A Review of Safety-Related Pregnancy Data Surrounding the Oral Disease-Modifying Drugs for Multiple Sclerosis

Abstract

The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS.

Family planning, antenatal and post partum care in multiple sclerosis: a review and update

“…In the current era of an increasing number of available disease‐modifying treatments (DMTs), there is a growing need for clinicians to provide their patients with appropriate counselling on family planning . Unfortunately, there are only a few robust studies assessing the impact of multiple sclerosis therapy on pregnancy as a reference for physicians and their patients, and many of those studies available are limited by ethical concerns, real‐world constraints and methodological issues . Even though data from larger observational registries are increasingly becoming available, these studies are still commonly hampered by small sample sizes that limit their ability to examine important outcomes such as specific birth defects or syndromes .…”

“…Unfortunately, there are only a few robust studies assessing the impact of multiple sclerosis therapy on pregnancy as a reference for physicians and their patients, and many of those studies available are limited by ethical concerns, real‐world constraints and methodological issues . Even though data from larger observational registries are increasingly becoming available, these studies are still commonly hampered by small sample sizes that limit their ability to examine important outcomes such as specific birth defects or syndromes . While avoiding any potential drug exposure risks to the fetus seems prudent, discontinuation of treatment pre‐conception is also associated with an increased risk of the reappearance of disease activity, especially if there are significant delays in conceiving …”

“…As a result, it is important not to overlook counselling men with regards to possible fertility issues. There are currently no data that suggest any effect of DMTs on male fertility, and data on the impact of DMTs on birth outcomes in children fathered by men with multiple sclerosis are currently lacking . A small study assessing birth outcomes in 32 paternity cases of 46 children (30 under interferon‐β, 12 under glatiramer acetate, two under natalizumab, one taking methotrexate, and one under azathioprine plus interferon‐β‐1b) suggested no negative impact on birth outcomes .…”

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

“…However, fingolimod crosses the placental barrier in animal models [42] leading to teratogenicity and embryo lethality in experimental studies. The FDA has given fingolimod a pregnancy category C (animal studies have shown an AE on the fetus and there are no adequate studies in humans).…”

Advances in the management of relapsing–remitting multiple sclerosis: role of oral dimethyl fumarate (BG-12)

“…Labeled a pregnancy category C therapeutic, BG-12 has demonstrated embryolethality, impaired growth, and birth defects in rats and rabbits. 56 Indeed, BG-12 is a small molecule and has the ability to cross the placenta into the fetal circulation. Limited human pregnancy registry data have not identified deleterious effects to children brought to term or an increased frequency of spontaneous abortions.…”