#ECTRIMS2019 – Tysabri During Pregnancy and After Delivery Seems Safe, Reduces Relapse Risk, Study Finds

Continuing Tysabri (natalizumab) treatment up to week 28 of pregnancy, and restarting soon after birth, reduces the risk of relapses in women with multiple sclerosis and appears to be safe for the mother and the baby, new research suggests.

Doriana Landi, MD, PhD, from Italy’s University of Rome Tor Vergata, presented the findings at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Sept. 11–13 in Stockholm, Sweden.

Her presentation was titled: “Continuation of natalizumab versus interruption is associated with lower risk of relapses during pregnancy and postpartum in women with MS.”

What therapy to choose, and for how long to take it, have been emerging issues for women with MS who are pregnant or planning to become pregnant.

“We all know that not all treatments are compatible with pregnancy planning, especially second-line treatments which are usually used for highly active MS women,” Landi said.

One problem is the lack of data that can elucidate the risks, and guide therapy choices before, during, and after pregnancy. In particular, there is a lack on information “on how to manage our highly active patients,” such as those treated with Tysabri (marketed by Biogen), Landi added.

Suspension of Tysabri treatment is currently discouraged in patients planning pregnancy, due to concerns of disease reactivation or worsening — patients may become exposed to a higher risk of relapses, Landi said.

A 2018 study showed that “suspending natalizumab treatment before conception was associated with a higher risk of disease relapses during pregnancy,” Landi said, while “receiving the last natalizumab infusion after the onset of the last menstrual period led to an approximately 3-fold reduction of the risk of relapses during pregnancy.”

Data from the German MS registry suggested that the best option would be to continue Tysabri treatment until the 30th week of gestation, as a way to minimize flares in the mother while assuring the safety of the fetus.

Further, recent guidelines from the Association of British Neurologists recommend maintaining Tysabri up to approximately 34 weeks of gestation, and restarting treatment soon after birth to mitigate the risk of rebound disease activity. Those guidelines recommend treatment be restarted within 8-12 weeks after the last dose pre-delivery.

Prior studies suggested that Tysabri use over the first trimester of pregnancy is not tied to major fetal risks. However, the medicine can be found in the blood of newborns, and they commonly have blood alterations, especially in the third trimester, such as low red blood cell or platelet counts. These alterations are usually self-resolving, Landi said.

Given the lack of information, the researchers said more data was needed. They sought to confirm Tysabri’s safety and efficacy, and to find the best management strategy for women taking this medicine who plan to become mothers.

The team therefore analyzed data from a group of 86 pregnant women with MS (90 pregnancies), who were on Tysabri treatment, and were followed at 19 Italian MS centers. The patients’ mean age was 31 years, and median EDSS was 2.0, indicating minimal disability.

The women were divided into three groups according to the time of the last Tysabri infusion: before conception (31 newborns); within the first trimester of pregnancy (30 newborns); and those who continued treatment after the first trimester (31 newborns). All women were asked to restart Tysabri after delivery, and all have at least one year data of follow-up.

No difference in terms of demographic characteristics were found among the study groups.

Most women who remained on treatment beyond the first trimester continued up to at least the 28 week of gestation. They received a median of five — ranging from 3 to 5 — Tysabri infusions, with a mean interval of 33 days between doses.

Importantly, these women restarted Tysabri treatment significantly earlier after giving birth — a median of 25 days after delivery — compared with women in the other groups. The women who stopped Tysabri before conception restarted treatment a median of 55 days after delivery. Those who stopped Tysabri during the first trimester restarted a median of 50 days after delivery.

Researchers then compared the annualized relapse rate (ARR) during pregnancy, and one year after delivery, as well as newborn outcomes, across groups.

During pregnancy, there was a significantly higher relapse rate in the women with “wash-out” pregnancies — those who stopped Tysabri before getting pregnant. Conversely, the lowest ARR was observed in women who continued on Tysabri while pregnant.

ARR was 1.06 in women stopping Tysabri before conceiving, 0.49 in those prolonging treatment up to the first trimester of pregnancy, and 0.09 in those continuing beyond this period.

A similar trend was maintained in the postpartum period, one year after delivery, the results showed. The women stopping Tysabri earlier had the highest relapse rates (0.39), while those who remained on treatment had fewer relapses — 0.23 in those prolonging treatment up to the first trimester of pregnancy, and 0.10 in those continuing beyond this period.

Researchers believe that early treatment resumption was important to lessen the risk of relapses in the group of women who continued Tysabri treatment after the first trimester of pregnancy.

Landi emphasized that “relapses are really relevant in terms of disability accumulation.” She noted that women who stopped Tysabri before conception had the highest accumulation of disability, as measured by EDSS, in the postpartum period.

Regarding newborn outcomes and fetal safety, no significant changes were registered between the three groups of mothers, either on mean gestational age (the number of weeks of the pregnancy), birthweight, or length.

Anemia — low red blood cell counts — was more frequent in newborns exposed to Tysabri beyond the first trimester. Five newborns from that group had anemia, versus none in the other two groups. However, Landi noted that three of these five babies were premature newborns, and a link has previously been reported between prematurity and anemia.

Major birth defects only happened in pregnancies exposed to Tysabri — both up to the first trimester (one case of a major malformation called clubfoot), and beyond the first trimester (four cases, all heart defects, specifically patent foramen ovale, patent ductus arteriosus, pulmonary valve stenosis, and coarctation of the aorta).

Nonetheless, Landi stressed that factors other than Tysabri treatment could have accounted for this higher number of birth defects. One such factor that raises the risk is the birth of twins — which occurred with two of the babies with heart defects.

Overall, the findings support that “continuation of natalizumab [Tysabri] beyond conception reduces the risk of relapse during pregnancy, and is not associated with major fetal risks,” Landi said.

“It is worth noting that in case of treatment prolongation up to the third trimester, it is desirable to resume infusions within 12 weeks from the last pre-partum infusion to minimize the risk of disease rebound,” she added.

Of note, more data on Tysabri was presented at ECTRIMS 2019. That data support Tysabri’s long-term benefit for people with early relapsing-remitting MS (RRMS). It also showed that Tysabri can reduce disease relapse rates when given at an extended interval dosing, specifically every six weeks, relative to standard dosing every four weeks.

In her presentation, Landi also said the question of whether “extending dosing [meaning at 6-week intervals] is as protective as regular dosing [4-week intervals] needs to be assessed by future studies, although no differences were seen in our cohort.”

Additional studies with larger patient samples also are needed “to correctly estimate the incidence of fetal complications in Tysabri-exposed pregnancies, and provide conclusive data useful for patient counseling,” Landi added.

Pregnancy was the topic of discussion in a large session on ECTRIMS’ first day. To learn more about that session, please see the following article.