Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
4
Pregnancy after heart and lung transplantation Robin Vos, MD, PhD, Senior Clinical Investigator a, b, *, David Ruttens, MD, Reseach Fellow a, b, Stijn E. Verleden, PhD, Post-doctoral Reseach Fellow a, b, Elly Vandermeulen, MsC, Reseach Fellow a, b, Hannelore Bellon, MsC, Reseach Fellow a, b, Bart M. Vanaudenaerde, PhD, Post-doctoral Research Professor a, b, Geert M. Verleden, MD, PhD, Clinical Director, Senior Clinical Investigator a, b a KU Leuven e University of Leuven, Department of Clinical and Experimental Medicine, Division of Pneumology, Lung Transplant Unit, B-3000 Leuven, Belgium b KU Leuven - University of Leuven, University Hospitals Leuven, Department of Respiratory Medicine, Lung Transplant Unit, B-3000 Leuven, Belgium
MeSH keywords: heart transplantation lung transplantation pregnancy
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 1e2 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 longterm 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
* Corresponding author. University Hospital Gasthuisberg, Dept. Respiratory Medicine, Lung Transplant and Respiratory Intermediate Care Unit, 49 Herestraat, B-3000 Leuven, Belgium. Tel.: þ32 16 341548; Fax: þ32 16 346803. E-mail address: [email protected] (R. Vos).
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.019 1521-6934/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
2
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
for obstetric reasons. Breastfeeding poses risks of neonatal exposure to immunosuppressants and is generally contraindicated. © 2014 Published by Elsevier Ltd.
Introduction In 1958, the first newborn following organ transplantation (living-related renal transplantation) was successfully delivered [1]. Nowadays, >14,000 solid-organ transplant (SOT) recipients, mostly renal recipients, have delivered, with >95% rate of successful pregnancies reported [2]. Pregnancy following heart (HTx), heartelung (H þ LTx), or lung transplantation (LTx), however, is much less prevalent. The first successful pregnancy after HTx was reported in 1988, following H þ LTx in 1993 and after LTx in 1996 [3e5]. 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 e 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 [2]. 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 [6]. 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 þ 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 [2]. During the past years, smaller case series additionally have reported on a limited number of HTx, H þ LTx, or LTx recipients [7e9]. 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 þ LTx recipients, compared to some 907 pregnancies by 596 kidney recipients and 103 pregnancies by 65 liver recipients [2]. 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 [7]. Indeed, few SOT recipients are properly educated regarding the effect of organ transplantation on fertility, posttransplant contraception, or pregnancy [10]. 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 þ 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 3e6 months following transplantation, the level of immunosuppression is initially high, after which it is subsequently tapered to maintenance levels over the following 6e12 months. Accordingly, SOT recipients are generally advised to delay pregnancy for at least 1e2 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. Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
3
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 [11]. 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) [12] (Table 1). In order to maximize fetal well-being, physicians should thus preferably switch to “older” and “safer” medications before or soon after conception. Fetalematernal 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 [13e15]. 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 [16]. 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 3e4%, which is similar to the general population [17]. 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 [18e20]. 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 [2,21,22]. In particular, babies of HTx recipients are born closer to term (mean gestational age 36.8 weeks) and have higher
Table 1 FDA pregnancy categories for commonly used immunosuppressive drugs in solid organ transplantation (adapted from Refs. [11], [23], and [58]). Drug Class (name)
FDA Category
Corticosteroid (prednisone, methylprednisolone/Medrol ) Antimetabolite agent (azathioprine/Imuran , mycophenolate/Cellcept /Myfortic ) Calcineurin inhibitor (cyclosporine/Neoral /Sandimmun , tacrolimus/Prograft /Prograf ) Mammalian target of rapamycin inhibitors sirolimus/Rapamune everolimus/Certican Anti-thymocyte globulin (Atgam , ATG , Thymoglobulin ) Monoclonal antibody Murine monoclonal Ab: Muromonomab-CD3/Orthoclone OKT3 Chimeric (murine-human) monoclonal Ab: Basiliximab/Simulect , Rituximab/Rituxan /Mabthera Humanized monoclonal Ab: Daclizumab/Zepanax , Alemtuzumab/Campath
B D C C D C C B C C
United States Food and Drug Agency (FDA) categories briefly defined: A: no evidence of increased risk of fetal abnormalities in well-controlled studies, B: no controlled studies, but no evidence of fetal risk, C: fetal risk cannot be ruled out, D: evidence of fetal risk, X: definitive evidence of fetal risks, such that use of the drug is contraindicated in women who are or may become pregnant, and N: FDA has not classified the drug Brand name.
Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
4
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
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. [23,24] 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 [2]. 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 [24]. 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 [25]. 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 [26]. 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) 1.97e5.69) [27]. However, no studies have demonstrated an increased incidence of other congenital malformations in the offspring of women treated with corticosteroids during pregnancy [27,28]. 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 [29]. 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 [30]. 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 [31]. 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. 4e5% 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 [13,32e34]. 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 [2]. No LTx recipients were exposed to mycophenolate during pregnancy [2]. It is recommended that female transplant recipients eliminate mycophenolate from the immunosuppressive regimen at least 6 weeks before planned conception [32]. 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% [35]. Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
5
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 [36e38]. 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 [39]. 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. [40] The prevalence of congenital anomalies after in utero exposure to CNI, however, is relatively low and comparable to the general population, approximately 5% [41], 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
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
4
Pregnancy after heart and lung transplantation Robin Vos, MD, PhD, Senior Clinical Investigator a, b, *, David Ruttens, MD, Reseach Fellow a, b, Stijn E. Verleden, PhD, Post-doctoral Reseach Fellow a, b, Elly Vandermeulen, MsC, Reseach Fellow a, b, Hannelore Bellon, MsC, Reseach Fellow a, b, Bart M. Vanaudenaerde, PhD, Post-doctoral Research Professor a, b, Geert M. Verleden, MD, PhD, Clinical Director, Senior Clinical Investigator a, b a KU Leuven e University of Leuven, Department of Clinical and Experimental Medicine, Division of Pneumology, Lung Transplant Unit, B-3000 Leuven, Belgium b KU Leuven - University of Leuven, University Hospitals Leuven, Department of Respiratory Medicine, Lung Transplant Unit, B-3000 Leuven, Belgium
MeSH keywords: heart transplantation lung transplantation pregnancy
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 1e2 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 longterm 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
* Corresponding author. University Hospital Gasthuisberg, Dept. Respiratory Medicine, Lung Transplant and Respiratory Intermediate Care Unit, 49 Herestraat, B-3000 Leuven, Belgium. Tel.: þ32 16 341548; Fax: þ32 16 346803. E-mail address: [email protected] (R. Vos).
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.019 1521-6934/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
2
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
for obstetric reasons. Breastfeeding poses risks of neonatal exposure to immunosuppressants and is generally contraindicated. © 2014 Published by Elsevier Ltd.
Introduction In 1958, the first newborn following organ transplantation (living-related renal transplantation) was successfully delivered [1]. Nowadays, >14,000 solid-organ transplant (SOT) recipients, mostly renal recipients, have delivered, with >95% rate of successful pregnancies reported [2]. Pregnancy following heart (HTx), heartelung (H þ LTx), or lung transplantation (LTx), however, is much less prevalent. The first successful pregnancy after HTx was reported in 1988, following H þ LTx in 1993 and after LTx in 1996 [3e5]. 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 e 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 [2]. 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 [6]. 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 þ 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 [2]. During the past years, smaller case series additionally have reported on a limited number of HTx, H þ LTx, or LTx recipients [7e9]. 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 þ LTx recipients, compared to some 907 pregnancies by 596 kidney recipients and 103 pregnancies by 65 liver recipients [2]. 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 [7]. Indeed, few SOT recipients are properly educated regarding the effect of organ transplantation on fertility, posttransplant contraception, or pregnancy [10]. 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 þ 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 3e6 months following transplantation, the level of immunosuppression is initially high, after which it is subsequently tapered to maintenance levels over the following 6e12 months. Accordingly, SOT recipients are generally advised to delay pregnancy for at least 1e2 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. Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
3
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 [11]. 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) [12] (Table 1). In order to maximize fetal well-being, physicians should thus preferably switch to “older” and “safer” medications before or soon after conception. Fetalematernal 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 [13e15]. 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 [16]. 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 3e4%, which is similar to the general population [17]. 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 [18e20]. 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 [2,21,22]. In particular, babies of HTx recipients are born closer to term (mean gestational age 36.8 weeks) and have higher
Table 1 FDA pregnancy categories for commonly used immunosuppressive drugs in solid organ transplantation (adapted from Refs. [11], [23], and [58]). Drug Class (name)
FDA Category
Corticosteroid (prednisone, methylprednisolone/Medrol ) Antimetabolite agent (azathioprine/Imuran , mycophenolate/Cellcept /Myfortic ) Calcineurin inhibitor (cyclosporine/Neoral /Sandimmun , tacrolimus/Prograft /Prograf ) Mammalian target of rapamycin inhibitors sirolimus/Rapamune everolimus/Certican Anti-thymocyte globulin (Atgam , ATG , Thymoglobulin ) Monoclonal antibody Murine monoclonal Ab: Muromonomab-CD3/Orthoclone OKT3 Chimeric (murine-human) monoclonal Ab: Basiliximab/Simulect , Rituximab/Rituxan /Mabthera Humanized monoclonal Ab: Daclizumab/Zepanax , Alemtuzumab/Campath
B D C C D C C B C C
United States Food and Drug Agency (FDA) categories briefly defined: A: no evidence of increased risk of fetal abnormalities in well-controlled studies, B: no controlled studies, but no evidence of fetal risk, C: fetal risk cannot be ruled out, D: evidence of fetal risk, X: definitive evidence of fetal risks, such that use of the drug is contraindicated in women who are or may become pregnant, and N: FDA has not classified the drug Brand name.
Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
4
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
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. [23,24] 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 [2]. 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 [24]. 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 [25]. 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 [26]. 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) 1.97e5.69) [27]. However, no studies have demonstrated an increased incidence of other congenital malformations in the offspring of women treated with corticosteroids during pregnancy [27,28]. 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 [29]. 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 [30]. 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 [31]. 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. 4e5% 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 [13,32e34]. 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 [2]. No LTx recipients were exposed to mycophenolate during pregnancy [2]. It is recommended that female transplant recipients eliminate mycophenolate from the immunosuppressive regimen at least 6 weeks before planned conception [32]. 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% [35]. Please cite this article in press as: Vos R, et al., Pregnancy after heart and lung transplantation, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.07.019
R. Vos et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e17
5
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 [36e38]. 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 [39]. 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. [40] The prevalence of congenital anomalies after in utero exposure to CNI, however, is relatively low and comparable to the general population, approximately 5% [41], 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
