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In this issue of Liver Transplantation, the article from the United Kingdom by Christopher et al.,1 provides important center-specific information with regard to pregnancy in the liver transplant recipient population. The authors note that infertility is common in women with end-stage liver disease, and with successful transplantation, recipients have the ability to successfully carry a pregnancy. This single-center experience illustrates favorable outcomes for the majority of the recipients studied.

Indications for liver transplantation among the recipients were varied. The comorbidities and pregnancy-related problems that were noted included the usual anticipated problems, and none of the maternal deaths reported appeared to be related to pregnancy. Percentages of prematurity, low birth weight, and cesarean section were similar to other reports in the literature.2–4 Immunosuppression included cyclosporine- and tacrolimus-based regimens. Interestingly, azathioprine without a calcineurin inhibitor was used in 1 case and mycophenolate mofetil was used together with tacrolimus in 2 cases.

One might argue, what could be new and interesting about another single-center report of successful pregnancies after transplantation? The first known posttransplant pregnancy, which occurred in 1958 and reported in 1963, was in a patient who had received a kidney from her identical twin.5 Some years later, in 1976, Davison and colleagues6 reported a single case of a successful pregnancy outcome in a kidney transplant recipient. More importantly, the authors summarized the literature and presented a management scheme useful during pregnancy, as well as a set of criteria for counseling female transplant recipients contemplating pregnancy. Although the criteria were originally designed for the renal recipient, they have been adapted for other organ recipients. Recommendations include the time interval from transplant to pregnancy, stability of graft function, management of comorbidities, and assessment of renal function. In the 1976 paper, the authors concluded that pregnancy did not appear to have an adverse effect on the recipient's transplant function. There remained the question as to the potential for effects on the newborn, as well as the question whether pregnancy might have a long-term effect on the function of the transplanted organ.6

The first known pregnancy in a liver transplant recipient occurred in 1978.7 The physicians were concerned that the transplant could have an unfavorable effect on the course of pregnancy, that the required immunosuppressive medications might be teratogenic, and that pregnancy could precipitate rejection of the transplanted liver. The recipient, who was maintained on prednisone and azathioprine, delivered a healthy boy at 40.5 weeks' gestation weighing 2,400 g. At the time of the report, 1 year after the delivery, the mother and infant were in excellent health.

Although we have learned much over the years from case reports, center reports, and registry data, how we counsel recipients considering pregnancy after transplantation may be related to how we view these data.

Interpreting the report from Christopher et al. from a more favorable perspective, there were 71 pregnancies reported in 45 women who previously had liver failure, and through a successful transplant, could now have children. None experienced graft loss, and there were no maternal deaths related to pregnancy. The majority of the births were by vaginal delivery; most of the pregnancies were not complicated by preeclampsia, rejection, or renal impairment. The median birth weight was above the range of low birth weight, defined as less than 2,500 g. None of the newborns had congenital birth defects. Most pregnancies occurred with a transplant-to-conception interval of more than 1 year, which would be considered appropriate timing. Successful pregnancy outcomes were also reported in the group that conceived less than 1 year from transplantation.

If one were to take a more pessimistic view of this report, there are some concerns. A pregnancy was terminated as a consequence of deterioration of graft function in a previously stable graft. Cesarean section occurred in 40% of the deliveries, compared with a background rate of 23% in England for all pregnancies. Although the median birth weight for live births was 2,688 g, the range started at 544 g; only 70% of the newborn were of normal birth weight. Thirty percent were low birth weight or very low birth weight, a higher percentage than the prevalence for all births in England. Also of note is that one of the children with very low birth weight demonstrated a delay in developmental milestones and has cognitive impairment. There are, of course, unknown potential long-term effects on the growth and development of the premature children and risks of in utero immunosuppressive exposure.

Although there were no graft losses during pregnancy, 7 patients subsequently underwent retransplantation, although all were more than 1 year postpartum. Five of these 7 had an episode of rejection during pregnancy. Could there be the potential that some events are initiated during pregnancy, even though we arbitrarily set certain time frame considerations for a pregnancy-related graft loss? The rates of acute cellular rejection were significantly higher in the group that had a pregnancy less than 1 year from transplant (33% vs. 14%, respectively). Finally, there were 3 patients who had been pregnant and died during follow-up, although all the deaths occurred more than 1 year postpartum and were thought to be unrelated to pregnancy. Depending on the timing of the death, this poses the problem of a young child left without a mother.

From the extremes of the interpretation of these data, one could conclude that pregnancy after liver transplantation is associated with favorable outcomes for mother and newborn, but also that pregnancy may be associated with unpredictable graft deterioration, with newborns who may have potential long-term disabilities, and with a risk of loss of a parent.

Case-control studies in kidney transplantation have suggested that pregnancy is not associated with an adverse effect on graft function.8, 9 A recent study by Rahamimov and colleagues10 showed that graft and patient survival from kidney transplantation to end of follow-up over a 15-year period in women who had conceived did not differ in the rates observed in 177 women in a matched control group, and there were no differences between the groups with regard to long-term graft function. Similar studies have not been performed in liver transplant recipients.

McKay and Josephson11 recently summarized pregnancy outcome data learned from 3 registries, including the United Kingdom Pregnancy Registry, the European Dialysis and Transplantation Association, and the National Transplantation Pregnancy Registry (NTPR) in the United States. The NTPR was established in 1991 for the purpose of studying the outcomes of pregnancy in solid organ recipients, in both female recipients and those pregnancies fathered by male recipients. The NTPR is an ongoing study that includes not only immediate outcomes but also follow-up of the recipient and offspring.

Ultimately, how can we counsel our patients and best manage them? Probably the most important message is to recognize that information is available. Transplant recipients present a unique set of issues. In order to remain healthy, they must take a number of medications and often have associated comorbidities. Outcomes of recipients differ among recipient organ groups and that comorbidities likely play more of a role than we realize.

Successful outcomes have been reported to the NTPR among 121 female liver recipients reporting 202 pregnancies with 205 outcomes.12 There were 151 live births, with a mean gestational age of 37 weeks and a mean birth weight of 2,687 g; newborn outcomes appear similar to that in the report by Christopher et al.1 Prematurity occurred in 35% of newborn, and 34% were low birth weight (<2,500 g). The incidence of birth defects in the newborn was not increased over that seen in the general population. Seven percent of the pregnancies were complicated by rejection, while 8% of recipients reported a graft loss within two years of pregnancy, most related to chronic rejection and hepatitis recurrence.

From another NTPR analysis, female liver transplant recipients with biopsy-proven acute rejection during pregnancy had worse newborn outcomes and an increased risk of recurrent rejection postpartum.2

We generally think of the ideal pregnancy as one without medication exposure. The myriad of complex medical problems and immunosuppressive and other medication exposures, however, make this impossible for a transplant recipient considering parenthood. Any comparison of pregnancy to the presumed ideal will not work in favor of the transplant recipient, whether from a standpoint of maternal survival or pregnancy outcome. Thus, the ideal should probably not be used for comparison. Within populations of women who must take medications to maintain their pregnancy, their outcomes will likely define their own specific issues and norms.

Worldwide efforts at data collection through case reports, center reports, and registries help to guide us and remain a valuable means to understand pregnancy and transplantation issues. All centers are encouraged to report long-term follow-up of their recipient pregnancies to the literature as well as to existing registries. Published case and center reports also provide valuable data. While we continue to evaluate long-term outcome data, assess risks, and strive to improve care, we are reminded that successful pregnancies can occur in the setting of multiple medication exposures and comorbidities.

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