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Timing natalizumab cessation, resumption may reduce MS relapse risk during pregnancy

Roshini Claire Anthony
11 Apr 2018

Cessation of natalizumab treatment just after conception and prompt resumption after delivery may reduce the risk of disease relapse in pregnant women with relapsing-remitting multiple sclerosis (MS), a new study has shown.

“[W]e found that receiving the last natalizumab infusion after the onset of the last menstrual period led to an approximately threefold reduction of the risk of relapses during the pregnancy. Moreover, early resumption of natalizumab [within 1 month of] delivery lowered to the same extent the risk of post-partum relapses,” said the researchers.

“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. While there is still a risk of increased disease activity, this course of action may lower that risk,” said study lead author Dr Emilio Portaccio from the Don Carlo Gnocchi Foundation in Florence, Italy.

After identifying 92 pregnancies in 83 women who were being treated with natalizumab at 19 participating sites in Italy, researchers followed the 74 live births (in 70 women) for ≥1 year. Women receiving natalizumab were divided into two categories – those whose last treatment was before or after the onset of the last menstrual period (washout or no washout, respectively) – and the maternal outcomes were compared with that of pregnant women who were untreated or treated with interferon-β (control group; n=350).

Glucocorticoids were administered for relapses in 36.5 percent of the pregnancies that produced live births.

Relapses during pregnancy were more common in women who had received natalizumab than in untreated or interferon-β-treated women, with a peak in relapse observed in the first trimester (mean 0.5 vs 0.1; p<0.001). Natalizumab-treated women also had a higher risk of relapse after delivery; in contrast, untreated or interferon-β-treated women experienced a reduction in relapse rate during pregnancy and an increase post-delivery. [Neurology 2018;90:e832-e839]

Women in the washout group had a higher risk of relapsing during and after pregnancy (55.9 percent) than those in the no washout group (20 percent) or control group (10 percent; p<0.001), with washout period being the sole predictor of relapse during pregnancy (odds ratio [OR], 6.01, 95 percent confidence interval [CI], 2.06–17.56; p=0.001).

Predictors of relapse post-partum were a higher number of relapses during pregnancy (OR, 2.14, 95 percent CI, 1.12–4.08; p=0.019) and a >1 month delay in resumption of disease-modifying drugs (DMDs) or no post-delivery treatment (OR, 4.40, 95 percent CI, 1.28–15.16; p=0.021).

“[P]atients with [no washout] and early DMD resumption appeared to be at lower risk of disease activity during the pregnancy and after the delivery,” said the researchers.

“Pregnancy planning can be difficult when a woman has MS because she and her physician must weigh the risks vs the benefits of medications that control MS disease activity,” said Portaccio.

“Although use of injectable [disease-modifying therapies] prepartum does not appear to alter the … pattern of disease activity in the third trimester or post-partum, this may not be the case for more effective therapies, such as natalizumab, which are associated with rebound disease activity when they are withdrawn,” said Dr Ruth Ann Marrie from the University of Manitoba, Winnipeg, Canada, in an editorial. [Neurology 2018;90:443-444]


Impact on foetal risk

Despite the positive findings, the authors cautioned that the risk of spontaneous abortion and birth defects following exposure to natalizumab has yet to be established. [Mult Scler 2015;21:198-205; BMC Neurol 2016;16:150]

Furthermore, the higher risks for foetal death and haematologic alterations following natalizumab exposure in preclinical studies led to regulatory bodies recommending a 3-month washout period prior to conception and natalizumab treatment cessation during pregnancy. However, disease reactivation or rebound can occur in approximately one-third of patients, said Portaccio. [CNS Drugs 2015;29:207-220]

Using the same cohort of pregnant women, researchers assessed the incidence of spontaneous abortion and congenital abnormalities following natalizumab exposure, with comparisons against 23 pregnancies that were untreated and 88 pregnancies in women treated with interferon-β. Seventy-five percent of the pregnancies had exposure to natalizumab with a mean exposure duration of 1.2 weeks.

Results showed that the risk of spontaneous abortion in women treated with natalizumab was higher than that of women who were treated with interferon-β or who were untreated (OR, 3.9, 95 percent CI, 1.9–8.5; p<0.001). However, the risk was comparable with that of the general population, which was also the case for incidence of congenital abnormalities, with no apparent increased risk with drug exposure. [Neurology 2018;90:e823-e831]

“This observation is consistent with the mechanism of action of natalizumab, which targets α4 integrins, a class of integrins that play critical roles in early pregnancy, including in fertilization, implantation, placentation, and promotion of immune tolerance in utero,” said Marrie.

Exposure to interferon-β and a higher score on the Expanded Disability Status Scale were predictors of preterm delivery (OR, 2.1; p=0.009 and OR, 1.4; p=0.002, respectively).

Predictors of lower birth weight were exposure to either drug (p<0.001), lower gestational age (p<0.001), smoking during pregnancy (p=0.006), and being primipara (p=0.045), while predictors of lower birth length were exposure to either drug (p=0.002) and lower gestational age (p<0.001).

“Overall, although continuous surveillance is called for, available evidence to date does not provide clear indication of safety concerns and foetal harms,” said the researchers, though they advised physicians to discuss the potential risks and benefits with their patients.


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Most Read Articles
Jairia Dela Cruz, 12 Oct 2018
Short-term daily consumption or probiotic lozenges containing Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis BB-12 confers benefits for gingival health, as well as reduces the plaque carriage of periodontal pathogens, in adolescent males, a study has shown.