|Year : 2014 | Volume
| Issue : 1 | Page : 4-11
Anesthetic considerations in parturients with liver transplant
Anil Agarwal1, Amit Jha1, Dalim Kumar Baidya2, Anjan Trikha2
1 Department of Liver Transplant Anaesthesia and Critical Care, Fortis Hospital, Noida, Uttar Pradesh, India
2 Department of Anaesthesia and Intensive Care, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||20-May-2014|
Department of Liver Transplant Anaesthesia and Critical Care, Fortis Hospital, Noida - 201 301, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Advances in the surgical technique, safer anesthetic agents, improved hemodynamic monitoring, better pre-operative optimization of cirrhotic patients and postoperative critical care facilities have led to drastic improvement in the outcomes following orthotopic liver transplantation (OLT). Reproductive dysfunction in patients with end-stage liver disease can be corrected within months of successful orthotopic liver transplantation. Consequently, there is a worldwide increase in the number of women of childbearing potential after orthotopic liver transplantation. Successful pregnancies are now increasingly being reported in these patients. These are high-risk pregnancies as increased medical and obstetric complications and adverse maternal and fetal effects of immunosuppressant medications are likely to be encountered in these patients following liver transplantation. Optimal antenatal and perioperative management in these parturients warrant a multidisciplinary approach and meticulous planning. There is little evidence available regarding anesthetic concerns in this high-risk pregnant population. This review is aimed at addressing important perioperative issues in parturients, who have undergone a successful liver transplantation.
Keywords: Anesthetic considerations, liver transplantation, pregnancy post-transplant
|How to cite this article:|
Agarwal A, Jha A, Baidya DK, Trikha A. Anesthetic considerations in parturients with liver transplant. J Obstet Anaesth Crit Care 2014;4:4-11
|How to cite this URL:|
Agarwal A, Jha A, Baidya DK, Trikha A. Anesthetic considerations in parturients with liver transplant. J Obstet Anaesth Crit Care [serial online] 2014 [cited 2020 Jan 25];4:4-11. Available from: http://www.joacc.com/text.asp?2014/4/1/4/132812
| Introduction|| |
Orthotopic liver transplant (OLT) has gradually evolved into a universally accepted treatment for end-stage liver disease (ESLD) over the last few decades. Improved outcomes following OLT (reported survival rates greater than 85% and 70% at one and five years post-transplant, respectively) have led to a concomitant increase in the number of women who are of childbearing age following transplantation. , Advanced liver disease leads to menstrual irregularities and infertility in nearly half the women of childbearing age.  Successful OLT can restore menstrual function and fertility within 3 to 10 months in majority of these female patients. ,, Analysis of available literature related to pregnancies in patients after liver transplantation revealed no mention of different pregnancy outcomes following either deceased-donor or live-related OLT. 
In 1978, the first successful pregnancy in a liver transplant recipient was reported.  In a recent meta-analysis (2012) of articles related to pregnancy outcomes post-OLT, 450 pregnancies were reported.  Pregnancy in post-OLT females is considered high risk owing to increased incidence of obstetric and medical complications, adverse effects of immunosuppression and sequels of liver failure, which failed to resolve after transplantation. , There are recommendations regarding antenatal management of parturients post-OLT, but there are only few reports regarding anesthetic concerns in this population. This review is aimed at addressing important perioperative concerns in parturients post-OLT.
Pregnancy in liver transplant recipients
Liver transplant recipients of childbearing age need appropriate contraception and pregnancy planning. The American Association for the Study of Liver Diseases (AASLD) and the American Society of Transplantation (AST) have recommended delaying conception for at least one year following OLT, so as to allow for stable graft function with reduced immunosuppressant drug requirements and optimal control of medical complications. 
Pregnancy does not appear to adversely affect graft function, if the function of the transplanted liver is stable prior to the pregnancy.
Maternal outcomes reported in pregnancy following OLT
The most frequent maternal complications in pregnancies reported post-OLT are hypertension (2-43%), pre-eclampsia (2-22%), hypercholesterolemia and gestational diabetes mellitus (GDM). ,,, The diagnosis of pre-eclampsia in a post-transplant patient is challenging due to frequent rise of blood pressure after 20 th week of gestation and elevated levels of uric acid due to calcineurin inhibitors. Other maternal complications include intrauterine infections, anemia of pregnancy and cholestasis.  Alterations in the liver enzymes (particularly alkaline phosphatase) without jaundice, is common (25% parturients) in these patients. Liver enzymes should be routinely monitored and liver ultrasonography or biopsy should be considered if this abnormality persists.
Significantly higher incidence (40-50%) of cesarean delivery has been noted among liver transplant recipients due to fetal distress or maternal indications like gestational hypertension or eclampsia. , Hemostatic abnormalities may enhance the risk of postpartum hemorrhage.
Fetal outcomes in pregnancies post-OLT
Though congenital abnormalities (4%) are uncommon, prematurity (rates ranging from 27-51%) and low birth weight (ranging from 17-57%) are the main complications.  A higher incidence of fetal distress (10.3-40%) has also been reported in pregnant females post-OLT.  There is an increased risk of congenital infections, including toxoplasmosis, viral hepatitis, cytomegalovirus and other autoimmune diseases. Immune suppression in these infants mostly normalizes by sixth month of life, with adequate immunoglobulin levels and lymphocyte counts.
Antepartum management considerations post-OLT
Pregnancy after OLT is classified as high-risk owing to the increased rate of maternal and fetal complications. Accordingly, such pregnancies should be closely monitored at a specialized center by a multidisciplinary team that includes a transplant hepatologist, transplant surgeon, obstetrician, neonatologist and anesthesiologist.
Hematinics and folic acid supplements should be started early in the pregnancy because of increased anemia reported in such parturients. Antenatal screening should include hypertension, urinary tract infections, presence of cytomegalovirus infection and toxoplasmosis, gestational diabetes and pre-eclampsia, along with serial assessments of fetal growth. The blood pressure of the parturient should be aggressively managed so as to improve the pregnancy outcome.  Oral methyl dopa and dihydropyridine calcium channel blockers are the drugs of choice, as angiotensin converting enzyme inhibitors and angiotensin receptor blockers, being teratogenic, are contraindicated in these patients. Treatment for gestational diabetes aims to keep strict glycemic control with special meal plans and scheduled physical activity. It may also include daily blood glucose testing and insulin injections.
Liver transplant recipients are always under various regimes of immunosuppressive drugs. The major classes of agents used are calcineurin inhibitors (CNIs), glucocorticoids and antimetabolites. These drugs can have many adverse effects in the parturient and the fetus as mentioned in [Table 1].  Calcineurin inhibitors and steroids are considered to be safe during pregnancy. Due to the increased blood volume, altered drug clearance and immunologic changes during pregnancy, graft function and immunosuppression dosing should be closely monitored. Allograft function and CNI serum levels need to be monitored every 4 weeks until 32 weeks of gestation, and then weekly until delivery. 
|Table 1: Immunosuppressant drugs which may be used in parturients following liver transplant |
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Preoperative assessment of the parturient post liver transplant
When a pregnant patient with a previous liver transplant presents for labor analgesia or cesarean section, a multidisciplinary, comprehensive pre-anesthetic evaluation is required. It should include the following:
- Assessment of the graft function,
- Assessment of common medical and obstetric complications after OLT,
- Persistent sequelae of ESLD (partial resolution/recurrence post OLT),
- Immunosuppression-related comorbidities,
- Presence of infection.
Assessment of graft function post OLT
Preoperative allograft liver function testing should include evaluation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), international normalized ratio (INR), bilirubin, alkaline phosphatase, serum albumin and platelet count. In a well-functioning graft, synthesis and clearance of coagulation factors normalize within the first week, whereas serum bilirubin and liver enzymes return to normal within two to three weeks.  Thrombocytopenia may persist in OLT recipients up to years after transplant due to increased platelet consumption and late resolution of splenomegaly.  Abnormal liver function tests (LFT) in a parturient post-OLT might be attributed to liver dysfunction unique to pregnancy, which include pre-eclampsia, HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, acute fatty liver of pregnancy, hyperemesis gravidarum and intrahepatic cholestasis of pregnancy.  However, abnormal LFT during pre-operative work-up in the females post-OLT may also be attributed to causes unrelated to pregnancy (as mentioned in [Table 2]) with significant implications.  The transplant hepatologist should be consulted regarding etiological work-up and appropriate management in such circumstances. 
|Table 2: Causes of abnormal LFT in parturients after orthotopic liver transplant |
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Medical complications post-OLT
Liver transplant recipients are at risk of certain metabolic complications in the years following transplant. These include hypertension (40-85%), diabetes mellitus (10-64%), obesity (24-64%), dyslipidemia (40-66%) and chronic kidney disease (30-80%).  In a long-term follow-up study in post-OLT recipients, allograft-related complications accounted for one-third of deaths whereas malignancy (22%), cardiovascular causes (11%), infection (9%) and renal dysfunction (6%) attributed for the mortality in the rest of the cases.  Other issues in long-term survivors post-OLT include osteoporosis, hyperuricemia and gout.  Preoperative preparation in post-OLT parturients should include assessment and optimization of these comorbidities. Renal insufficiency (pre-conception serum creatinine level >1.5 mg/dl) has been associated with adverse obstetric outcomes in these parturients.  Strict control of hypertension from the first trimester has been identified as a key target in improving outcomes in these pregnancies post-transplantation.  The risk-factors, management options and perioperative implications of these co-morbidities are summarized in [Table 3]. 
|Table 3: Medical complications post-OLT and relevant perioperative concerns |
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Persistent complications of ESLD post-OLT
Preoperative work-up in parturients post-OLT should also include evaluation of sequelae of ESLD, which did not resolve completely despite functioning allograft. Thrombocytopenia has been reported to persist up to years of post-OLT in many patients due to late resolution of splenomegaly despite improvement in portal blood flow.  This is relevant while considering neuraxial block for labor analgesia or operative delivery in these patients.
Hypoxemia due to hepatopulmonary syndrome might not be completely resolved in some patients post-OLT probably owing to persistent portosystemic shunts.  This is particularly relevant in pregnancy during first year after OLT or acute liver failure requiring postpartum transplantation and might warrant prolonged oxygen therapy. Respiratory changes during pregnancy, particularly reduced FRC, might also complicate the gas-exchange abnormalities in such patients.
Persistent pulmonary hypertension due to pre-existing portopulmonary hypertension or developing de novo after OLT has been reported in survivors post-transplant. , This could be explained by vascular remodeling of pulmonary vasculature, which fail to resolve post-OLT. Pregnant patients with unexplained dyspnea should be evaluated for pulmonary hypertension with echocardiography because it can have significant anesthetic implications and might contribute to increased peripartum morbidity.  Patients might need medical optimization with pulmonary vasodilators (epoprostenol, iloprost, sildenafil) and diuretics perioperatively.
Cirrhotic cardiomyopathy might persist in some patients post OLT. Diastolic dysfunction might take up to six to twelve months to resolve after transplant.  In a recent follow-up study in 970 liver transplant recipients, new-onset heart failure was observed in 98 patients. Pre-transplant diastolic dysfunction and prolonged QT interval (>450 ms) characteristic of cirrhotic cardiomyopathy were found to be significant predictors of cardiac dysfunction in this study.  Most of these patients had a comprehensive cardiac evaluation pre OLT. These records should be reviewed and usually further cardiac workup is not required unless there is clinical deterioration post OLT.
Assessment of issues related to immunosuppression drugs in pregnancy
Immunosuppressant drugs have many adverse effects and can lead to hypertension, hyperglycemia, renal dysfunction, bone-marrow suppression, increased risk of infection, adrenal insufficiency and significant interactions with other medications. The maternal and fetal effects are mentioned in [Table 1]. Thorough neurological examination is important in patients on CNIs as it contributes to tremors, seizures and paresthesia. Hypomagnesemia needs to be corrected pre-operatively because it potentiates the neurotoxicity of the CNIs. Documentation of any pre-existing paresthesia is essential if regional anesthesia is planned.
Exposure to surgery leading to increase in serum interleukin-6 levels can alter immunocompetence by inducing the release of glucocorticoids and catecholamines. Immunomodulation by anesthetic agents is a topic of ongoing research with contradictory results.  These issues are, therefore, more relevant to the post-OLT parturient receiving immunosuppressant medications. Communication with the transplant hepatologist is crucial before any planned surgical procedure in such patients for planning the perioperative immunosuppression regimen.
Presence of infection
Preoperative evaluation in parturients post OLT should also include screening for any active infection. There is an increased prevalence of UTI and CMV infection in these patients. Moreover, the immunosuppressed state may mask many manifestations of a systemic infection in these patients. Presence of infection is an independent risk factor for increased morbidity in these patients. Hence, vigilance is required to exclude any systemic infection before an elective surgical procedure and microbiological culture of sputum, blood and urine should be performed with a low index of suspicion of infection.
| Anesthetic management in parturients post-OLT|| |
Parturients post OLT are at risk of acquiring infections in the perioperative period owing to immunosuppression. Antibiotic prophylaxis should therefore be used appropriately according to the planned surgical procedure and need not be expanded to include atypical or opportunistic organisms.  Prophylaxis is however advisable even in clean surgical procedures for this high-risk patient population. There is currently no evidence to support significant deviation from the usual antibiotic policy for post-transplant patients compared to non-transplant parturients before cesarean section as there are no reports of different microbial etiology for surgical site infections in such patients.
Tacrolimus should be administered 4-7 hours before surgery because of reduced gastric emptying.  The dose of the immunosuppressive medications should not be altered perioperatively unless the drug has to be administered intravenously except for azathioprine, which has equivalent oral and intravenous (i.v.) doses.  The oral dose of prednisone and the i.v. methylprednisolone dose are equal. Supplementation of stress-dose steroid is debatable but need to be definitely considered in transplant recipients recently withdrawn from steroid therapy and those with refractory hypotension.  The drugs that affect cytochrome P-450 3A metabolism may alter the immunosuppressant drug levels and should be used with caution perioperatively because of increased risk of graft rejection or drug-toxicity. These include cimetidine, omeprazole, fluconazole, voriconazole, metoclopramide, diltiazem, nicardipine and verapamil, which increase serum levels of CNIs whereas carbamazepine and phenytoin are known to decrease these levels. 
Intraoperative monitoring in the parturients post OLT should be based on the current hemodynamic status, medical comorbidities (hypertension, coronary artery disease, diabetes, renal dysfunction), residual cardiopulmonary complications of ESLD (hepatopulmonary syndrome, pulmonary hypertension) and the planned surgical procedure. Strict asepsis should be paramount if invasive hemodynamic monitoring is planned. Such patients have a history of prolonged intensive care unit stay before and post-OLT requiring repeated central venous access. Hence, the possibility of thrombosis and stenosis of the central veins should be kept in mind in these patients and the ultrasound guidance is advisable. 
Availability of blood products
Abdominal surgery in patients post OLT is reported to be associated with increased risk of bleeding.  The same should hold good for cesarean section as well. There is also an increased incidence of anemia in pregnancy post liver transplantation. Hence, adequate amount of blood products should be arranged preoperatively. These patients might have a history of multiple transfusions and are at risk of acquiring antibodies. Therefore, cross-matched, leucocyte-poor and irradiated blood products are preferred in this immunosuppressed population.
Intraoperative concerns with denervated liver allograft
The transplanted liver allograft differs from the native liver in that it is denervated leading to significantly decreased catecholamine concentration in the graft, effect on hepatic microcirculation and its diminished response to stress.  Innervation of the native liver responds to hypovolemia or blood loss by redistribution of splanchnic blood volume to the central circulation and this compensatory mechanism is lost in patients post OLT. Moreover, the normal physiological mechanism that protects the liver blood flow is blunted in these patients and the liver allograft is more susceptible to hypoperfusion and hypovolemia.  These facts should be kept in mind perioperatively in parturients post OLT.
Choice of anesthesia technique
The choice of anesthesia is based on the preoperative assessment of the parturient including graft function, cardiopulmonary status, renal involvement and presence of obstetric complications (pregnancy induced hypertension, PIH; gestational diabetes mellitus, GDM).
Epidural analgesia for labor or spinal block for cesarean section can be considered if the coagulation profile and platelet count is within normal range. Thrombocytopenia due to immunosuppressive therapy or persistent splenomegaly post-OLT may increase the risk associated with spinal and epidural technique. Risk of epidural abscess may be increased in immunocompromised patient population, and hence strict antisepsis is critical during neuraxial block in these patients. Vigilant monitoring is important in the postoperative period as the diminished inflammatory response may mask the usual signs and symptoms of neuraxial infections in such patients.  Epidural analgesia for vaginal delivery has been successfully reported in a parturient post OLT.  Early removal of epidural catheter might be considered postoperatively in these patients. Combined spinal epidural anesthesia may be feasible in these parturients though there are no reports of its use in the limited evidence available regarding anesthetic management for operative delivery in these patients. Pre-loading before subarachnoid block and early vasopressor use to treat hypotension is advisable in these patients as the denervated liver allograft is more susceptible to hypovolemia. 
The anesthetic agents should be chosen based on allograft liver function, presence or absence of biliary stasis and renal impairment post-OLT. General anesthesia with rapid sequence induction might be required more frequently in these parturients because of increased incidence of fetal distress. Adequate anti-aspiration prophylaxis and preparation for difficult airway management should be considered in view of pregnancy and immunosuppressant medications. Succinylcholine should be used with caution in patients receiving CNIs or with post-OLT renal dysfunction due to risk of hyperkalemia. The choice of anesthetic agents should be based on preoperative liver and renal function tests. Drugs with significant biliary elimination should be used with caution in parturients with biliary stasis (e.g. due to stricture) post-OLT. Similarly, renal insufficiency is quite common in these patients and drugs with renal elimination should be preferably avoided. Anesthetic agents with organ-independent elimination, e.g. atracurium, cisatracurium, remifentanil etc. are preferred. Left lateral tilt of 15° should be maintained till the delivery of the baby to minimize the effect of aortocaval compression on uteroplacental blood flow. Maintenance of hepatic perfusion is also critical in post-OLT parturients to ensure stable graft function perioperatively. This is even more relevant because of a high incidence of pre-eclampsia in pregnancies post-OLT and doppler ultrasonography revealing decreased total liver blood flow and increased hepatic arterial resistance in pre-eclampsia. , Etomidate, propofol or fentanyl supplemented with non-depolarizing muscle relaxants can also be used for induction of anesthesia. Ketamine should be used with caution in patients receiving CNIs with known neurotoxicity as seizures have been reported following ketamine administration in a child post-OLT receiving cyclosporine.  Agents that do not compromise the splanchnic circulation, e.g. opioids, sevoflurane, desflurane, isoflurane can be used to maintain anesthesia. Neuromuscular function should be monitored especially in cyclosporine receiving patients with altered magnesium levels. Transplant patients receiving cyclosporine as immunosuppressive therapy may require smaller doses of non-depolarizing muscle relaxant as delayed neuromuscular recovery has been reported in these patients. , Use of disposable breathing circuits is preferred. Liver transplant recipients have a higher prevalence of risk factors for cardiovascular disease, hence, strict hemodynamic and glycemic control are imperative. Pulmonary hypertension may occur de novo or persist in patients with ESLD post liver transplantation and nitrous oxide should be preferably avoided in such parturients as it may increase pulmonary vascular resistance and potentiate hypoxemia. 
In the postpartum period, patient should continue to receive analgesics, antibiotic prophylaxis, immunosuppressive therapy, antihypertensive therapy and prophylaxis against venous thromboembolism in a high dependency or intensive care unit. Narcotics given through epidural catheter, inserted for labor analgesia or parenterally, can be continued postoperatively. Non-steroidal anti-inflammatory drugs should be avoided as they reduce renal blood flow via prostaglandin inhibition and exacerbate CNI toxicity. Paracetamol can be used for postoperative analgesia in these patients. Epidural catheter should be removed at the earliest to avoid infection. Immunosuppressant drugs should be resumed early postoperatively in consultation with the transplant hepatologist. Prophylaxis against postoperative nausea and vomiting should be considered in all parturients to facilitate early resumption of oral intake and minimize interruptions of immunosuppressant medications. Allograft function and drug levels should be checked weekly for at least one month after the delivery. Most of the immunosuppressant medications are excreted in breast milk as shown in [Table 1]. Tacrolimus and corticosteroids can be safely continued in the postoperative period in lactating females.  Although, the known benefits of breast feeding outweigh the probable risks, there are no definite recommendations regarding breast feeding in these patients.
Peripartum liver transplantation for acute liver failure (ALF)
Pregnancy-specific liver conditions, such as HELLP syndrome or acute fatty liver, may cause fulminant hepatic failure during the third trimester and urgent diagnosis and immediate delivery mostly leads to reversal of the underlying process and maternal and fetal survival. The King's College criteria for prognostication in ALF are not validated during pregnancy.  Increased lactate level and encephalopathy at the time of admission have recently been reported to be the best predictors of the need for LT in pregnancy-related ALF.  Uncontrolled hemorrhage despite surgical intervention and extensive hepatic necrosis have been identified as the indications for LT in HELLP syndrome.  Occasionally, a salvage double surgical approach emergency delivery and LT is required in such cases.  LT has also been reported in non-pregnancy related causes of ALF like viral infection, toxins, autoimmune, sickle cell disease and Budd-Chiari syndrome More Details). ,, OLT as a therapeutic option and corticosteroids to hasten fetal lung maturity should be considered based on the clinical condition and fetal viability.  In cases of previable gestation, one may consider OLT followed by supporting pregnancy till fetal viability is achieved while concurrent OLT and cesarean delivery has been suggested in those with postviable gestation.  Anesthetic management of liver transplantation with fetus in utero should emphasize on maintaining optimal maternal hemodynamics, uteroplacental flow, intraoperative positioning and fetal monitoring.
| Conclusion|| |
There is a large population of post-OLT surviving females of childbearing age that may present to the obstetric anesthesiologists, who are not otherwise involved in treating patients undergoing transplant surgery. Careful preoperative assessment, a multidisciplinary approach and meticulous planning are crucial for safe outcome in this high-risk pregnancy. It is important to encourage reporting these pregnancies to the national transplant registries to enhance our knowledge regarding post-OLT pregnancy outcomes, which might lead to further refinement in the perioperative management of these patients.
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[Table 1], [Table 2], [Table 3]