Interferon Alfa Risk Summary

Fetal Risk Summary

Interferon alfa is a family of at least 23 structurally similar subtypes of human proteins and glycoproteins that have antiviral, antineoplastic, and immunomodulating properties (1). Five preparations are available in the United States: interferon alfa-n3, interferon alfa-NL (orphan drug status), interferon alfa-2a, interferon alfa-2b, and peginterferon alfa-2B. Interferon alfa-2c has been used in pregnancy, but this product is not available in the United States. No reports describing the placental transfer of interferon alfa have been located.

Shepard reviewed four studies in which human interferon alfa (subtype not specified) was administered by various parenteral routes to rats and rabbits during pregnancy (2,3,4 and 5). No teratogenicity or adverse developmental changes were observed in the offspring.

Interferon alfa-2a produced a statistically significant increase in abortions in rhesus monkeys given 20500 times the human dose (6). No teratogenic effects, however, were observed in this species when doses of 125 million IU/kg/day were administered during the early to midfetal period (day 22 to day 70 of gestation) (6). Interferon alfa-2b also had abortifacient effects in rhesus monkeys treated with 7.530 million IU/kg (90360 times the human dose) (7). Reproduction studies have not been conducted with interferon alfa-n3 (8).

Administration of interferon alfa to female sheep before conception resulted in an increased number of pregnant ewes and embryonic survival (9). This effect may have been the result of enhanced biochemical communication between the mother and conceptus (9). A study published in 1986 demonstrated that human fetal blood and organs, placenta, membranes, amniotic fluid, and decidua contain significant concentrations of interferon alfa (10). In contrast, maternal blood and blood and tissues from nonpregnant adults contained little or none of these proteins. The investigators concluded that one of the effects of interferon alfa may involve the preservation of the fetus as a homograft (10). Other effects and actions of endogenous interferons (alfa, beta, and gamma) in relation to animal and human pregnancies and the presence of these proteins in various maternal and fetal tissues have been summarized in two reviews (11,12).

Interferon Alfa Med Template

A number of reports have described the use of interferon alfa in all phases of pregnancy for the treatment of leukemia (13,14,15,16,17,18,19 and 20). The first reported case involved a woman with chronic myelogenous leukemia (CML) who was treated before conception and throughout a normal pregnancy with 4 million units/m2 (6.4 million units) of interferon alfa-2a every other day (13). She delivered a term, healthy, 3487-g female infant whose growth and development continued to be normal at 15 months of age. The newborn had an elevated white blood cell count (40,000/mm3) that normalized at 48 hours of age with no signs or symptoms of infection. Since this report, 10 other pregnancies have been described in which interferon alfa was used for CML or hairy cell leukemia (14,15,16,17,18,19 and 20). In one case, a woman was treated with interferon alfa-2c (not available in the United States) (16). In two of the pregnancies, the concentrations of interferon alfa in the newborns were <0.6 and <1 U/mL, respectively, while those in the mothers were 20.8 and 58 U/mL, respectively (18). Normal pregnancy outcomes were observed in all of the above cases and there were no fetal or newborn toxic effects attributable to interferon alfa (13,14,15,16,17,18,19 and 20). In addition, four infants have been followed for periods ranging from 6 to 44 months and all had normal growth and development (14).

A 1995 Reference reported the use of interferon alfa-2a for the treatment of multiple myeloma before and during approximately the first 6 weeks of pregnancy (21). The woman delivered a normal male infant at 38 weeks' gestation.

As noted above, interferon alfa does not appear to cross the placenta to the fetus. A study published in 1995 specifically evaluated this in two HIV-seropositive women who were undergoing abortions at 19 and 24 weeks (22). Both women were given a single IM injection of 5 million U interferon alfa-2a. Peak blood concentrations of the drug were reached at 3 hours in both women, 100 U and 400 U, respectively. Fetal blood and amniotic fluid samples were drawn at 1 hour from one fetus and at 4 hours from the other. Concentrations in the four samples were all below the detection limit of the assay (<2 U).

A number of pregnant women have been treated with interferon alfa (usually interferon alfa-2a) for essential thrombocythemia (23,24,25,26,27,28,29,30 and 31), although not without controversy (32,33 and 34). In some of these cases, the women were receiving interferon therapy at the time of conception (23,24,26,28,29) and, in most, the treatment was continued throughout pregnancy (26,28,29). No adverse effects in the fetuses or in the newborns attributable to the drug therapy were reported.

An HIV-infected pregnant woman was treated with IM interferon alfa, 2 million units twice weekly, and oral and IV glycyrrhizin during the 3rd trimester (35). Two weeks after interferon alfa was started, an elective cesarean section was performed at 37 weeks' gestation. The healthy, 2320-g female was alive and well at 4 years of age without evidence of HIV infection.

Two reports have described the use of interferon alfa for the treatment of chronic hepatitis C (36,37). In both cases treatment was started before conception and continued into the 2nd trimester. Interferon alfa treatment throughout the 1st trimester also occurred in a woman with advanced Hodgkin's disease (38). Normal newborns resulted in all three of these pregnancies.

In summary, based on a limited number of human cases, the maternal administration of interferon alfa does not appear to pose a significant risk to the developing embryo and fetus. There does not seem to be a difference in risk among the subtypes but, in many cases, the actual product used was not specified. Although very high doses are abortifacient in rhesus monkeys, doses used clinically apparently do not have this effect. No teratogenic or other reproductive toxicity, other than that noted above, has been observed in animals, and no toxicity of any type attributable to interferon alfa has been observed in humans. However, because of the antiproliferative activity of these agents, they should be used cautiously during gestation until more data are available to assess their risk.

Breast Feeding Summary

Interferon alfa is excreted into breast milk. A study published in 1996 measured interferon alfa milk concentrations in two women who had been treated with the drug throughout the 2nd and 3rd trimesters for CML (18). Both women were receiving 8 million units SC 3 times a week at the time of delivery. Immediately postpartum, milk concentrations in the two patients were 1.4 and 6 U/mL (time of the last dose in relationship to milk sampling not specified), while the serum levels in the mothers were 20.8 and 58 U/mL, respectively. The authors did not specify if the infants were allowed to breast-feed.

Breast feeding was allowed in a second Reference (25). The woman was being treated with interferon alfa-2a, 3 million units SC 3 times weekly, for essential thrombocythemia. Nursing was halted 2 weeks postpartum because of the onset of bilateral mastitis.

References

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  3. Matsumoto T, Nakamura K, Imai M, Aoki H, Okugi M, Shimoi H, Hagita K. Reproduction studies of human interferon a (interferon alpha). (III) Teratological study in rats. Iyakuhin Kenkyu 1986;17:41738. As cited by Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD:Johns Hopkins University Press, 1992:2201.
  4. Matsumoto T, Nakamura K, Imai M, Aoki H, Okugi M, Shimoi H, Hagita K. Perinatal studies of human interferon a (interferon alpha). (IV) Teratological study in rats. Iyakuhin Kenkyu 1986;17:43957. As cited by Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD:Johns Hopkins University Press, 1992:2201.
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