Pregnancy After Transplantation

Advances in surgical techniques and immunosuppressive therapy have helped to increase the numbers of women who undergo allogeneic organ transplantation each year. Many times, a transplanted organ normalizes a woman’s hormonal imbalance and restores fertility, thus offering the prospect of pregnancy and providing many women with end-stage organ disease a chance to conceive and bear children. ^[1]

Several issues should be discussed with female potential transplant recipients and their partners, preferably prior to transplantation. Such issues include preconception counseling (eg, fertility issues, vaccinations, contraceptive options) and the timing of pregnancy.

Types of organ transplantations in women

The following are types of organ transplants women receive, in descending order of frequency:

• Kidney
• Liver
• Heart
• Lung
• Kidney/pancreas
• Pancreas
• Intestine
• Heart/lung

Types of organ transplants reported among female transplant recipients who subsequently conceived include the following, in descending orderof frequency ^{[2, 3, 4]} :

• Kidney
• Liver
• Kidney/pancreas
• Heart
• Lung
• Liver/kidney
• Heart/lung

Factors that affect pregnancy outcomes

Factors that are associated with favorable pregnancy outcomes include the following:

• Good general health for about 2 years after transplantation
• No graft rejection in the last year
• Adequate and stable graft function
• No acute infections that might affect the fetus
• Maintenance immunosuppression at stable doses
• Patient compliance with treatment and follow-up
• Normal blood pressure or blood pressure that is well controlled with one medication
• Normal allograft ultrasonography results ^{[5, 6]}

Comorbid factors that may worsen pregnancy outcomes include the following:

• Etiology of the original disease that necessitated transplantation (ie, risk of recurrence)
• Chronic allograft dysfunction
• Renal insufficiency
• Cardiopulmonary diseases
• Hypertension
• Diabetes mellitus
• Obesity
• Maternal infection with hepatitis B (HBV) or C (HCV) or cytomegalovirus (CMV)

Pregnancy outcomes among liver transplant recipients

Although reports show a good success rate of pregnancy in liver transplant recipients, these pregnancies carry high risk to the patient, fetus, and allograft and need to be closely monitored in specialized centers by an integrated team that includes a transplant hepatologist, a transplant surgeon, an obstetrician experienced in high-risk pregnancies, and a perinatologist or neonatologist. ^[7]

Although planned pregnancy after liver transplantation is relatively common, acute liver failure during pregnancy is very uncommon, and acute liver failure requiring liver transplantation during early stages of pregnancy is rare. ^[8] When abnormal liver function in a pregnant woman acts as a harbinger for acute liver failure, transplant hepatologists try to manage their care until the women are postpartum and, in some cases, might even induce birth as early as the 30th week before performing an orthotopic liver transplantation. ^[8]

Complications in fertile, antepartum, and postpartum orthotopic liver transplant recipients include the following:

• Maternal: Pregnancy-induced hypertension ^[9] ; intrauterine infections, anemia, preeclampsia, cholestasis, pyelonephritis ^{[9, 8]}

• Obstetric and delivery: Congenital CMV infection (highest in pregnancies occurring < 6 months after transplantation) ^[10] ; perinatal infection with HBV (≤80%) or HCV (7%) ^[9]

• Fetal: Prematurity (40% of live births) ^{[9, 7]} ; intrauterine growth restriction (approximately 20%), prenatal infections, birth defects; immune suppression

Owing to a low rate of successful fetal delivery in case reports of antepartum liver transplantation, many hepatologists may be hesitant to select orthotopic liver transplantation as the treatment of choice in pregnant women with end-stage liver disease.

Medical and obstetric management of pregnant transplant recipients

Medical management of pregnant transplant recipients includes the following:

• Patient self-monitoring of daily blood pressure
• Aggressive management of hypertension: The drug of choice is methyldopa ^[5] ; second-line agents include clonidine and calcium channel alpha blockers ^[5] ; contraindicated drugs include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) ^[10]
• Close monitoring of graft function; if rejection is suspected, consider biopsy ^[3]
• In cases of acute rejection, steroids are the preferred drugs

Obstetric management of pregnant transplant recipients includes the following:

• Frequent evaluations, preferably every 2 weeks ^[5]
• Vaginal delivery (preferred): Usually delayed until labor onset unless maternal/fetal indications for induction exist ^[3] ; cesarean delivery is only indicated for obstetric reasons (in such cases, avoid injury to the allograft by knowing its exact location) ^[5]
• Antibiotic prophylaxis for all surgical procedures ^[2]
• Increased steroid dose at labor onset to overcome the stress of labor and prevent postpartum transplant rejection ^[10]

Immunosuppression in pregnant transplant recipients

Immunosuppressive agents used to treat pregnant transplant recipients include the following:

• Corticosteroids: For induction, acute rejection, and maintenance immunosuppression
• Cyclosporine (cyclosporin A): To prolong the survival of liver transplants ^[11]
• Azathioprine: Mainly for maintenance immunosuppression ^[12]
• Mycophenolate mofetil: For maintenance immunosuppression and for treating chronic rejection ^[12]
• Tacrolimus: For immunosuppression in solid organ transplant recipients
• Sirolimus: For immunosuppression in solid organ transplant recipients ^[12]
• Anti-CD3 (OKT3): (Rare) To treat acute rejection in pregnant transplant recipients

The safety of these immunosuppressive agents for use in pregnancy has not been established, except for azathioprine and mycophenolate mofetil—both are unsafe in pregnancy. Clinicians are strongly encouraged to report all cases of pregnancy to the National Transplantation Pregnancy Registry (NTPR) in order to provide more updated information on the safety of newer immunosuppressive drugs and their adverse effects on mothers and fetuses.

As a result of the recent advances in surgical techniques and immunosuppressive therapy, the number of women who undergo allogeneic organ transplantation increases each year. Table 1 shows the numbers of female transplant recipients in the United States from 1988 through 2020. ^[13]

Table 1. Female Transplant Recipients in the United States, by Organ* (Open Table in a new window)

In many cases, a transplanted organ normalizes the hormonal imbalance and restores fertility and, thus, offers the prospect of pregnancy. This has provided many patients with end-stage organ disease a chance to conceive and bear children.

The reported number of pregnancies in transplant recipients has grown over the last several years, though even large transplantation centers have limited experience with this type of pregnancy. Information about pregnancies in transplant recipients is obtained from case reports, retrospective single center studies, and voluntary registries. The 3 registries that provide such information are the National Transplantation Pregnancy Registry (USA), the European Dialysis and Transplant Association Registry, and the United Kingdom Transplant Registry. ^[14] All 3 registries show similar trends in miscarriages, stillbirths, ectopic pregnancies, preterm births, low birth weight infants, and neonatal deaths.

The National Transplantation Pregnancy Registry (NTPR) was established in 1991. Since then, the NTPR has studied and analyzed thousands of cases. Interestingly, guidelines proposed in 1976 for counseling patients still remain applicable. Although these guidelines were proposed for kidney transplant recipients, they have been extrapolated to other organ recipients as well. ^[2] For example, recipients should be in good health, with stable graft function, rejection-free, and with optimal control of comorbidities such as hypertension and diabetes mellitus. Although the optimum time for conceiving remains unclear, it is generally accepted that waiting until 1 year posttransplant is reasonable, provided the recipient remains in good health.

Table 2 shows the number of female transplant recipients who conceived, as voluntarily reported to the NTPR between 1991 and January 2005. ^[3]

Table 2. Number of female transplant recipients who subsequently conceived* (Open Table in a new window)

Data from the NTPR show a 70% success rate of pregnancies in solid organ transplant recipients. ^[3] Most of these pregnancies had good outcomes for the mother, child, and graft. Although this success is encouraging, these pregnancies are still considered high-risk, and they are believed to carry an increased morbidity and risk of mortality to both the mother and the fetus. Therefore, conception should be discussed thoroughly and planned. The selection of patients who are likely to have a low risk of complications from pregnancy remains of paramount importance. In addition, each type of organ transplant has its own particular medical management issues and risks of complications during pregnancy and, thus, should be studied separately. ^[15]

Kidney transplant recipients

Most patients with advanced renal failure have impaired reproductive function, mainly related to dysfunction in the hypothalamo-pituitary-gonadal axis. ^{[16, 5]} Sexuality and fertility are usually restored in these women 1-12 months after renal transplantation. ^[17] This offers a chance for many patients with end-stage renal disease (ESRD) to have children. ^[18] Reports show that pregnancy is common after kidney transplantation and occurs in 5-12% of women who undergo kidney transplantation and are of childbearing age; ^{[19, 20]} 50% of these pregnancies are unintended. ^[20]

According to the Organ Procurement and Transplantation Network (OPTN) database, 194,907 female patients received kidney transplants in the United States from 1988 through 2020; the kidney is the organ most often transplanted. ^[13] The first reported successful pregnancy in a kidney transplant recipient occurred in 1958. ^[21] Since then, thousands of pregnancies in kidney transplant recipients have been reported worldwide, with a success rate of 60-80%. ^{[18, 3, 6]}

Despite the large number of reported pregnancies in this patient group, the high rate of complications indicates that such pregnancies should still be considered high risk and need to be monitored closely by a medical team that consists of a transplant nephrologist surgeon, obstetrician, urologist, and pediatrician. ^[16]

The mother, fetus, and allograft are at risk of complications from the pregnancy. Maternal risks include infection, ectopic pregnancy, gestational diabetes, and increased likelihood of cesarean delivery. In addition, hypertension and preeclampsia are common; these conditions affect 27-38% of patients. ^{[20, 6, 18]}  Although preeclampsia commonly complicates pregnancies after renal transplantation, it is not associated with long-term renal dysfunction or graft loss. ^[22]

The newly and rapidly developing fetus is affected to a greater degree than the mother. This results in prematurity in up to 50% of newborns, intrauterine growth retardation in 20% of cases, low birth weight, immune deficiency, and perinatal infections, especially with hepatitis B virus (HBV) and cytomegalovirus (CMV). The incidence of congenital anomalies is reported to be similar to that in the general population, though few data exist with regard to the effect of the newer drugs. ^{[20, 6, 5]}

Studies have shown that pregnancy does not appear to cause excessive or irreversible problems in the graft, if the function of the transplanted organ is stable prior to pregnancy. ^{[3, 6]}  A meta-analysis of 38 studies with 2453 patients found no effect on long-term graft survival and only a possible effect on graft function within 2 years postpartum. ^[23]  Pregnancy is known to increase glomerular filtration rates, which, in theory, could lead to hyperfiltration and glomerulosclerosis. However, this hyperfiltration is related to increased plasma flow with normal intraglomerular pressure; thus, no glomerular damage occurs. ^{[20, 6]}  

Studies have shown a better success rate and fewer complications if conception occurred more than 24 months after the transplantation took place. ^[20]  However, a meta-analysis of pregnancy outcomes in 6712 pregnancies in 4174 kidney transplant recipients from 87 global studies reported the most favorable fetal outcomes in pregnancies less than 24 months after transplantation. ^[24]   

Pregnancies that occur 5 or more years after transplantation may result in persistent impairment of postpartum renal function. This decrease in renal function seems to be related to poor tolerance to the stress of pregnancy by a kidney weakened by chronic rejection. ^[25]  

Other factors that favor a good outcome of pregnancy include the following ^{[20, 6]} :

• Serum creatinine level less than 1.5 mg/dL
• No recent episodes of acute rejection
• Blood pressure within the reference range
• Proteinuria level less than 500 mg/d
• Maintenance level of immunosuppression
• Normal appearance of allograft ultrasonography

Levidiotis et al reported 40 years of pregnancy and maternal outcomes among kidney transplant recipients using data from the Australian and New Zealand Dialysis Transplant Registry. ^[26] This study analyzed 444 live births from 577 pregnancies. The investigators reported that 97% of pregnancies occurred after the first year of transplantation, that the mean age of pregnancy was 29+/- 5 years, and that the mean age of pregnancy during the last decade increased significantly to 32 years (P< 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined. Pre-eclampsia and gestational diabetes occurred in 27% and 1%, respectively. Overall, the data confirmed that a live birth in a woman with a functioning renal allograft did not adversely affect graft or patient survival.

Pregnancy outcome in kidney transplant recipients does not appear to be affected by the mother's age at transplantation. In another study using data from the Australian and New Zealand Dialysis Transplant Registry, Wyld et al found no difference in the rate of live births, gestational age, or small for gestational age neonates in 101 pregnancies in 66 mothers who received a kidney transplant during childhood compared with 626 pregnancies in 401 mothers who received a transplant as an adult. ^[27]

Liver transplant recipients

Orthotopic liver transplantation (OLT), one of the treatment choices for patients with end-stage liver disease (ESLD), has been considered a life-saving event for men and women; however, women of reproductive age might encounter some difficulties depending on where they are in the childbearing process: preconception, antepartum, or postpartum.

According to data from OPTN, 67,767 women received liver transplants in the United States from 1988-2020. ^[13] Historically, 40% of all female recipients have been women of reproductive age (18-49 y); this subset of the patient population has fallen since 2005 and made up 24.9% of all female recipients in 2018 but rose to 34.5% in 2020. ^[13] This trend may be explained by advances in transplant medicine and surgery that are allowing for OLT to be performed under increasingly challenging circumstances, such as older recipients with increased comorbidity undergoing transplantation with high MELD (Model for End-Stage Liver Disease) scores and suboptimal donor organs; or, on the other hand, pediatric infant and toddler candidates with cholestatic disease.

Advanced liver disease causes menstrual dysfunction and infertility in women of reproductive age; more than half of such patients experience amenorrhea. ^[9] Successful OLT helps restore the menstrual function and childbearing potential in 97% of cases. ^[9] Although the primary indication for liver transplantation in the United States is hepatitis C, autoimmune hepatitis is the most common reason for women of childbearing age to undergo liver transplantation. ^[7] Studies have shown that menstrual function is restored in more than 85% of these patients at a median of 1 month after liver transplantation. ^{[28, 29]}

The first successful pregnancy in a liver transplant recipient was reported in 1978. Since then, the reported number of such pregnancies has grown dramatically. There are approximately 15,000 female recipients of reproductive age currently living in the United States and an additional 500 women who will undergo OLT annually. ^[9] Improved transplantation techniques, better immunosuppressive agents, and intensive monitoring after the operation have helped many of these patients restore hormonal balance and even have children.

Pancreas and kidney/pancreas transplant recipients

Patients with diabetes mellitus type I may qualify for allogeneic pancreas transplantation. However, concomitant renal failure is a common problem in patients with brittle diabetes that makes them candidates for combined kidney/pancreas transplantation. Successful pancreas transplantation results in an insulin-independent normoglycemic state in recipients with diabetes who are insulin-dependent. Data show that insulin independence is achieved in more than 80% of simultaneous kidney and pancreas transplant recipients, in more than 70% of pancreas after kidney transplant recipients, and in more than 60% of nonuremic pancreas alone transplant recipients. ^{[30, 31, 32, 12]}

According to data from OPTN, 4350 female patients received pancreas transplants and 9,985 female patients received kidney/pancreas transplants in the United States from 1988 through 2020. ^[13] As of 2004, 38 kidney/pancreas recipients had been reported to conceive; some of them had multiple pregnancies, raising the number of pregnancies reported to the NTPR to 56. ^[3] aq

Studies have shown that the rates of prematurity and low birth weight are 78% and 63%, respectively. Fifty-seven percent of the infants were delivered by cesarean delivery. Hypertension, infections, and preeclampsia were frequent among recipients, with reported rates of 75%, 55%, and 34%, respectively. ^[3]

Lung and heart/lung transplant recipients

The first successful heart transplantation was performed in 1967; the first combined heart-lung transplant was performed in 1981. The first reported successful lung transplantation was performed in 1983. Since then, many cases have been performed worldwide (see Table 1).

Even though 16,000 heart, lung, and heart/lung transplantations have been performed, pregnancy is still rare among thoracic organ transplant recipients. The most recent data from NTPR report pregnancy in 50 female transplant recipients, including 33 heart transplantations, 3 heart-lung transplantations, and 14 lung transplantations. These 72 pregnancies resulted in 48 live births (see Table 2). ^[3]

Heart transplant recipients

Studies of pregnancy in recipients of heart transplants have reported that 69% of such pregnancies resulted in live births, although 32% of newborns were premature and had low birth weight. Nine percent of the pregnancies were terminated by therapeutic abortion; 17% were terminated by spontaneous abortion. The most common reported maternal complications were hypertension (occurring in 46% of women), acute allograft rejection (21%), infection (11%), preeclampsia (10%), and gestational diabetes (4%). Graft function was reported to be adequate in 72% of recipients. Newborn complications were observed in 22% of cases, with no neonatal deaths reported. Maintenance immunosuppression was achieved in most patients with a combination of cyclosporine, azathioprine, and prednisone, and, in a few patients, with tacrolimus alone. ^[3]

Out of the 37 children born to recipients of heart transplants reported to the NTPR, 34 children are developing well and are healthy, and 3 children inherited heart problems transmitted via maternal mitochondrial DNA. Post–heart transplantation pregnancies may have successful outcomes, but they also have high rates of perinatal mortality, prematurity, and low birth weight. For patients with heart transplantation secondary to inheritable disorders such as mitochondrial myopathy, preconception genetic counseling is mandatory, as such a condition may be transmitted to the fetus. ^[33]

Lung transplant recipients

The worldwide experience with pregnancy after lung transplantation is limited, but, when compared to other recipients of solid organs, female recipients of lung transplants are at high risk for acute allograft rejection, low birth weight in the infant, and complications of pregnancy. ^[3] The long-term graft and patient outcomes of 50% 5 year mortality need to be carefully explained to patient and family members while counseling the patient on the impact of pregnancy on survival and the ability to participate in child raising. ^[34] For example, although the physiological changes of pregnancy are well tolerated by these patients, the risk of graft rejection (independent of pregnancy) is higher and entails management by a multidisciplinary team.

Out of the 14 pregnancies in recipients of lung transplant reported to the NTPR, 53% ended with live births, but 63% of the newborns were premature with low birth weight. Therapeutic abortions and spontaneous abortion terminated 33% and 13% of the pregnancies, respectively. ^[3] Maternal complications included hypertension (in 53% of the women), acute rejection (27%), infection (20%), and preeclampsia (13%). ^[3] Gestational diabetes affected 27% of pregnant female lung transplant recipients. Graft loss within 2 years of delivery was reported in 21% of lung transplant recipients. In addition, 5 cases of recipient death were reported to the NTPR. Whether preconception factors can help predict which recipients are at risk for adverse outcomes is still unclear and requires further study. ^[3] Three recipients of combined heart-lung transplants reported 3 successful pregnancies to NTPR. ^[3]

Intestine transplant recipients

To date, eight pregnancies with 100% successful live births have been reported worldwide in intestinal/multivisceral transplant recipients. Important factors to be considered in these cases are the absorptive function of the transplanted bowel and higher need for immunosuppressants. ^[35]  In addition it has been reported that abdominal scarring restricted accurate fetal growth measurements as only narrow ultrasound windows were available for imaging. ^[36]

Several issues should be discussed with female potential transplant recipients and their partners, including preconception counseling, the timing of pregnancy, factors associated with positive outcomes, and factors that may worsen the outcome of a pregnancy.

Preconception counseling

Fertility issues should be discussed with the patient and her partner, preferably prior to transplantation.

The patient should be vaccinated for hepatitis B virus, Streptococcus pneumoniae, tetanus, and influenza. The patient should be vaccinated before transplantation, if possible. If that timing is not feasible, the patient should be vaccinated before pregnancy. Women who are not immune to rubella should receive the rubella vaccine before transplantation, because live-virus vaccines are contraindicated post transplantation. There are both risks to the patient and her partner and the risks of pregnancy to the mother, fetus (ie, prematurity), and graft.

Women with solid organ transplantation may be offered a variety of contraceptive options. The more recent studies have shown that they are safe among women in immunocompetent and immunocompromised states. Intrauterine devices and subdermal implants have been shown to have great efficacy as well as low systemic drug absorption, allowing clinicians to provide a vast range of options to women in their child bearing age.

Factors associated with favorable pregnancy outcomes

Factors that are associated with favorable pregnancy outcomes include the following:

• Good general health for about 2 years after transplantation
• No graft rejection in the last year
• Adequate and stable graft function
• No acute infections that might affect the fetus
• Maintenance immunosuppression at stable doses
• Patient compliance with treatment and follow-up
• Normal blood pressure or blood pressure well controlled with one medication
• Normal allograft ultrasonography results ^{[5, 6]}

Comorbid factors that may worsen pregnancy outcome

Comorbid factors that may worsen pregnancy outcomes include the following:

• Etiology of the original disease that necessitated transplantation (ie, chances of recurrence)
• Chronic allograft dysfunction
• Renal insufficiency
• Cardiopulmonary diseases
• Hypertension
• Diabetes mellitus
• Obesity
• Maternal infection with hepatitis B virus, hepatitis C virus, or cytomegalovirus (CMV)

In the United States, the National Transplantation Pregnancy Registry (NTPR) has examined and tracked thousands of relevant cases since 1991. ^[37] Additionally, case reports, retrospective single center studies, and data collected from the other 2 international voluntary registries in the United Kingdom and European subcontinent comprise a comprehensive population of unique studies that can be analyzed to form an opinion on pregnancy outcomes in liver transplant recipients. ^[37] Although reports show a good success rate of pregnancy in liver transplant recipients, these pregnancies carry high risk to the patient, fetus, and allograft and need to be closely monitored in specialized centers by a team that includes a transplant hepatologist, a transplant surgeon, and an obstetrician experienced in high-risk pregnancies, in addition to a perinatologist or neonatologist. ^[7]

Pregnancy in women who are recipients of liver transplants is generally associated with good outcomes. As in the case of any major surgery, pregnancies in these patients are considered high risk. The timing of conception should be well planned and discussed with the transplant hepatologist, who will want to make sure that any chances of graft rejection are diminished before a woman plans on becoming pregnant. ^{[7, 10, 38]} Although there is no established optimal interval between OLT and pregnancy, reports from the NTPR and the American Society of Transplantation recommend that liver transplant recipients wait at least 1 year before conceiving in order to stabilize graft function and immunosuppression dosage. ^[9] Liver transplant recipients who wait at least 2 years ensure best maternal and fetal outcomes.

In 2012, the Johns Hopkins School of Medicine and John Hopkins Bloomberg School of Public Health conducted and published a systematic review and meta-analysis study of NTPR’s data and several hundred unique reports. The team evaluated 450 pregnancies in 306 OLT recipients, which resulted in 76.9% live births. ^[9] This is a marked improvement over a 2006 study completed by NTPR, in which only 58% of 202 pregnancies in 121 liver transplant recipients resulted in live births. ^[3] Interestingly, the live birth rate was higher for OLT recipients versus the general population (76.9% vs 66.7% in the United States) in the United States, United Kingdom, and European subcontinent. Similarly, the Johns Hopkins study reported only 28 abortions (6.2%) and 4 stillbirths (0.9%), which is significantly less than the 39% figure reported by NTPR in 2006. ^[3] Furthermore, the miscarriage rate was lower for OLT recipients versus the general population (15.6% vs 17.1%). ^[9]

Maternal complications

The most frequent maternal complication in this patient population is pregnancy-induced hypertension. ^[9] Pregnancies in patients with comorbid factors, such as hypertension, diabetes, cardiopulmonary disease, or any combination of the foregoing, tend to have worse outcomes. Preconception renal dysfunction has the strongest association with adverse outcomes of pregnancy in liver transplant recipients. ^[10] If these conditions can be controlled prior to conception, then the chance of a successful outcome increases dramatically. Other maternal complications include intrauterine infections, anemia, preeclampsia (21.9% vs 3.8% for the general population), cholestasis, and pyelonephritis. ^{[9, 8]}

Interestingly, gestational diabetes was not reported in these patients. ^{[7, 10]} Pregnancy did not seem to impair graft function or accelerate rejection in patients receiving immunosuppressive therapy. ^{[7, 38]} Mild-to-moderate elevations of liver enzymes are not unusual and should be monitored. Liver ultrasonography or biopsy should be considered if this abnormality does not stabilize or abate. ^[10]

Overall, maternal mortality is not worse compared with the general population, despite these concerns. ^[39]

Obstetric and delivery complications

The risk of congenital CMV infection is highest in pregnancies that occur less than 6 months after transplantation, which coincides with the period of maximal immunosuppression. ^[10] Perinatal transmission of hepatitis B virus infection is as high as 80% if not prevented by hepatitis B immunoglobulin (IVIG) and vaccination. The transmission rate of hepatitis C virus from the mother is 7%. The cesarean delivery rate was higher than the rate for the general population (44.5% vs 31.9%). ^{[9, 8]}

Fetal complications

Although it might be expected for the offspring of this patient population to have an increased risk of fetal complications, prematurity, and low birth compared with the general population, no statistically significant difference in rates of malformation was observed. ^[40] The incidence of congenital malformations, reported as 4-7%, which is only slightly higher than that in the general population. These malformations could not be attributed to a specific pattern and were minor and easily reparable. ^{[7, 38]}

Prematurity is the main fetal complication, which affects nearly 40% of live births. ^{[9, 7]} The mean reported gestational age at delivery is 36.5 weeks, while the mean birth weight is approximately 14% less than general population (6 lb 5 oz vs 7 lb 4 oz). ^{[9, 10]} Other fetal complications that have been observed include intrauterine growth restriction (approximately 20%), prenatal infections, and birth defects. Immune suppression is also noticed in these infants, including low immunoglobulin levels and lymphocyte counts. Most of these deficits seem to normalize by the sixth month of life, with no noted impact on the infants' health. ^[41]

Maternal complications

The most frequent maternal complication in this patient population is pregnancy-induced hypertension. ^[9] Pregnancies in patients with comorbid factors, such as hypertension, diabetes, cardiopulmonary disease, or any combination of the foregoing tend to have worse outcomes. Preconception renal dysfunction has the strongest association with adverse outcomes of pregnancy in liver transplant recipients. ^[10] If these conditions can be controlled prior to conception, then the chance of a successful outcome increases dramatically.

Other maternal complications include intrauterine infections, anemia, preeclampsia (21.9% vs 3.8% for the general population), cholestasis, and pyelonephritis. ^{[9, 8]} Interestingly, gestational diabetes was not reported in these patients. ^{[7, 10]} Pregnancy did not seem to impair graft function or accelerate rejection in patients receiving immunosuppressive therapy. ^{[7, 38]}

Mild-to-moderate elevations of liver enzymes are not unusual and should be monitored. Liver ultrasonography or biopsy should be considered if this abnormality does not stabilize or abate. ^[10]

Overall, maternal mortality is not worse compared with the general population, despite these concerns. ^[39]

Obstetric and delivery complications

The risk of congenital CMV infection is highest in pregnancies that occur less than 6 months after transplantation, which coincides with the period of maximal immunosuppression. ^[10] Perinatal transmission of hepatitis V virus infection is as high as 80% if not prevented by hepatitis B immunoglobulin (IVIG) and vaccination. The transmission rate of hepatitis C virus from the mother is 7%. The cesarean delivery rate was higher than the rate for the general population (44.5% vs 31.9%). ^{[9, 8]}

Fetal complications

Although it might be expected for the offspring of this patient population to have an increased risk of fetal complications, prematurity, and low birth compared with the general population, no statistically significant difference in rates of malformation was observed. ^[40] The incidence of congenital malformations, reported as 4-7%, which is only slightly higher than that in the general population. These malformations could not be attributed to a specific pattern and were minor and easily reparable. ^{[7, 38]}

Prematurity is the main fetal complication, which affects early 40% of live births. ^{[9, 7]} The mean reported gestational age at delivery is 36.5 weeks, while the mean birth weight approximately 14% less than general population (6 lb 5 oz vs 7 lb 4 oz). ^{[9, 10]} Other fetal complications that have been observed include intrauterine growth restriction (approximately 20%), prenatal infections, and birth defects. Immune suppression is also noticed in these infants, including low immunoglobulin levels and lymphocyte counts. Most of these deficits seem to normalize by the sixth month of life, with no noted impact on the infants' health.

Although planned pregnancy after liver transplantation is relatively common, acute liver failure requiring OLT during earlier stages of pregnancy is rare. ^[8] In fact, the exact incidence is unknown. In a 2012 study published by the Carolinas Medical Center (Charlotte, NC), the team conducted a comprehensive literature search and was able to find only 15 documented cases of antepartum liver transplantation. ^[8]

Acute liver failure during pregnancy is very uncommon. Abnormal liver function is observed in 3-5% of all pregnant women and is almost always diagnosed in the third trimester, usually due to late-term pregnancy-related conditions, such as intrahepatic cholestasis of pregnancy (ICP), preeclampsia, HELLP (hemolysis, elevated liver enzymes), and acute fatty liver of pregnancy. ^[8] In cases in which abnormal liver function acts as a harbinger for acute liver failure, transplant hepatologists try to manage this patient population’s care until they are postpartum and, in some cases, might even induce birth as early as the 30th week before performing an OLT. ^[8] Management of acute liver failure or ESLD in pregnancy is complicated, as both maternal and fetal well-being needs to be considered; although, maternal outcome takes precedent.

Of the 15 cases of antepartum liver transplantation, only 6 (40%) resulted in successful delivery of the fetus. ^[8] This outcome emphasizes the hesitance that hepatologists have when it comes to selecting OLT as the treatment of choice for ESLD in pregnant women.

The patient should monitor her blood pressure daily. Hypertension, which is a common problem in this patient group, should be aggressively managed. ACE inhibitors and angiotensin receptor blockers (ARBs) are contraindicated. ^[10] Methyldopa is the drug of choice. ^[5] Clonidine and calcium channel alpha-blockers may be used as second-line therapy. ^[5] Graft function should be monitored closely; biopsy should be considered if rejection is suspected. ^[3]

In the case of acute rejection, steroids are the preferred drugs. Steroids are considered safe, while the safety of antilymphocyte antibodies and rituximab is not known.

Obstetrical management

The pregnancy of a transplant recipient should be managed by an obstetrician experienced in high-risk pregnancies, in collaboration with a transplant physician and perinatologist or neonatologist. ^[5] Frequent evaluations, preferably every 2 weeks, are recommended. ^[5] Vaginal delivery is preferred and is usually delayed until the onset of labor, unless maternal or fetal indications for induction exist. ^[3] Cesarean delivery is indicated only for obstetrical reasons. In the case of cesarean delivery, the exact location of the graft should be known to avoid injury to the allograft. ^[5]

Prophylactic antibiotics should be administered for all surgical procedures. ^[2] No specific anesthetic agents for general or regional anesthetics are contraindicated. ^[10] Patients who undergo lung or heart-lung transplants have a decreased threshold for developing pulmonary edema secondary to disruption of lymphatic vessels. ^[3] Pelvic osteodystrophy was described in patients with prolonged exposure to corticosteroids. This may necessitate cesarean delivery. ^[10] The dose of steroids should be increased at the onset of labor to overcome the stress of labor and prevent postpartum transplant rejection. ^[10]

Various immunosuppressive therapies can be considered to treat transplant recipients who are pregnant. ^[12] Table 3 summarizes these therapies.

Corticosteroids

Corticosteroids block the production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by macrophages and inhibit all stages of T-cell activation. ^[12] These agents are used for induction, acute rejection, and maintenance immunosuppression. Maternal adverse effects of these medications include peptic ulcer disease, osteoporosis, increased bruisability, pancreatitis, hypertension, aseptic skeletal necrosis, weight gain, fluid retention, and hyperglycemia. Both prednisone and prednisolone can cross the placenta, but ratios of maternal-to-cord blood are approximately 10:1. ^[42] Prenatal exposure to prednisone may cause fetal growth restriction and low birth weight. ^[43] Adrenal insufficiency and thymic hypoplasia have occasionally been described in these infants. ^[44] Long-term steroid therapy may be associated with premature rupture of membranes. The American Academy of Pediatrics (AAP) classifies both prednisone and prednisolone as compatible with breastfeeding classifies. ^[45]

Cyclosporine

Cyclosporine (also referred to as cyclosporin A) is a potent immunosuppressive agent administered to prolong the survival of liver transplants. ^[11] Adverse effects include nephrotoxicity, hyperkalemia, hypomagnesemia, nausea, vomiting, diarrhea, hypertrichosis, hirsutism, gingival hyperplasia, hyperlipidemia, glucose intolerance, infection, malignancy, and hyperuricemia. ^[46] Cyclosporine crosses the placenta and produces fetal levels 30-64% of those in the mother's plasma. ^[47] Studies have not associated any teratogenicity to cyclosporine. Growth restriction, premature birth, and low birth weight have been observed in pregnancies during which cyclosporine has been used. ^{[47, 48]}

Cyclosporine metabolism appears to be increased during pregnancy, and higher doses may be required to maintain plasma levels in the therapeutic range. ^[49] Some of the pregnancies in women treated with cyclosporine were complicated by preeclampsia, believed to be related to increased production of thromboxane and endothelin. ^[14] There has been concern about the effects of the child’s exposure to cyclosporine excreted into the breast milk. However, no lingering effects due to breast-feeding have been found in infants who were breast-fed while their mothers were taking CsA. ^[50]

Azathioprine

Azathioprine (Imuran) is an antimetabolite that inhibits DNA and RNA synthesis and is used mainly for maintenance immunosuppression. ^[12] Azathioprine is metabolized to 6-mercaptopurine, which is capable of crossing the placenta. Maternal adverse effects of this drug include leukopenia, thrombocytopenia, nausea, vomiting, hepatitis, cholestasis, and alopecia. The immature fetal liver lacks the enzyme inosinate pyrophosphorylase needed for conversion of azathioprine to its active metabolite, rendering it relatively protected from the toxicity.

Reports exist of azathioprine causing growth restriction and, probably, an increased rate of congenital malformations that ranges from 4-9%; however, these malformations have had no specific pattern. ^{[43, 51]} Azathioprine has been associated with dose-related fetal myelosuppression, although leukopenia is not usually a problem in the neonate if the maternal white blood cell count is maintained at values higher than 7500/μL. Because this drug is excreted in small amounts in breast milk, breastfeeding is not recommended while receiving azathioprine. ^[52]

Mycophenolate mofetil

Mycophenolate mofetil (CellCept) is administered for maintenance immunosuppression and for treating chronic rejection. ^[12] This agent impairs B- and T-cell proliferation, sparing other rapidly dividing cells. Maternal adverse effects include nausea, vomiting, diarrhea, leukopenia, anemia, thrombocytopenia, and an increased risk of lymphomas and other malignancies. Exposure to mycophenolate during pregnancy is associated with increased risk of first trimester pregnancy loss, and approximately 20% of live-born infants exposed to mycophenolate in utero  have congenital structural malformations.

The US Food and Drug Administration (FDA) and European guidelines regarding pregnancy in kidney transplant recipients recommend discontinuing mycophenolate mofetil 6 weeks before conception is attempted. ^{[16, 53]} To minimize fetal exposure to mycophenolate, the FDA has instituted a Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) program for healthcare professionals who prescribe mycophenolate-containing medicines Whether mycophenolate mofetil passes into the breast milk of nursing mothers is not known; therefore, breastfeeding should be avoided. ^[6]

In contrast, a retrospective cohort study that included 382 cases in which kidney transplant recipients who were taking mycophenolate became pregnant found that rates of birth defects and miscarriages were similar in patients who discontinued mycophenolate less or more than 6 weeks before pregnancy and during the first trimester. However, discontinuing mycophenolate during the second trimester or later significantly increased the risk of miscarriages (odds ratio [OR] 9.35 P < 0.001) and birth defects (OR 6.06, P = 0.002). ^[54]

Tacrolimus

Tacrolimus (FK-506, Prograf) is a calcineurin inhibitor that has been used for immunosuppression in solid organ transplant recipients since 1994. Common maternal adverse effects are nephrotoxicity, hypertension, and diabetes mellitus. Animal experiments have shown that tacrolimus may cause miscarriage. Neonatal adverse effects include transient perinatal hyperkalemia and an increased incidence of diabetes mellitus. ^[55] Pregnancy in transplant recipients who were treated with tacrolimus resulted in favorable outcomes in a retrospective analysis of 100 pregnancies. ^[56]

As with patients taking cyclosporine, patients taking tacrolimus require frequent monitoring of renal function and drug levels. According to some studies, the serum levels of tacrolimus are increased because of inhibition of hepatic cytochrome P450 enzymes. ^[56] Other data have shown that tacrolimus levels may decrease during pregnancy because of volume expansion. Thus, tacrolimus levels should be monitored on a biweekly or monthly basis. ^[6] In addition, because tacrolimus is excreted in breast milk, breastfeeding during tacrolimus treatment is not recommended. ^[56]

Sirolimus

This T-cell proliferation inhibitor was approved in 1999 for immunosuppression in solid organ transplant recipients. ^[12] Animal studies have shown decreased fetal weight and delayed skeletal ossification, but no specific teratogenicity was noted. Since this drug is relatively new, limited data on its effects in pregnant humans are available, and, based on the small number of patients, early sirolimus exposure during pregnancy does not appear to be associated with structural defects in offspring. ^[55]

Monoclonal antibody anti-CD3 and polyclonal antibodies

The monoclonal antibody anti-CD3 (OKT3) is an immunoglobulin G (IgG) rarely used in the treatment of acute rejection in pregnant transplant recipients. The NTPR has reported the use of OKT3 in 5 pregnancies, 4 of which ended in live births. ^[57] The effect of polyclonal antibodies on the developing fetus is not known, though the IgG would be expected to cross the placenta. ^[57]

Table 3. Immunosuppressive Therapies for Pregnant Transplant Recipients (Open Table in a new window)

Multidrug immunosuppressive therapy

The specific cause of toxicity may be more difficult to identify in patients exposed to multiple immunosuppressive agents. However, with lowered doses of multiple agents, exposure to each individual drug is lowered, and, therefore, the potential for teratogenicity is theoretically less. ^[55] Healthcare providers should make a diligent effort to report all cases of pregnancy to the NTPR to provide more updated information on the safety of newer immunosuppressive drugs and their adverse effects on the mother and the fetus.

Prematurity occurs in up to 50% of cases. It is associated with increased risk for neonatal death, cerebral palsy, deafness, learning disability, and low IQ. Intrauterine growth retardation (IUGR) occurs in up to 20% of cases. Infants may be born at a low birth weight.

Immune suppression is noticed in these infants, including low immunoglobulin levels and lymphocyte counts. Most of these deficits seem to normalize by the 6th month of life with no noted impact on the infants' health.

Although the rate of congenital malformations is similar to that in the general population, the number of pregnancies reported is still small; therefore, no definite decision can be made yet about a possible correlation between these malformations and immunosuppressive medications. Risk is increased for congenital infections, including toxoplasmosis, HBV, HCV, and CMV. Risk is increased for autoimmune diseases.

Failure to do any of the following is problematic:

• Inform the patient that ovulatory cycles may begin within 1-2 months after transplantation, so pregnancy can occur after that time
• Advise the patient that adequate contraceptive measures should be taken to prevent unwanted pregnancy
• Inform the patient about the optimal timing of pregnancy
• Inform the patient that pregnancy in a transplant recipient is considered a high-risk pregnancy; patients should be made aware of the potential risks before conception
• Send the patient for genetic counseling if the transplant was performed to treat an inheritable disease
• Inform the patient about the potential fetal risks of immunosuppressive agents
• Inform the patient that breastfeeding must be avoided if the patient is taking certain immunosuppressive therapies