March 20, 2009

Pregnancies, risk of heart transplant rejection studied

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Cheri Silverstein, M.D., is studying pregnancy’s impact on the risk of heart transplant rejection. (photo by Joe Howell)

Pregnancies, risk of heart transplant rejection studied

An analysis of the United Network for Organ Sharing (UNOS) database indicates that women who have had cumulative pregnancies may be at higher risk for heart transplant rejection.

Cheri Silverstein, M.D., a clinical research fellow in the Division of Cardiovascular Medicine, was a resident on the heart failure service when she cared for a 17-year-old patient who had had just received a heart transplant. The patient had given birth six months prior.

The patient later developed rejection when Silverstein was no longer caring for her. Her death, which was presented at a morbidity and mortality conference, sparked Silverstein's interest in looking at pregnancy and rejection.

“There has been longstanding debate on this topic, but there is evidence that females, in general, are at increased risk for rejection. Smaller studies have found that women who had been pregnant were at increased risk for rejection versus women who had never been pregnant,” Silverstein said.

According to these studies, prior pregnancy, rather than gender alone, is the risk factor.
Panel reactive antibody (PRA) is very useful for predicting risk of rejection. People with PRAs higher than 50 are thought to be at very high risk for hyperacute rejection.

Pregnancy is widely promoted as a cause of increased PRA but there is surprisingly little research on this. In the renal literature, one study showed that more than two pregnancies put women at risk for an increased PRA.

“In the heart literature, however, nobody had looked at whether the important factor is having just been pregnant or whether cumulative pregnancies increase risk, so that is what we studied,” she said.

Why does pregnancy increase PRA? A fetus has half of its genes from the mother and half from the father, therefore the fetus has antigens that would be recognized as foreign by the mother. There is a natural mechanism in the placenta to protect against an immune response by the mother. Nevertheless, the mother is ultimately exposed to fetal antigens during pregnancy.

The same thing that contributes to an increased risk for a higher PRA is similar to what contributes to a woman's increased risk of autoimmune diseases like rheumatoid arthritis and lupus.

“We queried the UNOS database to determine the rate of rejection by number of prior pregnancies. It was just one of a number of things we thought might be contributing to rejection,” Silverstein said. “The level of correlation, the clarity and data were particularly impressive.”

The UNOS database comprises a registry of 47,000 heart transplant recipients over a 10-year period. About 75 percent of them are male. Once Silverstein removed females under the age of 16 from the query, she was left with a database of 2,644 female heart transplant recipients.

Less than 50 percent of women with more than five prior pregnancies had a PRA of zero. In women with zero or one prior pregnancy, 80 percent had a zero PRA.

“With women with five or more pregnancies, you see the PRA level gets very high. It's clearly cumulative pregnancies. There's a compounding risk with additional pregnancy numbers,” Silverstein said.

“That may not be the whole story. We found pregnancy remains a significant predictor even when we controlled for the PRA level. We didn't control for every variable. It's possible that not all risk acquired from pregnancy is captured by the PRA.”

As age increases, the risk of a high PRA and rejection goes down. One of the things the UNOS database can't capture is the influence of the time between the pregnancy and the transplant.

“Someone like my patient, who was 17 and had her heart transplant within a year of having her baby, may be very different from a woman who is 65 and had her children 30 years ago,” Silverstein said.

Silverstein, who presented her findings at the American Heart Association national conference, said the results could impact how physicians counsel mothers who have been diagnosed with advanced heart failure and are facing transplantation.