Pregnancy in Kidney Transplant Patients
1. What every clinician should know
Kidney transplantation for end-stage renal disease is now a common procedure worldwide. Many of these women are of reproductive age and become pregnant. They need expert obstetric management since these are high-risk pregnancies with a number of potential complications. Also, virtually all transplant patients have other underlying chronic medical diseases. There are no randomized controlled trials to guide physicians in managing pregnancy in renal allograft recipients. Experience has shown that data from observational studies and voluntary registries can be biased and tend toward more favorable outcomes than actually occur. Important components of care include
Pre-pregnancy assessment and counseling
Close antepartum and intrapartum monitoring
An appreciation for how to prevent and manage complications
It is important to understand and anticipate that previous hypertension, underlying chronic medical disorders and immunosuppressant therapy are factors that commonly predispose these women to infections and pregnancy problems such as preeclampsia, fetal growth restriction, preterm birth and cesarean delivery.
2. Diagnosis and differential diagnosis
Pre-pregnancy counseling for each kidney transplant patient and her spouse is highly desirable. The approach should be supportive but realistic, keeping in mind that 5-year graft survival rates are in the range of 70% and overall patient survival rates are approximately 85%. Transplant patients who are planning a pregnancy should be in good general health with no graft rejection episodes. The optimum time for pregnancy is usually between 2 and 5 years after transplantation when it is known that the patient’s allograft function and immunosuppressive medication doses are stable. The couple should be made aware of common pregnancy problems in transplant patients and the possibility and implications of delivering a premature infant. Because the long-term survival rate of transplant recipients is not 100%, not all will live to raise their children to adulthood. Therefore, a tactful but realistic discussion of ethical issues and family support is also warranted. It should include
The possibility of the mother’s limited life span
Care for children if her medical problems later worsen
Underlying medical disorders should be controlled before pregnancy. It may be necessary to recommend against pregnancy if the patient has severe or uncontrolled diseases such as diabetes mellitus, cardiovascular or pulmonary disease, recurrent infections, or major side effects from immunosuppressive drugs. The serum creatinine level is one of the most useful prognostic markers for the course of pregnancy. Patients with a creatinine level less than 1.5 mg/dL tend to do well, those between 1.5-2.0 mg/dL have a greater chance of pregnancy complications, and those above 2.0 often have a complicated course. Serum creatinine levels also have prognostic value regarding the risk of future graft deterioration.
It is important that patients who are taking mycophenolate mofetil (CellCept, Myfortic) are switched to a different immunosuppressive agent before pregnancy because of its teratogenic potential. Currently, azathioprine, cyclosporine and tacrolimus are the immunosuppressive drugs of choice during pregnancy. In fact, all allograft recipients of childbearing potential who are taking mycophenolate mofetil must receive contraceptive counseling and should use two reliable forms of contraception simultaneously. These women should be made aware that this drug reduces blood levels of the hormones in oral contraceptives and could theoretically reduce their effectiveness. They should continue contraceptive use for 6 weeks after stopping mycophenolate mofetil and before attempting pregnancy.
An accurate diagnosis of gestational age is important because of decisions that may need to be made about early delivery for pregnancy complications. A careful history to obtain an accurate last menstrual period and a baseline first trimester as well as serial ultrasound examinations are useful to confirm the estimated day of delivery and to detect fetal growth restriction.
In addition to routine prenatal laboratory tests (complete blood count, blood type, indirect Coombs, rubella, syphilis, cervical cytology, screening for gestational diabetes) that are indicated in all pregnant patients, baseline and serial tests to monitor renal function are indicated. These include a urine culture, serum creatinine and 24-hour urine collections for total protein and creatinine clearance.
Transplant patients should also be evaluated for a number of acquired viral infections common with suppression of the immune system and that present risks for both the mother and the fetus. These include cytomegalovirus (CMV), herpes genitalis (HSV), human papilloma (HPV), human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV). The transplanted graft is most commonly a source of CMV for 1-3 months postoperatively.
The primary risk of congenital infection in the fetus in most pregnant women is with a primary CMV infection, but recurrent CMV infection has also caused congenital CMV in immunosuppressed women. It is often difficult to clear condyloma accuminata, and obstetricians should be aware that the risk of cervical, vulvar and skin malignancies is increased in these immunosuppressed women.
It is prudent to see the pregnant kidney transplant patient more often than the normal pregnant patient in order to watch closely for infections, fetal growth restriction, preeclampsia and premature labor. Prenatal visits at least every 2 weeks until 36 weeks, then weekly until delivery allow the obstetrician to closely monitor the progress of pregnancy. Management of most antepartum obstetric complications is no different than with non-transplant patients, but the increased incidence of infection requires a careful and aggressive approach with avoidance of any unnecessary invasive procedures. Asymptomatic bacteriuria should be treated for 2 weeks and follow-up urine cultures obtained. Prophylactic antibiotics to prevent recurrent urinary tract infections may be needed for the rest of pregnancy. The obstetrician should also be prepared for other potentially serious infections associated with immunosuppression such as endometritis, wound and skin infections and pneumonia, often with unusual organisms such as Aspergillus, Pneumocystis, Mycobacterium tuberculosis and Listeria.
Immunosuppressive drugs during pregnancy
Although rejection of the renal allograft can occur during pregnancy, the risk is no greater than in the nonpregnant state. It is important for the obstetrician to be familiar with the immunosuppressive drugs the patient is taking and their potential side effects. The immunosuppressive drug doses are usually continued as they were before pregnancy, but blood concentrations should be assessed monthly in order to make dosage adjustments if needed.
Corticosteroids – These are usually continued after transplantation, and most patients are maintained on moderate doses such as prednisone 10-30mg/day. Familiar maternal side effects include glucose intolerance, hirsutism, acne, weight gain, cushingoid features, hypertension, impaired wound healing, osteoporosis and mood changes. Prednisone has been used for many years in patients with a number of diseases with no proven adverse effects in the fetus.
Azathioprine (Imuran) – The most experience in pregnancy over the years has been with this agent, and it is one of the safest despite a Category D classification. The primary maternal hazards are increased risk of infection and neoplasia. Maternal liver toxicity with jaundice and bone marrow depression has occurred but usually resolves when the dose is decreased. Most azathioprine that crosses the placenta is in an inactive form, and no patterns of congenital abnormalities in the infant have been observed.
Calineurin Inhibitors – cyclosporine ( Sandimmune, Neoral, Gengraf) and tacrolimus (Prograf) have been increasingly used because they have decreased rejection episodes and improved survival in transplant recipients. They are often standard components of current immunosuppressive therapy. Cyclosporine predisposes some patients to nephrotoxicity and hypertension; other problems include bone marrow depression, hirsutism, tremor, gingival hyperplasia, hepatotoxicity and a risk of neoplasia such as lymphomas. Tacrolimus side effects include a propensity toward diabetes mellitus, nephrotoxicity, hyperkalemia and a variety of neurotoxicities such as headache, tremor, change in motor function, mental status or sensory function. Neither of these agents is associated with fetal abnormalities.
Newer Agents – Much less is known about the newer immunosuppressants during pregnancy. Sirolimus (Rapamune), a macrolide antibiotic, has been linked to small-for-gestational-age infants and delayed bone ossification but has not been implicated in specific fetal malformations.
Mycophenolate mofetil (Cell Cept, Myfortic) is a newly available agent currently used in many non-pregnant transplant patients. It is very important for obstetricians to know about this immunosuppressant because of its teratogenic properties, and it should be discontinued before pregnancy. The FDA has labeled it a Category D drug. Its use during pregnancy is associated with an increased risk of spontaneous abortion (miscarriage) and congenital abnormalities. These malformations include bilateral microtia or anotia, sometimes accompanied by atresia of the external auditory canals, cleft lip and cleft palate, and other major structural malformations involving the eye, hands and fingers, cardiac, bowel and skeletal systems. Maternal adverse effects with this drug include progressive multifocal leukoencephalopathy, sometimes fatal, sepsis, neutropenia, pure red cell aplasia and GI symptoms including bleeding.
Preeclampsia, IUGR or other pregnancy complications may require that the infant be delivered preterm. Two doses of betamethasone 12mg 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 Induction of labor, and normal uterine contractions usually ensue with a normal progression of labor. The progress of labor is assessed in the usual manner, but excessive vaginal examinations, artificial rupture of membranes and internal FHR monitoring should be avoided to decrease the risk of infection. Although the transplanted kidney is located low in the pelvis in the iliac fossa, it almost never interferes with vaginal delivery. Acyclovir can be used safely and with all immunosuppressants for prophylaxis and to treat HSV during pregnancy.
A high cesarean rate has been common in reported series but the indications for cesarean have often been unclear. Vaginal delivery is safer for the mother. Cesarean should be reserved for bonified obstetric indications. Prophylactic antibiotics, consideration of replacement glucocorticoids, asepsis, and careful surgical technique are necessary with operative delivery. With cesarean, the obstetrician should be aware of the location of the pelvic kidney, implantation of the ureter into the bladder and possible adhesions from previous surgery to avoid inadvertent damage to these vital structures.
Hepatitis B immune globulin and HBV vaccine should be given to all of these infants to prevent chronic hepatitis. Most babies have had a relatively uncomplicated course other than complications associated with prematurity. Small amounts of immunosuppressive drugs can be found in breast milk, but the advantages of breast feeding are considered to outweigh any potential 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 Aggressive 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 and renal vessel anastomosis. These are serious complications best managed in a setting where the obstetrician has access to a team of transplant surgeons, nephrologists and other necessary subspecialists.
5. Prognosis and outcome
Most transplant patients ultimately have a successful pregnancy with delivery of a healthy infant. Pregnancy does not have a detrimental effect on the renal allograft or health of the mother. These infants usually grow and develop normally throughout childhood, but little is known about their long-term health since most are just now entering adulthood. Therefore, it is important that all offspring exposed in utero to immunosuppressants have long-term follow-up. Further studies on the safety of these drugs on the progeny are also warranted.
6. What is the evidence for specific management and treatment recommendations
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