Pregnancy in solid organ transplant patients
1. What every clinician should know
Pregnancies are increasingly common in recipients of a variety of solid organ allografts. These include transplant patients who have received a heart, lung, liver or pancreas. It is not clear how many of each organ transplants have been performed or how many pregnancies have occurred worldwide. The pregnancy prognosis may be less favorable than the literature indicates and subject to bias because the observational studies have relatively small numbers of patients and the registries are voluntary. Each of these transplanted organs has its unique issues, but pregnancies tend to follow the same pattern as in women with kidney transplants. These patients are at high risk for pregnancy complications. Important components of this care include:
Pre-pregnancy assessment and counseling.
Close antepartum and intrapartum monitoring.
An appreciation for how to prevent and manage complications.
Coordination of team and necessary consultants.
As with kidney transplant patients, it is important to understand that previous hypertension, underlying chronic medical diseases and immunosuppressant therapy are factors that predispose these women to infections and to pregnancy problems such as preeclampsia, fetal growth restriction, preterm birth and cesarean delivery.
2. Diagnosis and differential diagnosis
Prepregnancy counseling for each organ allograft recipient and her spouse will lead to optimum obstetric care. It is best to take a supportive but realistic approach, keeping in mind that 5-year survival rates of the transplanted organs are in the range of 50-75%, and overall patient survival rates are approximately 50-80%. Transplant patients should be in reasonably good general health with no graft rejection episodes.
Pregnancy should not be attempted until the allograft function and immunosuppressive drug doses are stable, but a long waiting period leaves the woman with fewer childbearing years. Since not all transplant recipients will live to raise their children to adulthood, that should be part of the discussion. Ethical issues and family support to be discussed with both prospective parents should include:
Care for the child should maternal medical problems arise.
Long-term plans in view of a potentially limited life span.
Underlying medical disorders, including those responsible for the transplant, should be controlled before pregnancy. Severe or uncontrolled diseases such as diabetes mellitus, unstable cardiac or pulmonary disease, infections and significant side effects from anti-rejection medications may make pregnancy inadvisable. If the patient has not been vaccinated pre-transplant, she should receive influenza, pneumococcus, hepatitis B and tetanus immunizations.
Mycophenolate mofetil (CellCept, Myfortic) should be discontinued before pregnancy because it is associated with a characteristic constellation of fetal congenital abnormalities (aural aplasia, oral-facial clefts, syndactyly and other cardiac and skeletal malformations). The patient should be advised to switch to an immunosuppressive drug without teratogenic potential such as azathioprine, cyclosporine or tacrolimus.
While a patient is taking mycophenolate mofetil, she should use two reliable forms of contraception simultaneously. She should be informed that this immunosuppressant can lower blood levels of the oral contraceptive hormones and could theoretically reduce their effectiveness. Patients should also continue contraception for 6 weeks after discontinuing mycophenolate mofetil and before attempting pregnancy.
With all pregnant organ transplant patients, an accurate diagnosis of gestational age becomes important in obstetric management because of decisions that often become necessary regarding early delivery for pregnancy complications. This can be ascertained by a careful history to determine the last menstrual period, and a baseline first trimester sonogram. Serial ultrasound examinations are also indicated to confirm the estimated day of delivery and are also useful to detect fetal growth restriction.
Routine prenatal laboratory tests include complete blood count, blood type, indirect Coombs, rubella, syphilis, cervical cytology, and screening for gestational diabetes. A unique problem in immunosuppressed and transplant pregnant women is the propensity for a number of acquired viral infections. These patients should have laboratory tests to evaluate for cytomegalovirus (CMV), herpes genitalis (HSV), human papillomavirus (HPV), human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV), which all present risks for both the mother and fetus.
The transplanted graft and previous blood transfusions can be a source of CMV, and patients usually recieve CMV prophylaxis within the first three months postoperatively. The risk for congenital infection in the fetus is usually with primary CMV infection, but in immunosuppressed women recurrent maternal CMV infection has also resulted in congenital CMV in the infant. Because of chronic HPV, it is often difficult to clear condylomatous lesions in these patients. Since genital malignancies have occurred in young immunosuppressed women, obstetricians should be alert to that possibility. Regular examinations for cervical, vulvar and skin neoplasia are indicated.
All pregnant organ transplant patients need careful monitoring for infections, fetal growth restriction, preeclampsia and premature labor. This is best accomplished with prenatal visits at least every 2 weeks until the third trimester and then weekly until delivery. Management of most antepartum obstetric complications is the same as with the non-transplant patient; however, a more aggressive approach to any infection that arises is necessary. Potential infections include the urinary tract, wound, skin and endometritis. Even more serious is pneumonia, particularly with unusual organisms such as Aspergillus, pneumocystis, Mycobacterium tuberculosis and Listeria.
The heart, lung, liver and pancreas are vital organs, and rejection during pregnancy is ominous and could lead to maternal death. These patients require continuation of prepregnancy specialized tests specific for each organ and close cooperation with the team of physician managing the allograft:
Heart – right ventricular biopsies to monitor for rejection.
Lung – pulmonary function tests, blood gases, imaging.
Liver – serum bilirubin and aminotransferase assays.
Pancreas – an early HbA1C and glucose tolerance testing (GTT) performed prior to 20 weeks gestation. If the GTT screen is normal, it should be repeated at 24-28 weeks as with any pregnant patient.
The primary indications for heart transplantation are coronary artery disease associated heart failure and non-coronary cardiomyopathy. Almost two-thirds of younger female patients without other serious conditions will survive the next 10 years and are likely to have an excellent quality of life.
Blood volume increases during pregnancy, and the transplanted heart must adapt to those physiologic changes. Central venous pressure and preload increases to produce and increased stroke volume. The transplanted heart may also increase heart rate and contractility to increase cardiac output, particularly during exercise. Arrhythmias can occur, and the heart may not respond as predictably to some vasopressor medications because it is denervated.
The cardiac allograft may be more sensitive to beta-adrenergic agonists. Tricuspid regurgitation, which occurs in some patients soon after transplantation, can worsen with the increased blood volume of pregnancy. Maternal graft rejection episodes may occur in up to 20-30% of pregnancies, often with few clinical signs but diagnosed by surveillance biopsies.
Pregnancy presents more risks after lung transplantation than other solid organ transplants, but successful outcomes are still possible. Many receive lung transplants for cystic fibrosis, and recipients tend to have shorter survival and graft survival than recipients of other solid organs. Pulmonary innervation, the bronchial arterial supply and pulmonary lymphatics are lost during transplantation. This interferes with the cough reflex and leads to difficulty protecting the airway, decreased lung compliance and persistent alveolar-arterial oxygen gradient. These patients tend to be more sensitive to volume shifts and need to be monitored for the possibility of pulmonary edema or cardiac dysfunction with pregnancy.
Survival rates and pregnancy outcomes continue to improve in these patients because of improvements in surgical techniques and immunosuppressive regimens. The majority of pregnant liver transplant recipients have been taking cyclosporine and prednisone with or without azathioprine, but tacrolimus has been increasingly used. Anemia affects up to 30% of these pregnancies and may be severe enough to necessitate transfusion.
HCV is of particular concern since this is one of the most common indications for liver transplantation. Clinical signs of rejection are fever, right upper quadrant pain, leukocytosis and elevated serum bilirubin and aminotransferase levels. Since these findings are nonspecific, suspected graft rejection usually requires biopsy confirmation. Most rejection episodes can be managed satisfactorily by adjusting the immunosuppressive drug regimen.
Whole or segmental cadaveric pancreas transplantation is often combined with kidney transplantation as a treatment for patients with severe juvenile-onset insulin dependent (type 1) diabetes mellitus. Patients with pancreatic cancer are not eligible because of the poor prognosis with this malignancy. The 10 year probability of insulin independence with a successful graft is about 90% if the graft is still functioning at 5 years.
The diabetogenic effects of pregnancy, corticosteroids and some of the immunosuppressive drugs can all lead to or aggravate maternal hypoglycemia and fetal macrosomia. Euglycemia throughout pregnancy is the goal, and if hyperglycemia is present, diet and insulin therapy should be instituted. Most pancreas transplant patients are able to maintain euglycemia throughout pregnancy and labor, but unique complications in these patients include osteoporosis, diabetic neuropathy, chronic vascular insufficiency, stillbirth, neonatal hypocalcemia and hypoglycemia.
Labor and delivery
Although solid organ allograft rejection is rare during pregnancy, it can occur. Also, all anti-rejection drugs cross the placenta to some degree. It is important for the obstetrician to be familiar with these drugs and their side effects, which have implications for both mother and fetus. Usually the non-pregnant dose is continued, but blood concentrations should be assessed monthly during pregnancy to determine whether dosages need adjustment.
Corticosteroids – Prednisone is the most commonly used corticosteroid in transplant patients. It is not teratogenic but does increase the risk for gestational diabetes. These women are usually maintained on moderate doses such as prednisone 10-30 mg/day. Most obstetricians are familiar with the common side effects, which include glucose intolerance, hirsutism, acne, weight gain, cushinoid features, hypertension, impaired wound healing, osteoporosis and mood changes.
Azathioprine (Imuran) – This immunosuppressant has been used extensively in transplant patients with no evidence of teratogenicity in the human.
Cyclosporine (Sandimmune, Neoral, SangCyA) is not teratogenic, but it is associated with small for gestational age infants.
Calcineurin Inhibitors – Sirolimus, (Rapamune) and tacrolimus (Prograf) are newer agents with limited data on safety during pregnancy.
Mycophenolate mofetil (CellCept, Myfortic) is another newer agent that warrants special attention. It is currently a widely used immunosuppressant, but it needs to be discontinued before pregnancy because of its serious teratogenic effects. The FDA has labeled it a Category D drug because of reports of an increased incidence of spontaneous abortion (miscarriage) and congenital abnormalities.
These malformations include bilateral microtia or anotia, sometimes accompanied by atresia of the external auditory canals, oropharyngeal clefts, and other structural abnormalities of the eyes, limbs, and cardiac, bowel and skeletal systems. Reported maternal side effects are progressive multifocal leukoencephalopathy, sepsis, neutropenia, pure red cell aplasia and GI symptoms, including bleeding.
An anesthesiology consultation before labor is useful since these patients can have an increased sensitivity to hypovolemia and catecholamines. Pregnancy complications are similar to those in kidney transplant patients and require close monitoring for preeclampsia, fetal growth restriction and preterm delivery. Two doses of betamethasone 12 mg 24 hours apart should be given to any patient delivering before 34 weeks of gestation to lessen the chance of respiratory distress syndrome (RDS). Chronic hypertension and preeclampsia are the most common complications, but the management is the same as it is with nontransplant patients.
There is no contraindication to the induction of labor, and contractions and progress are the same as in normal non-transplant patients. Progress is assessed in the usual manner, but excessive vaginal examinations, artificial rupture of membranes and internal FHR monitoring should be avoided to minimize the chance of infection. If herpes simplex lesions are present, acyclovir can be safely used to treat the infection.
A high cesarean rate for these patients is reported in the literature, but the indications for cesarean have not always been clear. Vaginal delivery is safer for the immunosuppressed mother and should be the goal, reserving cesarean for accepted obstetric indications. Standard preoperative prophylactic antibiotics, consideration of replacement glucocorticoids, maintaining asepsis and careful surgical technique are important components of optimum care with operative delivery.
Hepatitis B immune globulin and HBV vaccine should be given to all of these infants to prevent chronic hepatitis. Most babies have a relatively uncomplicated neonatal course other than the complications associated with prematurity. Small amounts of immunosuppressive drugs can be found in breast milk, but the advantages of breast feeding are generally accepted as outweighing any risks.
Chronic hypertension and preeclampsia are the most common maternal complications, and prematurity is the greatest risk for the infant. Severe preeclampsia, fetal growth restriction, non-reassuring fetal status or other pregnancy complications may require that the infant be delivered preterm. Meticulous evaluation and management is warranted should signs of graft rejection, sepsis, worsening of hypertension, onset of preeclampsia or deterioration of fetal status occur.
A number of rare and unusual emergencies have been reported that include allograft rejection, overwhelming sepsis, eclampsia, stroke, and rupture of the uterus. These are serious complications that are best managed in a setting where the obstetrician has access to a team that includes the transplant surgeon(s) and other subspecialists with special expertise regarding that specific allografted organ,
5. Prognosis and outcome
Most transplanted patients ultimately have a successful pregnancy with delivery of a healthy infant. The pregnancy itself has not resulted in any recognized long-term adverse effect on the allograft or health of the mother. These infants usually have the same growth and developmental potential as offspring from non-transplant patients, but little is known about their health later in life and most are just now entering adolescence and adulthood. They should have long-term follow up to confirm the safety of in utero exposure to the immunosuppressive drugs and that there are no later detrimental effects or unintended consequences.
6. What is the evidence for specific management and treatment recommendations
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