Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties. Interferons (IFNs) beta-1a and beta-1b have been first line treatment for MS for decades. The transfer of IFN to breast milk is likely limited by its large molecular weight and the fact that it binds to T cells (21).

A study conducted in 2012 on 6 women receiving 30 μg/week IFN beta-1a found that the highest milk concentrations of IFN beta1a (179 pg/ml) corresponded to a relative infant dose of 0.006% of the maternal dose, strongly suggesting that IFN beta-1a does not significantly transfer into human breast milk (22) and, since the poor oral absorption, it is not likely to reach the bloodstream of the infant (22).

Another study was conducted on 39 infants from women with MS who were breastfeeding while on IFN beta-1a and were followed by the Germanic Multiple Sclerosis and Pregnancy Registry. Most infants included in this study were also exposed during pregnancy and infants were breastfed for an average of 9.2 months (range 1.6–28.5 months) during interferon therapy. No uncommon adverse outcomes were seen during the first year of life and developmental delay, courses of antibiotics and hospitalizations did not differ from the reference German population (23).

According to the LactMed database, none of the mothers receiving IFN beta-1a while breastfeeding has noticed any adverse effects in their breastfed infants (24). Experts' opinion also suggests that IFNs can be used safely by breastfeeding mothers (11). According to the European Medicines Agency (EMA) Summaries of Product Characteristics of IFN beta-1a and beta-1b, no harmful effects on breastfed infants are anticipated, and the products can be used during breastfeeding (25, 26).

Instead, the FDA distinguishes between IFN beta-1a that could be used with caution in nursing women (27, 28) and IFN-beta-1b in which a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother (29).

GA, indicated for the treatment of relapsing forms of multiple sclerosis (MS), is a polymer of the aminoacids tyrosine, alanine, glutamate, and lysine with a molecular weight of 5,000–9,000 Daltons (30). Even if there are no data on the transfer of glatiramer acetate into breast milk in humans (30), it is highly unlikely given its large size (21). Additionally, the compound is metabolized into its parent amino acids which pose no risk to the breastfed infant (21). Hellwig et al. reported no noticeable problems in newborns exclusively breastfed for 6 months by three mothers who were receiving glatiramer acetate (31). Another study on nine mothers receiving glatiramer acetate during pregnancy and postpartum who breastfed for 3.6 months on average, no effects were reported in their breastfed infants except for one otherwise normal infant with delayed language development at the 1-year follow-up (32). In an observational study in 34 women who were receiving glatiramer acetate while breastfeeding, no increase in common adverse events was seen (23). Safety data were confirmed for up to 18 months in an extension study including 60 exposed infants and 60 controls (33).

Experts' opinion suggests that GA can be used safely by breastfeeding mothers (11), although according to the EMA Summary of Product Characteristics, a decision must be made whether to discontinue breastfeeding or to discontinue from glatiramer acetate, considering the benefits of breastfeeding for the infant and the benefit of therapy for the mother (30). Also, the FDA label states that it is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when glatiramer acetate is administered to a nursing woman (34).

Dimethyl fumarate is the methyl ester of fumaric acid and it is an oral treatment indicated for the treatment of adult patients with relapsing remitting multiple sclerosis. Dimethyl fumarate is metabolized rapidly with a half-life of about 1 hour and has a large volume of distribution of 60–90 liters for a 240 mg dose (35). While these characteristics would likely indicate that significant transfer of dimethyl fumarate to breast milk does not occur, on the other hand it has a small molecular weight and low protein binding capacity (27–40%) (35), which could indicate significant transfer into milk (11, 21). A recent case study in two lactating women on therapy with dimethyl fumarate calculated the relative infant dosages to be 0.019% and 0.007% of the maternal dosage (36). According to the LactMed database (37), no relevant information has been published so far on the effects in the exposed infants. Given the limited data on the transfer of dimethyl fumarate to breast milk, according to the EMA Summary of Product Characteristics, a risk to infants cannot be excluded accordingly, a decision must be made whether to discontinue breast-feeding or to discontinue dimethyl fumarate therapy, taking into account the benefits of breastfeeding for the infant and the benefit of therapy for the mother (35). In addition, the FDA label states that caution should be exercised when it is administered to a nursing woman (38).

Teriflunomide, the active metabolite of leflunomide, is an immunomodulatory drug inhibiting pyrimidine de novo synthesis indicated for the treatment of adult patients with relapsing remitting multiple sclerosis. Animal studies have documented the transfer of teriflunomide to milk (39). Teriflunomide showed to be teratogenic and embryotoxic in animal studies (39). Moreover, it is eliminated slowly from the plasma, and in the absence of an accelerated elimination procedure, it takes about 8 months to reach plasma concentrations <0.02 mg/l, although due to individual variation in clearance may take up to 2 years (39). According to the LactMed database (40), there is no published experience with teriflunomide during human lactation. Teriflunomide is labeled as contraindicated during lactation by the EMA Summary of Product Characteristics (39). Similarly, the FDA label states that a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (41).

Fingolimod is metabolized to the active metabolite fingolimod phosphate, which inhibits the sphingosine-1-phosphate (S1P) receptor (42), and is extensively distributed to body tissues with a volume of distribution of about 1,200 liters with an apparent terminal half-life of 6–9 days (42). The sphingosine 1-phosphate receptor is known to be involved in vascular formation during embryogenesis (32). Fingolimod is an oral treatment indicated for adults and children over 10 years of age with highly active relapsing-remitting multiple sclerosis (MS) (42). Fingolimod showed to be teratogenic in animal studies, where induced fetal loss and organ defects (42). Fingolimod is excreted in milk of treated animals during lactation (32). According to the LactMed database there is no relevant published experience with fingolimod during human breastfeeding. The EMA Summary of Product Characteristics states that women receiving fingolimod should not be breastfeed given the potential for serious adverse reactions in nursing infants (42). The FDA label states that the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breastfed infant from fingolimod or from the underlying maternal condition (43).

Siponimod and ozanimod have also recently entered the treatment landscape of MS (44, 45). For siponimod, it is unknown whether the compound or its major metabolites are excreted in human milk, although they are excreted in the milk of rats (44). Ozanimod and its metabolites are excreted in milk of treated animals during lactation and pose a potential for serious adverse reactions in nursing infants (34). For both treatments there is no published experience of their use in nursing women. The EMA Summaries of Product Characteristics state that siponimod (44) should not be used during breastfeeding and that women receiving ozanimod (45) should not breastfeed, respectively. Similarly, for fingolimod the FDA labels state that their use during breastfeeding should take into account the mother's clinical need for the drug and any potential adverse effects on the breastfed infant (46, 47).

Natalizumab is a recombinant humanized anti-α4-integrin antibody (48), an infusion treatment indicated in adults with highly active relapsing remitting multiple sclerosis (RRMS). It has been detected in low amounts in breast milk of nursing women (49). Proschmann et al. reported that in the majority of the mother–infant serum pairs (6/11) and in all breast milk samples, free Natalizumab was detectable with a significant association with the time since the last infusion (49). According to the conventional model of drug passage into breast milk, large molecules such as maternal immunoglobulins can pass into colostrum because of the wide spaces between mammary epithelial cells (49).

In a case-report of a lactating woman with MS who was taking natalizumab while breastfeeding, the mean concentration of natalizumab in breast milk was 0.93 μg/ml/day, with a relative infant dose of 1.74% of the maternal dose (50). Moreover, transfer of natalizumab into human milk was seen to increase with time and subsequent injections; the highest concentration (2.83 μg/ml) was seen at day 50 with a relative infant dose of 5.3% (50).

Ciplea et al. recently reported on 17 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received natalizumab during lactation (51). No negative impact was observed on infant health or development that was attributable to breast milk exposure after a median follow-up of 1 year (51). Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life (51). However, the concentration of natalizumab in breast milk and serum of infants was low (51). According to the EMA Summary of Product Characteristics, since the effect of natalizumab on newborn/infants is unknown, breastfeeding should be discontinued during treatment with natalizumab (48). The FDA product label does not contain specific contraindications during breastfeeding, and only reports that natalizumab has been detected in human milk and that the effects of this exposure are unknown (52).

Cladribine tablets, an oral DMT indicated for the treatment of highly active RRMS patients, is a chlorinated analog of deoxyadenosine that is relatively resistant to ADA-mediated deamination (53). Therefore, cladribine accumulates in lymphocytes and depletes them through apoptosis (53). Evidence from the cladribine clinical development program were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis (54). There were showed no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose (54). Furthermore, a non-interventional post-authorization safety study has been initiated to obtain more information (54).

To date, there are only very limited data on the transfer of cladribine into breast milk. A recent case study documented the transfer of cladribine into human milk in a woman with MS who was breastfeeding (55). The patient experienced a relapse at 4 months postpartum and began therapy with 20 mg cladribine; although she discontinued breastfeeding, she donated milk samples for study. Cladribine levels in milk were 281.2 ng/mL at 1 hour following a 20-mg dose, with a rapid decline in milk concentration over a period of 12–24 h. The levels were undetectable in the milk samples collected after administration of her last dose at 48, 72, and 96 h (55).

In the EMA label, cladribine is contraindicated during breastfeeding and for a period of one week following the last dose (53). Similarly, the FDA contraindicates breastfeeding during cladribine treatment and until 10 days after the last dose (56).

Two anti-CD20 therapies have already received EMA and FDA approval for the treatment of MS: Ocrelizumab and Ofatumumab.

Ocrelizumab is a recombinant humanized anti-CD20 monoclonal antibody (57). It is unknown whether ocrelizumab or its metabolites are transferred in human milk, and the available pharmacodynamic/toxicological data in animals have shown excretion of ocrelizumab in milk (57). Given its large molecular weight, the amount of ocrelizumab transferred in milk is likely to be low and would likely be degraded in the infant's gastrointestinal tract. Considering that most monoclonal antibodies used in MS are either for induction or have a prolonged dose interval, this will undoubtedly limit the infant's exposure (20). Only a few infants have been exposed to ocrelizumab during breastfeeding with no evidence of harm (58). Ciplea et al. recently reported on 6 patients from the DMSKW (German MS and Pregnancy Registry) who received anti-CD20 antibodies (3 rituximab, 2 ocrelizumab, and 1 rituximab and ocrelizumab) during lactation (51). Low levels of transfer into breast milk were detected. Notwithstanding, whether these minimally detectable breast milk levels pose any risk to the infants is unknown, leading many experts to be cautious (51). According to the EMA Summary of Product Characteristics, women should be advised to discontinue breastfeeding during therapy with ocrelizumab (57). The FDA label states that the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition (59).

Ofatumumab is a CD20-directed cytolytic antibody that is approved by the FDA and EMA for the treatment of RRMS (60). According to LactMed database (61) there are currently no data about the secretion of ofatumumab in human milk or its effects on breastfed infants, in particular, about the potential B-cell depletion The EMA label states that the use of ofatumumab in women during lactation has not been studied. Since, the excretion of IgG antibodies in human milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, a risk to the breast-fed child cannot be excluded during this short period. Afterwards, ofatumumab could be used during breastfeeding, if clinically needed. If the patient was treated with ofatumumab up to the last few months of pregnancy, breast-feeding can be started immediately after birth (62). The FDA label states that the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ofatumumab and any potential adverse effects on the breastfed infant from ofatumumab or from the underlying maternal condition (63).

Alemtuzumab is a humanized IgG1 kappa monoclonal antibody specific for CD52 (64), indicated for adults with highly active relapsing remitting multiple sclerosis. Alemtuzumab has been detected in the milk and offspring of lactating female mice, but no information is available on the use of alemtuzumab during breastfeeding in humans (64). As with other monoclonal antibodies, considering its large molecular weight it is unlikely to be transferred to breast milk in amounts that are clinically significant. The EMA Summary of Product Characteristics specifies that breastfeeding should be discontinued during each course of treatment with alemtuzumab and for 4 months following the last infusion of each treatment course (64). However, it is also noted that the benefits of conferred immunity through breast milk may outweigh the risks of potential exposure to alemtuzumab for the suckling newborn/infant (64). The FDA label states that, because of the potential for serious adverse reactions in nursing infants from the drug, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother (65).

Three inhibitors of Bruton's tyrosine kinase (BTK) are currently in development for treatment of MS (66). BTK is responsible for signal transmission through several receptors in B cells and myeloid cells and is thus a valid target in MS (67). Evobrutinib has shown promising results in a Phase 2 study (67) and is currently being investigated in a Phase 3 trial (68). There is still no information on the transfer of evobrutinib into breast milk, and women who are pregnant or breastfeeding have been excluded from clinical trials.