Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1123e1136
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2
Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation C. Blume, MD, Nephrologist a, b, *, S. Pischke, MD, Gastroenterologist c, € ynck, MD, Gynecologist d, F. von Versen-Ho H.H. Günter, MD, Gynecologist d, M.M. Gross, PhD, Midwife e a
Leibniz University Hannover, Institute of Technical Chemistry, Hannover, Germany Department of Nephrology, Hannover Medical School, Hannover, Germany Outpatient Clinic for Liver Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany d Department of Obstetrics, Gynaecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany e Midwifery Research and Education Unit, Department of Obstetrics, Gynaecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany b c
Keywords: pregnancy liver transplantation kidney transplantation immunosuppression outcome
In this article, we focus on the biggest groups of organ transplant recipients, patients with a kidney or liver graft. Among these patients, about one sixth included women of childbearing potential. Therefore, the wish of getting pregnant is frequent in these peculiar patients, and careful planning and management of the pregnancies requires the expertise of obstetricians, midwives and transplant experts. Altogether, the outcome of the pregnancies in these women is acceptable. About 75% off all pregnancies ended successfully with live births, and this is comparable if not superior to pregnancies in healthy women. This success might be caused not only by the special and intensive care provided to these high-risk pregnancies by the transplant centres but also by the low rate of unplanned pregnancies. The risk of rejections and organ loss after delivery is about 10%, and it is slightly enhanced in liver transplant recipients (LTRs) in comparison to kidney graft recipients (KTRs) but the number of organ losses in direct association with a pregnancy is rare. However, there is not only a higher frequency of pregnancy-associated
* Corresponding author. Cornelia Blume, Institute for Technical Chemistry, Callinstr. 3, 30167 Hannover, Germany. Tel.: þ49 511 762 2963. E-mail addresses: [email protected], [email protected] (C. Blume).
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.021 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
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disorders such as pre-eclampsia and preterm delivery but also an acceleration of hypertension, new-onset diabetes mellitus and newly arising infections also favoured by the maintained immunosuppressive therapy. This implies a specialized ‘control system’ for these pregnant women that comprises ultrasound and Doppler investigation for risk assessment, infection screening, suitable therapy and the choice of non-teratogenic immunosuppressives. Antihypertensive treatment must be well balanced and adjusted to the possible growth-retarding effect on the foetus as well as on the co-morbidity of the mother. Finally, supplementation of vitamin D and iron is much more important in these transplanted women than in healthy pregnant women as vitamin D deficiency and anaemia are discussed to have an impact on pre-eclampsia and preterm delivery. These claims are widely discussed. Furthermore, the current literature is systematically reviewed by Scopus analysis. © 2014 Elsevier Ltd. All rights reserved.
Introduction Pregnancies in kidney or liver transplant recipients (KTRs/LTRs) are difficult to manage for transplant physicians and obstetricians. Counselling of female transplant recipients wishing to give birth and supervision of a pregnancy in transplanted women require expertise and tactful counselling as previous abdominal surgery, concomitant chronic diseases and immunosuppressive medication might present a possible source of complications. The first pregnancies in a KTR and in an LTR have been described in 1958 [1] and 1978 [2]. Since then, there have been numerous successful pregnancy outcomes in many types of transplant recipients. However, the safety of pregnancy for individual recipients must include the consideration of risk for the mother, baby and transplanted organ and requires the partnership and support of the obstetrician, transplant team and other specialists. In 2011, 100,528 recipients received a solid organ transplant worldwide, of which about 26,000 were transplanted in Europe (http://de.statista.com/) and about 25,000 in the United States (http://de.statista.com/). Among these recipients, one sixth consisted of women of childbearing age or girls (17 years) who may become pregnant later in life. Pregnancy, whether planned or unplanned, has been considerably more common in recent years due to the increased fertility of transplanted women as a result of the modern immunosuppressive drugs that do not affect hormonal regulation as negatively was the case previously. Therefore, the topic ‘pregnancy after organ transplantation’ is nowadays as relevant as never before. In this article, we focus on the largest groups among solid organ recipients, which are the groups of patients receiving kidney or liver transplants. In recent years, several studies investigated the circumstances of pregnancies in transplant recipients. However, most of these studies rely on retrospectively assessed uni-centre experiences. Since the 1990s, three large multi-centric registries have been established: the National Transplantation Pregnancy Registry (NTPR) in the United States, a registry in the United Kingdom and another one in Australia/New Zealand [3,4]. In addition to including a review of these registries, here we report on the recently published single-centre reports on pregnancies in LTRs or KTRs. This overview should provide co-orientation to physicians and midwives confronted with transplanted women who wish to become pregnant or are already pregnant. Chances and risks Actually, there are 100,000 female KTRs and 14,000 female LTRs living in the United States who are of reproductive age [3,4]. As restoration of fertility has become frequent after kidney or liver transplantation, this situation presents a chance for young women wishing to have a baby. Nevertheless, a pregnancy after transplantation can be associated with several risks (Fig. 1).
C. Blume et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1123e1136
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Fig. 1. Risks of pregnancy in transplant recipients for mother and child.
A pregnancy under the circumstances of organ transplantation is a balancing act between the efforts of the mother and the child. A pregnancy bears the risk of deterioration of the transplanted organ of the mother, which is far more life threatening in LTRs as there is no alternative such as continuous liver replacement therapy to liver transplantation so far, whereas KTRs can always rely on dialysis therapy. The full burden of a pregnancy in an organ recipient also includes the threat of aggravation of certain co-morbidities such as cardiovascular diseases, hypertension, anaemia as well as the insecurity of adaptation of the immunosuppressive therapy management during the whole gestation as a contribution to the growing foetus. About one third of all pregnancies during organ transplantation are not successful and do not continue longer than the first trimester due to a higher rate of miscarriages. The rest of the pregnancies carried out are mostly happy, and the rate of intrauterine or neonatal deaths is low. Furthermore, malformations and disabilities in children of mothers with organ transplantation are rare. In live-born infants of transplanted women and of the non-transplant population, major congenital malformations have been observed in nearly the same frequency of approximately 3% [5]. Whether or not unsuccessful pregnancies are associated with the more frequent infectious diseases in organ transplant recipients or with the necessity of a continuous immunosuppressive treatment in these patients cannot be answered. However, a pregnancy in a woman with liver or kidney transplantation needs careful management by an experienced team consisting of obstetricians, midwives and transplant specialists and close medical guidance. In 2011 and 2012, two large meta-analyses by Deshpande et al. investigated 50 studies on pregnancy in KTRs [3] and eight studies on pregnancies in LTRs [4]. In 4706 pregnancies of 3570 kidney transplant recipients, live birth occurred in 73.5%, whereas in 450 pregnancies of 306 LTRs, live birth was even more frequent with 76.9% (Fig. 2a), but this difference failed to reach statistical significance (p ¼ 0.08). Generally, the live birth rate of transplanted women was higher than the live birth rate in the general US population with 66.7% (Fig. 2) [3,4]. A direct statistical comparison of the registry data of the different groups is not possible, as there is no matched-pair study comparing pregnant transplant recipients and pregnant non-transplanted women. However, this strongly suggests that the rate of live births in transplant recipients is not lower in comparison to the general population. The majority of pregnancies in transplant recipients is safe and uncomplicated.
Differences between pregnancies after kidney or liver transplantation Women with kidney transplants often suffer from hypertension and kidney graft function may not be comparable to a healthy pregnant woman's kidney function. The newly transplanted kidney graft may
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Fig. 2. (a) Rate of life births in the US general population, kidney and liver transplant recipients. (b) Statistically significant different rates of pre-eclampsia in the US general population after kidney and liver transplant recipients. (c) Statistically significant different rates of caesarean section in the US general population after kidney and liver transplant recipients. (d) Rate of preterm birth in the US general population, kidney and liver transplant recipients.
start with a glomerular filtration rate (GFR) of >60 ml/min which slowly decreases in the following years after transplantation to 50% of this best value or lower. Normally, kidney graft function is lowered by an average of 2e3 ml/min and year due to chronic damage, and the survival rate of these organs is between 9 and 12 years in Europe and between 5 and 9 years in the United States (http://de.statista.com/). There is a strong linkage between kidney function and the onset of pregnancy-associated diseases such as preeclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets syndrome) or others. Shortly, affected kidney function or a vascular pathology associated with kidney disease builds up a strong predisposition for these pregnancy disorders. KTRs have an already pathologically altered and inflamed endothelium. The pregnancy lifts this immunological stress in these cases, and therefore the rate of complicated pregnancies in KTRs is comparably higher than in LTRs. As a result, pre-eclampsia, preterm delivery and caesarean sections could be observed more frequently in KTRs than in LTRs (Figs. 2bed; the data of these figures rely on meta-analyses of different study cohorts [3,4]). In contrast to this comparison of the meta-analyses, there are currently two uni-centric studies summarizing the outcome of pregnancies in LTRs and KTRs in Poland [6] and in Germany [7]. In the latter, 115 pregnancies within a cohort of 37 LTRs and 34 KTRs were retrospectively analysed. Of these, 70% had a successful outcome. Coinciding with the previous meta-analyses, this study confirms an increased rate of preterm birth in KTRs in comparison to LTRs. Furthermore, as KTRs usually have a more hypertensive treatment than LTRs, this may negatively affect the perfusion of the uterine vasculature and therefore affect the nutrition of the growing foetus, and consequently the rate of babies with abnormally low birth weight is higher. Small-for-date babies are frequent in pregnancies of transplant patients and in pregnancies of women with hypertension; thus, an optimal adjustment of the blood pressure in pregnant transplant recipients is relevant to rule this cofactor out. The National High Blood Pressure Education Program (NHBPEP) Working Group Report on high blood pressure in pregnancy and the American College of Obstetrics and Gynaecology (ACOG) guidelines recommend the treatment of hypertension in pregnant women when the diastolic blood pressure is persistently above 105e110 mm Hg. Whether or not this causes damage to the transplanted kidney is not fully evaluated.
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KTRs need a higher total dosage of immunosuppressant than LTRs in which the phenomenon of graft tolerance with only low or no immunosuppressants is much more frequent [8]. As a consequence, immunosuppressive drug levels have to be adapted in response to the increasing weight all through the duration of a pregnancy in KTRs because rejection episodes have to be prevented. As the use of calcineurin inhibitors (CNIs) in KTRs also has a facilitating influence on hypertension, hyperlipidaemia and vasculopathy, it frequently aggravates these pregnancy disorders. The only available meta-analysis reported those complications in 44.5% of all pregnancies analysed [9]. Furthermore, the increased rate of post-transplant diabetes mellitus with tacrolimus treatment finds its equivalent in an increased rate of gestational diabetes mellitus in pregnant KTRs [10]. In consideration of these aggravating facts, it is quite astonishing that about 75% of all pregnancies in renal graft recipients are successful as measured by live births [11,12]. The determining factor for a positive outcome (defined by the absence of preeclampsia, foetal growth retardation and preterm delivery) was a good kidney graft function [13], estimated by a serum creatinine level of 1 mg/dl in a recent retrospective study of 41 pregnancies [14]. In any case, we consider that the suitable time point for a pregnancy in a female kidney transplanted woman of childbearing age should be carefully planned and be accompanied by a balanced antihypertensive treatment with close monitoring of foetal growth. Pregnancies in KTRs present more frequent complications than pregnancies in LTR. Systematic literature review As the two systematic reviews from Deshpande [3,4] included the most recent single-centre studies until 15 November 2010 [3] and 1 January 2011 [4], we performed a search via Scopus in May 2014. The search strategy encompassed the following terms: #1 “kidney transplant*” OR “renal transplant*”, #2 “liver Transplant”, #3 “pregnancy outcome”, #4: maternal outcome. The results were limited to English or German and covered the period from 2011. We excluded reviews, case reports and all further studies that did not present single- or multi-centre results or based on limited data. This resulted in several studies of the recent years [6,15e20]. Rejections and organ loss during or after pregnancy The specificity in pregnancy after liver transplantation is the fact that liver graft dysfunction or loss might lead to early maternal death, and this could be favoured by the general stress of a pregnancy on the grafted organ. The rate of rejections as observed in the big registries is generally higher in LTRs, especially post partum, in comparison to KTRs (Tables 1 and 2). Yet, the association of rejection with graft loss remains unclear. In line with this observation, the uni-centric studies comparing pregnancies in LTRs and KTRs confirmed an increased risk of rejections in pregnant LTRs in comparison to KTRs [7]. Rejections in the context of a pregnancy were present in 13% of LTRs, but only in 4% of KTRs. However, this comparison failed to reach statistical significance. In the NTPR [11], 13 of 121 women analysed died between 6 months and up to 13 years after a successful pregnancy. Importantly, this was due to recurrence of the liver disease (mostly hepatitis C) and other complications, not due to ongoing or relapsing liver graft rejection. In addition, KTRs experienced up to 14% kidney graft rejections during pregnancy and graft loss occurred in up to 6.9% within a time interval of 5 years after delivery, but renal graft function was only slightly decreased in most of the Table 1 Rejections and liver graft loss during or after pregnancies in liver transplant recipients. Reference/number of pregnancies
Rejection rate/acute events
Graft loss
1
Deshpande, 2012[4]/450 pregnancies
2e17% acute rejections
2
Kubo, 2014[20]/38 pregnancies
3 4
Blume, 2013[7]/62 pregnancies Alvaro, 2013[50]/30 pregnancies
6% LTRs during pregnancy, 3% LTRs after delivery 6% % rejections 10%
Up to 10.5% graft loss reported within 2 years after delivery Not reported No graft loss Not reported
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Table 2 Rejections and renal graft loss during or after pregnancies in kidney transplant recipients. Reference/number of pregnancies
Rejection rate/acute events
Graft loss
1
Hebral, 2014 [10]/61 pregnancies
No case of rejection
2
Rocha, 2013p[12]/24 pregnancies
No case of rejection
3 4 5 6 7
Blume, 2013[7]/53 pregnancies Bramham, 2013 [15]/105 pregnancies Celik, 2011[16]/31 pregnancies Deshpande, 2011[3]/4706 pregnancies Aivazoglou, 2011[13]/43 pregnancies
14% biopsy proven rejections 2% cases of acute rejection No case of rejection 3e4% acute rejections 2/31 KTRs (6% acute rejections)
11 cases of graft loss at a median time of 6 years after delivery No increased risk of graft loss versus non pregnant KTRs No graft loss No graft loss 2 graft losses within 2 years after delivery Up to 6.9% within 5 years after delivery 3% (1/31 KTRs)
studies (references 3e7 of Table 2). Altogether, kidney graft loss did not appear to be favoured by the pregnancy. There has always been the suggestion that new donor-specific antibodies are generated during pregnancy by exposion of paternal antigens by the growing fetus. In contrast, one recent study (reference 1 of Table 2) found only in 5.9% of all 46 KTRs with 61 pregnancies analysed the formation of antibodies relevant for the graft; the risk of anti-human leucocyte antigen (HLA) alloimmunization caused by pregnancies therefore was low. In fact, there are several tolerogenic mechanisms during pregnancy, supporting the acceptance of the growing foetus with paternal HLA antigens by the maternal immune system that might play a beneficial role in preventing organ rejection. One of these is the formation of HLA-G molecules as an inhibitor of the T lymphocytes, natural killer (NK) cells and antigen-presenting cells (APCs). In allogeneic transplantation, the expression of HLA-G protein significantly reduced acute rejection and showed an absence of chronic rejections [21]. Of note, the rate of rejections is highest in LTRs (Table 1) who usually have a lower total dosage of immunosuppression. This might reflect the underestimation of the importance of maintaining immunosuppressive therapy in this peculiar time interval when mothers tend to give their attention to the growing foetus or newborn. Rejections are more frequent in LTR than in KTR. Immunosuppressive drugs and pregnancy Lifelong immunosuppressive medication in solid organ transplant recipients is required to avoid rejection, but in the situation of a pregnancy this medication may present a potential danger for the unborn (Table 3). Most immunosuppressive drugs are able to reach the foetal circulation by crossing the placental barrier. However, due to an extensive first-pass metabolism in the foetal liver, the drug concentration of cyclosporine, tacrolimus and mycophenolate mofetil in the foetal blood was shown to be lowered as compared to non-pregnant women[22]. Calcineurin inhibitors Neither cyclosporine (4.9%) nor tacrolimus (4.2%) showed an increased rate of birth defects in comparison to the general US population (3e5%). Azathioprine There are several reports on azathioprine medication in pregnant women. While there is no increase in birth defects caused by this drug, a neonatal leukopenia could frequently be observed, but this usually normalizes within 1 year. Mammalian target of rapamycin inhibitors There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy. These drugs are well known for their antiproliferative effect, which is a benefit in patients who
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Table 3 Safety of immunosuppressive drugs during pregnancy (modified: Hirachan et al. Arab Journal of Nephrology and Transplantation. 2012). FDA safety classification
Observations There is no evidence of teratogenicity of steroids.
Tacrolimus
B e No evidence of risk in humans C e Risks cannot be ruled out
Cyclosporine
C e Risks cannot be ruled out
Everolimus/Sirolimus
C e Risks cannot be ruled out
Azathioprine
D e Positive evidence of risk
Mycophenolate Mofetil
D e Positive evidence of risk
Steroids
Preterm birth, transient hyperkalaemia and renal impairment have been observed frequently. Cyclosporine treatment does not lead to an increased ratio of malformations but it is associated with a low birth weight. Limited knowledge is available on the use of mTor inhibitors in pregnant women. But these medications are contraindicated in pregnancy and the antiproliferative effect of these drugs makes them a bad choice for immunosuppression in pregnant transplant recipients. Prematurity and low birth weight has been observed in pregnancies with azathioprine medication. Neonatal immunological manifestations as leukopenia, thrombocytopenia, thymic hypoplasia and decreased serum IgG, IgM and/or IgA levels have been observed, but these findings usually normalized within 1 year. Mycophenolate mofetil is strictly contraindicated in pregnancy. It has been associated with miscarriage and a wide spectrum of malformations in the offspring affecting ears, limbs, heart, oesophagus and kidney.
underwent transplantation for malignancies or developed malignancies after transplantation. In the situation of pregnancy, an antiproliferative effect might harm the foetus and disturb the development of the unborn. Future studies and data from the registries are necessary to obtain insights into the safety profile of these drugs in pregnancy. Mycophenolate mofetil The use of mycophenolate mofetil is contraindicated in pregnant women. This drug has been associated with an increased risk of miscarriage during the first trimester and several possible malformations, including ears, limbs, heart, oesophagus or kidneys or deformations in the upper oral tract such as cleft lip and palate [23]. Many pregnant transplant patients have the wish to lower the dose of immunosuppressive drugs or even to omit these drugs to avoid the potential side effects harming the development of the foetus. Thus, it is relevant to advise these patients that the regular intake of their immunosuppressive drugs is important to avoid potential rejection [24]. It is important to observe the clinical course and the levels of the immunosuppressive drugs closely to detect upcoming problems as early as possible [24]. Different problems may occur in different phases of the pregnancy: for example, morning sickness with potential vomiting and consecutive doubtful levels of the immunosuppressive therapy might occur within the first trimester, and a higher dose of immunosuppression is required in the second and the third trimesters to reach a stable level, while the body mass of the women and the metabolism capacity of the foetus increase [24]. Breastfeeding with immunosuppressive treatment The American Association of Pediatrics has made recommendations supporting breastfeeding by mothers taking prednisone and warns against breastfeeding by mothers taking cyclosporine, but there are still no recommendations for mothers taking tacrolimus, azathioprine or a mammalian target of rapamycin (mTor) inhibitor such as sirolimus or everolimus [25,26]. Mycophenolate mofetil, sirolimus and everolimus are contraindicated in pregnant women.
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Birth control e methods to be used Birth control is crucial, as unplanned pregnancies often bear several risks as early abortion due to not adaptation of drugs and others. The methods to be used have to be judged according to their possible side effects on the organ transplant recipients. The most commonly available methods are combined oral contraceptives, progesterone-only contraceptives, etonogestrel-containing contraceptive implants (e.g., Implanon) or levonorgestrel-containing intrauterine systems (LNG-IUS, trade name Mirena) and the progesterone-only injectable (Depo Provera). Estradiol-containing anti-contraceptives may increase hypertension and the risk of thrombosis in these patients [27], and their use has to be carefully weighed as there is a concern that drug interaction through the cytochrome 450 system may decrease the efficacy of immunosuppressive medications or hormonal contraception. Therefore, oestrogen-related contraindications combined with an 8% failure rate with typical use make combined hormonal methods less than ideal in transplanted women. The World Health Organization has issued Medical Eligibility Criteria (MEC) for contraceptive use among women with specific medical conditions, and combined hormonal methods are Category 4 (unacceptable risk) (WHO, Medical eligibility criteria for contraceptive use [28]). Depot medroxyprogesterone acetate (Depo-Provera), which has to be administered usually every three months by subcutaneous injection, is contraindicated in patients with active liver disease and therefore not suitable in LTRs and has been shown to have a depressing effect on bone density, and although reversible, this anti-contraceptive therefore is not favourable in transplanted patients with an already decreased mineralization due to the necessity of (mostly continuous) glucocorticoid therapy. In addition, contraceptive sub-dermal implants as a progestin-only method are considered to have this side effect. Intrauterine devices (IUDs) are mostly used, but here a careful infection screening should be performed as the milieu of the vagina may be altered by the use of immune suppression, which might favour bacterial infections or mycosis. By contrast, the use of copper-containing IUDs was not associated with increased vaginal or pelvic infections in human immunodeficiency virus (HIV)-infected patients [29]. Conventional birth control using preservatives is uncomplicated, but this method is not highly reliable. Anti-contraceptive drugs in transplant recipients might cause side effects and their reliability might be reduced. Care during pregnancy, labour and birth Antenatal care schemes vary according to their national guidelines. In general, healthy pregnant women visit every four weeks. The infection screening should include urine screening and vaginal floor, and suitable anti-infective drugs not interacting with the ongoing immunosuppressant therapy or potentially causing malformations are to be elected. Here, especially antimycotics but also certain antibiotics have to be handled with care. Furthermore, a careful infection screening, blood pressure screening and therapy should be performed in cooperation with the transplant medical team. Hypertension in KTRs is more common compared to hypertension in LTRs (54.2% vs. 27.2% [3,4]) and favours pregnancy disorders. As soon as the viability of the baby is reached at 24 weeks of gestation, foetal well-being should be monitored at least every 2 weeks. These visits should include a Doppler screening of the uterine and umbilical arteries and of the kidney graft artery as an indicator of an increased risk of development of pre-eclampsia and intrauterine growth restriction [30]. Furthermore, routine laboratory parameters, including the determination of serum creatinine and urine examination, should be investigated and vital parameters should be examined. As instrumental delivery should be performed for obstetric reasons only, and the presence of a transplanted organ as the renal graft in the pelvis is not an adequate reason to decide for caesarean sections [24], the women's preferences may be considered in the mode of birth. These women have experienced chronic diseases and major abdominal surgery, and are aware of their lifelong immunosuppressive medication. Expecting a child may be a very real experience of being healthy at least in reproductive terms. Pregnancies in transplant recipients should been monitored by a multidisciplinary team of transplant physicians, obstetricians and midwives.
Centre/Ref K ¼ kidney L ¼ liver
No. pregn.
Maternal age in years, mean (range)
Live births in n (%)
Abortions in % Ectopic preg. in % Stillbirth in %
Gestation, mean in weeks, ± SD (range)
Caesarean section, n (%)
Birth weight, mean in g, ± SD (range)
Gestation
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
2
Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation C. Blume, MD, Nephrologist a, b, *, S. Pischke, MD, Gastroenterologist c, € ynck, MD, Gynecologist d, F. von Versen-Ho H.H. Günter, MD, Gynecologist d, M.M. Gross, PhD, Midwife e a
Leibniz University Hannover, Institute of Technical Chemistry, Hannover, Germany Department of Nephrology, Hannover Medical School, Hannover, Germany Outpatient Clinic for Liver Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany d Department of Obstetrics, Gynaecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany e Midwifery Research and Education Unit, Department of Obstetrics, Gynaecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany b c
Keywords: pregnancy liver transplantation kidney transplantation immunosuppression outcome
In this article, we focus on the biggest groups of organ transplant recipients, patients with a kidney or liver graft. Among these patients, about one sixth included women of childbearing potential. Therefore, the wish of getting pregnant is frequent in these peculiar patients, and careful planning and management of the pregnancies requires the expertise of obstetricians, midwives and transplant experts. Altogether, the outcome of the pregnancies in these women is acceptable. About 75% off all pregnancies ended successfully with live births, and this is comparable if not superior to pregnancies in healthy women. This success might be caused not only by the special and intensive care provided to these high-risk pregnancies by the transplant centres but also by the low rate of unplanned pregnancies. The risk of rejections and organ loss after delivery is about 10%, and it is slightly enhanced in liver transplant recipients (LTRs) in comparison to kidney graft recipients (KTRs) but the number of organ losses in direct association with a pregnancy is rare. However, there is not only a higher frequency of pregnancy-associated
* Corresponding author. Cornelia Blume, Institute for Technical Chemistry, Callinstr. 3, 30167 Hannover, Germany. Tel.: þ49 511 762 2963. E-mail addresses: [email protected], [email protected] (C. Blume).
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.021 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
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disorders such as pre-eclampsia and preterm delivery but also an acceleration of hypertension, new-onset diabetes mellitus and newly arising infections also favoured by the maintained immunosuppressive therapy. This implies a specialized ‘control system’ for these pregnant women that comprises ultrasound and Doppler investigation for risk assessment, infection screening, suitable therapy and the choice of non-teratogenic immunosuppressives. Antihypertensive treatment must be well balanced and adjusted to the possible growth-retarding effect on the foetus as well as on the co-morbidity of the mother. Finally, supplementation of vitamin D and iron is much more important in these transplanted women than in healthy pregnant women as vitamin D deficiency and anaemia are discussed to have an impact on pre-eclampsia and preterm delivery. These claims are widely discussed. Furthermore, the current literature is systematically reviewed by Scopus analysis. © 2014 Elsevier Ltd. All rights reserved.
Introduction Pregnancies in kidney or liver transplant recipients (KTRs/LTRs) are difficult to manage for transplant physicians and obstetricians. Counselling of female transplant recipients wishing to give birth and supervision of a pregnancy in transplanted women require expertise and tactful counselling as previous abdominal surgery, concomitant chronic diseases and immunosuppressive medication might present a possible source of complications. The first pregnancies in a KTR and in an LTR have been described in 1958 [1] and 1978 [2]. Since then, there have been numerous successful pregnancy outcomes in many types of transplant recipients. However, the safety of pregnancy for individual recipients must include the consideration of risk for the mother, baby and transplanted organ and requires the partnership and support of the obstetrician, transplant team and other specialists. In 2011, 100,528 recipients received a solid organ transplant worldwide, of which about 26,000 were transplanted in Europe (http://de.statista.com/) and about 25,000 in the United States (http://de.statista.com/). Among these recipients, one sixth consisted of women of childbearing age or girls (17 years) who may become pregnant later in life. Pregnancy, whether planned or unplanned, has been considerably more common in recent years due to the increased fertility of transplanted women as a result of the modern immunosuppressive drugs that do not affect hormonal regulation as negatively was the case previously. Therefore, the topic ‘pregnancy after organ transplantation’ is nowadays as relevant as never before. In this article, we focus on the largest groups among solid organ recipients, which are the groups of patients receiving kidney or liver transplants. In recent years, several studies investigated the circumstances of pregnancies in transplant recipients. However, most of these studies rely on retrospectively assessed uni-centre experiences. Since the 1990s, three large multi-centric registries have been established: the National Transplantation Pregnancy Registry (NTPR) in the United States, a registry in the United Kingdom and another one in Australia/New Zealand [3,4]. In addition to including a review of these registries, here we report on the recently published single-centre reports on pregnancies in LTRs or KTRs. This overview should provide co-orientation to physicians and midwives confronted with transplanted women who wish to become pregnant or are already pregnant. Chances and risks Actually, there are 100,000 female KTRs and 14,000 female LTRs living in the United States who are of reproductive age [3,4]. As restoration of fertility has become frequent after kidney or liver transplantation, this situation presents a chance for young women wishing to have a baby. Nevertheless, a pregnancy after transplantation can be associated with several risks (Fig. 1).
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Fig. 1. Risks of pregnancy in transplant recipients for mother and child.
A pregnancy under the circumstances of organ transplantation is a balancing act between the efforts of the mother and the child. A pregnancy bears the risk of deterioration of the transplanted organ of the mother, which is far more life threatening in LTRs as there is no alternative such as continuous liver replacement therapy to liver transplantation so far, whereas KTRs can always rely on dialysis therapy. The full burden of a pregnancy in an organ recipient also includes the threat of aggravation of certain co-morbidities such as cardiovascular diseases, hypertension, anaemia as well as the insecurity of adaptation of the immunosuppressive therapy management during the whole gestation as a contribution to the growing foetus. About one third of all pregnancies during organ transplantation are not successful and do not continue longer than the first trimester due to a higher rate of miscarriages. The rest of the pregnancies carried out are mostly happy, and the rate of intrauterine or neonatal deaths is low. Furthermore, malformations and disabilities in children of mothers with organ transplantation are rare. In live-born infants of transplanted women and of the non-transplant population, major congenital malformations have been observed in nearly the same frequency of approximately 3% [5]. Whether or not unsuccessful pregnancies are associated with the more frequent infectious diseases in organ transplant recipients or with the necessity of a continuous immunosuppressive treatment in these patients cannot be answered. However, a pregnancy in a woman with liver or kidney transplantation needs careful management by an experienced team consisting of obstetricians, midwives and transplant specialists and close medical guidance. In 2011 and 2012, two large meta-analyses by Deshpande et al. investigated 50 studies on pregnancy in KTRs [3] and eight studies on pregnancies in LTRs [4]. In 4706 pregnancies of 3570 kidney transplant recipients, live birth occurred in 73.5%, whereas in 450 pregnancies of 306 LTRs, live birth was even more frequent with 76.9% (Fig. 2a), but this difference failed to reach statistical significance (p ¼ 0.08). Generally, the live birth rate of transplanted women was higher than the live birth rate in the general US population with 66.7% (Fig. 2) [3,4]. A direct statistical comparison of the registry data of the different groups is not possible, as there is no matched-pair study comparing pregnant transplant recipients and pregnant non-transplanted women. However, this strongly suggests that the rate of live births in transplant recipients is not lower in comparison to the general population. The majority of pregnancies in transplant recipients is safe and uncomplicated.
Differences between pregnancies after kidney or liver transplantation Women with kidney transplants often suffer from hypertension and kidney graft function may not be comparable to a healthy pregnant woman's kidney function. The newly transplanted kidney graft may
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Fig. 2. (a) Rate of life births in the US general population, kidney and liver transplant recipients. (b) Statistically significant different rates of pre-eclampsia in the US general population after kidney and liver transplant recipients. (c) Statistically significant different rates of caesarean section in the US general population after kidney and liver transplant recipients. (d) Rate of preterm birth in the US general population, kidney and liver transplant recipients.
start with a glomerular filtration rate (GFR) of >60 ml/min which slowly decreases in the following years after transplantation to 50% of this best value or lower. Normally, kidney graft function is lowered by an average of 2e3 ml/min and year due to chronic damage, and the survival rate of these organs is between 9 and 12 years in Europe and between 5 and 9 years in the United States (http://de.statista.com/). There is a strong linkage between kidney function and the onset of pregnancy-associated diseases such as preeclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets syndrome) or others. Shortly, affected kidney function or a vascular pathology associated with kidney disease builds up a strong predisposition for these pregnancy disorders. KTRs have an already pathologically altered and inflamed endothelium. The pregnancy lifts this immunological stress in these cases, and therefore the rate of complicated pregnancies in KTRs is comparably higher than in LTRs. As a result, pre-eclampsia, preterm delivery and caesarean sections could be observed more frequently in KTRs than in LTRs (Figs. 2bed; the data of these figures rely on meta-analyses of different study cohorts [3,4]). In contrast to this comparison of the meta-analyses, there are currently two uni-centric studies summarizing the outcome of pregnancies in LTRs and KTRs in Poland [6] and in Germany [7]. In the latter, 115 pregnancies within a cohort of 37 LTRs and 34 KTRs were retrospectively analysed. Of these, 70% had a successful outcome. Coinciding with the previous meta-analyses, this study confirms an increased rate of preterm birth in KTRs in comparison to LTRs. Furthermore, as KTRs usually have a more hypertensive treatment than LTRs, this may negatively affect the perfusion of the uterine vasculature and therefore affect the nutrition of the growing foetus, and consequently the rate of babies with abnormally low birth weight is higher. Small-for-date babies are frequent in pregnancies of transplant patients and in pregnancies of women with hypertension; thus, an optimal adjustment of the blood pressure in pregnant transplant recipients is relevant to rule this cofactor out. The National High Blood Pressure Education Program (NHBPEP) Working Group Report on high blood pressure in pregnancy and the American College of Obstetrics and Gynaecology (ACOG) guidelines recommend the treatment of hypertension in pregnant women when the diastolic blood pressure is persistently above 105e110 mm Hg. Whether or not this causes damage to the transplanted kidney is not fully evaluated.
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KTRs need a higher total dosage of immunosuppressant than LTRs in which the phenomenon of graft tolerance with only low or no immunosuppressants is much more frequent [8]. As a consequence, immunosuppressive drug levels have to be adapted in response to the increasing weight all through the duration of a pregnancy in KTRs because rejection episodes have to be prevented. As the use of calcineurin inhibitors (CNIs) in KTRs also has a facilitating influence on hypertension, hyperlipidaemia and vasculopathy, it frequently aggravates these pregnancy disorders. The only available meta-analysis reported those complications in 44.5% of all pregnancies analysed [9]. Furthermore, the increased rate of post-transplant diabetes mellitus with tacrolimus treatment finds its equivalent in an increased rate of gestational diabetes mellitus in pregnant KTRs [10]. In consideration of these aggravating facts, it is quite astonishing that about 75% of all pregnancies in renal graft recipients are successful as measured by live births [11,12]. The determining factor for a positive outcome (defined by the absence of preeclampsia, foetal growth retardation and preterm delivery) was a good kidney graft function [13], estimated by a serum creatinine level of 1 mg/dl in a recent retrospective study of 41 pregnancies [14]. In any case, we consider that the suitable time point for a pregnancy in a female kidney transplanted woman of childbearing age should be carefully planned and be accompanied by a balanced antihypertensive treatment with close monitoring of foetal growth. Pregnancies in KTRs present more frequent complications than pregnancies in LTR. Systematic literature review As the two systematic reviews from Deshpande [3,4] included the most recent single-centre studies until 15 November 2010 [3] and 1 January 2011 [4], we performed a search via Scopus in May 2014. The search strategy encompassed the following terms: #1 “kidney transplant*” OR “renal transplant*”, #2 “liver Transplant”, #3 “pregnancy outcome”, #4: maternal outcome. The results were limited to English or German and covered the period from 2011. We excluded reviews, case reports and all further studies that did not present single- or multi-centre results or based on limited data. This resulted in several studies of the recent years [6,15e20]. Rejections and organ loss during or after pregnancy The specificity in pregnancy after liver transplantation is the fact that liver graft dysfunction or loss might lead to early maternal death, and this could be favoured by the general stress of a pregnancy on the grafted organ. The rate of rejections as observed in the big registries is generally higher in LTRs, especially post partum, in comparison to KTRs (Tables 1 and 2). Yet, the association of rejection with graft loss remains unclear. In line with this observation, the uni-centric studies comparing pregnancies in LTRs and KTRs confirmed an increased risk of rejections in pregnant LTRs in comparison to KTRs [7]. Rejections in the context of a pregnancy were present in 13% of LTRs, but only in 4% of KTRs. However, this comparison failed to reach statistical significance. In the NTPR [11], 13 of 121 women analysed died between 6 months and up to 13 years after a successful pregnancy. Importantly, this was due to recurrence of the liver disease (mostly hepatitis C) and other complications, not due to ongoing or relapsing liver graft rejection. In addition, KTRs experienced up to 14% kidney graft rejections during pregnancy and graft loss occurred in up to 6.9% within a time interval of 5 years after delivery, but renal graft function was only slightly decreased in most of the Table 1 Rejections and liver graft loss during or after pregnancies in liver transplant recipients. Reference/number of pregnancies
Rejection rate/acute events
Graft loss
1
Deshpande, 2012[4]/450 pregnancies
2e17% acute rejections
2
Kubo, 2014[20]/38 pregnancies
3 4
Blume, 2013[7]/62 pregnancies Alvaro, 2013[50]/30 pregnancies
6% LTRs during pregnancy, 3% LTRs after delivery 6% % rejections 10%
Up to 10.5% graft loss reported within 2 years after delivery Not reported No graft loss Not reported
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Table 2 Rejections and renal graft loss during or after pregnancies in kidney transplant recipients. Reference/number of pregnancies
Rejection rate/acute events
Graft loss
1
Hebral, 2014 [10]/61 pregnancies
No case of rejection
2
Rocha, 2013p[12]/24 pregnancies
No case of rejection
3 4 5 6 7
Blume, 2013[7]/53 pregnancies Bramham, 2013 [15]/105 pregnancies Celik, 2011[16]/31 pregnancies Deshpande, 2011[3]/4706 pregnancies Aivazoglou, 2011[13]/43 pregnancies
14% biopsy proven rejections 2% cases of acute rejection No case of rejection 3e4% acute rejections 2/31 KTRs (6% acute rejections)
11 cases of graft loss at a median time of 6 years after delivery No increased risk of graft loss versus non pregnant KTRs No graft loss No graft loss 2 graft losses within 2 years after delivery Up to 6.9% within 5 years after delivery 3% (1/31 KTRs)
studies (references 3e7 of Table 2). Altogether, kidney graft loss did not appear to be favoured by the pregnancy. There has always been the suggestion that new donor-specific antibodies are generated during pregnancy by exposion of paternal antigens by the growing fetus. In contrast, one recent study (reference 1 of Table 2) found only in 5.9% of all 46 KTRs with 61 pregnancies analysed the formation of antibodies relevant for the graft; the risk of anti-human leucocyte antigen (HLA) alloimmunization caused by pregnancies therefore was low. In fact, there are several tolerogenic mechanisms during pregnancy, supporting the acceptance of the growing foetus with paternal HLA antigens by the maternal immune system that might play a beneficial role in preventing organ rejection. One of these is the formation of HLA-G molecules as an inhibitor of the T lymphocytes, natural killer (NK) cells and antigen-presenting cells (APCs). In allogeneic transplantation, the expression of HLA-G protein significantly reduced acute rejection and showed an absence of chronic rejections [21]. Of note, the rate of rejections is highest in LTRs (Table 1) who usually have a lower total dosage of immunosuppression. This might reflect the underestimation of the importance of maintaining immunosuppressive therapy in this peculiar time interval when mothers tend to give their attention to the growing foetus or newborn. Rejections are more frequent in LTR than in KTR. Immunosuppressive drugs and pregnancy Lifelong immunosuppressive medication in solid organ transplant recipients is required to avoid rejection, but in the situation of a pregnancy this medication may present a potential danger for the unborn (Table 3). Most immunosuppressive drugs are able to reach the foetal circulation by crossing the placental barrier. However, due to an extensive first-pass metabolism in the foetal liver, the drug concentration of cyclosporine, tacrolimus and mycophenolate mofetil in the foetal blood was shown to be lowered as compared to non-pregnant women[22]. Calcineurin inhibitors Neither cyclosporine (4.9%) nor tacrolimus (4.2%) showed an increased rate of birth defects in comparison to the general US population (3e5%). Azathioprine There are several reports on azathioprine medication in pregnant women. While there is no increase in birth defects caused by this drug, a neonatal leukopenia could frequently be observed, but this usually normalizes within 1 year. Mammalian target of rapamycin inhibitors There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy. These drugs are well known for their antiproliferative effect, which is a benefit in patients who
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Table 3 Safety of immunosuppressive drugs during pregnancy (modified: Hirachan et al. Arab Journal of Nephrology and Transplantation. 2012). FDA safety classification
Observations There is no evidence of teratogenicity of steroids.
Tacrolimus
B e No evidence of risk in humans C e Risks cannot be ruled out
Cyclosporine
C e Risks cannot be ruled out
Everolimus/Sirolimus
C e Risks cannot be ruled out
Azathioprine
D e Positive evidence of risk
Mycophenolate Mofetil
D e Positive evidence of risk
Steroids
Preterm birth, transient hyperkalaemia and renal impairment have been observed frequently. Cyclosporine treatment does not lead to an increased ratio of malformations but it is associated with a low birth weight. Limited knowledge is available on the use of mTor inhibitors in pregnant women. But these medications are contraindicated in pregnancy and the antiproliferative effect of these drugs makes them a bad choice for immunosuppression in pregnant transplant recipients. Prematurity and low birth weight has been observed in pregnancies with azathioprine medication. Neonatal immunological manifestations as leukopenia, thrombocytopenia, thymic hypoplasia and decreased serum IgG, IgM and/or IgA levels have been observed, but these findings usually normalized within 1 year. Mycophenolate mofetil is strictly contraindicated in pregnancy. It has been associated with miscarriage and a wide spectrum of malformations in the offspring affecting ears, limbs, heart, oesophagus and kidney.
underwent transplantation for malignancies or developed malignancies after transplantation. In the situation of pregnancy, an antiproliferative effect might harm the foetus and disturb the development of the unborn. Future studies and data from the registries are necessary to obtain insights into the safety profile of these drugs in pregnancy. Mycophenolate mofetil The use of mycophenolate mofetil is contraindicated in pregnant women. This drug has been associated with an increased risk of miscarriage during the first trimester and several possible malformations, including ears, limbs, heart, oesophagus or kidneys or deformations in the upper oral tract such as cleft lip and palate [23]. Many pregnant transplant patients have the wish to lower the dose of immunosuppressive drugs or even to omit these drugs to avoid the potential side effects harming the development of the foetus. Thus, it is relevant to advise these patients that the regular intake of their immunosuppressive drugs is important to avoid potential rejection [24]. It is important to observe the clinical course and the levels of the immunosuppressive drugs closely to detect upcoming problems as early as possible [24]. Different problems may occur in different phases of the pregnancy: for example, morning sickness with potential vomiting and consecutive doubtful levels of the immunosuppressive therapy might occur within the first trimester, and a higher dose of immunosuppression is required in the second and the third trimesters to reach a stable level, while the body mass of the women and the metabolism capacity of the foetus increase [24]. Breastfeeding with immunosuppressive treatment The American Association of Pediatrics has made recommendations supporting breastfeeding by mothers taking prednisone and warns against breastfeeding by mothers taking cyclosporine, but there are still no recommendations for mothers taking tacrolimus, azathioprine or a mammalian target of rapamycin (mTor) inhibitor such as sirolimus or everolimus [25,26]. Mycophenolate mofetil, sirolimus and everolimus are contraindicated in pregnant women.
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Birth control e methods to be used Birth control is crucial, as unplanned pregnancies often bear several risks as early abortion due to not adaptation of drugs and others. The methods to be used have to be judged according to their possible side effects on the organ transplant recipients. The most commonly available methods are combined oral contraceptives, progesterone-only contraceptives, etonogestrel-containing contraceptive implants (e.g., Implanon) or levonorgestrel-containing intrauterine systems (LNG-IUS, trade name Mirena) and the progesterone-only injectable (Depo Provera). Estradiol-containing anti-contraceptives may increase hypertension and the risk of thrombosis in these patients [27], and their use has to be carefully weighed as there is a concern that drug interaction through the cytochrome 450 system may decrease the efficacy of immunosuppressive medications or hormonal contraception. Therefore, oestrogen-related contraindications combined with an 8% failure rate with typical use make combined hormonal methods less than ideal in transplanted women. The World Health Organization has issued Medical Eligibility Criteria (MEC) for contraceptive use among women with specific medical conditions, and combined hormonal methods are Category 4 (unacceptable risk) (WHO, Medical eligibility criteria for contraceptive use [28]). Depot medroxyprogesterone acetate (Depo-Provera), which has to be administered usually every three months by subcutaneous injection, is contraindicated in patients with active liver disease and therefore not suitable in LTRs and has been shown to have a depressing effect on bone density, and although reversible, this anti-contraceptive therefore is not favourable in transplanted patients with an already decreased mineralization due to the necessity of (mostly continuous) glucocorticoid therapy. In addition, contraceptive sub-dermal implants as a progestin-only method are considered to have this side effect. Intrauterine devices (IUDs) are mostly used, but here a careful infection screening should be performed as the milieu of the vagina may be altered by the use of immune suppression, which might favour bacterial infections or mycosis. By contrast, the use of copper-containing IUDs was not associated with increased vaginal or pelvic infections in human immunodeficiency virus (HIV)-infected patients [29]. Conventional birth control using preservatives is uncomplicated, but this method is not highly reliable. Anti-contraceptive drugs in transplant recipients might cause side effects and their reliability might be reduced. Care during pregnancy, labour and birth Antenatal care schemes vary according to their national guidelines. In general, healthy pregnant women visit every four weeks. The infection screening should include urine screening and vaginal floor, and suitable anti-infective drugs not interacting with the ongoing immunosuppressant therapy or potentially causing malformations are to be elected. Here, especially antimycotics but also certain antibiotics have to be handled with care. Furthermore, a careful infection screening, blood pressure screening and therapy should be performed in cooperation with the transplant medical team. Hypertension in KTRs is more common compared to hypertension in LTRs (54.2% vs. 27.2% [3,4]) and favours pregnancy disorders. As soon as the viability of the baby is reached at 24 weeks of gestation, foetal well-being should be monitored at least every 2 weeks. These visits should include a Doppler screening of the uterine and umbilical arteries and of the kidney graft artery as an indicator of an increased risk of development of pre-eclampsia and intrauterine growth restriction [30]. Furthermore, routine laboratory parameters, including the determination of serum creatinine and urine examination, should be investigated and vital parameters should be examined. As instrumental delivery should be performed for obstetric reasons only, and the presence of a transplanted organ as the renal graft in the pelvis is not an adequate reason to decide for caesarean sections [24], the women's preferences may be considered in the mode of birth. These women have experienced chronic diseases and major abdominal surgery, and are aware of their lifelong immunosuppressive medication. Expecting a child may be a very real experience of being healthy at least in reproductive terms. Pregnancies in transplant recipients should been monitored by a multidisciplinary team of transplant physicians, obstetricians and midwives.
Centre/Ref K ¼ kidney L ¼ liver
No. pregn.
Maternal age in years, mean (range)
Live births in n (%)
Abortions in % Ectopic preg. in % Stillbirth in %
Gestation, mean in weeks, ± SD (range)
Caesarean section, n (%)
Birth weight, mean in g, ± SD (range)
Gestation
