Drug Therapy of Myasthenia Gravis During Breastfeeding

Cholinergic Drugs

Increasing acetylcholine at the AChR with anticholinesterase drugs is the most common therapy of MG. Anticholinesterase drugs work by decreasing the breakdown of acetylcholine. These drugs are used for symptomatic treatment of MG and work rapidly.

Pyridostigmine is the most widely used anticholinesterase. Milk concentrations have been measured in two women. One mother who was taking pyridostigmine 60 mg 3 times daily (3 mg/kg daily) had milk pyridostigmine levels of 13–24 mcg/L at various times during the 8-hour dosage interval. At 102 days postpartum while taking 40 mg twice daily (2 mg/kg daily), milk pyridostigmine levels ranged from the limit of detection to 5 mcg/L during a dosage interval. The time of the peak milk level was ∼4 hours after a dose.

Another mother who was taking pyridostigmine 60 mg 5 times daily (5 mg/kg daily) had milk pyridostigmine levels of 22–25 mcg/L at 60 days postpartum. The authors estimated that an exclusively breastfed infant would receive a maximum of only 0.1% of the maternal weight-adjusted dosage. The exclusively breastfed 60-day-old infant of the second mother had undetectable (<2 mcg/L) pyridostigmine levels in serum at the time of a dose and 2.6 hours later. Infants whose mothers were taking pyridostigmine while breastfeeding had no cholinergic side effects and developed normally.

Neostigmine was not detected in milk in a case series of 12 patients with 21 pregnancies in the 1950s and 1960s; however, details of the dosage, timing, and assay sensitivity (probably poor by today's standards) were not stated. Six infants of mothers treated with neostigmine for MG reportedly breastfed successfully. One newborn infant appeared to have abdominal cramps after each breastfeeding, probably caused by neostigmine, although it could not be detected in the breast milk of the infant's mother. Pyridostigmine is preferred over neostigmine in general and in nursing mothers.

Edrophonium is a short-acting anticholinesterase drug that is mostly used for diagnostic purposes. No information is available on the use of edrophonium during breastfeeding. Because of its short half-life and chemical structure, it is unlikely to be excreted into breast milk or orally absorbed by the infant. Administering the drug just after breastfeeding and waiting 2–3 hours before breastfeeding again should avoid any adverse reactions in the infant.

Immunosuppressive Therapy

Because MG is an immune-mediated condition, various immunosuppressive therapies are used to treat it. Conventional small-molecule immunosuppressants and newer monoclonal antibodies are maintenance therapies. Most of the information on these drugs during breastfeeding comes from their use in conditions other than MG.

Glucocorticoids improve myasthenic weakness in most patients. Most commonly, prednisone is used. Prednisone has been well studied in nursing mothers and only trivial levels of drug have been found in milk. No adverse effect has been reported in breastfed infants with maternal use of any corticosteroid during breastfeeding. The oft-repeated recommendation of avoiding breastfeeding for 4 hours after a dose of prednisone is unnecessary. Only with a dose of 1 g of methylprednisolone intravenously might avoidance of breastfeeding be required during the infusion and for as little as 2 hours to markedly reduce infant exposure.

Intravenous immunoglobulin (IVIG) is used for acute exacerbations of MG and as maintenance therapy by either the intravenous or, more recently, the subcutaneous route. ⁵ Data from two mothers indicate that immunoglobulin G (IgG) concentrations in milk are normal or higher and immunoglobulin M levels in milk are normal or lower during IVIG therapy. The antibacterial activity of milk in these women was normal. More than 200 infants have been reported who breastfed during maternal IVIG therapy with no serious adverse effects. Rare cases of transient rash in breastfed infants have been reported, but not necessarily caused by IVIG during maternal therapy.

Azathioprine can be used in MG for long-term maintenance therapy and to reduce prednisone dosage. A response usually occurs in 1–3 months, but it can take up to a year to have a full effect. There is extensive experience with azathioprine in nursing mothers with other conditions. Studies of azathioprine doses up to 200 mg daily for immunosuppression have found either low or unmeasurable levels of the active metabolites in milk and infant serum. Some evidence indicates a lack of adverse effects on the health and development of infants exposed to azathioprine during breastfeeding up to 3.5 years of age, but long-term follow-up for effects such as carcinogenesis have not been performed.

North American and European expert guidelines, the National Transplantation Pregnancy Registry, and other experts consider azathioprine to be acceptable to use during breastfeeding. Cases of mild asymptomatic neutropenia have been reported in breastfed infants, so it might be desirable to monitor exclusively breastfed infants with a complete blood count with differential and liver function tests if azathioprine is used during lactation, although some authors feel that monitoring is unnecessary. Avoiding breastfeeding for 4 hours after a dose (usually once daily) markedly decreases the amount received by the infant in breast milk.

Cyclosporine is used off-label for MG. Milk levels varied considerably in several case reports and series, but with typical maternal cyclosporine blood levels, a completely breastfed infant would usually receive no more than about 2% of the mother's weight-adjusted dosage or the pediatric transplantation maintenance dosage, and often <1%. In most breastfed infants of mothers receiving cyclosporine, the drug is not detectable in blood; however, occasionally infants have had detectable blood levels, even when milk levels and infant dosage were apparently low. Numerous infants have been breastfed during maternal cyclosporine therapy post-transplant, usually with a concurrent corticosteroid and sometimes with concurrent azathioprine. At least two mothers taking cyclosporine successfully breastfed a second infant after successfully breastfeeding their first infant.

No reports of adverse effects on infants' growth, development, or kidney function have been reported. United States and European expert guidelines, the National Transplantation Pregnancy Registry, and other experts consider cyclosporine to be acceptable to use post-transplant and for inflammatory bowel disease during breastfeeding. Breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.

Mycophenolate is used similarly to azathioprine, but it has much less information in breastfeeding. A study of one patient indicates that relatively large amounts of mycophenolate are excreted into breast milk, with peak milk levels at about 2 hours after a dose of the delayed-release formulation. A few infants have been breastfed during mycophenolate therapy, with no adverse effects. Because little information is available on the use of mycophenolate during breastfeeding, another immunosuppressant drug is preferred, especially while nursing a newborn or preterm infant.

Eculizumab is a monoclonal antibody immunosuppressant approved for maintenance therapy for MG that works in 1–3 months. Studies of ∼30 women treated for paroxysmal nocturnal hematuria with eculizumab have found no drug in milk. About 60 infants who were breastfed during maternal eculizumab therapy have had no short- or long-term adverse effects reported.

Ravulizumab is another monoclonal antibody approved for use in MG that is similar in action to eculizumab. No information is available on the use of ravulizumab during breastfeeding. Similar to other monoclonal antibodies, ravulizumab is a large protein molecule with a molecular weight of about 148,000 Da, so little is expected to enter breast milk and absorption by the infant is unlikely. Nevertheless, the product information recommends that breastfeeding be discontinued during ravulizumab therapy and for 8 months after the final dose, presumably because of the lack of information in breastfeeding. Eculizumab would be preferred over ravulizumab.

Efgartigimod alfa is an antibody fragment that binds to the neonatal Fc receptor (FcRn). The blockade of FcRn reduces IgG antibody concentrations, including the abnormal antiAChR antibodies that are present in patients with generalized MG. No information on the use of efgartigimod alfa in nursing mothers is available. Because efgartigimod alfa is also a large protein molecule with a molecular weight of 54,000 Da, the amount of drug in milk is likely to be very low with poor oral bioavailability in the infant. Product labeling does not contraindicate its use, but until more data become available, efgartigimod alfa should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant.

Summary

Drug therapy of MG in nursing mothers does not need to be changed markedly from the standard therapies. The first-line agent, physostigmine, is tolerated well by breastfed infants who receive it in milk and several common immunosuppressants such as azathioprine, cyclosporine, and eculizumab appear to be acceptable to use during breastfeeding with minimal monitoring. Breastfeeding may cause excessive fatigue in mothers with MG and occasionally breastfeeding will need to be discontinued for this reason.