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Editorial

Multiple sclerosis and pregnancy prescriptions

, MD FAAN FANA
Pages 1565-1568 | Published online: 19 Nov 2014

Abstract

Multiple sclerosis (MS) is a major neurologic disorder which preferentially affects young women of childbearing age. In the last two decades, a number of disease-modifying therapies have become available to treat relapsing forms of MS. None of these agents is approved for use in pregnancy. The timing of treatment versus conception, and risk of drug pregnancy exposures, are frequent discussion topics when caring for MS patients. This editorial will try to put into context available data, approaches, controversies and future needs.

Multiple sclerosis (MS) is the major acquired CNS disorder of young adults, short of trauma. One striking and unexplained characteristic is the increasing female predominance, now approaching 3 to 1 Citation[1,2]. In fact, it is fair to say that the prototypic MS patient is a young woman of childbearing age. Because MS is a chronic (as yet incurable) disease, which presents when many are considering marriage and parenthood, family planning issues are usually major topics Citation[3].

There is a fairly extensive literature on pregnancy and MS. It is now well accepted that MS disease activity goes down during pregnancy, particularly in the last trimester, then temporarily rebounds in the first 3 months postpartum Citation[4,5]. Disease activity then returns to the pre-pregnancy level. However, pregnancy is not completely safe; patients can certainly experience a relapse. An important research focus has been to identify the key protective pregnancy-related factors. A bench-to-bedside translational approach has led to studies examining sex hormone therapy for MS Citation[6].

Prescription drug use during pregnancy is always a concern. For MS, it falls into three categories: use of drugs to treat disease-related symptoms, use of short courses of high-dose corticosteroids to treat clinical disease relapses and use of the disease-modifying therapies (DMTs) Citation[7].

Most pregnant MS women have relapsing disease (87 – 97%), and show little to no disability Citation[5,8]. They are often not on any symptomatic therapy. Since unnecessary medications are avoided during pregnancy, a symptomatic drug prescription would be continued, or initiated, only if the risk–benefit ratio justified its use. The current standard of care is to discontinue such therapies before conception, or to use minimal effective doses as briefly as possible in pregnant MS patients Citation[9].

Routine therapy for MS relapses involves several days of high-dose (typically intravenous) methylprednisolone. This is generally restricted to significant clinical attacks that occur after the first trimester, to avoid cleft palate concerns. Steroids do not improve degree of recovery, but can shorten the time frame of recovery. They are never mandatory.

The most important prescription decisions for pregnancy really revolve around the DMTs. None is approved for use during pregnancy or breastfeeding (). The general recommendation remains not to use DMTs in MS patients who are pregnant, trying to become pregnant or who are breastfeeding. Patients on therapy who are at risk are supposed to use appropriate techniques to avoid conception. There should be a documented knowledgeable contraception discussion between patient and healthcare provider. When a woman with MS decides she wants to try to become pregnant, it is typical for her DMT to be discontinued. Various washout periods are recommended depending on the agent. It is also typical for a DMT to be discontinued if pregnancy is discovered. To date, it is reassuring that post-marketing reproductive safety data, based on case reports, prospective cohort studies, pregnancy registries and safety databases from the various pharmaceutical companies, have not reported human teratogenicity Citation[10]. There is a single case report of Pierre Robin syndrome associated with mitoxantrone use Citation[11]. The most extensive data sets are associated with the long-standing parenteral DMTs, glatiramer acetate and the IFN-βs. There are conflicting reports that exposure to IFN-β may be associated with smaller infant size and length, and higher rates of prematurity, but these adverse effects are based on small numbers and have not been confirmed in other analyses Citation[12-14]. Studies evaluating long-term effects on exposed children are quite limited, but have not reported any negative outcomes Citation[15]. Recent studies focusing on DMT use in fathers with MS have also not identified any associations with adverse fetal outcomes Citation[16,17]. In fact, the only DMT with implications for the male MS patient is teriflunomide, which is detected in semen at very low levels (mean 10.6 μg/ml). Men on teriflunomide may consider going through a washout protocol. One way to assess this need would be to check drug levels in the unaffected female partner.

Table 1. Multiple sclerosis disease-modifying therapies and pregnancy-related issues.

There are several issues of controversy. The first is whether, for newly diagnosed young women interested in having a family, it is better to try to get pregnant immediately, or delay pregnancy to go on a DMT for a period of time. A recent large MS registry analysis found that prior DMT use in the 2 years before pregnancy significantly decreased risk for postpartum attacks, suggesting that it might be preferable (particularly in patients with high disease activity and poor prognostic profile) to delay pregnancy and commit to therapy for a year or so Citation[8].

A second area of controversy surrounds DMT washout before attempting pregnancy. There has been recent discussion that a formal washout for glatiramer acetate and the IFN-βs may not be needed () Citation[18]. Because dimethyl fumarate has such a short half-life (it is not detectable in blood after 24 h), it too may require little to no washout period. Fingolimod requires 8 weeks. Although natalizumab takes 12 weeks to completely washout, a 1-month washout prior to attempting conception seems reasonable. Teriflunomide requires a formal washout procedure over several days, to bring the blood level down to < 0.02 μg/ml. It does not have to be on consecutive days Citation[7].

A third area of controversy surrounds whether the DMTs, in special circumstances, can be used in pregnancy. In fact, glatiramer acetate, natalizumab and IFN-β have all been used during pregnancy, without obvious harm Citation[19-21]. Hematologic issues (anemia, thrombocytopenia) have been seen in some newborns exposed to natalizumab in utero Citation[19].

There is a current knowledge gap, with the most extensive data on pregnancy exposure and impact from the IFN-βs and glatiramer acetate, but relatively limited data from the newer DMTs. It will be important to continue to collect information on pregnancy exposures and outcomes. Future needs involve better clarification of true DMT risks to the fetus, as well as effective predictors to select those MS women who are likely to have sufficient disease activity during pregnancy to justify treatment.

A final area of controversy surrounds whether the postpartum MS patient should commit to breastfeeding, or forego this and start a DMT Citation[22-24]. It is not yet clear whether exclusive breastfeeding and use of an effective DMT provide equivalent protection against MS disease activity.

Expert opinion

Untreated MS patients undergo ongoing injury to their CNS. This reflects both macroscopic and microscopic pathology, and results in accumulating permanent damage. Injury may not be clinically apparent, at least initially. Therefore, any decision not to treat a relapsing patient with an appropriate DMT involves tangible risk. There needs to be a careful assessment of the level of disease activity (both clinical and MRI), as well as a comprehensive review of favorable and unfavorable prognostic factors, to determine whether an MS patient should commit to initial therapy, or forego therapy to attempt to become pregnant. When there is real concern, patients should be counseled to delay pregnancy until their disease process has been controlled.

The author believes that there are now sufficient data to change the approach to certain issues. Washout periods, when a patient has decided to become pregnant, should be minimized. It should be stated clearly that the IFN-βs and glatiramer acetate require no washout; these DMTs can be discontinued once the patient becomes pregnant. For the other approved DMTs, washouts should be limited to no more than 1 – 2 months, and use of the teriflunomide formal washout protocol should be determined by blood levels. Use of DMTs during pregnancy is ultimately guided by patient decision. It is acceptable to use glatiramer acetate during pregnancy, and it can be considered for the IFN-βs. There are too many unknowns to endorse this for the other DMTs, although natalizumab use can be considered in very active patients. Women who come off fingolimod or natalizumab to become pregnant need to be monitored particularly closely, because of concerns about rebound. Finally, patients should be counseled that new data indicate postpartum disease activity is significantly lessened for those patients who commit to a DMT in the 2-year preconception period.

Declaration of interest

PK Coyle has participated as a consultant for AbbVie, Accordant, Acorda, Bayer, Biogen, Genentech/Roche, Genzyme/Sanofi, Mylan, Novartis, Serono and Teva. She has participated in research for Actelion, Genzyme/Sanofi, Novartis and Opexa. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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