Discontinuation of natalizumab may increase risk of relapse, spontaneous abortion

Women with relapsing-remitting multiple sclerosis (RRMS) who discontinue treatment with natalizumab before conception are at a 3.5-fold increased risk of MS relapse, and those exposed to natalizumab for up to 12 weeks of gestation are at an increased risk of spontaneous abortion, according to results from two related studies published in Neurology.

Regulatory agencies recommended that women taking the disease-modifying drug natalizumab for MS discontinue the drug 3 months before conception.

“Pregnancy planning can be difficult when a woman has MS because she and her physician must weigh the risks versus the benefits of medications that control MS disease activity. We chose to conduct two studies to investigate the risks of natalizumab to mother and child so that women, with the help of their physicians, may make more informed decisions about pregnancy,” said lead author of both studies Emilio Portaccio, MD, Don Carlo Gnocchi Foundation, Florence, Italy.

In the two studies, researchers focused on maternal and fetal risks. They tracked 92 pregnancies among 83 women with RRMS who were treated with natalizumab.

Women were tracked throughout the entire gestational period and divided into two groups based on the length of the washout period. Researchers followed up with subjects every 6 months, and in cases of MS relapse.

The first group consisted of subjects who received their final natalizumab infusion before their last menstrual period (washout pregnancies). The second group consisted of participants who received their final natlizumab infusion after their last menstrual period (no washout pregnancies). In total, 69 pregnancies (75%) were exposed to natalizumab, for an average exposure period of 1.2 weeks.

Postpartum follow-up lasted for at least 1 year, and researchers compared results with a historical control comprised of 350 previously published pregnancies in which women with MS received either no treatment or injectable immunomodulatory agents (interferon βs).

In the maternal-risks study, researchers defined relapse “as the appearance or reappearance of one or more symptoms attributable to MS, accompanied by objective deterioration, as shown by neurologic examination, lasting at least 24 hours, in the absence of fever and preceded by neurologic stability for at least 30 days.”

Using stepwise multivariable logistic regression models, researchers assessed the possible predictors of MS relapse in participants both during pregnancy and in the year following pregnancy, with relapse being the dependent variable.

Independent variables in these models included current age, disease duration, and Functional Systems and Expanded Disability Status Scale (EDSS) at conception, number of relapses in the year before pregnancy, smoking status, alcohol and toxin exposure during pregnancy, and natalizumab washout period.

In the maternal-risks study, MS relapse in women treated with natalizumab was higher than in the control group (10% vs 36.5%, respectively; P < 0.001). Women treated with natalizumab also had a similar relapse rate during the first postpartum trimester compared with those in the control group (13.7% vs 21.7%, P=0.084).

In the fetal-risks study, researchers observed 12 spontaneous abortions (17.4%) in pregnant women who were exposed to natalizumab as compared with 22 spontaneous abortions (6.5%) in pregnant women who were not exposed to this drug. Nevertheless, the ratio of 12 spontaneous abortions to 54 live births was not different from that observed in general Italian population in 2013.

Those women exposed to natalizumab had a 3.7% rate of congenital anomalies in offspring, which was not significantly greater than either that observed in women who were not exposed to the drug (0.9%) or that of the general population (2.2%-2.4%). Of note, in interferon-β–exposed pregnancies, there was a 1.3% risk of congenital anomalies. Ultimately, these results reflecting birth defects were not conclusive, and the researchers recommend more studies using larger cohorts.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” concluded Dr. Portaccio.