Patients awaiting transplantation should be counseled regarding posttransplant contraception and the potential adverse outcomes associated with posttransplant conception. Pregnancy should be avoided for at least 1–2 years post transplant to minimize the risks to allograft function and fetal well-being. Transplant patients, particularly lung transplant recipients, have an increased risk of maternal and neonatal pregnancy-related complications, including prematurity and low birth weight, postpartum graft loss, and long-term morbidity and mortality compared to other solid-organ recipients. Therefore, careful monitoring by a specialized transplant team is crucial. Maintenance of immunosuppression is recommended, except for mycophenolate and mammalian target of rapamycin inhibitors (mTORi), which should be replaced before conception. Immunosuppressants must be regularly monitored and dosing adjusted to avoid graft rejection. Monitoring during labor is mandatory and epidural anesthesia recommended. Vaginal delivery should be standard and cesarean delivery only performed for obstetric reasons. Breastfeeding poses risks of neonatal exposure to immunosuppressants and is generally contraindicated.
Highlights
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Pregnancy following heart, heart–lung, or lung transplantation is feasible.
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Transplant recipients should be offered proper counseling regarding fertility, contraception, and posttransplant pregnancy.
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Conception should be delayed at least 1 year and preferably 2 years after transplantation.
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Careful monitoring before, during, and after pregnancy in a specialized transplant center is mandatory.
Introduction
In 1958, the first newborn following organ transplantation (living-related renal transplantation) was successfully delivered . Nowadays, >14,000 solid-organ transplant (SOT) recipients, mostly renal recipients, have delivered, with >95% rate of successful pregnancies reported . Pregnancy following heart (HTx), heart–lung (H + LTx), or lung transplantation (LTx), however, is much less prevalent. The first successful pregnancy after HTx was reported in 1988, following H + LTx in 1993 and after LTx in 1996 .
In order to ascertain outcome data in pregnancies following SOT, registries were established in the United States (National Transplantation Pregnancy Registry, NTPR), the United Kingdom (UK Transplant Pregnancy Registry, UKTPR), and Europe (European Renal Association – European Dialysis and Transplant Association, ERA-EDTA). The largest registry is the NTPR, founded in 1991 and currently with the data of >2400 pregnancies in >1500 graft recipients . In 2003, a consensus conference organized by the Women’s Health Committee of the American Society of Transplantation established the first guidelines on pregnancy and transplantation for optimizing care for the pregnant transplant recipient, fetus, and graft . In general, the NTPR reports on pregnancy outcomes, including not only live births, spontaneous abortions, therapeutic abortions, stillbirths, and ectopic pregnancies but also long-term follow-up to determine any long-term effects of pregnancy for the recipient, graft, or the offspring. Currently, 103 pregnancies in 58 HTx recipients, 30 pregnancies in 21 LTx recipients, and five pregnancies in five H + LTx recipients were registered in the NTPR as of 2010, compared to some 1422 pregnancies in 886 kidney recipients and 292 pregnancies in 166 liver recipients . During the past years, smaller case series additionally have reported on a limited number of HTx, H + LTx, or LTx recipients . Moreover, the NTPR also reports on pregnancy data of SOT recipients who have fathered pregnancies. Similarly, 154 pregnancies were fathered by 106 HTx, four pregnancies by four LTx recipients, and five pregnancies by two H + LTx recipients, compared to some 907 pregnancies by 596 kidney recipients and 103 pregnancies by 65 liver recipients . Pregnant SOT recipients may experience graft function worsening, allograft rejection, and opportunistic infections. Furthermore, the medical therapy following transplantation may influence teratogenicity as immunosuppressants pass through the placenta and are excreted into the breast milk. Some 26% of SOT recipients were therefore advised against pursuing pregnancy by their physician in a recent survey, one third of the respondents needed to find a new physician to support them in their pregnancy attempts . Indeed, few SOT recipients are properly educated regarding the effect of organ transplantation on fertility, posttransplant contraception, or pregnancy . As such, however, NTPR data provide treating physicians with valuable information for counseling to all pre- and posttransplant recipients of childbearing age.
In this article, immunosuppressants, preconception counseling, management during pregnancy, delivery and postpartum care, and pregnancy outcomes and contraceptive options in SOT recipients, with particular attention for HTx, H + LTx, or LTx recipients, are discussed.
Immunosuppressive medications
Immunosuppressives are essential to maintain graft function and maternal survival. Because the risk of graft rejection is highest in the initial 3–6 months following transplantation, the level of immunosuppression is initially high, after which it is subsequently tapered to maintenance levels over the following 6–12 months. Accordingly, SOT recipients are generally advised to delay pregnancy for at least 1–2 years after transplantation, by which time low maintenance doses of immunosuppressants are being used. Commonly, a combination of various agents, including a corticosteroid, an antimetabolite drug, and a calcineurin inhibitor (CNI), is used, allowing synergistic effects and decreased risk of drug toxicity.
In general, pregnancy affects drug absorption, distribution, and elimination. For instance, gut motility is slowed in pregnancy, but drug transfer through the gastrointestinal membranes is enhanced as a result of increased local blood flow. Nausea and hyperemesis gravidarum may affect immunosuppressant intake. The distribution of drugs into tissues is modified by the increase in blood volume and fat stores. Immunosuppressants that are cleared through the kidney are affected by the increased glomerular filtration rate in pregnancy. As a result of these changes in pregnancy, serum levels of immunosuppressants should be monitored closely and dosage adjustments made accordingly . Moreover, all immunosuppressants cross the placental barrier and thus enter the fetal circulation. As a consequence, the use of immunosuppressants during pregnancy remains controversial. Therefore, the United States Food and Drug Agency (FDA) has classified the commonly used immunosuppressants as either C (fetal risk cannot be ruled out) or D (evidence of fetal risk) ( Table 1 ). In order to maximize fetal well-being, physicians should thus preferably switch to “older” and “safer” medications before or soon after conception.
| Drug Class (name) | FDA Category |
|---|---|
| Corticosteroid (prednisone, methylprednisolone/Medrol°) | B |
| Antimetabolite agent (azathioprine/Imuran°, mycophenolate/Cellcept°/Myfortic°) | D |
| Calcineurin inhibitor (cyclosporine/Neoral°/Sandimmun°, tacrolimus/Prograft°/Prograf°) | C |
| Mammalian target of rapamycin inhibitors | |
| sirolimus/Rapamune° | C |
| everolimus/Certican° | D |
| Anti-thymocyte globulin (Atgam°, ATG°, Thymoglobulin°) | C |
| Monoclonal antibody | |
| Murine monoclonal Ab: Muromonomab-CD3/Orthoclone OKT3° | C |
| Chimeric (murine-human) monoclonal Ab: Basiliximab/Simulect°, | B |
| Rituximab/Rituxan°/Mabthera° | C |
| Humanized monoclonal Ab: Daclizumab/Zepanax°, Alemtuzumab/Campath° | C |
Fetal–maternal circulation and fetal drug metabolism
The majority of immunosuppressants enter the fetal circulation via simple diffusion across the placenta, although some are actively transported via carriers or undergo placental enzymatic conversion . Subsequently, these pharmacologic agents and their metabolites pass through the fetal liver, which, despite being relatively immature, demonstrates the activation of enzyme pathways needed for drug metabolism . Because fetal pharmacokinetics and pharmacodynamics are different from that in adults, it is difficult to predict the drug concentrations that will be achieved in the fetus.
Theoretically, in utero exposure to immunosuppressants may place the fetus at risk of both structural malformations and immunologic alterations. Overall, the rate of congenital malformations in SOT recipients is approximately 3–4%, which is similar to the general population . Although the altered immune function (e.g., low concentrations of B- and T-cell numbers and low levels of circulating immunoglobulins (Ig) G, IgA, and IgM) in infants exposed to immunosuppressants during pregnancy usually normalizes within the first year of life, this transient immune dysfunction can affect the response to immunization. As such, this may prompt intentional delay in the administration of routine vaccinations in order to prevent a suboptimal response and to avoid unintended childhood illness . Besides preterm birth and low birth weight are the rates of autoimmune disorders, childhood infectious illnesses, or developmental outcomes (such as learning disabilities) beyond the neonatal period, however, generally not higher than in the general population . In particular, babies of HTx recipients are born closer to term (mean gestational age 36.8 weeks) and have higher birth weights (mean 2600 g) compared with babies from LTx recipients (34 weeks, 2200 g), which may be due to factors related to cystic fibrosis in LTx recipients, such as nutritional status, diabetes, liver disease, etc. Childhood follow-up for 66 live births in HTx recipients revealed that one had died a traumatic death, two had mitochondrial cardiomyopathy (same diagnosis as mother), and four had birth anomalies, including facial defects, duodenal atresia, atrioventricular canal defect, Tetralogy of Fallot, laryngomalacia, and bicuspid aortic valve (all maternal immunosuppression included mycophenolate). The remaining 59 children were reported to be healthy and developing well . Childhood follow-up for 16 live births in LTx recipients revealed that all were healthy and developing well after a mean follow-up of 7 years .
Corticosteroids
Corticosteroids have broad anti-inflammatory effects and inhibit all types of lymphocytes. Both betamethasone and dexamethasone, fluorinated corticosteroids, cross the placenta in their active form and achieve relatively high fetal blood concentrations and are therefore often used antenatally to promote fetal lung maturity . On the other hand, prednisone and methylprednisolone, short-acting nonfluorinated corticosteroids, are substantially metabolized by 11-beta-hydroxysteroid dehydrogenase within the placenta so that only low levels are detected in the fetal circulation . Although prednisone and methylprednisolone do not accumulate sufficiently to promote fetal lung maturity, maternal treatment can achieve sufficient fetal concentrations to theoretically impact fetal adrenal function and structural formation. As such, one meta-analysis has concluded to a significantly increased risk of cleft palate (odds ratio 3.4, 95% confidence interval (CI) 1.97–5.69) . However, no studies have demonstrated an increased incidence of other congenital malformations in the offspring of women treated with corticosteroids during pregnancy . Conversely, maternal glucocorticoid therapy has been associated with accelerated diabetes and aggravated hypertension, as well as an increased rate of premature rupture of the membranes and intrauterine growth restriction .
Antimetabolic agents azathioprine and mycophenolate mofetil
Azathioprine is an inhibitor of purine metabolism that inhibits clonal proliferation of T cells. Azathioprine also crosses the placenta, but remains in its inactive form and is not converted to the teratogen 6-mercaptopurine in the fetus . Nevertheless, the in utero exposure of azathioprine has been associated with reports of isolated fetal immunodeficiency, thymus atrophy, and congenital malformations, including hypospadias and preaxial polydactyly .
Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase that blocks de novo purine synthesis on which lymphocytes are dependent. Toxicities include nausea, gastritis, diarrhea, and leukopenia. Treatment with mycophenolate has been clearly associated with a number of structural malformations (i.e., 23% birth defects vs. 4–5% without mycophenolate), such as hypoplastic nails, shortened fifth fingers, abnormal ears, cleft lip/palate, agenesis of the corpus callosum, severe fetal anemia, hydrops, microtia with atresia of the external auditory canal, micrognathia, hypertelorism and ocular anomalies, heart defects, kidney malformations, and diaphragmatic hernia. Current recommendations therefore do not support its use in pregnant transplant recipients . The NTPR reported 21 pregnancies (23 outcomes) in HTx exposed to mycophenolate, 15 of which had spontaneous abortions, and eight live births. Four of the live born children demonstrated severe birth defects . No LTx recipients were exposed to mycophenolate during pregnancy . It is recommended that female transplant recipients eliminate mycophenolate from the immunosuppressive regimen at least 6 weeks before planned conception . On the other hand, analysis of pregnancy outcomes in 152 male transplant recipients with exposure to mycophenolate revealed similar to outcomes compared to the general population with 93% live births (194 live births in 205 pregnancies or 208 outcomes, including three pairs of twins), a prematurity rate of 10.8%, and 6.7% spontaneous abortions and no therapeutic abortions or stillbirths. Among the live births, six malformations, without a specific pattern, were reported, for an incidence of 3.1% .
CNIs: cyclosporine and tacrolimus
CNIs block the transcription of cytokine genes necessary for T-cell activation and proliferation. Known CNI toxicities include nephrotoxicity, hypertension, tremor, hyperlipidemia, and diabetes. Fetal cyclosporine blood concentration can approach half that seen in the mother and it also accumulates to a lesser degree in the placenta, amniotic fluid, and fetal tissue . Tacrolimus has also been shown to concentrate in the placenta, reaching concentrations three times greater than seen in the maternal circulation, whereas concentrations in the fetal circulation were noted to be less than half that in the mother .
Cyclosporine metabolism is increased in pregnancy due to an increase in maternal blood volume and changes in renal and hepatic function, necessitating titration of dosage to maintain therapeutic concentrations. There are multiple factors that can increase the fraction of unbound tacrolimus, including, but not limited to, pregnancy-associated inhibition of the hepatic cytochrome p450 enzyme and decreased metabolism, low albumin concentration, or red blood cell count. Clinical titration of dosage to maintain whole blood tacrolimus concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia.
The prevalence of congenital anomalies after in utero exposure to CNI, however, is relatively low and comparable to the general population, approximately 5% , without any specific pattern of malformations detected. On the other hand, pregnancies in SOT recipients treated with cyclosporine are more likely to be complicated by gestational diabetes, arterial hypertension, preterm delivery, and low birth weight: approximately 50% of infants were delivered <37 weeks gestation and weighed <2500 g . Studies of SOT recipients treated with tacrolimus in pregnancy demonstrated preterm birth in 40–60%, which is again markedly higher compared to the general population . Another finding with both cyclosporine and tacrolimus is an increased prevalence of preeclampsia, respectively in some 25% and 23% of pregnancies .
mTORi: sirolimus and everolimus
mTORi block cytokine-driven T-cell proliferation. The fetal effects of mTORi are still poorly defined, but no structural defects have yet been reported after exposure in a limited number of recipients . In the NTPR, overall 18 female transplant recipients with 19 pregnancies with exposure to sirolimus were reported, including 12 kidney recipients with 13 pregnancies, 10 of which resulted in live birth and three ended with spontaneous abortion. Birth defects were seen in two of the 10 live births, which included cleft lip, palate, microtia, and Tetralogy of Fallot. In two HTx recipients, two pregnancies with exposure to sirolimus were also documented, one live birth with facial malformations (maternal immunosuppression also included mycophenolate) and one spontaneous abortion . No LTx recipients with exposure to sirolimus during pregnancy have been reported. Current recommendations do not support the use of mTORi in pregnancy and these should ideally also be discontinued at least 6 weeks before conception.
Other drugs
Potential toxicological and teratogenic effects of concomitantly used drugs, besides immunosuppressants, should also be taken into account. For instance, α-methyldopa (FDA Pregnancy Category A) and hydralazine (Category C) are harmless and therefore most frequently used in pregnant patients. Beta-blockers, such as metoprolol (Category C), can be safely used, but preferably not during early pregnancy as this may be associated with intrauterine growth retardation. Nonspecific beta-blockers should not be administered given the risk of premature uterine contractions. Calcium channel blockers (Category C) during the first trimester are associated with congenital malformations and should therefore be discontinued before conception. Similar advice is true for angiotensin-converting enzyme inhibitors (Category C), which are associated with renal failure and intrauterine death. Diuretics (mostly Category C) should be avoided during pregnancy due to their negative impact on plasma volume and placental blood flow . Macrolides are increasingly being used in LTx recipients to maintain or improve pulmonary function . However, macrolides may increase the risk of prolonged QT interval and potentially fatal torsades de pointes. Therefore, azithromycin (Category B), erythromycin (Category B), and especially clarithromycin (Category C) should be stopped if possible, or else used with caution. Statins are a common part of therapy in SOT recipients, but are contraindicated during pregnancy owing to their potential teratogenic effects (Category X). The risks of other therapeutic agents commonly used in SOT recipients, such as voriconazole (Category D), valganciclovir (Category C), and ganciclovir (Category C), should always be weighed against their perceived benefits for maternal and fetal well-being.
Immunosuppressive medications
Immunosuppressives are essential to maintain graft function and maternal survival. Because the risk of graft rejection is highest in the initial 3–6 months following transplantation, the level of immunosuppression is initially high, after which it is subsequently tapered to maintenance levels over the following 6–12 months. Accordingly, SOT recipients are generally advised to delay pregnancy for at least 1–2 years after transplantation, by which time low maintenance doses of immunosuppressants are being used. Commonly, a combination of various agents, including a corticosteroid, an antimetabolite drug, and a calcineurin inhibitor (CNI), is used, allowing synergistic effects and decreased risk of drug toxicity.
In general, pregnancy affects drug absorption, distribution, and elimination. For instance, gut motility is slowed in pregnancy, but drug transfer through the gastrointestinal membranes is enhanced as a result of increased local blood flow. Nausea and hyperemesis gravidarum may affect immunosuppressant intake. The distribution of drugs into tissues is modified by the increase in blood volume and fat stores. Immunosuppressants that are cleared through the kidney are affected by the increased glomerular filtration rate in pregnancy. As a result of these changes in pregnancy, serum levels of immunosuppressants should be monitored closely and dosage adjustments made accordingly . Moreover, all immunosuppressants cross the placental barrier and thus enter the fetal circulation. As a consequence, the use of immunosuppressants during pregnancy remains controversial. Therefore, the United States Food and Drug Agency (FDA) has classified the commonly used immunosuppressants as either C (fetal risk cannot be ruled out) or D (evidence of fetal risk) ( Table 1 ). In order to maximize fetal well-being, physicians should thus preferably switch to “older” and “safer” medications before or soon after conception.
| Drug Class (name) | FDA Category |
|---|---|
| Corticosteroid (prednisone, methylprednisolone/Medrol°) | B |
| Antimetabolite agent (azathioprine/Imuran°, mycophenolate/Cellcept°/Myfortic°) | D |
| Calcineurin inhibitor (cyclosporine/Neoral°/Sandimmun°, tacrolimus/Prograft°/Prograf°) | C |
| Mammalian target of rapamycin inhibitors | |
| sirolimus/Rapamune° | C |
| everolimus/Certican° | D |
| Anti-thymocyte globulin (Atgam°, ATG°, Thymoglobulin°) | C |
| Monoclonal antibody | |
| Murine monoclonal Ab: Muromonomab-CD3/Orthoclone OKT3° | C |
| Chimeric (murine-human) monoclonal Ab: Basiliximab/Simulect°, | B |
| Rituximab/Rituxan°/Mabthera° | C |
| Humanized monoclonal Ab: Daclizumab/Zepanax°, Alemtuzumab/Campath° | C |
Fetal–maternal circulation and fetal drug metabolism
The majority of immunosuppressants enter the fetal circulation via simple diffusion across the placenta, although some are actively transported via carriers or undergo placental enzymatic conversion . Subsequently, these pharmacologic agents and their metabolites pass through the fetal liver, which, despite being relatively immature, demonstrates the activation of enzyme pathways needed for drug metabolism . Because fetal pharmacokinetics and pharmacodynamics are different from that in adults, it is difficult to predict the drug concentrations that will be achieved in the fetus.
Theoretically, in utero exposure to immunosuppressants may place the fetus at risk of both structural malformations and immunologic alterations. Overall, the rate of congenital malformations in SOT recipients is approximately 3–4%, which is similar to the general population . Although the altered immune function (e.g., low concentrations of B- and T-cell numbers and low levels of circulating immunoglobulins (Ig) G, IgA, and IgM) in infants exposed to immunosuppressants during pregnancy usually normalizes within the first year of life, this transient immune dysfunction can affect the response to immunization. As such, this may prompt intentional delay in the administration of routine vaccinations in order to prevent a suboptimal response and to avoid unintended childhood illness . Besides preterm birth and low birth weight are the rates of autoimmune disorders, childhood infectious illnesses, or developmental outcomes (such as learning disabilities) beyond the neonatal period, however, generally not higher than in the general population . In particular, babies of HTx recipients are born closer to term (mean gestational age 36.8 weeks) and have higher birth weights (mean 2600 g) compared with babies from LTx recipients (34 weeks, 2200 g), which may be due to factors related to cystic fibrosis in LTx recipients, such as nutritional status, diabetes, liver disease, etc. Childhood follow-up for 66 live births in HTx recipients revealed that one had died a traumatic death, two had mitochondrial cardiomyopathy (same diagnosis as mother), and four had birth anomalies, including facial defects, duodenal atresia, atrioventricular canal defect, Tetralogy of Fallot, laryngomalacia, and bicuspid aortic valve (all maternal immunosuppression included mycophenolate). The remaining 59 children were reported to be healthy and developing well . Childhood follow-up for 16 live births in LTx recipients revealed that all were healthy and developing well after a mean follow-up of 7 years .
Corticosteroids
Corticosteroids have broad anti-inflammatory effects and inhibit all types of lymphocytes. Both betamethasone and dexamethasone, fluorinated corticosteroids, cross the placenta in their active form and achieve relatively high fetal blood concentrations and are therefore often used antenatally to promote fetal lung maturity . On the other hand, prednisone and methylprednisolone, short-acting nonfluorinated corticosteroids, are substantially metabolized by 11-beta-hydroxysteroid dehydrogenase within the placenta so that only low levels are detected in the fetal circulation . Although prednisone and methylprednisolone do not accumulate sufficiently to promote fetal lung maturity, maternal treatment can achieve sufficient fetal concentrations to theoretically impact fetal adrenal function and structural formation. As such, one meta-analysis has concluded to a significantly increased risk of cleft palate (odds ratio 3.4, 95% confidence interval (CI) 1.97–5.69) . However, no studies have demonstrated an increased incidence of other congenital malformations in the offspring of women treated with corticosteroids during pregnancy . Conversely, maternal glucocorticoid therapy has been associated with accelerated diabetes and aggravated hypertension, as well as an increased rate of premature rupture of the membranes and intrauterine growth restriction .
Antimetabolic agents azathioprine and mycophenolate mofetil
Azathioprine is an inhibitor of purine metabolism that inhibits clonal proliferation of T cells. Azathioprine also crosses the placenta, but remains in its inactive form and is not converted to the teratogen 6-mercaptopurine in the fetus . Nevertheless, the in utero exposure of azathioprine has been associated with reports of isolated fetal immunodeficiency, thymus atrophy, and congenital malformations, including hypospadias and preaxial polydactyly .
Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase that blocks de novo purine synthesis on which lymphocytes are dependent. Toxicities include nausea, gastritis, diarrhea, and leukopenia. Treatment with mycophenolate has been clearly associated with a number of structural malformations (i.e., 23% birth defects vs. 4–5% without mycophenolate), such as hypoplastic nails, shortened fifth fingers, abnormal ears, cleft lip/palate, agenesis of the corpus callosum, severe fetal anemia, hydrops, microtia with atresia of the external auditory canal, micrognathia, hypertelorism and ocular anomalies, heart defects, kidney malformations, and diaphragmatic hernia. Current recommendations therefore do not support its use in pregnant transplant recipients . The NTPR reported 21 pregnancies (23 outcomes) in HTx exposed to mycophenolate, 15 of which had spontaneous abortions, and eight live births. Four of the live born children demonstrated severe birth defects . No LTx recipients were exposed to mycophenolate during pregnancy . It is recommended that female transplant recipients eliminate mycophenolate from the immunosuppressive regimen at least 6 weeks before planned conception . On the other hand, analysis of pregnancy outcomes in 152 male transplant recipients with exposure to mycophenolate revealed similar to outcomes compared to the general population with 93% live births (194 live births in 205 pregnancies or 208 outcomes, including three pairs of twins), a prematurity rate of 10.8%, and 6.7% spontaneous abortions and no therapeutic abortions or stillbirths. Among the live births, six malformations, without a specific pattern, were reported, for an incidence of 3.1% .
CNIs: cyclosporine and tacrolimus
CNIs block the transcription of cytokine genes necessary for T-cell activation and proliferation. Known CNI toxicities include nephrotoxicity, hypertension, tremor, hyperlipidemia, and diabetes. Fetal cyclosporine blood concentration can approach half that seen in the mother and it also accumulates to a lesser degree in the placenta, amniotic fluid, and fetal tissue . Tacrolimus has also been shown to concentrate in the placenta, reaching concentrations three times greater than seen in the maternal circulation, whereas concentrations in the fetal circulation were noted to be less than half that in the mother .
Cyclosporine metabolism is increased in pregnancy due to an increase in maternal blood volume and changes in renal and hepatic function, necessitating titration of dosage to maintain therapeutic concentrations. There are multiple factors that can increase the fraction of unbound tacrolimus, including, but not limited to, pregnancy-associated inhibition of the hepatic cytochrome p450 enzyme and decreased metabolism, low albumin concentration, or red blood cell count. Clinical titration of dosage to maintain whole blood tacrolimus concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia.
The prevalence of congenital anomalies after in utero exposure to CNI, however, is relatively low and comparable to the general population, approximately 5% , without any specific pattern of malformations detected. On the other hand, pregnancies in SOT recipients treated with cyclosporine are more likely to be complicated by gestational diabetes, arterial hypertension, preterm delivery, and low birth weight: approximately 50% of infants were delivered <37 weeks gestation and weighed <2500 g . Studies of SOT recipients treated with tacrolimus in pregnancy demonstrated preterm birth in 40–60%, which is again markedly higher compared to the general population . Another finding with both cyclosporine and tacrolimus is an increased prevalence of preeclampsia, respectively in some 25% and 23% of pregnancies .
mTORi: sirolimus and everolimus
mTORi block cytokine-driven T-cell proliferation. The fetal effects of mTORi are still poorly defined, but no structural defects have yet been reported after exposure in a limited number of recipients . In the NTPR, overall 18 female transplant recipients with 19 pregnancies with exposure to sirolimus were reported, including 12 kidney recipients with 13 pregnancies, 10 of which resulted in live birth and three ended with spontaneous abortion. Birth defects were seen in two of the 10 live births, which included cleft lip, palate, microtia, and Tetralogy of Fallot. In two HTx recipients, two pregnancies with exposure to sirolimus were also documented, one live birth with facial malformations (maternal immunosuppression also included mycophenolate) and one spontaneous abortion . No LTx recipients with exposure to sirolimus during pregnancy have been reported. Current recommendations do not support the use of mTORi in pregnancy and these should ideally also be discontinued at least 6 weeks before conception.
Other drugs
Potential toxicological and teratogenic effects of concomitantly used drugs, besides immunosuppressants, should also be taken into account. For instance, α-methyldopa (FDA Pregnancy Category A) and hydralazine (Category C) are harmless and therefore most frequently used in pregnant patients. Beta-blockers, such as metoprolol (Category C), can be safely used, but preferably not during early pregnancy as this may be associated with intrauterine growth retardation. Nonspecific beta-blockers should not be administered given the risk of premature uterine contractions. Calcium channel blockers (Category C) during the first trimester are associated with congenital malformations and should therefore be discontinued before conception. Similar advice is true for angiotensin-converting enzyme inhibitors (Category C), which are associated with renal failure and intrauterine death. Diuretics (mostly Category C) should be avoided during pregnancy due to their negative impact on plasma volume and placental blood flow . Macrolides are increasingly being used in LTx recipients to maintain or improve pulmonary function . However, macrolides may increase the risk of prolonged QT interval and potentially fatal torsades de pointes. Therefore, azithromycin (Category B), erythromycin (Category B), and especially clarithromycin (Category C) should be stopped if possible, or else used with caution. Statins are a common part of therapy in SOT recipients, but are contraindicated during pregnancy owing to their potential teratogenic effects (Category X). The risks of other therapeutic agents commonly used in SOT recipients, such as voriconazole (Category D), valganciclovir (Category C), and ganciclovir (Category C), should always be weighed against their perceived benefits for maternal and fetal well-being.
Preconceptional care
Timing of pregnancy
Adequate counseling about the return of fertility, contraception, and possibility of pregnancy is imperative for any woman of childbearing age undergoing evaluation for transplantation. Indeed, following transplantation, the disruption of the hypothalamic–gonadal axis associated with end-organ disease is often corrected within 2–6 months . Adequate contraception before and after transplantation and optimal timing of pregnancy, if desired, are important issues to discuss with the patient and his/her partner. Adequate, individualized contraception should be started at least before hospital discharge after transplantation.
In general, female recipients should be advised to wait 1–2 years after the transplant to become pregnant . This allows recovery from surgery and time to ensure stable graft function, with a lower risk of acute rejection. Additionally, immunosuppressants will be at lower maintenance levels, opportunistic infections less prevalent, and concomitant medical conditions (hypertension and diabetes) adequately controlled. In order to decrease the risk of adverse outcomes in renal transplantation, the EDTA published recommendations regarding conception in renal recipients . These management guidelines can be extrapolated to other SOT recipients, including HTx, H + LTx, or LTx recipients ( Table 2 ).
