing Surgery. The Journal of Heart and Lung Transplantation.

      Bry et al (2019)
      • Lorts A
      • Conway J
      • Schweiger M
      • et al.
      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.
      Thakrar et al (2014)
      • Leard LE
      • Holm AM
      • Valapour M
      • et al.
      Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.
      Number of pregnancies (number of women)50 (37)39 (35)*14 (14)
      Includes lung and heart-lung transplant recipients
      Unplanned pregnancies, n (%)30 (60)16 (41)5 (36)
      Mean time from transplant (years)4.2±3.15.3±3.76.4 (range: 2.2-11.6)
      Mean age at transplant (years)2623±5Not reported
      Mean age at pregnancy (years)Not reported28±531.4
      FEV1 pre-pregnancy, (% predicted)Not reported83 ± 25Not reported
      Maternal complications (as % of pregnancies)
      Hypertension, n (%)30 (60)Before pregnancy: 18 (51)

      During pregnancy: 17 (59)

      Gestational HTN: 3 (10)
      Not reported
      Preeclampsia, n (%)7 (13)1 (3)2 (14)
      Diabetes mellitus, n (%)15 (30)Before pregnancy: 19 (51)

      During pregnancy: 18 (55)

      Gestational diabetes: 2(6)
      Before pregnancy: 4(29

      Gestational diabetes: 1 (7)
      Renal failure, n (%)Not reportedBefore pregnancy: 21 (58)

      During pregnancy: 19 (61)

      New during pregnancy: 1 (3)
      Before pregnancy: 7 (50)
      Infection, n (%)Not reported8 (24)3 (21) within 6 months of delivery
      Decrease in FEV1 % predicted > 5%, n (%)Not reported14 (36)Not reported
      Graft loss (within 2 years of delivery/termination), n (%)3 (6)2 (5)1 (7)
      Rejection (%)7 (14)Before pregnancy: 15 (39)

      During pregnancy: 0 (0)

      After pregnancy: 13 (33)
      Within 6 months of pregnancy: 1 (7)
      Maternal Death during Pregnancy, n (%)01 (3)0
      Maternal death, n (%)11 (29)6 (43; time post pregnancy not reported)
      Mean time from pregnancy to maternal death (yrs)Not reported4.6 ± 6.5Not reported
      Obstetric and Fetal outcomes (as % of pregnancies except as noted)
      Live birth, n (%)30 (60)26 (67)8 (42)
      Mean gestational age at delivery (weeks)34±536±5Not reported
      Fertility treatments used, n (%)Not reported7 (18)3 (21)
      Cesarean delivery, n (% of live births)24 (47)12 (46)Not reported
      Miscarriage, n (%)15 (29)7 (18)6 (32)
      Ectopic pregnancies, n (%)1 (2)Not reported1 (7)
      Terminations, n (%)5 (10)5 (11)2 (14%) (including ectopic pregnancy)
      Low birth weight (<2500g), n (%)32 (64)12 (46)Not reported
      Preterm (<37 weeks), n(%)25 (50)11 (42)Not reported
      Congenital malformations, n (% of live births)2 (4)
      One child with hypospadias and arteriovenous malformation; one child with atrial and ventricular septal defects.
      n/an/a
      FEV1, forced expiratory volume in 1 second; TPRI, Transplant Pregnancy Registry International
      Mean values or N (%) are reported.
      low asterisk Includes lung and heart-lung transplant recipients
      low asterisklow asterisk One child with hypospadias and arteriovenous malformation; one child with atrial and ventricular septal defects.
      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.
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      Other series have observed postpartum CLAD in almost 30% of LT recipients
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      and another reported a 40% incidence in decline in lung function and death due to CLAD within 3 years of delivery.
      • Gyi KM
      • Hodson ME
      • Yacoub MY.
      Pregnancy in cystic fibrosis lung transplant recipients: Case series and review.
      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.
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      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.
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      However, post-pregnancy mortality after LT increases over time to 43% over the next of 3-7 years
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      in one series and 29% died over 9 years in another.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      Strikingly, the mean age of the child at the time of maternal death was 7.4 years.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      Information regarding these outcomes may impact the shared decision-making process of pregnancy planning.

      Fetal outcomes

      The rate of live birth is 42-67% in pregnant LT recipients with a relatively high rate of miscarriage of 18-32% (Table 5).
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Vos R
      • Ruttens D
      • Verleden SE
      • et al.
      Pregnancy after heart and lung transplantation.
      ,
      • Daly TA
      • Coscia L
      • Nathan HM
      • Hasz RD
      • Constantinescu S
      • Moritz MJ.
      PREGNANCY OUTCOMES IN 36 LUNG TRANSPLANT RECIPIENTS.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      Cesarean delivery is common, occurring in up to 47% of LT recipients.
      • Kallapur A
      • Jang C
      • Yin O
      • Mei JY
      • Afshar Y.
      Pregnancy care in solid organ transplant recipients.
      Preterm delivery and low birth weight are also common, with one case series showing 50% of deliveries occurring before 37 weeks,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      and 64% of neonates having a mean birth weight of <2500g.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      Despite the theoretical risk of in utero exposure to immunosuppressants, no specific patterns of birth defects in offspring have been reported in LT recipients.
      • Gadre S
      • Gadre SK.
      Pregnancy and Lung Transplantation.
      However, congenital anomalies have been reported in 5% of offspring of LT recipients,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      which appears comparable to the 3.8% of congenital anomalies reported in a series of 1000 consecutive healthy pregnancies at a tertiary care center.
      • Babu RS
      • Pasula S.
      Frequency of foetal anomalies in a tertiary care centre.

      Breastfeeding considerations

      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 and, prior to planned conception, 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.
      • Löwenstein BR
      • Vain NW
      • Perrone SV
      • Wright DR
      • Boullón FJ
      • Favaloro RG.
      Successful pregnancy and vaginal delivery after heart transplantation.
      As the proportion of female transplant recipients have increased from 21.3% in 1992-2000 to 28.1% in 2010-2018,
      • Khush KK
      • Hsich E
      • Potena L
      • et al.
      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.

      Personal communication with Josef Stehlik February 14, 2022.

      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 one year.
      • Khush KK
      • Cherikh WS
      • Chambers DC
      • et al.
      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 this large pool of candidates of potential 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 2010 ISHLT guidelines for post-transplant care advise that pregnancy should not be attempted within the first year.
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      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.
      • McKay DB
      • Josephson MA
      • Armenti VT
      • et al.
      Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.

      Patient risk assessment

      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 5
      Figure 5Factors to be considered in risk assessment for pregnancy after heart transplantation. ACE = angiotensin-converting enzyme, CHD = congenital heart disease, CM = 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 30-45% is mWHO classification II-III as intermediate risk),
      • Regitz-Zagrosek V
      • Roos-Hesselink JW
      • Bauersachs J
      • et al.
      2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy.
      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).
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      ,
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      ,
      • DeFilippis EM
      • Haythe J
      • Farr MA
      • Kobashigawa J
      • Kittleson MM.
      Practice Patterns Surrounding Pregnancy After Heart Transplantation.
      Prior rejection is a concern. While treated acute cellular rejection more than 1 year prior to 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.
      • Davis MB
      • Arendt K
      • Bello NA
      • et al.
      Team-Based Care of Women With Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 1/5.
      ,

      Siu SC, Lee DS, Rashid M, Fang J, Austin PC, Silversides CK. Long‐Term Cardiovascular Outcomes After Pregnancy in Women With Heart Disease. Journal of the American Heart Association 2021;10:e020584.

      • Botero D
      • Senior J
      • Velasquez J
      • et al.
      Validation of the CARPREG II risk stratification model and the WHOm scale in pregnant women with heart disease.
      • Silversides CK
      • Grewal J
      • Mason J
      • et al.
      Pregnancy Outcomes in Women With Heart Disease: The CARPREG II Study.
      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).

      Personal communication with Josef Stehlik February 14, 2022.

      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 presence of CAV negatively affects survival,
      • Khush KK
      • Hsich E
      • Potena L
      • et al.
      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.
      • Chih S
      • Chong AY
      • Mielniczuk LM
      • Bhatt DL
      • Beanlands RS.
      Allograft Vasculopathy: The Achilles' Heel of Heart Transplantation.
      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.
      • Khush KK
      • Potena L
      • Cherikh WS
      • et al.
      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.
      • Khush KK
      • Potena L
      • Cherikh WS
      • et al.
      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
      • Rasmusson K
      • Brunisholz K
      • Budge D
      • et al.
      Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database.
      and 10-23% of women with PPCM require transplantation as definitive treatment.
      • Amos AM
      • Jaber WA
      • Russell SD.
      Improved outcomes in peripartum cardiomyopathy with contemporary.
      • Goland S
      • Bitar F
      • Modi K
      • et al.
      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.
      • McNamara DM
      • Elkayam U
      • Alharethi R
      • et al.
      Clinical Outcomes for Peripartum Cardiomyopathy in North America: Results of the IPAC Study (Investigations of Pregnancy-Associated 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% versus 2.1%).
      • Rasmusson K
      • Brunisholz K
      • Budge D
      • et al.
      Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database.
      The mechanisms implicated in this remain poorly understood but may be related to a higher degree of pre-transplant antibody sensitization.
      • Genyk PA
      • Liu GS
      • Nattiv J
      • et al.
      Heart Transplantation Outcomes in Adults with Postpartum Cardiomyopathy.
      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.

      Personal communication with Josef Stehlik February 14, 2022.

      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,
      • Rasmusson K
      • Brunisholz K
      • Budge D
      • et al.
      Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database.
      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 3–7%
      • Mastrobattista JM
      • Gomez-Lobo V.
      Pregnancy after solid organ transplantation.
      ,
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      ,
      • Fesslova V
      • Brankovic J
      • Lalatta F
      • et al.
      Recurrence of congenital heart disease in cases with familial risk screened prenatally by echocardiography.
      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 13–18%.
      • Gill HK
      • Splitt M
      • Sharland GK
      • Simpson JM.
      Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography.
      ,
      • Jenkins KJ
      • Correa A
      • Feinstein JA
      • et al.
      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.

      Heritable Cardiomyopathies

      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.38 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.
      • Lopes R
      • Sousa M
      • Silva J
      • et al.
      Clinical outcomes after preimplantation genetic diagnosis of patients with Corino de Andrade disease (familial amyloid polyneuropathy).
      • Valdrez K
      • Silva S
      • Coelho T
      • Alves E.
      Awareness and motives for use and non-use of preimplantation genetic diagnosis in familial amyloid polyneuropathy mutation carriers.
      • Lakdawala NK.
      Using genetic testing to guide therapeutic decisions in cardiomyopathy.
      • Liu Y
      • Bock MJ
      • Gold J-A.
      The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring.

      Surveillance

      Baseline evaluation of graft function and risk-assessment

      If not completed as part of usual post-transplant surveillance within the previous six 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.
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      ,
      • Defilippis EM
      • Kittleson MM.
      Pregnancy after Heart Transplantation.
      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).
      • Defilippis EM
      • Kittleson MM.
      Pregnancy after Heart Transplantation.
      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.
      • O'Boyle PJ
      • Smith JD
      • Danskine AJ
      • Lyster HS
      • Burke MM
      • Banner NR.
      De novo HLA sensitization and antibody mediated rejection following pregnancy in a heart transplant recipient.
      The list of recommended exams, with rationale and impact of results is shown in Table 3.
      • McKay DB
      • Josephson MA
      • Armenti VT
      • et al.
      Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.
      ,
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.

      Surveillance of rejection

      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.
      • Moayedi Y
      • Foroutan F
      • Miller RJH
      • et al.
      Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients.
      ,
      • Khush KK
      • Patel J
      • Pinney S
      • et al.
      Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study.
      However, dd-cfDNA testing will detect fetal DNA and thus, cannot be reliably used in pregnancy.
      Pregnancy also represents a unique immunologic challenge, known to promote sensitization towards fetal HLA-antigens,
      • Cerci Gurbuz B
      • Soyoz M
      • Ozkale Okyay D
      • Kilicaslan Ayna T
      • Pirim I
      Comparison of Anti-HLA Antibody Production According to Gestational Periods in Pregnant Women.
      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,
      • O'Boyle PJ
      • Smith JD
      • Danskine AJ
      • Lyster HS
      • Burke MM
      • Banner NR.
      De novo HLA sensitization and antibody mediated rejection following pregnancy in a heart transplant recipient.
      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.
      • Costanzo MR
      • Costanzo MR
      • Dipchand A
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      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.
      Series (year)Punnoose et al. (2020)
      • Mehta LS
      • Warnes CA
      • Bradley E
      • et al.
      Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association.
      (includes TPRI data (2019)

      McGlothlin D, Granton J, Klepetko W, et al. ISHLT CONSENSUS STATEMENT: Peri-operative Management of Patients with Pulmonary Hypertension and Right Heart Failure Undergoing Surgery. The Journal of Heart and Lung Transplantation.

      )
      Macera et al. (2018)
      • Davis MB
      • Arendt K
      • Bello NA
      • et al.
      Team-Based Care of Women With Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 1/5.
      D'Souza et al. (2018)
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      Dagher et al.(2018)
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      Bhagra et al (2016)
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      Number of pregnancies (number of women)157 (91)17 (11)17 (16)18 (8)22 (17)
      Unplanned pregnancies, n (%)59 (46)Not reportedNot reported10 (56)18 (82)
      Mean time from transplant (years)7 ±65.67.3 ± 48.2 (2.6 – 24.6)8.2± 5.2
      Mean age at transplant (years)20 ± 8Not reportedNot reported16.0 (6.2-26.6)Not reported
      Mean age at pregnancy (years)27 ± 5.63328 ± 5.825.5 (17.6 – 33.3)25.3 ± 5.8
      LVEF (%) pre-pregnancyNot reportedAll with normal graft function but no LVEF reportedAll with normal graft function but LVEF not reported61 (55-65)All with normal graft function, no LVEF reported
      Maternal complications (as % of pregnancies)
      Hypertension, n (%)Before pregnancy: 65 (42)

      During pregnancy: 72 (46)
      Before pregnancy: 5 (45)

      During pregnancy: 1 (6)
      -Before pregnancy: 2 (25)

      During pregnancy: 5 (39)
      Before pregnancy: 5 (36)

      During pregnancy: 3 (14)
      Preeclampsia, n (%)27 (23)0 (0)2 (12)2 (15)13 (4)
      Diabetes mellitus, n (%)Before pregnancy: 7 (5)

      During pregnancy: 11 (7)
      0 (0)During pregnancy: 1 (6)Before pregnancy: 1 (13)

      During pregnancy: 2 (15)
      0 (0)
      Renal failure, n (%)Not reportedNot reported4 (24)Not reportedNot reported
      Infection, n (%)22 (14)0 (0)2 (12)3 (23)Not reported
      Graft loss (within 2 years of delivery/termination), n (%)2 (2)000 (0)0
      Rejection, n (%)14 (9)0 (0)2 (12)0 (0)1 (5)
      Maternal Death during Pregnancy, n (%)00 (0)0 (0)0 (0)1 (during immediate postpartum period from postpartum hemorrhage)
      Maternal death, n (%)30 (33)3 (27)2 (12)3 (38)4 (24)
      Mean time from pregnancy to maternal death (yrs)9.4 (0.5 – 26)11At 10 and 18 months after delivery (attributed to rejection from nonadherence with immunosuppression)3.9 (2.6-5.4)Not reported
      Obstetric and Fetal outcomes (as % of pregnancies except as noted)
      Live birth, n (%)111 (69)12 (71)14 (81)13 (72)20 (91)
      Mean gestational age at delivery (weeks)3636.5Not reported3534±4
      Fertility treatments used, n (%)Not reportedNot reportedNot reportedNot reported1 (5)
      Cesarean delivery, n (% of live births)45 (42)10 (83)8 (46)5 (39)11 (55)
      Miscarriage, n (%)41 (25)3 (18)1 (6)3 (17)2 (9)
      Ectopic pregnancies, n (%)2 (1)Not reportedNot reportedNot reportedNot reported
      Terminations, n (%)7 (4)2 (12)2 (12)2 (11)0 (0)
      Low birth weight (<2500g), n (%)41 (37)4 (36)Not reported6 (46)9 (45)
      Preterm (<37 weeks), n (%)45 (41)4 (36)6 (46)7 (54)9 (45)
      Congenital malformations, n (% of live births)9 (8)
      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
      Not reported2 (14%)
      Frontonasal dysplasia, bilateral radial ray anomalies with oligodactyly ⁎⁎⁎Only fetal cardiac malformations noted; perimembranous ventricular septal defect
      1 (8)0
      LVEF, left ventricular ejection fraction; TPRI, Transplant Pregnancy Registry International
      low asterisk 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
      low asterisklow asterisk Frontonasal dysplasia, bilateral radial ray anomalies with oligodactyly⁎⁎⁎Only fetal cardiac malformations noted; perimembranous ventricular septal defect

      Maternal outcomes

      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.
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      ,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      ,
      • Dagher O
      • Alami Laroussi N
      • Carrier M
      • et al.
      Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.
      ,
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      ,
      • D'Souza R
      • Soete E
      • Silversides CK
      • et al.
      Pregnancy Outcomes Following Cardiac Transplantation.
      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.
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      ,
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      However, rejection in HT recipients may also occur after delivery, noted in 7% of patients within 3 months after delivery.
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      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.
      • Rajapreyar IN
      • Sinkey RG
      • Joly JM
      • et al.
      Management of reproductive health after cardiac transplantation.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      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.
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      In a large series of HT recipients, mortality during pregnancy was low at 0.5%.
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      However, the longer-term survival of HT recipients after pregnancy warrants consideration. In one 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.
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      In other series, post-pregnancy mortality in HT recipients ranges from 10.8% over 3-7 years follow-up
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      to 33% with 8.7 years of follow-up.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      Notably, the mean age of the child at the time of maternal death was 10.8 years.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      This real-world data reinforces 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%
      • Daly TA
      • Coscia L
      • Nathan HM
      • Hasz RD
      • Constantinescu S
      • Moritz MJ.
      PREGNANCY OUTCOMES IN 36 LUNG TRANSPLANT RECIPIENTS.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      compared to 16% in non-transplant pregnancies.
      • Collier AY
      • Molina RL.
      Maternal Mortality in the United States: Updates on Trends, Causes, and Solutions.
      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 69-91%.
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      ,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      ,
      • Dagher O
      • Alami Laroussi N
      • Carrier M
      • et al.
      Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.
      ,
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      ,
      • D'Souza R
      • Soete E
      • Silversides CK
      • et al.
      Pregnancy Outcomes Following Cardiac Transplantation.
      Cesarean delivery occurs commonly in HT recipients, 39% to 83%.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Daly TA
      • Coscia L
      • Nathan HM
      • Hasz RD
      • Constantinescu S
      • Moritz MJ.
      PREGNANCY OUTCOMES IN 36 LUNG TRANSPLANT RECIPIENTS.
      ,
      • Kallapur A
      • Jang C
      • Yin O
      • Mei JY
      • Afshar Y.
      Pregnancy care in solid organ transplant recipients.
      Nonetheless, about half of infants in published series were delivered preterm, prior to 37 weeks’ gestation, and 35-40% were low birth weight (<2500g).
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      ,
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      ,
      • Dagher O
      • Alami Laroussi N
      • Carrier M
      • et al.
      Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.
      ,
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      ,
      • D'Souza R
      • Soete E
      • Silversides CK
      • et al.
      Pregnancy Outcomes Following Cardiac Transplantation.
      About 20% of infants born to HT recipients are admitted to neonatal intensive care units
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      and 6.5-9% have congenital anomalies.
      • Moritz MJ
      • Constantinescu S.
      • Coscia L.A.
      • et al.
      ,
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      Data are limited regarding detailed longer-term follow up of offspring of HT recipients.
      Consensus statements on Risk Assessment, Management, and Outcomes of Pregnancy after Heart Transplantation
      • Heart transplant recipients should wait at least 1 year post heart transplant before pursuing pregnancy and, prior to planned conception, have stable heart function (LVEF > 45% without significant allograft vasculopathy or donor-specific antibodies), no rejection in the past 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.
      • The pre-transplant diagnosis may have an impact of the risk for pregnancy: 1) those with PPCM have worse post-transplant outcomes compared to those without PPCM; 2) there is a risk of recurrence of congenital heart disease (CHD) in offspring of those with CHD; 3) heritable cardiomyopathies may be passed on to the fetus.
      • Clinical evaluation and echocardiography form the cornerstone of rejection surveillance; echocardiogram should be performed at least every trimester but ideally every 1-2 months until 24 weeks of gestation and then monthly until delivery. Noninvasive assessment of rejection with donor-derived cell-free DNA cannot be used as current assays cannot distinguish fetal from donor DNA.

      Management of Comorbid Conditions During Pregnancy

      While there are considerations regarding patient risk assessment, contraindications, and graft assessment and surveillance that are unique to HT versus LT recipients, the management of comorbidities including hypertension, diabetes, and infections is similar and discussed below.

      Diabetes

      Pregnancy can exacerbate pregestational diabetes and lead to gestational diabetes with significant impacts on both the fetus and pregnant individual.
      • Deputy NP
      • Kim SY
      • Conrey EJ
      • Bullard KM.
      Prevalence and Changes in Preexisting Diabetes and Gestational Diabetes Among Women Who Had a Live Birth - United States, 2012-2016.
      Pregestational diabetes, both type 1 and type 2, is associated with congenital anomalies and both pregestational and gestational diabetes are associated with fetal growth abnormalities, fetal growth restriction and macrosomia, and fetal demise if glycemic control is poor.
      • Kitzmiller JL
      • Wallerstein R
      • Correa A
      • Kwan S.
      Preconception care for women with diabetes and prevention of major congenital malformations.
      Infants of diabetic individuals are at increased risk of congenital heart disease, including isolated ventricular septal defects, transposition of the great arteries and aortic stenosis.
      • Øyen N
      • Diaz LJ
      • Leirgul E
      • et al.
      Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study.
      Pregestational diabetes is common in both LT and HT recipients. Over 20% of LT recipients have diabetes;

      Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Adult Lung and Heart–Lung Transplant Report—2014; Focus Theme: Retransplantation. The Journal of Heart and Lung Transplantation 2014;33:1009-24.

      and is even more common among those with CF.
      • Hackman KL
      • Snell GI
      • Bach LA.
      Prevalence and predictors of diabetes after lung transplantation: a prospective, longitudinal study.
      In HT recipients, 21% develop diabetes within 5 years of transplant.
      • Vest AR
      • Cherikh WS
      • Noreen SM
      • Stehlik J
      • Khush KK.
      New-onset Diabetes Mellitus After Adult Heart Transplantation and the Risk of Renal Dysfunction or Mortality.
      Gestational diabetes occurs in up to 16% of LT recipients
      • Acuna S
      • Zaffar N
      • Dong S
      • Ross H
      • D'Souza R
      Pregnancy outcomes in women with cardiothoracic transplants: A Systematic review and meta-analysis.
      and up to 11% of HT recipients have pregestational and gestational diabetes.
      • Macera F
      • Occhi L
      • Masciocco G
      • Varrenti M
      • Frigerio M.
      A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.
      ,
      • Punnoose LR
      • Coscia LA
      • Armenti DP
      • Constantinescu S
      • Moritz MJ.
      Pregnancy outcomes in heart transplant recipients.
      ,
      • Bhagra CJ
      • Bhagra SK
      • Donado A
      • et al.
      Pregnancy in cardiac transplant recipients.
      This is not surprising, as pregnancy is physiologically associated with insulin resistance, mediated by progesterone, cortisol, and prolactin. Furthermore, compensatory increases in insulin production may be impaired in transplant recipients, due to predisposing factors and diabetogenic effects of calcineurin inhibitors and steroids.
      • Ramlakhan KP
      • Johnson MR
      • Roos-Hesselink JW.
      Pregnancy and cardiovascular disease.
      Consistent with ACOG recommendations, screening for gestational DM should be performed at 24-28 weeks in pregnant LT and HT recipients, potentially earlier in those with an increased risk for diabetes.
      • Chamberlain JJ
      • Johnson EL
      • Leal S
      • Rhinehart AS
      • Shubrook JH
      • Peterson L.
      Cardiovascular Disease and Risk Management: Review of the American Diabetes Association Standards of Medical Care in Diabetes 2018.
      ,

      National Institute for Health and Care Excellence: Guidelines. Diabetes in pregnancy: management from preconception to the postnatal period. London: National Institute for Health and Care Excellence (NICE) Copyright © NICE 2020.; 2020.

      Treatment of DM during pregnancy should occur in consultation with a maternal-fetal-medicine specialist or an endocrinologist. ACOG recommends a pre-pregnancy HgbA1c level less than 6%, as at this level the fetal malformation rate is close to that of a normal pregnancy (2-3%).
      • Kallapur A
      • Jang C
      • Yin O
      • Mei JY
      • Afshar Y.
      Pregnancy care in solid organ transplant recipients.
      Non-pharmacological strategies for management of diabetes include daily exercise, diet, and self-monitoring of blood glucose. The cornerstones of pharmacological measures are insulin or metformin; other oral agents such as sulfonylureas, GLP-1 receptor agonists or SGLT-2 inhibitors are not recommended due to a lack of safety data. Optimal glycemic control is essential in early pregnancy to reduce the risk of miscarriage and other potential harm to the fetus. In fact, diabetic control improves both maternal and fetal outcomes, with reduced risk of maternal hypertensive disorders and fetal macrosomia with potential associated obstetric trauma such as shoulder dystocia.
      • Pillay J
      • Donovan L
      • Guitard S
      • et al.
      Screening for Gestational Diabetes: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

      Hypertension

      Hypertension is common in LT recipients, occurring in 51.5% of patients at 1 year and 54.6% of patients at 5 years post-transplant.

      Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Adult Lung and Heart–Lung Transplant Report—2014; Focus Theme: Retransplantation. The Journal of Heart and Lung Transplantation 2014;33:1009-24.

      In HT recipients, hypertension is even more common, with a prevalence of 72% at 1 year and 92% at 5 years after HT.