Is natalizumab (Tysabri) compatible with pregnancy?/nThe question concerns a woman treated with nat

Fråga: Is natalizumab (Tysabri) compatible with pregnancy?

The question concerns a woman treated with natalizumab for multiple sclerosis who wants to become pregnant.

Sammanfattning: Human data regarding pre-natal exposure to natalizumab is lacking and use of this drug in pregnant women cannot be considered safe.

Svar: Natalizumab is a monoclonal antibody directed against the alpha-4 subunit of human integrins, thereby inhibiting leukocyte migration to sites of inflammation (1). It is an immunoglobulin G antibody and is consequently expected to penetrate the placental barrier. In addition, integrins appear to be critically involved in mammalian fertilization, implantation and placental and cardiac development. By interfering with these processes, natalizumab could theoretically have effects on fertility as well as fetal development (2).

In the Swedish medical birth registry, there is only a single report of a child exposed to natalizumab in utero (2). This child did not exhibit any birth defects, but the data are obviously insufficient to draw any conclusions regarding the reproductive safety of natalizumab. According to the manufacturer, safety data from pregnant women is lacking, and use of natalizumab during pregnancy is not recommended (1). A brief report from the annual meeting of the American Academy of Neurology was recently published on the website MedPage Today (3). This report refers to preliminary data from the Tysabri Pregnancy Exposure Registry. Currently, the register contains outcome data from 125 pregnancies in natalizumab-exposed women. Twenty miscarriages occurred among these pregnancies, and an additional six women elected to terminate their pregnancies. Malformations were reported in eight out of 99 live-born children (8%), but the data is preliminary and further information about the malformations is not yet available. No additional reports of natalizumab exposure in pregnant women were identified in Medline, Drugline or standard pharmacologic literature.

Animal studies are complicated by the fact that natalizumab does not bind to the apha-4 integrin subunits in several species commonly used in reproduction toxicity studies (e.g. rat, mouse and rabbit). However, the drug does bind to these molecules in guinea pigs and cynomolgus monkeys, producing pharmacological effects similar to those observed in humans (4). In guinea pigs, high doses of natalizumab reduce pregnancy rates by approximately 50 percent, but no increased risk of malformations has been observed (4,5). In cynomolgus monkeys, natalizumab seems to increase the risk of spontaneous abortion and hematologic abnormalities. For example, increased white blood cell counts, reduced platelet counts and increased extramedullary hematopoiesis have been observed in offspring exposed in utero (6,7). There are no reports of cardiac or other gross malformations following natalizumab exposure in these species, but the number of animals studied is small and another integrin antagonist (IVL984) has been known to cause cardiac malformation in at least two species (rat and rabbit) (8).

If natalizumab is withdrawn prior to a planned pregnancy, it should be noted that the drug has a very long elimination half-life and will remain in circulation for several months following the last administration (1).