Reproductive issues and multiple sclerosis: 20 questions

Alise K. Carlson; Daniel Ontaneda; Mary R. Rensel; Jeffrey A. Cohen; Amy Kunchok

doi:10.3949/ccjm.90a.22066

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TABLE 1

Special considerations for use of disease-modifying therapies in pregnancy^{^a,^b}

Medication	Recommended washout period	Use in pregnancy
Interferons Interferon beta-1a^14,15 Peginterferon beta-1a¹⁶ Interferon beta-1b^13,17	2 weeks	Use only if benefit outweighs risks
Glatiramer acetate^18,19	None	Use only if benefit outweighs risks
Fumarates Dimethyl fumarate²⁸ Diroximel fumarate²⁹ Monomethyl fumarate³⁰	1 week	Not advised
Sphingosine 1-phosphate receptor modulators Fingolimod³² Siponimod³³ Ozanimod³⁴ Ponesimod³⁵	Fingolimod: 2–3 months Siponimod: 2 weeks Ozanimod: 3 months Ponesimod: 1 week	Spingosine 1-phosphate receptor modulators are not advised Risk for rebound disease activity Consider transition to a B-cell-depleting agent before discontinuing contraception
Cladribine¹⁰	6 months	Not advised
Teriflunomide³¹	Rapid-elimination procedure required: cholestyramine 8 g every 8 hours orally for 11 days (if not tolerated, reduce dose to 4 g every 8 hours) or activated charcoal powder 50 g every 12 hours for 11 days until a serum concentration below 0.02 mg/L is reached	Not advised; stop treatment and eliminate drug before discontinuing contraception
Natalizumab²¹	2–3 months	Generally not advised Use in special circumstances; high risk for rebound disease activity Consider transition to a B-cell-depleting agent before discontinuing contraception
B-cell–depleting agents Ocrelizumab²² Ofatumumab²³ Rituximab^24,25 Ublituximab²⁶	1–3 months^{^c}	B-cell–depleting agents are generally not advised; package inserts recommend washout periods of 6 months for ocrelizumab, 6 months for ofatumumab, 6 months for ublituximab, and 12 months for rituximab^c
Alemtuzumab²⁷	4 months	Use not advised

↵a This table reflects our clinical practice and review of combined recommendations of prescribing information and key articles.
↵b Pregnancy testing is recommended before starting or re-dosing for all disease-modifying therapy in women of childbearing potential.
↵c See Question 7 in the article for an in-depth discussion of B-cell-depleting therapies and pregnancy timing.
Based on information in references 1,5,10,11, and 13–41.

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TABLE 2

Risks and management recommendations: Fetal exposure to disease-modifying therapies^{^a}

Medication	First-trimester exposure recommendations	Exposure risks
Interferons Interferon beta-1a^14,15 Peginterferon beta-1a¹⁶ Interferon beta-1b^13,17	No additional fetal or neonatal monitoring	With interferons, slight risk of decreased birthweight and increased embryo or fetal death based on animal data
Glatiramer acetate^18,19	No additional fetal or neonatal monitoring	None
Fumarates Dimethyl fumarate²⁸ Diroximel fumarate²⁹ Monomethyl fumarate³⁰	Early ultrasonography for major malformations	Dimethyl fumarate: uncertain risk to fetus; animal studies have shown low birthweight, delayed development, delayed ossification, spontaneous abortions, decreased fetal viability, and impaired learning and memory Diroximel fumarate: based on animal data, may cause fetal harm including skeletal abnormalities, increased mortality, decreased body weight, and neurobehavioral impairment Monomethyl fumarate: Based on animal data, may cause fetal harm including adverse embryotoxicity, reduction in body weight, and delayed sexual maturation
S1Pr modulators Fingolimod³² Siponimod³³ Ozanimod³⁴ Ponesimod³⁵	Early ultrasonography for major malformations	All: teratogenic effect likely; risk of neural tube defects, fetal loss and fetal abnormalities Fingolimod: based on animal studies, increased risk of congenital malformations and embyrolethality, fetal growth retardation, and neurobehavioral deficits Siponimod: based on animal studies, increased risk of congenital malformations and embyrolethality, increased incidence of skeletal variations, decreased body weight, and delayed sexual maturation Ozanimod: based on animal studies, increased risk of congenital malformations and embyrolethality, skeletal variations, vascular malformations, and neurobehavioral deficits Ponesimod: based on animal studies, increased risk of congenital malformations and embyrolethality, visceral , cardiac, and skeletal malformations
Cladribine¹⁰	Follow up with high-risk obstetrician	Risk of congenital malformations and embyrolethality based on animal studies
Teriflunomide³¹	Early screening for major and minor malformations; option to follow up with high-risk obstetrician	Highly teratogenic; risk of serious birth defects in fetus; risk of preterm labor; risk of low birthweight
Natalizumab²¹	Screen neonate for liver dysfunction, pancytopenia	Risk of mild to moderate hematologic alterations (pancytopenia with late pregnancy exposure)
B-cell–depleting agents Ocrelizumab²² Ofatumumab²³ Rituximab^24,25 Ublituximab²⁶	Screen neonate for B-cell depletion, pancytopenia	With B-cell–depleting agents, there is a risk of B-cell depletion in fetus or infant with second-trimester and third-trimester exposure Rituximab: risk of congenital malformations in fetus, and neonatal infections
Alemtuzumab²⁷	Monitor thyroid studies	Risk of thyroid disease in mother (autoimmune thyroiditis in up to 40%); risk of low birthweight, preterm birth, preeclampsia; risk of neonatal Graves disease and cognitive impairment

↵a This table reflects our clinical practice and review of combined recommendations of prescribing information and key articles.
S1Pr = sphingosine 1-phosphate receptor
Based on information in references 1,5,10,11, and 13–41.