Heart transplantation in adults: Pregnancy after transplantation

INTRODUCTION — Experience with pregnancy after cardiac transplantation has grown since the first report in 1988 [1,2]. The number of women of childbearing age who have received heart transplants has risen due partly to some overall increase in heart transplantation in adults and to survival of pediatric heart transplant recipients to childbearing age. Pregnancy after cardiac transplantation is associated with risks to the prospective mother and fetus and with concerns regarding maternal longevity [2-7].

The maternal and fetal risks associated with pregnancy after cardiac transplantation and recommendations for management of these patients during pregnancy will be reviewed here. The indications and complications of cardiac transplantation are discussed separately. (See "Heart transplantation in adults: Indications and contraindications" and "Heart transplantation in adults: Diagnosis of allograft rejection".)

PRECONCEPTION CARE

Preconception counseling — Family planning and pregnancy including individualized maternal and fetal risks [8], alternatives, and timing should be discussed with all women of childbearing age undergoing cardiac transplantation as many transplant recipients are fertile. As recommended by the American Society of Transplantation (AST) consensus conference on reproductive issues, preconception counseling should be introduced during the pretransplant evaluation (or earlier) and should be followed up throughout the post-transplant process [9]. Transplant recipients need to know what to expect in terms of their own outcome and that for their potential children [10].

The reason for the mother's cardiac transplant should be investigated and discussed in terms of risk of recurrence of the underlying cardiac disease in mother or offspring. As an example, women who have received cardiac allografts because of severe peripartum cardiomyopathy are theoretically at risk for recurrent problems in future pregnancies (see "Peripartum cardiomyopathy: Etiology, clinical manifestations, and diagnosis"). Another example is the risk of cardiac defects (concordant or discordant with the mother) in offspring of women with congenital or familial/genetic types of heart disease (eg, 20 to 50 percent of idiopathic dilated cardiomyopathy cases may be familial). (See "Genetics of dilated cardiomyopathy" and "Pregnancy in women with congenital heart disease: General principles", section on 'Inheritance'.)

Timing of pregnancy — Most experts recommend that cardiac transplant recipients avoid pregnancy during the first year post-transplantation when the risk of rejection is greatest and immunosuppressive therapy most aggressive [8]. (See "Heart transplantation in adults: Prognosis".)

Contraception (including during the first year post-transplant) is important as fertility is not affected by immunosuppressive medications. Long-acting highly effective reversible options for contraception include the etonogestrel implant, copper intrauterine device (IUD), and levonorgestrel-releasing IUD [11]. Nulliparity and immunosuppression are not contraindications to IUD use and the IUD is not associated with an increased risk of pelvic infection, except in the first 20 days after insertion. (See "Contraception: Etonogestrel implant" and "Intrauterine contraception: Candidates and device selection" and "Intrauterine contraception: Insertion and removal", section on 'Sexually transmitted infections'.)

Estrogen-progestin contraceptives are another effective option, but should be avoided in patients with contraindications to estrogen therapy (eg, increased risk of venous or arterial thrombosis, uncontrolled hypertension). Immunosuppressant drug blood levels should be monitored carefully when starting estrogen-progestin contraception due to inhibition of the cytochrome P450 3A4 pathway [8]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

Baseline assessment — A baseline assessment should be performed prior to planned conception, including [8]:

●Renal function tests (eg, serum creatinine, creatinine clearance, and protein excretion)

●Evaluation of cardiac function including electrocardiogram and echocardiogram (and coronary angiography if not performed within the previous six months)

●Right-heart catheterization and endomyocardial biopsy to look for evidence of rejection

●Liver function tests

The AST consensus conference recommended the following criteria (not specific for cardiac transplantation) for timing of pregnancy [9]:

●No rejection in the past year

●Adequate and stable graft function

●No acute infections that might impact the fetus

●Maintenance immunosuppression at stable dosing

As noted in the International Society of Heart and Lung Transplantation (ISHLT) guidelines, pregnancy should be discouraged if graft dysfunction and significant cardiac allograft vasculopathy are expected to preclude a successful outcome [8]. A multidisciplinary care team with members from maternal-fetal medicine, neonatology, genetics, psychology, transplant cardiology, pharmacy, anesthesiology, specialty nursing, and social services should be available for counseling and care of the woman, as needed, throughout pregnancy and the postpartum period [8].

Medications should be reviewed for teratogenic risk prior to conception, and risks and benefits of each drug should be considered. (See 'Maternal medications' below.)

Vaccination — Patients should ideally be vaccinated pretransplant against influenza, pneumococcus, hepatitis B, and tetanus [9]. If not, the patient should be vaccinated before pregnancy. (See "Immunizations during pregnancy".)

MATERNAL PHYSIOLOGY AND MONITORING

Physiologic changes — Many physiologic adaptive changes occur during early pregnancy, which serve to promote fetal growth and development (see "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes"). However, several of these changes may lead to clinical problems in the cardiac transplant recipient [4]. As an example, pregnancy-associated sodium retention may increase edema and thus exacerbate edema associated with prednisone use. The physiologic changes associated with pregnancy and the attendant concerns in the pregnant heart transplant recipient are listed in the table (table 1).

In addition, the normal resting sinus rate of the denervated heart is usually greater than 80 bpm and may exceed 100 bpm in hearts transplanted from young donors. The heart rate is higher than in normals because of the loss of vagal neural input, which has a negative chronotropic effect. There may be partial reinnervation of cardiac sympathetic nerves following cardiac transplantation, but sinus tachycardia is common. (See "Heart transplantation in adults: Arrhythmias".)

Maternal monitoring — Monitoring of the pregnant heart transplant recipient should include frequent testing of blood pressure, urine cultures, and surveillance for preeclampsia, gestational diabetes, and rejection [8]. Blood levels of calcineurin inhibitor (cyclosporine or tacrolimus) should be closely monitored since wide fluctuations are expected with pregnancy-related changes in distribution and clearance of these drugs (table 1) [8].

MATERNAL RISKS IN PREGNANCY — Significant potential concerns for the pregnant cardiac transplant recipient are rejection, infection, hypertension, and preeclampsia [3,6,7,12-14]. Limited data are available on the incidence of each of these problems.

Rejection — The incidence of acute rejection is not increased in pregnant transplant recipients. Rejection during pregnancy was reported in 11 percent of 103 pregnancies in 57 heart recipients in the 2010 National Transplantation Pregnancy Registry (NTPR) [2] (see "Heart transplantation in adults: Diagnosis of allograft rejection" and "Heart transplantation in adults: Treatment of rejection"). The process of chronic rejection of the allograft is also not affected by pregnancy-related changes in the maternal immune system; thus immunosuppressive agents must be continued and adjusted to maintain prepregnancy drug levels. (See "Immunology of the maternal-fetal interface".)

Hyperemesis gravidarum may lead to decreased absorption and inadequate immunosuppression [9]. Its incidence is not increased in these patients, but it can be a serious complication due to its effects on drug levels. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation".)

Infection — Infections from bacterial, viral, and fungal organisms are common in immunosuppressed individuals (see "Infection in the solid organ transplant recipient"). Infection was reported in 13 percent of pregnancies in the 2010 NTPR report [2]. The obstetrician should be vigilant in assessing for community acquired infection (eg, pneumonia, urinary tract infection) and preventing infections related to pregnancy complications (eg, preterm premature rupture of membranes) and obstetrical procedures (eg, cesarean section).

Cardiac transplant recipients who were initially seronegative for cytomegalovirus (CMV), but received a graft from a CMV-positive donor, are at high risk for CMV disease, similar to the observations with other organ transplants. Seropositive recipients are also at risk for both reactivation of latent virus and superinfection with a new viral strain (see "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients"). The risk is highest in the first six months after transplant. The possibility and perinatal consequences of maternal CMV viremia should be considered in these women and they should be counseled of the potential risk. (See "Cytomegalovirus infection in pregnancy" and "Infection in the solid organ transplant recipient" and "Congenital cytomegalovirus infection: Clinical features and diagnosis".)

Abnormal liver function — Abnormal liver function tests during pregnancy are common in transplant recipients. The cause can be difficult to identify and may be multifactorial, including drug toxicity, cholestasis, and/or preeclampsia.

Hypertension and preeclampsia — Hypertension and preeclampsia are major factors responsible for the increased prevalence of preterm delivery and fetal growth restriction in transplant recipients (see "Preeclampsia: Clinical features and diagnosis"). As an example, one review of 25 completed pregnancies in heart transplant recipients reported 18 cases of hypertension/preeclampsia, 10 preterm deliveries, and five small for gestational age infants [15]. Hypertension during pregnancy was reported in 39 percent of pregnancies and preeclampsia was reported in 18 percent in the 2010 NTPR report [2].

The 2005 American Society of Transplantation (AST) consensus opinion stated that blood pressure should be maintained close to normal [9], although it was noted that this target differs from higher blood pressure goals of current guidelines for pregnant women with chronic hypertension without end organ damage (see "Treatment of hypertension in pregnant and postpartum patients"). The treatment of hypertension is not affected by pregnancy, with the exception of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which should be avoided because of teratogenic effects, and aldosterone antagonists, which are also avoided during pregnancy. There is neither data nor clinical experience to support the safety of aldosterone antagonists during pregnancy. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Treatment of hypertension in pregnant and postpartum patients".)

Measures to reduce the risk of preeclampsia are discussed separately. (See "Preeclampsia: Prevention".)

FETAL RISKS — Potential fetal risks among cardiac transplant recipients include premature delivery and low birth weight, although the total number of fetuses studied is too low for definitive conclusions. The incidence of spontaneous abortion among heart transplant recipients (rates of 6 percent [16] and 17 percent [17]) appears to be similar compared with that in nontransplanted populations. High rates of preterm delivery <37 weeks (eg, 38 percent in 2010) and low birth weight (2500 g) (eg, 39 percent in 2010) have been observed [2]. Any infant born preterm or small for gestational age is at risk of long-term complications, such as neurodevelopmental abnormalities. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality" and "Infants with fetal (intrauterine) growth restriction".)

Radiation — Fluoroscopically guided maternal right ventricular biopsies to monitor for rejection expose the fetus to radiation, so alternative approaches such as echocardiographically guided biopsies or fluoroscopy with leaded patient draping may be employed [8,9].

Maternal medications — Glucocorticoids (eg, prednisone and methylprednisolone), calcineurin inhibitors (cyclosporine and tacrolimus), and azathioprine are generally continued in pregnant cardiac transplant recipients since the potential benefits generally outweigh the potential risks. Evidence on effects of these agents on pregnancy outcomes are discussed separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

There are little data on the safety of the mTOR inhibitors sirolimus or everolimus during pregnancy, so their use should generally be avoided.

Of note, mycophenolate mofetil (MMF) poses a high risk of teratogenicity [8,18,19]. The United States Food and Drug Administration has issued a boxed warning concerning the risk of first trimester fetal loss and congenital malformations [20]. Azathioprine is commonly substituted for MMF prior to conception, since azathioprine likely entails lesser risk (see "Safety of rheumatic disease medication use during pregnancy and lactation"). The 2010 International Society for Heart and Lung Transplantation (ISHLT) guidelines note that use of azathioprine as a substitute for MMF during pregnancy is somewhat controversial and avoidance of these drugs during pregnancy should be decided by weighing maternal and fetal risks [8].

It should be emphatically stated that the benefits of immunosuppressive therapy in transplant recipients generally outweigh the slightly increased risk of adverse pregnancy outcome and most women taking these drugs will have normal, healthy babies [7]. Transplant recipients are generally maintained at the lowest effective dose of their maintenance immunosuppressive regimen of glucocorticoids, azathioprine, and cyclosporine or tacrolimus.

INTRAPARTUM RISKS AND MANAGEMENT — An intrapartum care plan should be established in conjunction with the multidisciplinary team caring for the pregnant transplant recipient. Questions regarding induction of labor, mode of delivery, analgesia/anesthesia, antibiotic prophylaxis, cardiovascular monitoring, and timing of delivery are best individualized to the woman's clinical circumstances.

Mode of delivery — Vaginal delivery induced at or near term helps to insure that the necessary clinical resources and personnel are available. Cesarean delivery should be reserved for the usual obstetrical indications [7,9]. However, in one review, the cesarean delivery rate among cardiac transplantation patients was higher than in a control group (33 versus 23 percent), despite this recommendation [13]. (See "Acquired heart disease and pregnancy", section on 'Management of labor and delivery'.)

Antibiotic prophylaxis — The 2014 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) valve guidelines and the 2007 AHA infective endocarditis guidelines recommend antibiotic prophylaxis to prevent endocarditis for patients at highest risk, including cardiac transplant recipients with valve regurgitation due to a structurally abnormal valve [21]. The AHA does not consider an uncomplicated vaginal or cesarean delivery an indication for antibiotic prophylaxis [3,9]. However, some experts favor antibiotic prophylaxis for delivery in patients with high risk lesions, since there is no assurance that a given delivery will be uncomplicated and potential risk factors for bacteremia during delivery have not been identified. Fortunately, high risk lesions are rare in the heart transplant recipient, so such prophylaxis is rarely necessary. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Anesthesia — Intramuscular or intravenous opiates are used to relieve pain and apprehension. Lumbar epidural anesthesia is effective in controlling labor pain and is recommended because it lowers pain-induced elevations of sympathetic activity. Epidural anesthesia has been used successfully in cardiac transplant recipients for both vaginal and cesarean delivery [5,22].

Stress dose steroids — Women who received greater than 20 mg of prednisone per day for more than three weeks in the six months prior to surgery should be assumed to have suppression of hypothalamic-pituitary-adrenal function (see "Pharmacologic use of glucocorticoids", section on 'HPA axis suppression'). These individuals should receive peripartum stress glucocorticoid coverage.

One approach is to provide high doses of glucocorticoids starting at the time of active labor. A continuous infusion of 10 mg of hydrocortisone per hour, or the equivalent amount of dexamethasone or prednisolone, eliminates the possibility of glucocorticoid deficiency. The glucocorticoid dose can be halved the day after delivery and the maintenance dose usually can be resumed on the second postpartum day. An alternative regimen is described in the table (table 2).

Maternal monitoring — The pregnant mother should have continuous electrocardiographic monitoring during delivery to evaluate for arrhythmias and serial electrocardiograms to evaluate for ischemia, in addition to routine assessment of vital signs (see "Ventricular arrhythmias during pregnancy" and "Supraventricular arrhythmias during pregnancy" and "Heart transplantation in adults: Arrhythmias"). Coronary vasculopathy is common in the transplanted heart, while the clinical signs and symptoms of ischemia are greatly attenuated owing to denervation of the allograft. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors" and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

Invasive cardiovascular monitoring is not routinely required. The risks of these devices outweigh the potential benefit in most clinical scenarios. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)

POSTPARTUM RISKS AND MANAGEMENT — Cardiac transplant recipients should be carefully monitored postpartum. The risks of maternal compromise increase substantially immediately postpartum. Cardiac output increases to 80 percent above prelabor values due to significant autotransfusion associated with uterine involution. (See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)

Drug toxicity is more likely postpartum. Careful attention to immunosuppressive drug levels, cyclosporine and tacrolimus in particular, is warranted as maternal intravascular volume and glomerular hyperfiltration return to normal.

Serial electrocardiograms, echocardiograms, and isoenzymes are helpful during this high risk period [23]. Cardiac biopsy is indicated if acute rejection is suspected.

Breastfeeding is generally discouraged because of passage of immunosuppressive drugs, particularly cyclosporine and tacrolimus, to the baby [8]. Continuing immunosuppressive therapy is vital for the mother and should be carefully maintained [7]. The American Society of Transplantation (AST) consensus opinion was that breastfeeding need not be viewed as absolutely contraindicated [9]. The International Society for Heart and Lung Transplantation (ISHLT) guidelines note that it is uncertain whether the risks of infant drug exposure outweigh the benefits and they do not recommend that heart transplant recipients breastfeed [8]. A discussion with the baby's pediatrician regarding the risks versus benefits of breastfeeding, taking into account individual circumstances, is worthwhile. Psychologic support is also important because postpartum depression can be exaggerated by chronic steroid use.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of cardiovascular diseases during pregnancy".)

SUMMARY AND RECOMMENDATIONS

●Family planning and pregnancy including risks, alternatives, and timing should be discussed with all women of childbearing age undergoing cardiac transplantation as many transplant recipients are fertile. (See 'Preconception counseling' above.)

●Mycophenolate mofetil (MMF) poses a high risk of teratogenicity. Azathioprine is commonly substituted for MMF prior to conception since azathioprine likely entails lesser risk. (See 'Maternal medications' above.)

●There are increased risks of infection, premature delivery, low fetal birth weight, hypertension, and preeclampsia associated with pregnancy in cardiac transplant recipients. (See 'Maternal risks in pregnancy' above and 'Fetal risks' above.)

●The pregnant cardiac transplant recipient should be cared for by a multidisciplinary team throughout pregnancy and the postpartum period. (See 'Timing of pregnancy' above.)

●Cardiac transplant recipients should be carefully monitored postpartum since autotransfusion associated with uterine involution may provoke decompensation. (See 'Postpartum risks and management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael R Foley, MD, who contributed to an earlier version of this topic review.