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Anesthetic Considerations for the Parturient After Solid Organ Transplantation

Moaveni, Daria M. MD; Cohn, Jennifer H. MD; Hoctor, Katherine G. MD; Longman, Ryan E. MD; Ranasinghe, J. Sudharma MD

doi: 10.1213/ANE.0000000000001391
Obstetric Anesthesiology: Narrative Review Article
Continuing Medical Education

Over the past 40 years, the success of organ transplantation has increased such that female solid organ transplant recipients are able to conceive and carry pregnancies successfully to term. Anesthesiologists are faced with the challenge of providing anesthesia care to these high-risk obstetric patients in the peripartum period. Anesthetic considerations include the effects of the physiologic changes of pregnancy on the transplanted organ, graft function in the peripartum period, and the maternal side effects and drug interactions of immunosuppressive agents. These women are at an increased risk of comorbidities and obstetric complications. Anesthetic management should consider the important task of protecting graft function. Optimal care of a woman with a transplanted solid organ involves management by a multidisciplinary team. In this focused review article, we review the anesthetic management of pregnant patients with solid organ transplants of the kidney, liver, heart, or lung.

Published ahead of print June 9, 2016

From the Departments of *Clinical Anesthesiology and Obstetrics and Gynecology, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, Florida.

Accepted for publication March 30, 2016.

Published ahead of print June 9, 2016

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Daria M. Moaveni, MD, Jackson Memorial Hospital, 1611 NW 12th Ave, Central 301, Miami, FL 33136. Address e-mail to dmoaveni@med.miami.edu.

Table 1

Table 1

Since the first successful live birth to a woman with a kidney transplant in 1958,1 an increasing number of women are conceiving posttransplant. Kidney and liver are the most commonly transplanted organs in the United States. Patients with solid organ transplantation may voluntarily report their pregnancies on their own or in conjunction with their health care providers to the National Transplantation Pregnancy Registry (NTPR), which began collecting data from recipients in North America in 1991. A total of 1396 female transplant recipients (kidney, liver, liver–kidney, kidney–pancreas, heart, heart–lung, and lung) have reported 2463 pregnancies according to the 2014 annual report2 (Table 1). In 2005, the Women’s Health Committee of the American Society of Transplantation released a consensus document summarizing clinical practice recommendations for the management of pregnant transplant recipients; the consensus document has not been updated since 2005. This focused review will address concerns important to the obstetric anesthesia management of pregnant solid organ transplant recipients.

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TIMING OF PREGNANCY AFTER TRANSPLANTATION

Data are lacking regarding the optimal transplant–conception interval. The 2005 American Society of Transplantation Consensus Conference suggested that pregnancy 1 year after transplant is safe as long as the patient has stable graft function (Table 2)3–14: no episodes of rejection in the past year, a low risk for opportunistic infections, stable renal function (including in those receiving organs other than a kidney), and a low stable dose of maintenance immunosuppression.15 Meta-analyses show improved maternal and neonatal outcomes and a decreased incidence of obstetric complications for renal recipients and liver recipients when conception is delayed for at least 1 year.16,17 For renal transplant patients, the initial recommendation was to wait 2 years before conceiving on the basis of the rejection risk. More recent and potent immunosuppressive strategies, however, have significantly decreased rejection rates in the first posttransplant year. Therefore, the advice to wait 2 years after a successful transplant is considered more restrictive than necessary.15 The consensus group emphasized that data regarding one transplant group cannot be extrapolated to those receiving another organ.15

Table 2

Table 2

Patients with end-organ failure experience hypothalamic–pituitary–gonadal dysfunction and thus impaired fertility.15 Gonadal dysfunction resolves in about 6 months after renal transplantation.15 Restoration of menstruation and fertility in renal and liver transplant recipients has been reported in meta-analyses.16–18 For the heart, lung, and heart–lung recipients, limited data regarding hypothalamic–pituitary–gonadal function after transplant are available; however, any pubertal delay caused by previous organ failure likely resolves with a well-functioning graft.18 Normal clinical and hormonal onset of puberty has been reported in adolescents after heart transplant.19

To avoid an unanticipated pregnancy within the first year after a transplant, it is suggested that posttransplant contraception be discussed with the patient. The optimal method of contraception has not been determined but should consider the type of transplanted organ, hormonal levels of the contraceptive, potential interactions of the contraceptive with immunosuppressive medications, the underlying medical conditions of the patient, and costs.15,20 Intrauterine devices may be the best option per expert opinion because they are long-acting, are reversible, are effective, have negligible drug interactions, and are low risk.20 Pregnancies in women with a history of a solid organ transplant are considered high risk and should be managed by a multidisciplinary team that includes a maternal-fetal medicine expert.20,21

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IMMUNOSUPPRESSION

Immunosuppressive medications are necessary to preserve graft function and prevent graft rejection during pregnancy.22 Physiologic changes during pregnancy may impact their pharmacodynamic properties, thus making it difficult to maintain appropriate blood levels during pregnancy.23 The maternal-fetal distribution of immunosuppressive medications is complex and can be affected by maternal weight gain, hemodynamic alterations, and drug metabolism by enzyme systems that are differentially expressed in placental and fetal tissues. The limited data available, along with the lack of controlled studies, suggest that monitoring drug levels during pregnancy and in the puerperium still provides the best guide for maintaining adequate immunosuppression, as doses may need to be increased or decreased.21

Table 3

Table 3

Mainstay immunosuppressive medications include corticosteroids, calcineurin inhibitors (cyclosporine, tacrolimus), and antiproliferative agents (azathioprine, sirolimus, mycophenolate mofetil). Maternal and fetal effects of these medications and monitoring variables are summarized in Table 3.14,21,24–43 All immunosuppressive medications have fetal and neonatal risks; however, current data suggest that administration of these medications during the first trimester is not strongly associated with an increased risk of congenital anomalies,44 with the exceptions of sirolimus and mycophenolate mofetil.31,35,37–39 During the second and third trimesters, effects on the fetal immune system may result in premature delivery and low-birth-weight neonates.44–46 However, underlying maternal disease and concurrent use of other medications may confound the association.

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PERIOPERATIVE AND ANESTHETIC MANAGEMENT OF TRANSPLANT RECIPIENTS

Labor analgesia and anesthesia for cesarean delivery do not differ significantly for most transplant recipients with a functioning graft compared with nontransplanted patients. However, general considerations common to all solid organ transplant recipients who receive anesthetic care in the peripartum period are discussed in the sections to follow.

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Increased Incidence of Obstetric Complications

The incidence of preeclampsia is reported as high as 30% in transplant recipients28; thus, patients are monitored routinely for hypertension, nephropathy, and preeclampsia.15 The risk of prematurity and low birth weight,14 as well as the rate of cesarean delivery (50% after liver transplant),32 are increased in transplant recipients.28,47 Preterm labor occurs in approximately 36% (liver) and 54% (renal) of transplant recipients. Data for heart and lung recipients are not known but are estimated to be similar.35

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Comorbidities

Hypertension, diabetes, and hyperlipidemia may exist before transplantation and can persist and worsen posttransplant because of immunosuppressive medications.24,35,48,49 The incidence of comorbidities varies by the type of immunosuppression.2 The NTPR reports that the incidence of diabetes during pregnancy ranges from 5% to 9% in kidney recipients, 1% to 13% in liver recipients, and 5% to 7% in heart recipients.2 Lung transplant recipients demonstrate the greatest incidence of diabetes (27%).2 The incidence of hypertension during pregnancy is reported as 25% to 60% in kidney recipients, 17% to 35% in liver recipients, 42% to 47% in heart recipients, and 57% in lung transplant recipients.2 Control of blood glucose may become difficult because of administration of corticosteroid immunosuppression administration.

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Graft Function Assessment

Transplanted organs normally adapt well to the physiologic changes of pregnancy, and pregnancy itself does not increase the incidence of organ rejection.21 Therefore, for most recipients, the graft should be functioning well at the time of delivery. Progressive deterioration in organ function tests may indicate rejection. Graft function assessment is summarized in Table 2.3–14

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Management of Immunosuppression

During pregnancy, clinical and laboratory monitoring of the organ’s functional status and immunosuppressive drug levels are performed every 4 weeks until 32 weeks, then every 2 weeks until 36 weeks, and then weekly until delivery as recommended by the NTPR.50,51 Immunosuppressive drug levels are monitored closely for a minimum of 1 month postpartum, especially if dosage is increased during pregnancy.50 Biopsy may be performed if rejection is suspected.50

Current medications, their side effects, and potential drug interactions with peripartum and anesthetic drugs should be considered (Table 3).14,21,24–43 During the peripartum period, patients should continue their immunosuppressive medications on their regular schedule. An augmented corticosteroid dose has been suggested because of the stress of labor and to prevent postpartum rejection33; however, there are no established dosing recommendations.

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Presence of Infection

Transplant recipients are at an increased risk for viral, bacterial, fungal, and protozoan infections because of immunosuppression.14 They may not present with typical signs of infection (such as fever and leukocytosis); thus, a high index of suspicion is required for diagnosis. Prenatal surveillance for cytomegalovirus, toxoplasmosis, hepatitis B and C, human immunodeficiency virus, herpes simplex virus, syphilis, and rubella is indicated. Live vaccines are contraindicated in transplant recipients, and most patients will have been vaccinated for hepatitis B before transplantation.35,50

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Prevention of Infection

Because transplant patients are immunosuppressed and prone to infection and subsequent graft loss, meticulous aseptic technique is essential for all procedures.9 Currently, there are no specific recommendations on prophylactic antibiotics before surgical procedures for immunosuppressed patients.14

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Neuraxial Technique for Labor Analgesia and Cesarean Delivery

Platelet or coagulation factor defects may exist secondary to preeclampsia, liver dysfunction, kidney dysfunction, or effects of immunosuppressive agents (eg, azathioprine, biologic agents) and may preclude the use of neuraxial anesthetic techniques. There are no guidelines for assessing platelet levels and coagulation studies before neuraxial techniques for transplant recipients; however, patients who have been followed consistently during their pregnancies and have normal graft function most likely do not need additional laboratory assessment of their coagulation status before initiating neuraxial procedures.

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Monitors

Standard monitoring is adequate in most cases. Perioperative invasive monitoring, such as arterial or central venous pressure monitoring, should be considered after assessing the risk–benefit ratio in individual patients. The use of transthoracic echocardiography may provide the least invasive method to evaluate left ventricular filling volume for any patient, and transesophageal echocardiography is an option for patients receiving general anesthesia.

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Blood Transfusion Concerns

Red blood cell antibodies arising from transplanted organs and directed against recipient red blood cells is a complication of solid organ transplantation.52 The blood bank should be contacted early to avoid delays in cross-matching blood. To avoid leukocyte-related reactions such as graft-versus-host disease, leukocyte-poor irradiated blood products should be used.53 Modern leukocyte depletion filters remove 99.9% of leukocytes.53

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Postpartum Considerations

Thromboprophylaxis should be administered because of the high risk of thromboembolic complications in these patients, especially after cesarean delivery.14 The threshold for admission to an intensive care or high-dependency unit should be low.

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ORGAN-SPECIFIC CONSIDERATIONS

Kidney Transplant Recipients

The kidney is the most frequently transplanted organ and has shown the best long-term survival rate of all transplanted organs.a It is important to select drugs that do not rely on renal excretion (eg, cisatracurium) and to avoid potentially nephrotoxic drugs (eg, nonsteroidal anti-inflammatory medications). Adequate intravascular fluid volume should be maintained to prevent renal hypoperfusion.

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Liver Transplant Recipients

Recovery of drug metabolism capacity appears immediately after reperfusion of the liver graft14; however, renal dysfunction is common in liver transplant recipients and is an important pharmacologic consideration.14,54

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Heart, Lung, and Heart–Lung Transplant Recipients

Since the first successful delivery of a parturient with a heart transplant in 1986,55 the NTPR reports a number of successful pregnancies in heart, lung, and combined heart-lung transplant patients (Table 1).2

The transplanted heart usually tolerates the hemodynamic changes during labor and delivery well.10 Concerns related to the anesthetic management of heart transplant recipients include physiologic and pharmacologic alterations secondary to cardiac denervation. All stress responses are delayed because of denervation but eventually occur. Under stress, endogenously released catecholamines directly stimulate the heart and slowly increase heart rate over 5 to 6 minutes, thus increasing the cardiac output.11 Signs of reinnervation of transplanted hearts after some years have been shown in canine models56; however, an electron microscopic study56 demonstrated that normal myocardial innervation is not likely to be restored. Therefore, for practical purposes, the heart can be regarded as denervated permanently.16 Anesthetic implications and considerations for the transplanted heart are summarized in Table 4.10,11,14,28,53,56–61

Table 4

Table 4

Neuraxial techniques may be performed for labor analgesia and cesarean delivery anesthesia. Epidural and spinal local anesthetics used for labor analgesia do not significantly affect hemodynamic and respiratory function. In the operating room, however, sudden development of a high neuraxial block with anesthetic dosing may be detrimental to organ function. Because of denervation, a decrease in cardiac output secondary to the decreased preload associated with a sympathectomy will not be compensated quickly by an increase in heart rate. Modified combined spinal-epidural dosing (ie, sequential combined spinal-epidural anesthesia), in which a low dose of spinal bupivacaine is followed by incremental epidural dosing through the catheter, or administration of incremental doses of local anesthetics through an epidural or continuous spinal catheter, may mitigate the risk of sudden hemodynamic changes. If vasopressors are required, the use of directly acting drugs such as norepinephrine are expected to produce dose-dependent positive inotropic and chronotropic effects in these patients, whereas indirectly acting drugs, such as ephedrine, cause a blunted response on heart rate and arterial blood pressure.14 Phenylephrine will increase systemic vascular resistance, and the reflex decrease in heart rate will not occur. Invasive monitoring is not routinely indicated unless more extensive surgery, such as cesarean hysterectomy, is planned, complications such as uterine atony or increased blood loss are anticipated, or there is poor graft function.

Heart transplant recipients have a frequent incidence of thromboembolic complications and left atrial thrombus; hence, thromboprophylaxis is recommended, especially after cesarean delivery.53 The timing of initiation of pharmacologic thromboprophylaxis should consider the timing of the neuraxial procedure to minimize the risk of neuraxial hematoma.

Lung and heart–lung transplant recipients appear to adapt well to the physiologic changes in pulmonary function during pregnancy in the absence of rejection.10,62 Ventilation and perfusion of the transplanted lung are considered equivalent to that of the normal lung, and gas exchange is normalized within 8 weeks of transplantation.63 The effects of the surgery itself, however, have implications for anesthetic management. Long-term complications of the bronchial anastomosis include stenosis, granulation, and mechanical distortion of the main bronchus.64 Patients with tracheal anastomosis lose the cough reflex because of denervation of afferent sensation below the level of the tracheal anastomosis.65–67 They may not be able to clear secretions and are prone to silent aspiration. Bronchoconstriction is common secondary to bronchial hyperresponsiveness.14 The lymphatic drainage in the transplanted lung is disrupted, thus excessive fluids may lead to pulmonary edema.64,65 After double lung transplantation with the en bloc technique,65 signs of cardiac denervation have been reported in >50% of double lung transplant recipients, most likely caused by surgical interruption of sympathetic and parasympathetic pathways during dissection of the recipient’s trachea.68

Neuraxial techniques may be performed for labor analgesia and cesarean delivery anesthesia. In the operating room, a neuraxial technique avoids instrumentation of the airway and the subsequent risk of bronchoconstriction and disruption of the tracheal or bronchial suture line. The use of a modified combined spinal–epidural technique, epidural catheter, or continuous spinal catheter in the operating room avoids sudden hemodynamic changes for patients with heart-lung transplants and also avoids further blunting of the cough reflex for recipients with tracheal anastomoses. Crystalloid volume should be given to maintain adequate preload in patients with concomitant heart transplant, but administered judiciously to avoid pulmonary edema in the transplanted lungs.64,65 Invasive hemodynamic monitoring and/or transthoracic echocardiography may be used to assist the careful titration of fluids and vasopressors.65

When general anesthesia is required in lung transplant patients, endotracheal intubation should be performed carefully to avoid traumatizing the tracheal suture line, especially after an en block heart–double–lung transplant, in which the suture line is proximal to the carina. The suture line for single-lung transplants generally is distal to the carina.64 Bronchodilators may be required after intubation because of bronchial hyperreactivity.63–65

After delivery, sudden severe bronchospasm has been reported after administration of the uterotonic agent carboprost (15-methyl prostaglandin F).69 Although there are no case reports of its use in lung transplant recipients, the risk of bronchospasm should be considered before the decision to administer carboprost is made.

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CONCLUSIONS

Pregnant women with solid organ transplants experience physiologic changes of pregnancy, physiologic changes related to the transplanted graft, and side effects of immunosuppressive therapy. Fetal risks such as low birth weight, prematurity, and fetal malformations may influence timing and route of delivery. The decision on when and how to deliver the fetus should be made by a multidisciplinary team. Anesthesiologists must consider the optimal analgesic and anesthetic management for each individual patient with attention to preservation of transplanted solid organ function. Most women will not have contraindications to neuraxial techniques; strict aseptic technique is essential. Understanding the underlying transplanted organ physiology and side effects related to immunosuppressive medications is important to optimal care of these high-risk parturients.

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DISCLOSURES

Name: Daria M. Moaveni, MD.

Contribution: This author helped write portions of the manuscript.

Name: Jennifer H. Cohn, MD.

Contribution: This author helped write portions of the manuscript.

Name: Katherine G. Hoctor, MD.

Contribution: This author helped write portions of the manuscript.

Name: Ryan E. Longman, MD.

Contribution: This author helped write portions of the manuscript.

Name: J. Sudharma Ranasinghe, MD.

Contribution: This author helped write portions of the manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

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ACKNOWLEDGMENTS

The authors thank Maria Elkordy for her support during manuscript preparation.

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FOOTNOTES

a US Department of Health and Human Services Health Resources and Services Administration. United States Organ Transplantation OPTN & SRTR Annual Data Report 2012. United States Organ Transplantation. 2014. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/2012_SRTR_ADR.pdf. Accessed April 27, 2015.
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