of Pregnancy After Transplantation: National Transplant Pregnancy Registry


Recipients


1005


Mean age at first transplant (yrs)


24 ± 6


Pretransplant pregnancy


31%


Pregnancies


1810


Mean transplant-conception interval (yrs)


5.3 ± 4


During pregnancy


Estimated conception range


July 1967–Aug 2015


Primary immunosuppressanta


Aza


CsA


Tac


Other


26%


47%


27%


<1%


MPA exposure


8%


Sirolimus exposure


1.2%


Hypertension treated


49%


Diabetes treated


8%


Preeclampsia


30%


Rejectionb


0.8%


After pregnancy


Postpartum rejectionb


1.8%


Graft loss within 2 yrs of delivery


5.8%


Outcomesc


1874


 Live births


75%


  Neonatal deaths


1.6%


 Miscarriages


18%


  Miscarriages with MPA exposure


21%


 Stillbirths


2%


 Ectopic pregnancies


1%


 Terminations


4%


Live births


1414


 Mean gestational age (wks)


35.9 ± 3.4


  Premature (<37 wks)


51%


  Early preterm (<34 wks)


21%


 Mean birthweight (g)


2567 ± 766


  Low (<2500 g)


42%


  Very low (<1500 g)


11%


 Cesarean section


54%


 Birth defects


4.3%


 Child follow-up (yrs)


13.7 ± 9.3


Long-term follow-up


Adult follow-up (yrs)


14.3 ± 9.5


Maternal deaths


18.2%


Average age of child at maternal death (yrs)


16 ± 7.9


214 children


Adequate graft function at last follow-up


63%



aAzathioprine and/or prednisone (Aza), cyclosporine or its modified form (CsA), tacrolimus (Tac), sirolimus, everolimus, mycophenolic acid products, or belatacept (other) mycophenolic acid products (MPA)


bBiopsy-proven-treated acute rejection


cIncludes multiple births




Murray et al. reported the first pregnancy after kidney transplant in a recipient who received a living donor kidney from her identical twin sister. The recipient was not on any immunosuppression. She became pregnant, had stable kidney function throughout her pregnancy, and delivered a healthy-term infant in 1958 [1]. This recipient had another pregnancy 2 years later and had good kidney function until she died from complications of dementia at the age of 76.


The first recipient with a pregnancy exposed to immunosuppression (azathioprine and prednisone) was reported in 1967 and delivered a healthy infant with no malformations. The mother’s graft function at 1.5 months postpartum and the infant’s health at 5 months were reported as favorable [2].


Since these first reports, there have been thousands of pregnancies reported worldwide. These pregnancies have demonstrated high incidences of hypertension and preeclampsia. Additionally, there are high rates of preterm and low-birthweight infants born to kidney transplant recipients. When recipients are maintained on drugs considered to be safe during pregnancy, the birth defect rate and long-term health of the children appear similar to that of the general population. Of note, mycophenolic acid (MPA)-based immunosuppressive medications are not considered safe during pregnancy due to increased risks of miscarriage and birth defects and a specific pattern of birth defects. Discontinuation of MPA or replacement with an alternative medication is recommended before conception and throughout pregnancy [35].


Pregnancy Management Guidelines


General posttransplant pregnancy management guidelines are outlined in Table 15.2. These guidelines have been expanded from the original preconception guidelines proposed in 1976 by obstetrician John Davison and colleagues [6]. Although proposed over 40 years ago, most of the original guidelines are still followed with adaptions for modern immunosuppression. These early guidelines included good general health for at least 2 years after the transplant, stature compatible with good obstetric outcome, no proteinuria, no significant hypertension, no evidence of renal rejection, no evidence of renal obstruction, stable renal function, and stable immunosuppressive therapy [6].


Table 15.2

Pregnancy after transplantation: management options
























































Prepregnancy


Counsel recipients to defer conception for at least 1 year after transplantation, using adequate contraception


Assess graft function


Consider comorbid conditions (i.e., diabetes, hypertension) and optimize their management


Assess vaccination status


Explore etiology of original disease; refer to genetic counseling where appropriate


Discuss the high-risk nature of these pregnancies and the need for close monitoring of graft function, overall health, and fetal growth and development


Prenatal


Perform accurate early diagnosis and dating of pregnancy


Monitor transplant function and immunosuppressive drug levels every 4 weeks until 32 weeks, then every 2 weeks until 36 weeks, and then weekly until delivery


Perform monthly urine culture


Monitor graft function; biopsy as needed


Monitor for infection


Monitor for hypertension, proteinuria, and preeclampsia


Screen for gestational diabetes


Discuss potential risks of intrauterine growth restriction, preterm birth, low birthweight


Perform fetal surveillance


Labor and delivery


Vaginal delivery is optimal; cesarean delivery for obstetric reasons


Postnatal


Monitor graft function closely; any graft dysfunction may require biopsy


Very closely monitor immunosuppressive drug levels for at least 3 months postpartum, especially if dosages changed during pregnancy


Discuss breastfeeding option


Discuss the need for contraception


Monitor for postpartum depression, medication nonadherence


Fertility, Contraception, and Family Planning


Fertility is usually restored after successful kidney transplantation, and one must be aware of the potential for pregnancy even shortly after transplantation. A discussion of contraception should take place prior to the recipient leaving the hospital [7]. It is recommended that female transplant recipients use adequate contraception and defer conception for 1–2 years after transplantation. “Active preparation for pregnancy” should be individualized to each woman’s needs [8].


Recommending the best contraception for kidney transplant recipients is challenging given the many considerations with comorbid conditions and potential interactions with medications. One must weigh the potential risks of an unplanned pregnancy versus the theoretical risks of contraception [9]. The Centers for Disease Control has adapted contraceptive recommendations from the World Health Organization, which are published as the US Medical Eligibility Criteria for Contraceptive Use (USMEC) [10]. These guidelines help practitioners when counseling transplant recipients regarding conceptive methods.


Tubal ligation and barrier methods were reported as the most commonly used contraceptive methods in surveys of kidney transplant recipients [1113]. Recently, intrauterine devices (IUDs) and the progesterone implants, which are long-acting, effective, and reversible contraceptives, have been recommended for kidney recipients [9]. Progesterone-only hormonal contraceptives are also considered safe for transplant recipients [14]. There are theoretical risks of IUD use including potential for infection and reduction in efficacy due to interactions with immunosuppressives [1517]; however, two studies have shown no reduction in efficacy of IUDs due to immunosuppression [12, 18]. It has been proposed that IUDs be recommended for transplant recipients with uncomplicated courses or for those who are maintaining IUDs that were inserted pretransplantation [14]. For those recipients with a complicated course, initiating use of an IUD is not recommended.


For kidney transplant recipients with well-controlled hypertension and stable graft function, recommending estrogen-containing contraceptives is reasonable for those who do not have thromboembolic risks [9]. In one study of 36 kidney recipients using oral or transdermal low-dose hormonal contraception, only two recipients discontinued the contraceptive: one due to thromboembolic event and the other due to liver test abnormalities. Overall, contraception was 100% effective with no pregnancies occurring, and despite the risks, i.e., hypertension and altered liver function, hormonal contraception should be considered [19]. An American Society of Transplantation (AST) consensus conference found no evidence that combined oral contraceptives were associated with adverse consequences among transplant patients whose hypertension was well-controlled [16]. Similarly, the theoretical concern that estrogen-containing contraceptives could affect immunosuppressant drug levels has not been shown to be clinically significant; thus it has been concluded that combined oral contraceptives are suitable for solid-organ transplant recipients when appropriately monitored [17]. For recipients with a complicated medical course, combined oral contraceptive use is not recommended [14].


Unplanned pregnancies increase the risks to the mother and child. Ideally, post transplant pregnancy should be planned with the involvement of the recipient, her partner, and her transplant team. Issues to consider in preparing a recipient for pregnancy are discussion of the high-risk nature of such pregnancies, genetic counseling, medication changes, plans for careful monitoring of graft function and drug levels, prompt treatment of infections, superimposed hypertension and other comorbidities, and coordination of obstetric, transplant, and neonatal care [7].


Overview of Immunosuppressive Agents


To prevent organ rejection, virtually all kidney transplant recipients take a primary immunosuppressive medication and one or two adjunct immunosuppressives, uninterrupted during pregnancy. Pregnancy outcomes reported to the NTPR as of January 2014 by primary immunosuppressant are listed in Table 15.3. Some recipients, in conjunction with their transplant team, may temporarily switch to different medications that are safer in pregnancy.


Table 15.3

NTPR: pregnancy outcomes in female kidney transplant recipients

























































































































































 

Azathioprine and/or prednisonea


Cyclosporine-basedb


Tacrolimus-basedb


Recipients (n)


243


482


254


 Maternal factors (n = pregnancies)


448


822


427


 Mean transplant-to-conception interval (yrs)


6.8 ± 4.9


4.7 ± 3.5


4.8 ± 3.3


 Hypertension during pregnancy


25%


60%


53%


 Diabetes during pregnancy


5%


9%


9%


 Infection during pregnancy


16%


21%


20%


 Preeclampsia


22%


32%


35%


 Rejection episode during pregnancyc


1%


1%


2%


 Mean serum creatinine (mg/dl)


  Before pregnancy


1.1 ± 0.4


1.4 ± 0.4


1.2 ± 0.3


  During pregnancy


1.2 ± 0.5


1.4 ± 0.6


1.3 ± 0.9


  After pregnancy


1.2 ± 0.6


1.5 ± 0.8


1.3 ± 0.5


 Graft loss within 2 yrs of delivery


4%


7%


9%


Outcomes (n)d


463


852


439


 Terminations


4%


5%


2.3%


 Miscarriages


12%


16%


24.4%


 Ectopic


1%


1%


0.5%


 Stillborn


2%


2%


1.4%


 Live births


81%


76%


71.5%


Live births (n)


374


645


314


 Mean gestational age (wks)


36.4 ± 3.3


35.8 ± 3.4


35.4 ± 3.6


  Premature (<37 wks)


47%


52%


52%


 Mean birthweight (g)


2734 ± 718


2507 ± 749


2522 ± 821


  Low birthweight (<2500 g)


35%


44%


42%


 Cesarean section


51%


51%


58%


 Newborn complications


37%


42%


52%


 Birth defects


2.2%


4%


8%b


  Neonatal deaths n (%)


6 (1.3%)


11 (1.7%)e


5 (1.6%)


  (Within 30 days of birth)



aNo calcineurin inhibitor


bMPA exposure during pregnancy: cyclosporine (4%), tacrolimus (23%)


cBiopsy-proven acute rejection only


dIncludes multiple births


eIncludes 24-week quadruplet pregnancy; all newborn died cyclosporine-based regimens (brand name or generic formulations of cyclosporine and cyclosporine, USP modified) and tacrolimus-based regimens (brand name and generic formulations of tacrolimus and brand name tacrolimus extended release); regimens may include azathioprine or MPA and/or prednisone


A description of the most commonly used maintenance immunosuppressive agents with their potential for teratogenicity follows.


Prednisone


Prednisone is generally considered safe for use during pregnancy and poses minimal risk to the developing fetus at therapeutic dosages. A meta-analysis of non-transplanted women who took oral corticosteroids during the first trimester did not show a higher rate of major anomalies, although there was a 3.4-fold increase in oral clefts. Animal reproductive studies had similar findings [20], but neither later analyses nor NTPR findings confirm the increase in oral clefts [21, 22].


Azathioprine


At an adjunctive dose (≤1 mg/kg/d), azathioprine is considered a safe option for use during pregnancy. Since the introduction of calcineurin inhibitors (CNI), azathioprine is most often used as adjunctive therapy. In the early days of transplantation, azathioprine was used as a primary immunosuppressant with or without steroids. Animal studies associated azathioprine with embryonic resorption and/or fetal anomalies, when administered at doses similar to the human primary immunosuppressant dose (>2 mg/kg/d). Preterm delivery and fetal growth restriction have been noted, but without any predominant structural malformation pattern [23]. Data from the NTPR and other large cohorts shows no increase in the incidence of malformations or an obvious pattern of malformations among offspring exposed to azathioprine [2426].


Cyclosporine


Clinical outcomes data have demonstrated that it is safe for recipients to be maintained on cyclosporine during pregnancy. In the 1980s, the CNI cyclosporine supplanted azathioprine as the preferred primary immunosuppressant due to lower rejection rate and increased graft survival. Although there is a potential risk of fetal growth restriction [27], the teratogenic risk of cyclosporine is minimal. In animal studies, fetal abnormalities and toxicities were noted at higher dosages than those used clinically [28]. Early reports raised concerns about the safety of cyclosporine use during pregnancy [29], but studies have not shown an increased incidence or pattern of birth defects with exposure to cyclosporine [3, 30].


Tacrolimus


Tacrolimus, a CNI introduced in the 1990s and currently the most commonly used primary immunosuppressant prescribed to transplant recipients, is also considered safe for use during pregnancy, although its pharmacokinetics during pregnancy renders trough levels more difficult to interpret [31, 32]. In animal studies, fetal resorptions occurred at doses higher than those in clinical use; surviving fetuses appeared no different than controls in a lower dosage group [33]. In general, clinical data from the NTPR and other large reports have not revealed an increase in the incidence of malformations or a specific pattern of malformations among offspring exposed to tacrolimus in utero [7, 34].


Mycophenolic Acid Products


Neither of the two available oral mycophenolic acid (MPA) products, the mofetil ester (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is considered safe for use during pregnancy. MPA products have widely replaced azathioprine as an adjunctive immunosuppressive to a primary CNI, with or without prednisone.


It is recommended that females of childbearing potential use two forms of effective contraception while taking MPA products, and whenever possible, MPA should be discontinued prior to conceiving. When a patient approaches her healthcare provider to plan a pregnancy, strategies such as replacement of MPA with azathioprine along with adding or increasing prednisone should be considered in an attempt to balance the risks to the transplanted kidney and the risks to the fetus [5]. A recent NTPR study showed no increase in acute rejections during pregnancy or postpartum in kidney transplant recipients who discontinued and/or switched MPA preconception [5].


Animal studies revealed developmental toxicity, malformations, intrauterine death, and intrauterine growth restriction at MPA doses within the recommended clinical doses based on body surface area [35, 36]. Post-marketing surveillance and NTPR data demonstrated that exposure to MPA during pregnancy is associated with an increased incidence of miscarriage, 42%, and a specific pattern and increased incidence of malformations, 15% [3537]. These risks have not been noted in pregnancies fathered by transplant recipients taking MPA [38].


Sirolimus and Everolimus


There have been successful pregnancies exposed to sirolimus and everolimus, and the limited clinical data regarding sirolimus and everolimus exposure in female transplant recipients have not demonstrated a specific pattern of birth defects in offspring. NTPR data include 19 recipients (all organ types) with 22 pregnancies, resulting in 18 live births; 2 infants had birth defects, 1 with tetralogy of Fallot and the other had vermian hypoplasia of the cerebellum [3]. Further studies are warranted to determine if these medications can be considered safe for use during pregnancy [7, 3941]. In animal studies, in utero sirolimus exposure resulted in decreased fetal weights and delayed ossification of skeletal structures, but no teratogenicity was noted. These agents are most often used in conjunction with a CNI. When administered in combination with cyclosporine to pregnant animals, there were increased fetal mortality, increased numbers of resorptions, and decreased numbers of live fetuses, suggesting increased toxicity in conjunction with calcineurin inhibition [41].


Similarly, animal studies exhibited preimplantation loss and fetal resorptions when everolimus was administered before mating through organogenesis [42]. No malformations were noted in the case reports of pregnancy exposure to everolimus to date.


Fertility may be reduced when male transplant recipients take sirolimus [43, 44]. Based on the 16 pregnancies fathered by male transplant recipients taking sirolimus (18 live births; no reported birth defects) reported to the NTPR, there does not appear to be an increased risk for pregnancies fathered while taking sirolimus. There are no studies to date whether everolimus has the same effect on male fertility as sirolimus.


Belatacept


Data regarding human pregnancy exposure to belatacept are very limited; therefore, its use during pregnancy is not recommended. Belatacept, introduced in 2011, is given via infusion monthly as primary maintenance immunosuppression in combination with MPA and prednisone. In animal studies, belatacept was associated with a small percentage of maternal toxicity (infections), resulting in increased pup mortality; at doses >20 times than the human dose, surviving pups displayed no abnormalities or malformations [45]. The NTPR has reported on one kidney recipient who took belatacept throughout two unplanned pregnancies. In addition to belatacept, she was maintained on MPA through the first 3 weeks of one pregnancy which was miscarried at 11 weeks. Her next pregnancy while being maintained on belatacept resulted in a healthy 38-week 3090 g infant with no reported birth defects, although MPA was not discontinued until the pregnancy was discovered in the second trimester [3]. To date, there are no additional reports of pregnancies exposed to belatacept.


Transplant to Conception Interval (TCI)


Based on clinical observation and historical data, it has long been recommended that transplant recipients wait between 1 and 2 years after transplant to conceive provided they meet preconception guidelines [6, 16, 46]. Early NTPR studies of cyclosporine-treated mothers associated lower live birthrates, lower birthweights, and more neonatal deaths with shorter TCIs [47, 48].


Comparative studies of kidney recipients who conceived at intervals greater than 2 years, 5 years, and 10 years posttransplant did not reveal significant differences in outcomes [49]. Graft function during pregnancy and postpartum was similar among the groups, as were pregnancy outcomes (Table 15.4). It was concluded that kidney recipients should not be discouraged from conceiving based on longer TCI.
Nov 3, 2020 | Posted by in Uncategorized | Comments Off on of Pregnancy After Transplantation: National Transplant Pregnancy Registry
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