While pregnancy does not appear to affect the disease course of multiple sclerosis (MS), questions remain about the best time to stop or resume treatment before conception and after delivery, the safety of new medications, and the importance of family planning.
Pregnancy was the “hot topic” discussion today in a session, titled “MS Pregnancy in the treatment era,” at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), which is being held Sept. 11–13 in Stockholm, Sweden.
Three presentations focused on different aspects of pregnancy, including the risks for the mother and child, and the importance of early counseling for patients wishing to become parents.
Until the 1980s, women with MS were discouraged from having children due to the false belief that pregnancy would worsen their disease course.
A shift in knowledge occurred in 1998 when the PRIMS study (Pregnancy in Multiple Sclerosis multicenter European study) showed that, overall, pregnancy did not affect the long-term clinical course of MS. In fact, the study provided evidence that relapse rates go down during pregnancy in MS women, and then restart after giving birth — of note, relapses can get particularly worse in the first three months after delivery.
The PRIMS study also showed that disability progression is similar between pregnant MS women and the general MS population, suggesting that the overall impact of pregnancy on MS course seems to be neutral.
However, over the last three decades, the emergence of a variety of disease-modifying therapies (DMTs) has raised many questions about the risks of each therapy for the fetus, and about which medicines to stop or restart and when to do so.
The mother’s perspective
As some DMTs can harm the fetus, many women with MS worry about the risks of taking medications while trying to get pregnant. Also, given the limited information about the treatments’ safety, most physicians are reluctant to prescribe them to women planning to conceive.
Although pregnancy itself is no longer discouraged by doctors, most women discontinue treatment when trying to get pregnant or when they find out that they are pregnant unintentionally.
However, as it becomes increasingly clear that DMTs should be started as early as possible, delaying or suspending treatment due to pregnancy “may deprive the patients of treatment benefit, exposing them to potential risk of relapses and disability progression, particularly in the post-partum period,” said Emilio Portaccio, a neurologist and MS specialist at the Hospital San Giovanni di Dio, in Italy, in his ECTRIMS presentation, “The maternal perspective – When to stop/resume treatment and risk for progression.”
In a 2014 research article, Portaccio and his colleagues showed results in line with those of the PRIMS study. Also, the researchers reported that women with higher disease activity before and during pregnancy had an increased risk of postpartum relapses and disability accrual. At the time, the team suggested that early DMT “resumption should be encouraged [postpartum], particularly in patients with more active disease.”
Regarding the different DMTs available, Portaccio noted that in women who stay untreated or receive beta-interferons (brand names Avonex, Rebif, Betaseron, Extavia, Plegridy) or glatiramer acetate (brand name Copaxone, or its generic Glatopa), relapse rates progressively drop during gestation, and peak soon after delivery. Resuming DMT treatment postpartum helps reduce those relapses, Portaccio said.
For those taking Tysabri (natalizumab), the scenario looks different, according to a 2018 research study led by Portaccio. In these patients, relapses and disability worsening occur both during pregnancy and after giving birth. Therefore, for these women, taking Tysabri until conception and resuming it early after delivery may help prevent relapses and reduce disability progression.
“Maintaining natalizumab [Tysabri] treatment at least until conception, and re-starting treatment early after delivery confirmed to be the optimal strategy in the perspective of maternal risk,” Portaccio said, although he added that the decision “must take into account possible fetal risks and breastfeeding choice.”
Overall, “the pregnancy-related decision-making process must be shared with the patient and her partner, on a case-by-case basis, with comprehensive information on known possible risks as well as current gaps in knowledge,” Portaccio said.
The researcher noted that little is known about maternal and fetal risks for newer medications, thus large data sets are needed “to inform patient counselling and clinical decision-making.”
The child’s perspective
When new medications are approved, most data available on reproductive toxicity come from animal studies — which are not always predictive of the risk in humans — and little is known from exposed pregnancies during clinical trials, said neurologist Kerstin Hellwig, PhD, from St. Josef Hospital, Ruhr University, in Germany, in her presentation, “The fetal/child perspective – Risks related drug exposure of the child, breastfeeding and when to reassume medication.”
This lack of data poses a challenge for neurologists, making it difficult to choose the best risk-benefit trade-off for mother and child, to decide when to stop or restart treatment, and to counsel future parents, she said.
One of the problems in measuring and collecting pregnancy outcomes is the “very slow recruitment of pregnancy registries,” Hellwig said.
In addition, “we need a lot of exposed pregnancies to measure the risk [of a therapy], because negative outcomes are not very frequent,” she added.
Another issue is the lack of standardization of data; for instance, the prevalence and details of major congenital malformations among fetal cases vary depending on the data source.
Based on current data available for fetal risks of exposure to therapies during pregnancy, “most MS drugs are not teratogenic [cause birth defects],” and interferons and glatiramer acetate therapies in particular are safe to use “up to conception and probably beyond,” Hellwig said.
“None of the current MS drugs justifies an elective termination of pregnancy per se,” she noted, emphasizing the need for more information on newer therapies.
Hellwig also said that breastfeeding should be supported for mothers who want to do so.
“There is no reason to believe that it’s harmful to breastfeed under medications …. Breastfeeding should NOT be discouraged in favor of resuming MS medications in most women,” she said.
The size of therapeutic molecules determines how likely they are to reach breastmilk, with larger molecules less likely to enter breastmilk, Hellwig noted. According to her, therapies based on interferon-beta and glatiramer acetate are compatible with lactation, and those based on monoclonal antibodies are most likely safe.
On the other hand, “if a woman does not want to breastfeed, [she can] start early (7–14 days) with MS treatment, especially those with active disease,” Hellwig said.
It is important for physicians “to encourage patients to think about family planning,” and clarify that MS per se does not appear to have an effect on reproductive outcomes, namely in terms of fertility, or pregnancy or neonatal outcomes, said Marie D’Hooghe, MD, PhD, who gave the session’s last presentation, titled “Patient awareness about family planning represents a major knowledge gap in multiple sclerosis.”
Fertility, pregnancy and delivery, breastfeeding, postpartum relapse risk, and the delay or discontinuation of DMTs are among the major concerns of women with MS, said D’Hooghe, a neurologist at National MS Center Melsbroek and professor at Vrije Universiteit Brussel, in Belgium.
A 2018 Danish research study, based on an online survey of 590 MS patients, revealed a lack of knowledge about the risks associated with DMTs and pregnancy among women and men with MS. About 10% of female MS patients said they experienced an unplanned pregnancy while on MS treatment, and of these, 49% chose to have an abortion.
A previous 2013 study — based on a NARCOMS (North American Research Committee on Multiple Sclerosis) survey with 5,949 MS participants — showed that about 79% of the patients had no plans for a future pregnancy or fathering a pregnancy following their MS diagnosis.
The main MS-related reasons for their decision to avoid pregnancy were: MS symptoms interfering with parenting (71.2%), followed by concerns of burdening their partners (50.7%), financial reasons (39.4%), and concerns about children inheriting MS (34.7%).
However, despite these findings, the pregnancy rate is increasing among MS patients, as well as the number of pregnancies conceived under DMT treatment, D’Hooghe noted.
Neurologists and physicians should “check pregnancy plans in women of childbearing age who desire a pregnancy,” she said.
“The timing of desired pregnancy and the need to prevent unintended pregnancies should be considered individually, allowing patients to make informed decisions,” she said.
She also stated that for patients trying to conceive, physicians should avoid prescribing medications that have:
- known teratogenic potential, such as teriflunomide (brand name Aubagio), and fingolimod (brand name Gilenya, among others).
- known risk of severe rebound relapses, such as fingolimod and natalizumab (Tysabri).
- unclear but plausible risks, such as dimethyl fumarate (Tecfidera) and alemtuzumab (brand name Lemtrada, among others).
A “case-by case approach based on MS-related and personal factors” should be taken into account, D’Hooghe said.
The researcher emphasized the need for clinical trials accounting for differences in sex and age, and an international pregnancy registry for MS patients with data on DMTs, and pregnancy and offspring outcomes.