Updated Perspectives on the Challenges of Managing Multiple Sclerosis During Pregnancy

Figures & data

Box 1 General Recommendations Before, During and After Pregnancy

Before pregnancy  - Ask about family plans at or soon after the diagnosis. Discussion about pregnancy-related issues.  - Consider family planning when choosing an initial therapy.  - Do not delay DMT onset.  - A non-teratogenic DMT is preferable in fertile women. Patients should be advised about available contraceptive methods especially during treatment with sphingosine-1-phosphate–receptor modulators and teriflunomide, and at least 4 months after alemtuzumab, 6 months after cladribine and 1 month after anti-CD20 therapies.  - A planned pregnancy and a relapse-free period prior to pregnancy are recommended (1 year in normal evolving MS and even 2 years in highly active MS).  - Pre-conceptional vitamin D and folic acid supplementation. Avoid alcohol and smoking.  - IFN-β, GA, DMF and NTZ could be maintained until conception.  - Teriflunomide, fingolimod, siponimod, ozanimod and ponesimod must be stopped before conception (see Table 1) and switching to other DMT could be recommended.

During pregnancy  - If a pregnancy is confirmed in a woman taking potentially teratogenic treatment, immediately discontinue DMT and recommend an ultrasound study.  - DMF must be discontinued immediately when pregnancy is confirmed. IFN-β and GA could be administered even throughout the pregnancy. NTZ could be maintained until the 30th–34th gestational week at 6- to 8-week intervals.  - Clinical and laboratory monitoring should continue, including John Cunningham virus serology in women treated with natalizumab and monthly blood and urine tests in those treated with alemtuzumab in the previous years.  - Advise that urinary tract infections are more frequent during pregnancy and recommend pelvic floor exercises.  - Apply standard protocols of blood pressure and glycemic control.  - Continue vitamin D and folic acid supplementation.  - If necessary, an MRI without gadolinium could be obtained.  - In case of a disabling relapse the standard high dose of intravenous methylprednisolone can be used, especially in 2nd and 3rd trimesters.  - In all cases of DMT or corticosteroids fetal exposure, consider an organ screening ultrasound at 20–22 weeks of gestation.  - In the 3rd trimester a visit should be programmed to update the neurological status and plan the postpartum period.  - Exclusive breastfeeding should be encouraged whenever possible.  - Advise that the choice of the type of anesthesia and delivery should be based on obstetric criteria.  - Follow the same vaccination indications as the general pregnant population: Inactivated influenza, inactivated diphtheria, tetanus, and acellular pertussis (Tdap) and mRNA Covid-19 vaccines.

After delivery  - Patients should be closely monitored during the first trimester postpartum.  - There is no clear evidence to support the use of intravenous corticosteroids or intravenous immunoglobulins to prevent postpartum relapses.  - Resuming DMT soon after delivery, especially high-efficacy therapies in high-risk patients, is associated with a reduced risk of postpartum relapse.  - Breastfeeding does not have a harmful effect for women with MS and must not be contraindicated.  - Exclusive breastfeeding could prevent relapses after childbirth, and it must be recommended unless a DMT contraindicated during lactation is going to be resumed.  - IFN-β and GA are considered safe during lactation.  - Intravenous methylprednisolone to treat postpartum relapses is not contraindicated. Consider delaying breastfeeding for 2–4 hours after administration to minimize infant exposure.

Table 1 Pregnancy-Related Aspects of Multiple Sclerosis Disease‐modifying Therapies

DMT	Pre-Pregnancy Washout	Pregnancy	Breastfeeding	Newborn Precautions
Beta interferon	Not required	EMA: May be considered during pregnancy FDA: Use only if the benefit justifies the potential risk to the fetus.	Can be used during breastfeeding
Glatiramer acetate	Not required	Use only if the benefit justifies the potential risk to the fetus	Limited data. Considered safe
Teriflunomide	Accelerated elimination procedure until plasma concentrations are less than 0.02 mg/L	Contraindicated during pregnancy	Contraindicated during breastfeeding	Risk of birth defects
Dimethyl fumarate	Not required	Use only if the benefit justifies the potential risk to the fetus	Limited data. Risks not excluded. Use with caution
Fingolimod	2 months (risk of rebound effect)	Contraindicated during pregnancy	Contraindicated during breastfeeding	Risk of fetal loss and birth defects in animal models
Siponimod	10 days	Contraindicated during pregnancy	Contraindicated during breastfeeding	Risk of fetal loss and birth defects in animal models
Ozanimod	3 months	Contraindicated during pregnancy	Contraindicated during breastfeeding	Risk of fetal loss and birth defects in animal models
Natalizumab	Not required (risk of rebound effect)	Use only if the benefit justifies the potential risk to the fetus at least until first trimester or 30–34 weeks	EMA: Contraindicated during breastfeeding FDA: Use only if the benefit justifies the potential risk to the infant	Risk of hematological abnormalities in infants exposed in the third trimester
Alemtuzumab	4 months after last dose	Use only if the benefit justifies the potential risk to the fetus	EMA: Discontinue during each course and for 4 months following the last infusion. Benefits may outweigh the risks for the infant FDA: Discontinue either alemtuzumab or breastfeeding	Untreated maternal hypothyroidism increases the risk for miscarriage and may have effects on the fetus. Risk of neonatal Graves` disease in mothers with Graves` disease
Ocrelizumab	EMA: 12 months FDA: 6 months	Use only if the benefit justifies the potential risk to the fetus	EMA: Contraindicated during breastfeeding FDA: Use only if benefit justifies the potential risk to the infant	Risk of B-cell depletion after intrauterine or breast milk exposure
Cladribine	6 months after last dose	Contraindicated during pregnancy	Breastfeeding contraindicated during treatment and for 1 week after the last dose	Risk of congenital anomalies
Ofatumumab^Citation271	6 months after last dose	Use only if the benefit justifies the potential risk to the fetus	Use only if benefit justifies the potential risk to the infant.	Risk of B-cell depletion after intrauterine or breast milk exposure
Ponesimod^Citation272	1 week after last dose	Contraindicated during pregnancy	Contraindicated during breastfeeding	Risk of fetal loss and birth defects in animal models

Abbreviations: DMT, disease-modifying therapy; EMA, European Medicines Agency; FDA, United States Food and Drug Administration.

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