Pregnancy After Renal Transplantation

Ogburn et al. compiled the experience of 9 diabetic women from several centers who had pregnancy after renal transplantation for DN [290]. All were managed with prednisone and azathioprine; no transplant rejections occurred during pregnancy. Complications were frequent, including PET in 6, fetal distress in 6, and preterm delivery in all. Armenti and the US National Transplant Pregnancy Registry (NTPR) reported 28 pregnancies in diabetic renal transplant recipients after cyclosporine A (CsA) was added to the immunosuppression regimen to decrease acute rejection [291]. Rejection was observed in 4% and graft dysfunction in 11%. Preeclampsia was diagnosed in 17% although 59% had hypertension - 47% of the infants had neonatal complications.

Most studies of pregnancy after renal transplant included limited numbers of diabetic women among patients with other renal diseases [292,293]. GFR increases ~30% during pregnancy in women with renal allografts, but not to the extent of normal controls, and the gradual decline in CrCl the last 6 weeks of gestation is similar to controls [292,294]. The extent of increase in CrCl is dependent on preconception levels [294]. Early reports of fetal growth delay with CsA [295,296] were not confirmed in other small studies [297,298] and are difficult to compare with results in larger surveys. These report a prevalence of low birth weight of 23-63% and delivery <37 weeks in 38-75%, but most do not provide data on size-for-dates, so the contribution from prematurity to low birth weight is unclear [218, 292,293, 299,300]. Perinatal mortality ranges 30-270/1000 in pregnancies after renal allografts across several decades, but the high figures are in earlier pregnancies without recent improvements in perinatal management and antihypertensive-immunosuppressive therapy [292,293,299,301]. Many of the perinatal losses were in poorly controlled diabetic women. Prevention of infection is especially important in these immunosuppressed diabetic patients, and monthly urine cultures are recommended [218].

Predictors of increased risk for premature delivery in renal transplant patients include increased Cr level, hypertension before 28 weeks gestation [292,293,299], and graft dysfunction in the peripartum period [302]. Azathioprine is not associated with excess congenital malformations [218], and the prevalence rate with CsA was 4.1%, but the odds ratio of 3.83 vs other agents was not significant [300]. The NTPR also found no excess fetal malformations in 154 pregnancies [303]. Concern for toxic effects of maternal CsA treatment on fetal-placental function was not borne out in a study of nitric oxide synthase, endothelin-1 and tissue factor in human placentas [304]. There is limited information on outcomes with use of the newer immunosuppressants tacrolimus [301], the potentially reprotoxic mycophenolate mofetil [304], or the immunoglobulin G muromonab-CD3 (OKT3) [306] during pregnancy.

These studies of immuno-suppressive agents on perinatal outcome are not well controlled for confounders such as degree of hypertension and renal failure prior to pregnancy. CsA is associated with more hypertension in pregnancy [218,293] and later cardiovascular disease, which might be related to impaired basal and stimulated endothelial production of nitric oxide [307] or increased production of endothelin and thromboxane [218]. One wonders if there is more PET with CsA treatment than other agents - Hou gives a frequency of 29% [218]. A preliminary registry study of pregnancy outcomes with the newer immunosuppressive agents Neoral and tacrolimus showed similar high rates of hypertension, PET, and prematurity [308]. In a survey of 175 children exposed to CsA in utero and followed to preschool and early school age, 16% were noted to have delays or need educational support [309]. This may not be significantly greater than for premature infants in the general population. Continuous fetal exposure to CsA seemingly impairs development or maturation of lymphocytes, with effects still apparent at one year of age, but none of 6 infants had clinical evidence of an immunodeficient state [310]. There is also concern about possible remote effects of maternal immunosuppression causing auto-immune or reproductive disorders in daughters of treated mothers [311,312], but long-term followup studies are still inadequate. Finally, the impact and potential mechanisms for effects of female gender on many aspects of renal transplantation have been reviewed [313,314].

Combined kidney-pancreas transplants prior to pregnancy have been reported several times [315-318], and the NTPR also reported 23 pregnancies after combined transplants [319]. In this group 25% had PET while 91% were hypertensive; 70% of deliveries were premature. Two-thirds of these gravidas were treated for some type of infections. Barrou et al reviewed 19 cases of pregnancy after simultaneous pancreas-kidney transplants reported to the International Pancreas Transplant Registry in the CsA era [320]. There were 19 live births with average birth weight 2150 + 680 gm and two major congenital malformations. Only one pancreas graft and one kidney graft were lost after pregnancy in two different recipients. Pancreas-kidney transplantation may reduce risk factors for the development of macroangiopathy but fails to halt progression of macrovascular diseases [321].

Beyond these studies, there has been hypothetical concern that pregnancy may adversely affect renal graft survival [294,297]. The NTPR reported an 11% frequency of rejection episodes during pregnancy or within 3 months postpartum in 197 CsA treated pregnancies [293]. CsA blood levels declined during pregnancy in groups with and without rejection. In a series of 29 women in southern Spain renal function remained stable during pregnancy in 72%, postpartum renal allograft deterioration was detected in 8 patients (28%), and 5 required reinitiation of dialysis at 4 months to 5 years after pregnancy [298]. Studies with long-term follow-up found no difference in graft survival or function between women who became pregnant and matched controls who did not [302,322,323]. Maternal and neonatal factors did not predict pancreas-kidney graft loss over two years postpartum in 6 of 37 diabetic women [324].On the other hand, renal graft failure seems to be greater after 2 or more pregnancies [325], an effect possibly related to pregnancy-induced anti-HLA immunization detected only by flow cytometric evaluation [326].

Lindheimer and Katz [327] and Susan Hou [218] provide guidelines on preconception counseling of women with renal transplants. Women should wait 2 years post-transplant with immunosuppression at maintenance levels (prednisone <15 mg/day, azathioprine <2 mg/kg/day, CsA <5 mg/kg/day) and no evidence of active graft rejection. This requires effective contraception. Renal function should show serum Cr <130 uM (<1.5 mg/dL) [327] or <163 uM (<2.0 mg/dl) [218] with 24-hr urine TPE <500 mg. Blood pressure and glycemic levels should be well controlled with medication, and post-transplant hyperglycemia should be ruled out in previously non-diabetic women [328,329].

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Blood Pressure Health

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