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 [24–26].

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% [35–37]. 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, 39–41]. 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.