Use Of Therapeutic Immunosuppressants During Pregnancy

Advances in available therapeutic immunosuppressive drug regimens, coupled with advances in organ transplant technology, have not only increased the life expectancy of recipients but also greatly improved quality of life. As a result, a population of women previously unable to conceive or maintain a conceptus, is now able to maintain a pregnancy following an organ or tissue (allograft) transplant procedure. Indeed, pregnancy as a rule is well tolerated after graft function has become stable and adequate, and many "normal" births have been documented in women undergoing immunosuppressive therapy throughout pregnancy (Lewis et al. 1983; Klintmalm et al. 1984; Pickrell et al. 1988; Ville et al. 1992; Tincani et al. 1992; Buchanan et al. 1992; Many et al. 1992; Markowitz et al. 1993; Farber and Nall, 1993). This is not to say that pregnancy after organ transplantation is no longer regarded as high-risk; clear associations with increased risk of hypertension, preeclampsia, intrauterine growth retardation, and prematurity exist (Riely 2001). For example, a study of 238 women receiving immunosuppressive drug regimens during pregnancy found that rates for both prematurity and small-for-gestational-age (SGA) infants were high (49% and 29%, respectively) (Pabelick et al. 1991). Regimens that included cyclosporine A resulted in 66% prematurity (43% with azathioprine), and 56% SGA-babies (19% with azathioprine). Nonetheless, successful pregnancies have been achieved following all kinds of solid organ transplantations, with thousands of pregnancies now reported (Armenti et al. 2000).

Pregnant women who have previously received allograph transplants require therapeutic immunosuppressants throughout pregnancy to maintain the allograft and to prevent rejection. Past and presently used drugs for immune suppression after organ transplant all cross the placenta (Little 1997; Scott et al. 2002; Prevot et al. 2002), a fact that has raised many concerns about possible harmful effects of the maternal immunosuppressant therapy on fetal development. Effectively evaluating such effects, or tracing adverse outcomes to individual drugs, is complicated by the previously mentioned general need for multiple drug therapy in transplant recipients. At the time of writing, immunosuppressive drug protocols to prevent allograph rejection typically combine use of one of the two most effective primary immuno-suppressants (cyclosporine A or tacrolimus) with one or more adjunctive agents (azathioprine, mycophenolate mofetil, sirolimus, corticosteroids) (Gaston 2001; Tendron et al. 2002). Different individuals then require uniquely tailored drug combinations to prevent rejection responses, a part of immunosuppressant management that can prove daunting and continues to complicate tracing of adverse effects to individual drugs or drug combinations.

For the above reasons, case reports and prospective studies of pregnancy outcome with different drug therapies, and following different transplant procedures, continue to be of considerable interest. The first study estimating maternal and fetal risk from tacrolimus therapy after organ transplantation was published by Jain et al. in 1997. These authors studied 27 pregnancies in 21 female liver recipients who received tacrolimus before and throughout pregnancy. On the day of delivery, mean tacrolimus concentrations were 4.3 ng/ml in placenta versus 1.5, 0.7 and 0.5 ng/ml in maternal, cord, and child plasma, respectively, and 0.6 ng/ml in first breast milk. Two premature infants of 23 and 24 weeks gestation died shortly after birth, and one live infant displayed unilateral renal polycystic disease; however, all 25 of the surviving infants showed satisfactory postnatal growth and development.

Wu et al. (1998) similarly examined pregnancy outcome in 22 liver transplant patients who received tacrolimus, cyclosporine A, azathioprine, and/or a low-dose steroid therapy. Twenty-three children were born (one set of twins) with three preterm births; no congenital malformations or unusual infections were observed in the children; and postnatal growth and development were appropriate during the course of the study. Miniero et al. (2002) recently reported pregnancy outcome for 56 renal transplant recipients who were maintained on cyclosporine A, azathioprine, tacroli-mus, or corticosteroids before and during pregnancy. There were four transplant rejections, two of which were irreversible; 36 infants were born, and 20 abortions reported. Complications occurred in 16 of 36 nonaborted pregnancies; 16 of these 36 infants were born at term, and 20 were pre-term. The children were followed up for periods ranging from 2 months to 13 years, and their development was described as normal.

The successful use of tacrolimus and prednisone in a pregnant lung transplant recipient was recently reported, with a healthy 2,208-g female infant born at 34 weeks gestation (Kruszka and Gherman 2002). The three-drug combination of mycophenolate mofetil, tacrolimus, and prednisone, was given to a kidney transplant patient throughout pregnancy; a female child was born prematurely at week 353/7, was reported to have possible teratogenic effects in the form of hypoplastic nails and short fifth fingers, but again was reported as growing and developing normally (Pergola et al. 2001).

Two of the studies mentioned previously reported a teratogenic outcome in pregnant women who received immunosuppressive therapy. Increased risk of such morphologic defects was an early concern of physicians monitoring pregnancies of transplant recipients. Early reports suggested that cyclosporine A administration during pregnancy may increase risk of some birth defects, including dysmorphic facial appearance (Reznik et al. 1987), cataracts (Tyden et al. 1989; Dieperink et al. 1987), and cleft palate (Bung and Dietmar 1991). However, recent retrospective investigations have examined considerably more births to immune-suppressed mothers, and concluded that structural birth defects are not increased by use of therapeutic immunosuppressants during pregnancy (Riely 2001; Armenti et al. 2002; Tendron et al. 2002).

Many collective reports and considerable data are available, therefore, showing increased pregnancy complications in organ transplant recipients, although apparently healthy children appear to be the most common result of such pregnancies. Relatively few studies have monitored immune development in these children, however, and later-life immune dysfunctions, including deficits or exacerbated responses (e.g., increased autoimmune diseases), remain a concern (Holladay 1999; Prevot et al. 2002). Long-term follow-up data from infants exposed to therapeutic immuno-suppressive drug regimens throughout pregnancy also remain limited due to the relatively recent advent of this population, and will be required to determine if postpubertal or adult immune dysfunctions are more prevalent in humans exposed to immune-suppressive drugs during development.

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