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Antirejection Drugs


 

Stopping a medication during pregnancy because of potential risks to the fetus is not an option for women who have had an organ transplant, because they risk losing the transplanted organ. Despite considerable concerns about the reproductive safety of cyclosporine, by far the most commonly used antirejection drug for several decades, the data have been reassuring.

Several years ago, a meta-analysis of 15 studies looking at pregnancy outcomes in women after cyclosporine therapy suggested that the prevalence rate of major malformations was not substantially different from the rate usually reported in studies in the general population. The analysis did suggest a trend toward an increased risk (Transplantation 2001;71:1051–5).

The neurotoxic side effects of cyclosporine in adult and pediatric patients have raised concerns about the potential effects on brain development in children exposed to the drug in utero. At Motherisk, we recently completed a prospective study evaluating IQ, language, and development in about 40 children of transplant recipients who took cyclosporine during pregnancy and in controls, correcting for the maternal socioeconomic education level and IQ. Follow-up of the children to ages 3–8 years found similar achievement in those exposed to cyclosporine and the controls. (This study has been presented at meetings, but not yet published.)

Cyclosporine use has decreased, largely because of its nephrotoxic side effects and the availability of newer, highly effective immunosuppressants. However, there are far fewer reproductive safety data available on the newer drugs. For one, mycophenolate mofetil (Cellcept), the available data are worrisome.

To date, the data do not suggest that tacrolimus (Prograf) is associated with an increased rate of major malformations, but there are still no data on the drug's effect on the neurobehavioral development of children exposed in utero.

Because cyclosporine, tacrolimus, and sirolimus are associated with some serious adverse effects, particularly chronic kidney damage, new drugs are being used—particularly mycophenolate mofetil (MMF)—which have similar effects on preventing rejection, but with far fewer nephrotoxic effects.

But evidence is beginning to emerge that MMF is associated with an increased rate of major malformations. The drug's label states that treatment should not be started until the patient has a negative pregnancy test, and women of childbearing age should use two forms of contraception.

In recent years, reports of malformations in babies exposed to MMF during the first trimester include microtia, cleft lip and palate, hypoplastic fingers and toenails, diaphragmatic hernia, congenital heart defects, and micrognathia. These reports come from small case series and case reports and do not prove causation, but they have raised concerns about the drug's reproductive safety because of the clustering of similar defects, instead of the distribution of malformations seen in the general population.

In a National Transplantation Pregnancy Registry (NTPR) study of outcomes of pregnancies exposed to MMF or sirolimus, there were 26 pregnancies, including 11 that ended in spontaneous abortions, in 18 kidney recipients treated with MMF. Of 15 live births, 4 (26.7%) had a structural malformation, including hypoplastic nails and shortened fifth fingers, microtia with and without cleft lip and palate, and a death in a neonate with microtia and other malformations.

Among the seven transplant recipients who received sirolimus (Rapamune) during pregnancy, there were three spontaneous abortions. Of the four live births, three had no malformations and one baby whose mother had been treated with MMF during pregnancy but had changed to sirolimus late in pregnancy had microtia and a cleft lip and palate (Transplantation 2006;82:1698–702).

Motherisk recently published a precautionary note about this drug in women in which we advised that a woman who has had a transplant and is on MMF and planning a pregnancy should consider switching to cyclosporine for a short period (Canadian Family Physician 2008;54:1112–3).

In addition, many women transplant recipients are also on corticosteroids, which are known to increase the risk for oral clefts. Many are also on azathioprine (Imuran). A trial comparing pregnancy outcomes in 189 women in Europe, Asia, and North America who took azathioprine during pregnancy with 230 women who took nonteratogenic drugs in pregnancy found no evidence of an increased rate of malformations, but the drug was associated with lower birth weight, gestational age, and prematurity (Birth Defects Res. A Clin. Mol. Teratol. 2007;696:701).

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