Neurology, Department of Myasthenia Gravis Medicine, Duke … · 2020-02-25 · myasthenia gravis...

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Pregnancy andMyasthenia Gravis

Janice M. Massey, MD, FAAN; Carolina De Jesus-Acosta, MD

ABSTRACTPurpose of Review: Myasthenia gravis (MG) is an acquired autoimmune disordercharacterized by fluctuating ocular, limb, or oropharyngeal muscle weakness due toan antibody-mediated attack at the neuromuscular junction. The female incidenceof MG peaks in the third decade during the childbearing years. A number ofexacerbating factors may worsen MG, including pregnancy. When treatment isneeded, it must be carefully chosen with consideration of possible effects on themother with MG, the pregnancy, and the fetus.Recent Findings: Decisions are complex in the treatment of women with MGcontemplating pregnancy or with presentation during pregnancy. While data islargely observational, a number of characteristic patterns and issues related to riskto the patient, integrity of the pregnancy, and risks to the fetus are recognized.Familiarity with these special considerations when contemplating pregnancy isessential to avoid potential hazards in both the patient and the fetus. Use ofimmunosuppressive agents incurs risk to the fetus. Deteriorating MGwith respiratoryinsufficiency poses risk to both the mother and the fetus.Summary: This article reviews available information regarding expectations andmanagement for patients with MG in the childbearing age. Treatment decisionsmust be individualized based on MG severity, distribution of weakness, coexistingdiseases, and welfare of the fetus. Patient participation in these decisions isessential for successful management.

Continuum (Minneap Minn) 2014;20(1):115–127.

INTRODUCTIONMyasthenia gravis is a chronic disordermanifested by fluctuating weakness andrapid fatigue of voluntary muscles. Theestimated prevalence of MG in theUnited States is 20/100,000 population.1

Acquired MG is an autoimmune disor-der in which antibodies at the neuro-muscular junction produce impairedneuromuscular transmission and fatiga-ble weakness in skeletal muscle(periocular, limb, or oropharyngealmuscles). Symptoms can present atany age, but the highest incidence infemale patients occurs during the thirddecade of life. MG is more common inwomen than in men, with a ratio of 3:2.Known triggers forMG include infection,

changes in thyroid function, generalanesthesia, certain medications, emo-tional or physical stress, menses, preg-nancy, and the postpartum state.2

Caring for the female patient ofchildbearing age involves anticipationof pregnancy, as well as care through-out pregnancy and the postpartumperiod. In preparation for pregnancy,women with MG need education andcounseling to address special thera-peutic issues, including the choice andrisks of treating or not treating, effectsof MG on the pregnancy, and risks tothe fetus and newborn. Women withMG benefit from a personalized inter-disciplinary approach to care duringpregnancy and the postpartum period,

Address correspondence to DrJanice M. Massey, Division ofNeurology, Department ofMedicine, Duke UniversityMedical Center, DUMC 3403,Durham, NC 27710,[email protected].

Relationship Disclosure:

Dr Massey has receivededucational grants fromAllergan, Inc; and MerzPharma. Dr De Jesus-Acostareports no disclosure.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:DrsMassey andDe Jesus-Acostadiscuss the use of drugs forthe treatment of myastheniagravis, none of which arelabeled by the US Food andDrug Administration for usein pregnancy.

* 2014, American Academyof Neurology.

115Continuum (Minneap Minn) 2014;20(1):115–127 www.ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

including neuromuscular, high-riskobstetric, and neonatal pediatric spe-cialists.2 Recognizing risks for both themother and the baby requires carefulmonitoring and attention during bothpregnancy and delivery. Even after thesuccessful delivery of a healthy infant,MG may impact the new mother. Awoman with MG should be fullyinformed and aware that a contem-plated pregnancy is a physical com-mitment that may be affected by MGbut also requires additional ability tocope with both the demands of par-enting and the ongoing disease. Thisarticle discusses the initial approach tofemale patients of childbearing agewith MG, including diagnosis andmanagement of the many challengingquestions that arise for the patient andthe treating physicians.

DIAGNOSIS OF MYASTHENIAGRAVIS DURING PREGNANCYMG is unmasked or worsened inapproximately one-third of patientsduring their pregnancy.3Y5 Symptomsof fluctuating weakness are the hall-mark of this condition, and whenassociated with evident weakness typ-ical of MG (ie, fatigable ptosis, diplo-pia, dysarthria, dysphagia, and/or limbweakness), they should prompt fur-ther diagnostic studies (in the as-yet-undiagnosed patient), includingelectrodiagnostic studies and acetyl-choline receptor (AChR)Ybinding anti-bodies. If AChR antibodies are notdetectable, antiYmuscle-specific kinase(MuSK) should be measured (Case 6-1).Elevated serum levels of antiYAChR-binding antibodies or anti-MuSK anti-bodies in patients with clinical signsand symptoms of MG confirm thediagnosis. In the seronegative patientelectrophysiologic demonstration ofan abnormality of neuromusculartransmission establishes the diagnosis.The electrophysiologic tests that dem-

onstrate a defect in neuromusculartransmission are repetitive nervestimulation studies and the moresensitive single-fiber EMG, both safelyperformed in pregnant patients. Pa-tients may undergo chest CT imagingwithout contrast to assess the thymusgland, however, postponement untilafter delivery is preferable, particularlyin antibody negative patients. Therisk of radiation is eliminated withchest MRI, but it does not visualizethe anterior mediastinum as well asCT imaging, which is the preferredtechnique.

Thymoma is uncommon in this agegroup, particularly if AChR-antibodytesting is negative.6,7 The decision toperform thymic imaging can usuallybe postponed until after delivery inrecognition of the potential risk to thefetus, unless there is strong clinicalsuspicion for thymoma.

CHANGES IN MYASTHENIAGRAVIS DURING PREGNANCYPregnancy may change the course ofMG, often in unpredictable ways.8 Theseverity of weakness at the beginningof pregnancy does not predict eitherremission or exacerbation,3,4 and infact disease exacerbations, myastheniccrisis, or even disease remission mayeach occur during pregnancy. Patientscan develop hypoventilation secondaryto respiratory muscle weakness. Thegrowing fetus may also restrict thediaphragm and compromise respiratoryfunction; late in the pregnancy, in-creased abdominal pressure and dia-phragm elevation reduce the capacityfor the lungs to inflate fully. At somepoint during pregnancy, approximately20% of patients develop respiratorycrisis requiring mechanical ventila-tion. Close monitoring for respiratorydifficulties is essential throughoutpregnancy to maintain the welfare ofboth mother and fetus.

KEY POINTS

h Women withmyasthenia gravisbenefit from apersonalizedinterdisciplinaryapproach to care duringpregnancy and thepostpartum period,including neuromuscular,high-risk obstetric, andneonatal pediatricspecialists.

h Myasthenia gravis isunmasked or worsenedin approximatelyone-third of patientsduring their pregnancy.

h Elevated serum levels ofantiYacetylcholinereceptor-bindingantibodies orantiYmuscle-specifickinase (MuSK)antibodies in patientswith clinical signsand symptoms ofmyasthenia gravisconfirm the diagnosis.In the seronegativepatient,electrophysiologicdemonstration ofan abnormality ofneuromusculartransmission establishesthe diagnosis.

h Patients may undergochest CT imagingwithout contrast toassess the thymusgland; however,postponement untilafter delivery ispreferable, particularlyin antibody-negativepatients.

116 www.ContinuumJournal.com February 2014

Pregnancy and Myasthenia Gravis


Rare complications of MG duringpregnancy, including bone marrowsuppression, have been reported. Ithas been postulated that suppressioncould be due to an autoimmunereaction against the megakaryocytecolony-forming unit.9,10 Patients onimmunosuppressive therapy also maydevelop infections secondary to de-creased immunity.

During labor, the uterine smooth mus-cle is not compromised, because unlikestriated muscle, it is not affected by AChR

antibodies. Patients may develop worsen-ing weakness especially during the secondstage of labor, when striated muscle isinvolved; some may become exhaustedand require assistance for delivery.

An association between MG andpreeclampsia has been suggested. Iftreatment is indicated, magnesiumsulfate should be used with extremecaution due to its direct deleteriouseffect on neuromuscular transmis-sion.11,12 Exacerbation of weaknessmay require respiratory support.

KEY POINTS

h The severity ofweakness at thebeginning of pregnancydoes not predicteither remission orexacerbation, and,in fact, diseaseexacerbations,myasthenic crisis, oreven disease remissionmay each occur duringpregnancy.

h Close monitoring forrespiratory difficulties isessential throughoutpregnancy to maintainthe welfare of bothmother and fetus.

Case 6-1Five weeks postpartum, a 29-year-old woman developed proximal upperextremity weakness. The weakness lasted for 4 weeks and was notassociated with changes in sensation. Pregnancy, cesarean delivery, andthe immediate postpartum period were uncomplicated. Two years later,she developed fatigable right ptosis and horizontal, binocular diplopiathat lasted 1 to 2 weeks. Neuro-ophthalmic evaluation noted ptosis andextraocular motility abnormalities. Myasthenia gravis (MG) did not appearto have been considered at that time, and the patient was diagnosed witha right Horner syndrome. MRI of the brain and magnetic resonanceangiogram of the intracranial and extracranial vessels were negative.

A year later she became pregnant and had an uneventful pregnancy.On the morning of her planned cesarean delivery, she was hypertensive,and possible preeclampsia was treated with magnesium sulfate withoutevent. She delivered a healthy daughter without weakness, feedingdifficulty, or respiratory distress. Two weeks postpartum, she developednasal dysarthria and dysphagia followed by right ptosis. Over the nextfew weeks, she had gradual worsening of generalized weakness.

Examination showed severe bilateral fatigable ptosis and limitedbilateral eye abduction with diplopia. Eye closure, cheek puff, tongueprotrusion, and the palate showed fatigable weakness. Neck flexion,proximal arm, and hip flexion were weak bilaterally. Electrodiagnosticstudies showed abnormal decrement on 3-Hz repetitive nerve stimulationconsistent with MG. AChR-binding antibodies were elevated. Given thedistribution of weakness with oropharyngeal muscle predominance,intervention seemed necessary. Prednisone was considered but not chosenas patients often worsen in the first 2 weeks of therapy before receivingbenefit, and worsening of her oropharyngeal weakness may have requiredintubation. She received five sessions of plasma exchange withoutcomplication and with significant improvement of her condition.

Comment. This patient represents a case of MG unmasked by herpregnancies. A high index of suspicion with focused history taking, payingspecial attention to the patient’s medical history, and correlation with thepatient’s physical examination should prompt the diagnosis. Appropriatemanagement includes caution with some medications that may contributeto worsening of MG symptoms.



FETUS DURING PREGNANCYAND DELIVERYRare circumstances affecting the fetusalso occur in pregnant women withMG. Transplacental passage of mater-nal autoantibodies may lead to fetalmuscle weakness in utero, thus reduc-ing fetal movements, producingpolyhydramnios, and resulting in still-birth. Fetal difficulty has been de-scribed even in mothers with mild orasymptomatic disease, who produceantibodies against the fetal AChRs. Inrare cases, babies of mothers with MGmay develop arthrogryposis multiplexcongenita, a disorder characterized bymultiple joint contractures and otheranomalies.13 This condition most likelyis secondary to decreased fetal move-ment in utero, which can be moni-tored with ultrasound. Having a childaffected with neonatal complications ofMG may be predictive of subsequentoffspring being affected. No evidencehas been published that babies bornto mothers with MG have any in-creased risk of developing autoimmune-mediated MG.14,15

Approximately 10% to 20% of in-fants born to mothers with MG de-velop transient neonatal MG.4 Whilemore common with AChR-positivemothers, transient neonatal MG mayoccur with anti-MuSK antibodyYpositive mothers16,17 and rarely evenwith seronegative mothers. Maternalantibodies are presumed to transferacross the placenta to the infant.Although most infants have detectablematernal antibodies, only a small per-centage of infants develop symptoms.Common symptoms include general-ized hypotonia as well as respiratory,feeding, and swallowing problems.Symptoms of transient neonatal MGusually develop a few hours after birthand typically resolve within 1 month(range of 1 to 7 weeks).18 Treatment issupportive, including ventilator sup-

port and nasogastric feedings, whenneeded. Pyridostigmine (0.5 mg/kg to1.0 mg/kg) in divided doses adminis-tered 30 minutes before feeding maybe useful to improve suck and reducerisk of aspiration.

Rarely, patients with transient neo-natal MGmay developmore permanentcomplications, including persistent bul-bar and facial weakness and hearingloss. Inactivation of the fetal subunit ofthe AChR during a critical period of fetalmuscle development has been pro-posed as the cause of this phenotype.19

The maternal fetal/adult AChR antibodyratio was reported as useful in pre-dicting the severity of these manifesta-tions.19Y21 Case reports suggest thatplasma exchange and possibly predni-sone during pregnancy may reducephenotypic severity in offspring, butfurther studies are needed.19,22

TREATMENT DECISIONS BEFOREPREGNANCYIn general, the severity and distribu-tion of weakness should guide therapydecisions for women with MG who areplanning a pregnancy. Patients withrecently diagnosed ocular or mild MGhave an increased risk of conversion tosevere generalized MG, particularlywithin the first 2 years after onset ofsymptoms. Also, the MG patient cur-rently using immunosuppressive med-ication presents another challenge.Initiation of immunosuppressiveagents other than prednisone beforeor during pregnancy is typicallyavoided. Table 6-1 lists medicationsused in the treatment of MG with theirassociated US Food and Drug Admin-istration (FDA) pregnancy categoryand reported teratogenic risks.23

The risk of generalized MG ishighest in the first 2 to 3 years afteronset. During these years, it is advis-able for a patient to delay pregnancy,thereby reducing potential worsening

KEY POINTS

h No evidence has beenpublished that babiesborn to mothers withmyasthenia gravis haveany increased riskof developingautoimmune-mediatedmyasthenia gravis.

h The risk of generalizedmyasthenia gravis ishighest in the first 2 to3 years after onset.During these years, it isadvisable for a patientto delay pregnancy,thereby reducingpotential worseningprovoked by pregnancyand clarifying herseverity and responseto treatment.




provoked by pregnancy and clarifyingher severity and response to treat-ment. In some women with severedisease, pregnancy would be danger-ous and is therefore considered tobe contraindicated. Abandoning theidea of pregnancy and continuing

immunosuppressive treatment maybe contrary to the patient’s desiresand necessitates a trusting physician-patient relationship. Without patientacceptance, this recommendation maylead to patient abandonment of care.Consideration of pregnancy must be

TABLE 6-1 Therapeutic Interventions in Myasthenia Gravis

Intervention Side Effects

FDAPregnancyCategorya Teratogenicity

Pyridostigmine Muscle twitching, diarrhea, coughwith increased mucus, bradycardia

C No clear data.

Prednisone Weight gain, hyperglycemia,hypertension, gastrointestinalupset and ulceration, mood changes,osteoporosis, and myopathy

C Animal studies have yieldedan increased incidence of cleftpalate in the offspring.

Plasma exchange Hypotension, tachycardia,electrolyte imbalances, sepsis,allergic reaction, nausea, vomiting,venous thrombosis, and hematoma

n/a No known data. Plasma exchangehas been used successfullyduring human pregnancy.24

Immunoglobulins Headache, aseptic meningitisdermatitis, pulmonary edema,allergic/anaphylactic reactions,acute kidney injury, venousthrombosis, stroke, and hepatitis

C Animal studies have not beenreported. IVIg has been usedsuccessfully during humanpregnancy.

Cyclosporine Renal toxicity, hypertension,seizures, myopathy, increasedrisk of infections

C Human data have revealedevidence of premature birthand low birth weight forgestational age.

Mycophenolatemofetil

Increased risk of infections,possible increased risk oflymphoma and othermalignancies such as skincancer

D Pregnancy loss in first trimesterand congenital malformationsin the face and distal limbs,heart, esophagus, and kidneyhave been reported.

Azathioprine Hepatotoxicity, bone marrowsuppression, nausea, vomiting,diarrhea, possible increased riskof lymphoma and leukemia

D Sporadic congenital defectssuch as cerebral palsy,cardiovascular defects,hypospadias, cerebralhemorrhage, polydactyly, andhypothyroidism. Reportedchromosomal aberrationsin utero.

Rituximab Fever, asthenia, headache,abdominal pain, hypotension,thrombocytopenia, progressivemultifocal encephalopathy

C B-cell lymphocytopeniagenerally lasting less than6 months can occur in infantsexposed to rituximab in utero.

FDA = US Food and Drug Administration; n/a = not applicable.a Please see Appendix A for the US Food and Drug Administration Pregnancy Category descriptions.



dealt with sympathetically, and the pa-tient should be reassured that regardlessof her decision, she will receive our care.With close monitoring, an otherwisehealthy woman with well-controlledMG can have an uneventful pregnancy.

Treatment is stepwise and dependson the clinical scenario. With onlyminimal manifestations of the disease,pyridostigmine for symptomatic treat-ment before contemplating pregnancymay be considered. Given the uncer-tainty of the course of MG, therapy inan asymptomatic myasthenic patient isnot suggested. Patients with moderateweakness may benefit from steroids, amedication with lower teratogenicprofile. A prior response to steroidsor other comorbid conditions aids inthe decision to choose this therapy.However, if a patient is on other therapy(eg, steroid-sparing immunosuppres-sive agents), she may have had aprevious incomplete response to ste-roids. Depending on the distribution ofweakness and severity of involvement,steroid use may be a reasonable alter-native. Side effects should be closelymonitored. If thymectomy is consid-ered, it should be performed beforepregnancy or after a stable postpartumperiod because of the delayed thera-peutic effect and surgical risks.

Another, less desirable alternativewould be to continue immunosuppres-sive therapy while attempting preg-nancy, during pregnancy, and delivery.The risk of precipitating myasthenicexacerbation or crisis by withdrawingimmunosuppressive therapy must beweighed against potential harm to thefetus. In this scenario, the mother willhave the greatest likelihood of main-taining her strength and overall health,but risk of teratogenicity to the fetus isincreased. If benefits are significantenough to outweigh the risk, it is impor-tant that the parents be well informedand the patient be registered in the

appropriate drug-risk pregnancy registryonce pregnancy is confirmed (eg, www.mycophenolatepregnancyregistry.com).

TREATMENT OPTIONS DURINGPREGNANCYDuring pregnancy, MG improves inapproximately 30% to 40% of patients,remains unchanged in 30% to 40%,and worsens in 20% to 30%.3,5,8 Thegreatest percentages of exacerbationsoccur during the first trimester, in thefinal 4 weeks of gestation, or puerpe-rium. Patients with only mild diseasemay not require treatment but needclose follow-up with assessment forweakness. When weakness is mild, notreatment may be necessary. Whenneeded, medications that have lessteratogenic effects are recommended.Potential treatment alternatives forsymptomatic relief, including pyrido-stigmine, can be used safely in recom-mended doses during pregnancy.Anticholinesterase medications arepregnancy category C. Because of thechanges in intestinal absorption andrenal function during pregnancy, thedose may need frequent adjustments.The overuse of cholinesterase inhibi-tors may induce uterine contractions,premature labor, and increase oralsecretions, which can be difficult forpatients with oropharyngeal weakness.

Corticosteroids, plasma exchange,and IV immunoglobulin (IVIg) havebeen used safely during pregnancyand are agents often chosen for treat-ment of exacerbation of weakness.These treatments are generally verywell tolerated, although they are notinnocuous. Prednisone, prednisolone,and IVIg are pregnancy category C. Allhave been used frequently duringpregnancy in many other autoimmunediseases. However, a small increase incleft palate with use of prednisone inthe first trimester is reported.25 In addi-tion, high doses of prednisone have

KEY POINTS

h Treatment is stepwiseand depends on theclinical scenario.With only minimalmanifestations of thedisease, pyridostigminefor symptomatictreatment beforecontemplating pregnancymay be considered.

h Corticosteroids, plasmaexchange, and IVimmunoglobulin havebeen used safely duringpregnancy and areagents often chosenfor treatment ofexacerbation ofweakness.




www.mycophenolatepregnancyregistry.com

www.mycophenolatepregnancyregistry.com

been associated with premature ruptureof membrane. With plasma exchangeor IVIg, a theoretical risk of inducingabortion during the postY24-hourperiod of coagulopathy is present.26

Given this risk, their use is reservedfor the management of more severeMG symptoms or myasthenic crisis.When using IVIg, hyperviscosity andvolume overload should be monitoredcarefully. Hypotension is a serious sideeffect associated with plasma exchange.To protect against hypotension, thepatient should be placed in a left lateraldecubitus position and her fluid statuscarefully monitored during treatment.During the third trimester, fetal moni-toring is recommended during plasma-pheresis. Benefit from plasma exchangeor IVIg is short-lived, and retreatmentmay be required.

Other medications routinely used inMG pose a greater risk to pregnantmothers, and their use is usually dis-couraged during pregnancy.27 Althoughcyclosporine is pregnancy category C,its use during pregnancy is notrecommended because of increasedrisk of spontaneous abortions, prema-turity, and low birth weight. Azathio-prine and mycophenolate mofetil arepregnancy category D, and methotrex-ate is category X. The use of thesemedications is not recommended inpregnancy because they pose significantrisk to the fetus.23 Case 6-2 demon-strates decisions in the treatment of apatient with MG throughout pregnancy.

LABOR AND DELIVERYMG typically does not hinder the earlystages of labor, as smooth musclecontraction is involved in the firststage of labor. In the second stage oflabor, fatigability may be pronouncedas striated muscle contraction be-comes more important. The obstetri-cian should be prepared to assist thedelivery with vacuum or forceps when

necessary. Cholinesterase inhibitorscan minimize fatigable weakness dur-ing labor. No correlation has beenproven between the mode of preg-nancy delivery and the rate of exacer-bation in the puerperium.3

During labor, regional anesthesiacan be used safely and lessens therisk of medication-induced neuro-muscular blockade from nondepo-larizing anesthetic or curare-likeagents (Table 6-2). It is also recom-mended for patients undergoing ce-sarean delivery. Those who receive ahigh level of spinal or epidural anesthe-sia may experience decreased respira-tory function, especially if they have hadprevious respiratory weakness or sig-nificant oropharyngeal symptoms.Nondepolarizing agents worsen neuro-muscular transmission and are thereforeavoided in MG. Immediate-acting drugs,carefully titrated, are recommended ifgeneral anesthesia is needed.28

Treating eclampsia with magnesiumsulfate in a woman with MG should beapproached with caution. Magnesiumblocks calcium entry at the nerveterminal and inhibits acetylcholine re-lease, further disrupting neuromuscu-lar transmission. If the potential benefitof administering magnesium sulfateoutweighs the risks, the physician andpatient should be prepared for poten-tial worsening of MG and be preparedto provide ventilator support. Phenyt-oin is an accepted alternative for thetreatment of eclampsia.29

Infections, electrolyte disturbances,and numerous drugs have been foundto unmask latent MG or trigger amyasthenic crisis. Additionally, theissue of appropriate vaccines mayarise. As a general rule, live virusvaccines should be avoided in any pa-tient with MG, particularly in the settingof immunosuppressive therapy.30,31

Table 6-2 summarizes medications thatmay exacerbate MG.

KEY POINTS

h Azathioprine andmycophenolate mofetilare US Food andDrug Administrationpregnancy category D,and methotrexate iscategory X. The use ofthese medications isnot recommended inpregnancy because theypose significant risk tothe fetus.

h Myasthenia gravistypically does not hinderthe early stages of labor,as smooth musclecontraction is involvedin the first stageof labor.

h During labor, regionalanesthesia canbe used safely andlessens the risk ofmedication-inducedneuromuscularblockade fromnondepolarizinganesthetic or curare-likeagents.

h Infections, electrolytedisturbances, andnumerous drugs havebeen found to unmasklatent myasthenia gravisor trigger a myastheniccrisis.



THE POSTPARTUM PERIODSymptoms may worsen in the puer-perium, typically within 6 to 8 weeksafter delivery. Close follow-up for po-tential worsening is recommended.Treatment selection during lactationmay pose another challenge. Most ofthe medications for the treatment ofMG can be secreted through the milkand therefore pose a potential risk to thenewborn.32,33 The American Academy ofPediatrics considers pyridostigmine, pred-

nisone, and prednisolone compatiblewith lactation.32 Pyridostigmine is ex-creted into human breast milk. Con-clusions from very limited data haveestimated that infants would ingestless than 0.1% of the maternal dose, soadverse effects in the infant are unlikely.Manufacturers for prednisone recom-mend that caution be used when admin-istering prednisone to nursing women.

Cyclosporine is excreted in humanbreast milk. Because of potentialeffects in a nursing infant such as

KEY POINT

h The American Academyof Pediatrics considerspyridostigmine,prednisone, andprednisolonecompatible withlactation.

Case 6-2A 17-year-old girl was diagnosed with oculobulbar myasthenia gravis (MG)based on clinical presentation, elevated acetylcholine receptor antibodies,abnormal repetitive stimulation, and single-fiber EMG. Her first symptomswere ptosis and diplopia followed by dysphagia. Mycophenolate mofetiltherapy was initiated and pre-pregnancy counseling was provided. Sheresponded well with only minimal stable signs of MG. Mycophenolatemofetil therapy was continued.

At 26 years of age, she was referred after discovering that she was inher fifth week of gestation. She reported recent decreased energy butdenied weakness. Physical examination demonstrated mild-moderateptosis accentuated by upgaze, minimal weakness of bilateral eye closure,and mild-moderate weakness of cheek puff. Extraocular muscles wereintact. She had no dysphagia or limb weakness.

After a long discussion, she agreed to discontinue mycophenolatemofetil. Counseling regarding the natural history of MG during pregnancywas provided. She was prescribed pyridostigmine 30 mg 3 times daily forher symptoms. She had frequent follow-up assessments and remainedstable. She was enrolled in the mycophenolate mofetil pregnancy registryand followed in a high-risk obstetric clinic.

She delivered a healthy son without complications, who had nodifficulties in the postnatal period. On no therapy, the mother had nosymptoms of MG until 1 year after delivery, when she began to developptosis and diplopia. One consideration was to restart mycophenolatemofetil at that time. However, she was not using contraception and hadno plans to do so. Given the unknown risks of fetal malformationsecondary to mycophenolate mofetil, corticosteroid therapy was initiated.She also resumed pyridostigmine 60 mg 3 times daily. With good clinicalresponse, prednisone was gradually tapered to 5 mg/d.

Comment. This case typifies management decisions that arise in apatient with known MG on immunosuppressive therapy who becomespregnant. Vast knowledge of medication side effects and potentialteratogenic effects is needed for appropriate therapeutic management inpatients with MG during childbearing age. Prepregnancy counseling isimportant for the care of both mother and fetus. Education andcounseling may need reinforcement at subsequent visits.




immunosuppression, neutropenia,growth retardation, and potential car-cinogenesis, cyclosporine is consideredcontraindicated by the AmericanAcademy of Pediatrics. Azathioprineand methotrexate are unsafe dur-ing breast-feeding. The safety ofmycophenolate mofetil, rituximab, orIVIg (human) during lactation is notknown. No data have been publishedon the excretion of mycophenolic acid(the active metabolite of myco-phenolate mofetil) in human breastmilk.32,33 Rituximab is secreted in themilk of lactating cynomolgus monkeys,and IgG is excreted in human breastmilk. Table 6-3 summarizes the safetyof the medications used in MG duringlactation.

Even after a successful pregnancy, thecare of the newborn poses new chal-lenges that may have an effect on the

mother with MG. Patients may developworsening of symptoms due to fatigueinduced by reduced sleep, frequentfeedings, and increased physical exertionrelated to caring for the baby. Symptomsduring this period can be transient andmanaged by conservative treatment, in-cluding engagement of a support system.

All women of childbearing potential(including pubertal girls and perimen-opausal women) who begin or restartan immunosuppressive regimen mustreceive contraceptive counseling anduse effective contraception. The pa-tient should begin using her chosencontraceptive method 4 weeks beforestarting therapy for MG and continuecontraceptive use during therapy. Whendiscontinuing immunosuppressive ther-apy, effective contraception shouldbe continued for 6 months beforeattempting pregnancy. Mycophenolate

KEY POINT

h All women ofchildbearing potential(including pubertal girlsand perimenopausalwomen) who beginor restart animmunosuppressiveregimen must receivecontraceptivecounseling anduse effectivecontraception.

TABLE 6-2 Medications That May Exacerbate Myasthenia Gravis

b D-Penicillamine and "-interferon should not be used in patients withmyasthenia gravis (can induce myasthenia gravis).

b The following drugs produce worsening of weakness. Use with caution andmonitor patients for exacerbation of myasthenic symptoms.

Succinylcholine, d-tubocurarine, vecuronium, and other neuromuscularblocking agents including botulinum toxins

Quinine, quinidine, and procainamide

Beta-blockers including propranolol, atenolol, and timolol maleate eye drops

Calcium channel blockers

Iodinated contrast agents

Magnesium including milk of magnesia, antacids containing magnesiumhydroxide, and magnesium sulfate

Selected antibiotics including

Aminoglycosides (eg, tobramycin,gentamycin, kanamycin,neomycin, streptomycin)

Macrolides (eg, erythromycin, azithromycin, telithromycin)

Fluoroquinolones (eg, ciprofloxacin, moxifloxacin, norfloxacin, ofloxacin,pefloxacin)

Colistin

b Many other drugs are reported to exacerbate weakness in some patients withmyasthenia gravis. All patients with myasthenia gravis should be observed forincreased weakness whenever a new medication is begun.

b Patientswithmyasthenia gravis or a history of thymoma should consider alternativesto receiving yellow fever vaccine, shingles vaccine, or any other ‘‘live virus’’ vaccine.



mofetil reduces blood levels of thehormones in oral contraceptive pillsand could theoretically reduce its effec-tiveness. Two reliable forms of contra-ception must be used simultaneouslyfor this particular medication un-less abstinence is the chosen method.Case 6-3 demonstrates counseling andtreatment decisions in a childbearingfemale patient before pregnancy andfollow-upmanagement after pregnancy.

CONCLUSIONMG can first present during pregnancyor the postpartum period. Exacerba-tions may also occur in patients withpreexisting MG. Pregnancy may affectthe course of MG in an unpredictableway, but worsening symptoms mostfrequently occur in the first trimesteror in the first 3 to 4 weeks postpartum.The effect of one pregnancy onMGdoesnot predict the effect in subsequent

Case 6-3A 23-year-old woman presented with diplopia, ptosis, then generalizedweakness over several months. The diagnosis of myasthenia gravis (MG)was established by an abnormal single-fiber EMG. She underwentthymectomy with partial improvement and had further benefit withazathioprine. Prepregnancy counseling was provided.

She decided to become pregnant and presented to discussdiscontinuation of azathioprine. She reported some fatigue and difficultyusing her arms over her head. Her examination was normal. Aftercounseling, she agreed to discontinue azathioprine and continue birthcontrol pills for several months to provide time for azathioprine clearance.She understood the possibility of her MG worsening and recognized therisks associated with pregnancy. She was also informed regarding possibleintervention with prednisone, pyridostigmine, or plasma exchange duringthe pregnancy, depending on her symptoms. The patient becamepregnant and was followed throughout her pregnancy with no significantcomplications apart from minimal weakness of her upper extremities.She also was followed by a high-risk pregnancy obstetric service. Her fetusremained very active and was delivered without difficulty.

She did very well through the immediate postpartum period, andtherefore, no medications were reinstituted. Her baby had slight head lagand was floppy. He had good suck, good grasp, and a robust cry andshowed no signs of difficulty breathing. He could bear weight on his legs

TABLE 6-3 Safety ofMedications Used inMyasthenia GravisDuring Lactation

b Safe: Considered CompatibleWith Breast-Feeding

Pyridostigmine

Prednisone

Prednisolone

b Contraindicated: Likely toAdversely Affect the Newborn

Azathioprine

Cyclosporine

Methotrexate

b Caution: No Significant DataAvailable

Mycophenolate mofetil

Rituximab

Immunoglobulin (human)

Continued on page 125




pregnancies. Clinical status does notreliably predict the course of MG duringpregnancy. Close follow-up of womenwith MG in the childbearing age isessential. Frequent evaluation duringand before pregnancy allows therapy

modification based on changes in sever-ity. Table 6-4 summarizes importantaspects that require attention and mon-itoring to ensure adequate manage-ment in patients with MG during thechildbearing age.

while supported. He had minimal manifestations of neonatal MG thatdid not require treatment and resolved after a few weeks.

At 9 months postpartum, the patient experienced a recurrence ofsymptoms and signs, and azathioprine was restarted. She was informedabout the risk of breast-feeding with this medication. Her symptomsresolved within 3 months with no further complications.

Comment. This case highlights management in a patient before, during,and after pregnancy. Patients should avoid pregnancy during the first6 months after discontinuing immunosuppression. Close follow-up in thisspecial population is partneredwith the guidance of a high-risk obstetric team.The patient should be aware of potential treatment interventions with lessteratogenic potential for the fetus. During the postpartum period, themotherand the baby are followed closely to determine whether additional treatmentis indicated. If immunosuppressive therapy needs to be initiated, adequatecounseling regarding breast-feeding and contraception must be provided.

Continued from page 124

TABLE 6-4 Issues for Women of Childbearing Age Who HaveMyasthenia Gravis

b Prepregnancy

Counseling about the effects of pregnancy on myasthenia gravis (MG)

Counseling about the effects of MG on pregnancy

Choice of therapy to optimize response may need to be altered inanticipation of pregnancy

Consideration of various drugs on fetal health

Counseling of risk of arthrogryposis on the fetus

Monitor long-term effect of therapy, eg, prednisone, immunosuppression,thymectomy

b Pregnancy

Need for close monitoring including high-risk obstetric clinic

Choice of therapy throughout pregnancy may need to be adjusted

Weighing the risk of immunosuppressive therapy

Thymectomy is not indicated during pregnancy

Monitor for worsening or onset of MG in the first trimester or postpartum

Patient may have improvement in the second and third trimesters

Physiologic changes of reduced diaphragm excursion may stress respiratoryreserve; greater body mass and blood volume increases fatigue

Continued on next page



Immunosuppressive medicationshave potential teratogenic effects, andpreferably their use should be dis-continued 4 to 6 months before con-ceiving. Corticosteroids, plasmaexchange, and IVIg have a lower poten-tial risk, have been used safely duringpregnancy, and therefore are morepreferred choices for treatment of MGexacerbation during pregnancy. An indi-vidualized and interdisciplinary ap-proach to care is needed throughoutpregnancy and the postpartumperiod ofpatients with MG and their newborns.

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TABLE 6-4 Issues for Women of Childbearing Age Who HaveMyasthenia Gravis, (continued)

b Fetal Health

Neonatal monitoring needed because of risk of arthrogryposis or transientneonatal MG

Monitor fetal effect of respiratory inadequacy in mother

Consideration of potential effects of therapy in the fetus, eg,immunosuppression, prednisone, IVIg, plasma exchange

Consideration of supportive treatment for transient neonatal MG if indicated

b Postpartum

Mother and baby are at risk for weakness

Breast-feeding issues including medications, antibodies present in milk; latefeedings may excessively fatigue patient

When restarting immunosuppressive regimen, patient must receivecontraceptive counseling and use effective contraception




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