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Immunosuppressants Pose Challenge in Pregnancy : Balancing immunosuppression with the health of the woman and fetus requires team approach.


 

WASHINGTON — Balancing immunosuppression in a pregnant allograft transplant patient with the health of the woman and her fetus requires a team approach between high-risk obstetricians and transplant physicians, according to one expert speaking at a meeting sponsored by the National Kidney Foundation.

“Pregnancy in the transplant recipient, aside from the issue of renal dysfunction, poses a unique set of considerations, and that's because of immunosuppressants,” said Michelle A. Josephson, M.D., of the University of Chicago.

None of the immunosuppressants used for transplantation—cyclosporine, tacrolimus, azathioprine, steroids, rapamycin, and mycophenolate mofetil—are rated pregnancy category A, using the Food and Drug Administration classification system. In fact, most are rated category C, meaning there are no data on their use in humans during pregnancy. “All medications used to prevent rejection cross the maternal-placental interface,” she pointed out.

Despite the lack of data and potential risks, a consensus group convened in 2003 by the Women's Health Committee of the American Society of Transplantation recommended immunosuppression be maintained during pregnancy to avoid rejection.

Graft rejection can be difficult to discern during pregnancy because serum creatinine levels are low during this period, and small changes can be missed, Dr. Josephson said. In addition, abnormalities that turn up on liver function tests can have a number of etiologies. For these reasons, graft dysfunction during pregnancy warrants appropriate investigation—by biopsy if necessary.

“If rejection occurs, it can be treated with steroids,” Dr. Josephson recommended. Inadequate immunosuppression, graft instability, and rejection likely affect the graft prognosis. However, age, number of allografts, and repeat pregnancies don't seem to impact graft function and prognosis.

The consensus group also agreed that a high-risk obstetrician and a transplant physician should manage pregnant transplant patients. Obstetricians should optimize maternal health, maintain normal glycemia, ensure adequate fetal growth, and anticipate preterm birth. The transplant physician should ensure maintenance of graft function and aggressively manage hypertension and preeclampsia. Cesarean section is not indicated except for standard obstetric reasons.

During the conference, experts addressed a number of concerns for this group of patients to develop management recommendations. “We recognized that the risk of prematurity in the population was high. We realized that intrauterine growth retardation is high,” said Dr. Josephson. In addition, during pregnancy renal transplant recipients may have renal insufficiency, hypertension, and preeclampsia.

Traditionally, it was recommended to wait 2 years after transplantation to try to become pregnant. However, newer immunosuppressants have made rejection less of an issue. This opens the possibility for a more individualized approach to timing. The group agreed pregnancy could be attempted once certain criteria had been met:

▸ No graft rejection in the year after transplant.

▸ Adequate and stable graft function (creatinine level less than 1.5 mg/dL, no or minimal proteinuria).

▸ No acute infections that could impact the fetus.

▸ Maintenance of immunosuppression at stable dosing.

There are, however, special circumstances that could impact the recommendations:

▸ Rejection outcome within the first year (consider further graft assessment with biopsy and GFR).

▸ Maternal age.

▸ Comorbid factors that may impact pregnancy and graft function.

▸ The patient's history of compliance.

The timing considerations could be met at 1 year post transplant, depending on the individual.

Care Varies for Transplant Recipients

A survey of the management practices of allograft transplant recipients who are or wish to become pregnant highlights the lack of consensus on the care of these patients.

Perhaps the most important finding of the survey was that the care of these women generally has been based on experience, patient preference, or center protocol, not on any available evidence, Dr. Josephson said.

“After nearly 50 years and thousands of deliveries, we should know what we're doing, but do we?” she asked.

The Women's Health Committee of the American Society of Transplantation sent out a questionnaire to all 257 transplant centers in the United States to determine the current practices for the care of transplant recipients who wish to become or are pregnant. The response rate was 56%.

The respondents had an average of 16 years' experience in transplant medicine.

A total of 82% said they recommend that their transplant patients not try to become pregnant for some period of time after receiving the transplant. Most who recommended a waiting period said their patients should wait 1–2 years. Almost 20% recommended that their patients never become pregnant. Most respondents—about three-quarters—did not limit their patients to one pregnancy.

Regarding immunosuppressant therapy in pregnancy, most respondents felt that older drugs—cyclosporine, tacrolimus, and steroids—were probably OK to use. “What I think was really interesting was that with azathioprine—one of the safest medications and actually the one that we have, aside from steroids, the most experience with—there was a little bit of debate,” she said.

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