How does myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) affect women?

MOGAD exhibits an equal sex distribution.1 Age at onset varies significantly, with the incidence rate in children being more than double that in adults.2 However, disease onset often occurs during childbearing years. Relapses and disability risk do not differ substantially between sexes, and there is no evidence demonstrating differential response to immunosuppressive / immunomodulatory therapy or long-term outcomes to date.1,3

What data are there to support management modifications related to women’s health in MOGAD?

Utilization of immunosuppressive / immunomodulatory therapy in some patients with MOGAD (i.e. those with a relapsing disease course) may be critical to prevent further disease activity; however, data pertaining to sex differences with use of the currently available therapies is lacking. Given there are limited data to guide management of family planning, pregnancy, and the post-partum phases of the female reproductive lifecycle in MOGAD, the general approach outlined below is similar to that in the Mellen Center Approach titled “Management of Multiple Sclerosis During Pregnancy”, with disease-specific commentary included where appropriate within this document.

What are the recommendations for preconception counseling?

Plans for pregnancy must be considered when choosing between various immunosuppressive / immunomodulatory treatment types when long-term therapy is indicated.4 Similar to what has been suggested in the multiple sclerosis (MS) literature, symptoms should ideally be adequately controlled and disease activity stable for at least 6-12 months prior to conception.5 Women who are planning to become pregnant are advised to take prenatal vitamins, including folic acid and vitamin D.6

MOGAD and fertility and assisted reproductive technology (ART)

No data currently exist regarding fertility or the use, safety, or outcomes of fertility / ART treatments in women with MOGAD. We advise that in general there are no significant differences in conception or fertility rates between patients with MOGAD and the general population, and that fertility treatments and ART can be utilized on a case-by-case basis. However, disease activity and disability may indirectly impact reproductive choices and outcomes. If fertility treatment is considered, multidisciplinary collaboration between the patient’s treating neurologist and reproductive medicine is recommended for individualized risk assessment.

What are the recommendations for contraception?

Women of childbearing potential with MOGAD on immunosuppressive / immunomodulatory therapy are encouraged to use some form of contraception. In general, all contraceptive methods are safe, though progestin-only and combined hormonal contraceptives may not be recommended in patients that have significant mobility limitations due to the risk of venous thromboembolism.7 Patients using any immunosuppressive treatment should ideally have a negative pregnancy test within one week of treatment initiation, repeated as needed if unprotected intercourse occurs prior to continuation of treatment. Pregnancy tests are not routinely checked prior to initiation of corticosteroid or intravenous immunoglobulin G (IVIg) treatment. Mycophenolate mofetil may theoretically reduce efficacy of oral contraceptives, and patients using this medication should use a combination of two forms of contraception.8 There are no known major interactions between the other commonly used immunosuppressive / immunomodulatory therapies used for treatment of MOGAD and oral contraceptives. Potential interactions of symptomatic therapies with contraceptives should also be considered.

What is the risk of relapse in pregnant patients with MOGAD?

Limited prior studies have demonstrated a marked reduction of MOGAD relapse rate during pregnancy and the post-partum period, similar to that which is seen in MS.9 However, relapses during pregnancy and the post-partum period have been reported.10

What is the impact of MOGAD on pregnancy outcomes?

MOGAD does not appear to be associated with an increased risk of adverse pregnancy outcomes compared to the general population.9-11 No specific antenatal care recommendations are implemented (unless indicated from an obstetric perspective or unless accidental fetal exposure to teratogenic immunosuppressive occurs (Table 1, Table 2)). Placental transfer of MOG antibodies has been reported, though it is not clear whether these antibodies are pathogenic / no cases of neonatal disease have been observed, and testing of infants for presence of MOG antibodies is not routinely recommended.10

What treatments for MOGAD are safe for use during pregnancy?

Given the overall risk for relapse during pregnancy in patients with MOGAD is considered to be low, and recovery from relapses is often favorable, the preferred approach is to hold immunosuppressive / immunomodulatory therapies until after delivery. The continued use of immunosuppressive / immunomodulatory therapy in women with MOGAD is not recommended during pregnancy unless the need outweighs the risks to the fetus (no treatment is considered entirely safe). Treatment plans must consider the benefits and risks posed to the mother (based on the level of disease activity and risk for relapse while off treatment) and the associated risks of exposure to the fetus (Table 2). Should a MOGAD patient be deemed high risk for relapse during pregnancy (i.e. those who have had recent or frequent relapses), continued use of either maintenance IVIg or strategically timed administration of rituximab prior to conception could be considered. In general, dosing rituximab several months prior to conception may be the preferred treatment approach (see paragraph pertaining to use of rituximab below). IVIg may also be used during pregnancy, though risk for increased coagulability / venous thromboembolism should be carefully considered.

What treatments require a washout (discontinuation period) in patients considering pregnancy?

Washout periods are considered for all women with MOGAD on immunosuppressive therapies (Table 1), taking the characteristics of the patient’s level of disease activity into consideration. Recommended washout periods are based on the pharmacology of individual treatments. Whenever feasible, treatment and conception timing are coordinated, with the aim of keeping washout periods as short as possible to mitigate the risk of relapse.

Anti-CD20 agents infused intravenously (rituximab-pvvr and rituximab) confer prolonged protective effects against relapses for several months (6-9 m) following administration. They are not recommended to be routinely administered during pregnancy but can be administered prior to conception in patients with highly active disease. The FDA-approved prescribing information recommends that women continue contraception 12 months following the last treatment of rituximab. However, in some cases (particularly women with highly active disease prior to a planned pregnancy) continued treatment may be necessary for minimization of time off immunosuppressive / immunomodulatory therapy. These patients may receive an infusion and then discontinue contraception/attempt to become pregnant after 1-3 months.12,13 The rationale for this is that these therapies are eliminated by 3.5-4.5 months after an infusion (based on half-life).14 In the first trimester, there is minimal placental transfer of IgG.15 Therefore, if a patient conceives 1-3 m after the last dose of anti-CD20 therapy, the risk of fetal exposure in the second trimester is low.12 The main risk to an exposed fetus is transient B cell lymphopenia. A pregnancy test should be checked prior to subsequent dosing. Decision-making regarding anti-CD20 therapy and pregnancy planning needs to consider the patient’s degree of disease activity and their individual preferences.

What if a patient becomes pregnant while on immunosuppressive / immunomodulatory therapy?

For most women with MOGAD, it is recommended that immunosuppressive / immunomodulatory therapy be discontinued at the time pregnancy is suspected. Patients who become pregnant on IVIg or B-cell depleting therapies do not require additional monitoring during pregnancy (Table 2). Those becoming pregnant on azathioprine, mycophenolate mofetil, or methotrexate are referred for an early ultrasound to screen for major malformations, and patients may consider being followed by a high-risk obstetrician. All pregnancy exposures should be registered through appropriate registries (Table 2).

How should relapses be managed during pregnancy?

Management of relapses during pregnancy is discussed and coordinated with the patient’s obstetrician. Mild relapses (with non-disabling symptoms or spontaneous improvement) may not require intervention. When indicated (for moderately to severely disabling relapses), the recommended first-line pharmacological treatment for relapses during pregnancy is high-dose corticosteroids. This therapy is used for clinically significant relapses, as it does carry a slightly increased risk for adverse fetal outcomes (specifically cleft palate and low birthweight).16 Corticosteroid use is avoided during the first trimester when possible. Plasma exchange may be considered for patients with disabling steroid-refractory relapses.17,18

Is magnetic resonance imaging (MRI) safe for pregnant or breastfeeding patients with MOGAD?

Routine MRI during pregnancy is not recommended but can be done if necessary. There are no studies to date which have demonstrated adverse outcomes or harms attributable to MRI during any trimester of pregnancy.19 However, gadolinium-based contrast use during pregnancy is contraindicated, as prior studies have demonstrated an increased risk of stillbirth, neonatal death, and various inflammatory conditions.20 Although it was previously recommended to abstain from use while breastfeeding, the American College of Radiology,21 American Academy of Pediatrics,22 and American College of Obstetricians and Gynecologists23 no longer recommend avoidance of gadolinium-based contrast, nor do they recommend discarding breastmilk after having received gadolinium-based contrast.

Are there special considerations for delivery?

For most women, we have no special recommendations for delivery. Additional considerations depend on the individual patient’s needs, such as planning for use of assisted delivery methods and/or Caesarean section in women with significant disease-related disabilities. The use of any anesthetic type is acceptable when clinically indicated.

How should patients be managed during the postpartum period?

Women with MOGAD should receive routine obstetric postpartum care. Given the rapid shift in gestation-related hormones, patients may be at increased risk for both clinical and MRI disease activity following delivery. We recommend that an MRI be obtained following delivery to evaluate radiographic disease activity if new symptoms arise but may otherwise be deferred until routine neurological care resumes at approximately 6 months postpartum.

When should immunosuppressive / immunomodulatory therapy be resumed after delivery?

In general, we recommend that plans for breastfeeding and the timing of immunosuppressive / immunomodulatory therapy resumption be discussed prior to delivery. The decision about when to resume treatment is an individual decision for each patient and needs to account for both previous disease activity and personal breastfeeding plans. Re-initiation of immunosuppressive / immunomodulatory therapy early in the postpartum period should be considered for patients who had very active disease prior to conception, had relapse(s) during pregnancy or the postpartum period. See sections pertaining to the use of immunosuppressive / immunomodulatory therapy during breastfeeding (below). For stable MOGAD patients it is thought that immunosuppressive / immunomodulatory therapy resumption may be deferred until after breastfeeding has ceased.

Is breastfeeding safe for patients taking immunosuppressive / immunomodulatory therapies?

The decision to breastfeed and the duration of breastfeeding is deferred to the patient’s decision after conferring with their obstetrician/pediatrician. Exclusive breastfeeding is recommended in most cases for about 6 months due to known benefits to the infant.

No immunosuppressive / immunomodulatory therapy is considered completely safe for use during breastfeeding. There have been no studies to date regarding the presence of IVIg in human milk or its effects on milk production.24 Mycophenolate mofetil has been shown to be excreted in breast milk of rats and humans and should not be used while breastfeeding. Women taking methotrexate should refrain from breastfeeding until one week after the final dose is taken.25

Monoclonal antibodies, such as anti-CD20 agents, are larger molecules (on the scale of 100,000 kDa), though the transfer to breast milk does occur and may have clinically significant implications for the infant (B-cell depletion and impaired vaccine responses). The low oral bioavailability is likely to limit the absorption by the newborn (with a relative infant dose of less than 10%).26 Therefore, in select situations, it is reasonable to resume treatment with rituximab (at least 14-21 days following delivery to ensure full benefits of colostrum have been transferred to the infant) when it is clinically necessary to minimize time off immunosuppressive / immunomodulatory therapy (though initiation this early in the postpartum course is not routine for MOGAD patients).

If a patient develops a relapse while breastfeeding, use of corticosteroids may be considered. Transfer of methylprednisolone through breastmilk is thought to be minimal and may be further minimized by delaying breastfeeding for 2-4 hours after infusion (as levels peak in approximately 2 hours and rapidly decline thereafter).27 For patients receiving oral steroids, the dose ingested by the infant through breast milk is thought to be negligible. It is no longer thought necessary to discard breastmilk following treatment, though individual mothers may choose to do so for 24-48 hours out of an abundance of caution.

Are there any considerations for men with MOGAD about childbearing?

Male patients treated with mycophenolate mofetil need to practice effective contraception until after the medication is cleared by metabolism, which takes approximately 3 months.8,25 Female partners of male patients on mycophenolate mofetil are also counseled on the potential risks of fetal exposure as well as use of effective contraceptive therapy. All men treated with these therapies are counseled on the importance of (and adherence to) contraceptive use for at least three months following the last dose, even when pregnancy is not planned, given the significant potential risks.

References

  1. Diem L, Hammer H, Hoepner R, Pistor M, Remlinger J, Salmen A. Sex and gender differences in autoimmune demyelinating CNS disorders: Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and myelin-oligodendrocyte-glycoprotein antibody associated disorder (MOGAD). Int Rev Neurobiol. 2022;164:129-178. doi:10.1016/bs.irn.2022.06.011
  2. de Mol CL, Wong Y, van Pelt ED, et al. The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults. Mult Scler. Jun 2020;26(7):806-814. doi:10.1177/1352458519845112
  3. Sutton P, Lutz MW, Hartsell FL, et al. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: Presentation and outcomes of adults at a single center. J Neuroimmunol. Dec 15 2022;373:577987. doi:10.1016/j.jneuroim.2022.577987
  4. Van Der Walt A, Nguyen AL, Jokubaitis V. Family planning, antenatal and post partum care in multiple sclerosis: a review and update. Med J Aust. Sep 2019;211(5):230-236. doi:10.5694/mja2.50113
  5. Coyle PK. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Disord. May 2016;9(3):198-210. doi:10.1177/1756285616631897
  6. Jalkanen A, Kauko T, Turpeinen U, Hämäläinen E, Airas L. Multiple sclerosis and vitamin D during pregnancy and lactation. Acta Neurol Scand. Jan 2015;131(1):64-7. doi:10.1111/ane.12306
  7. Coyle PK, Oh J, Magyari M, Oreja-Guevara C, Houtchens M. Management strategies for female patients of reproductive potential with multiple sclerosis: An evidence-based review. Mult Scler Relat Disord. Jul 2019;32:54-63. doi:10.1016/j.msard.2019.04.003
  8. Administration FaD. CellCept (mycophenolate mofetil). FDA Drug Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf.
  9. Carra-Dallière C, Rollot F, Deschamps R, et al. Pregnancy and post-partum in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease. Mult Scler. Feb 2023;29(2):270-276. doi:10.1177/13524585221134214
  10. Yamamoto S, Yano M, Miyamoto Y, Hanaoka T, Nishida Y, Kawano Y. The Postpartum Period Can Worsen Myelin Oligodendrocyte Glycoprotein Antibody-associated Encephalomyelitis. Intern Med. Apr 01 2023;62(7):1063-1066. doi:10.2169/internalmedicine.0170-22
  11. Collongues N, Alves Do Rego C, Bourre B, et al. Pregnancy in Patients With AQP4-Ab, MOG-Ab, or Double-Negative Neuromyelitis Optica Disorder. Neurology. Apr 13 2021;96(15):e2006-e2015. doi:10.1212/WNL.0000000000011744
  12. Dobson R, Hellwig K. Use of disease-modifying drugs during pregnancy and breastfeeding. Curr Opin Neurol. Jun 01 2021;34(3):303-311. doi:10.1097/WCO.0000000000000922
  13. Langer-Gould AM. Pregnancy and Family Planning in Multiple Sclerosis. Continuum (Minneap Minn). Jun 2019;25(3):773-792. doi:10.1212/CON.0000000000000745
  14. Administration FaD. Rituxan (rituximab). FDA Drug Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf.
  15. Pels SG, Paidas MJ. Microangiopathic disorders in pregnancy. Hematol Oncol Clin North Am. Apr 2011;25(2):311-22, viii. doi:10.1016/j.hoc.2011.01.005
  16. Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. Rheum Dis Clin North Am. Aug 2017;43(3):489-502. doi:10.1016/j.rdc.2017.04.013
  17. Mao-Draayer Y, Thiel S, Mills EA, et al. Neuromyelitis optica spectrum disorders and pregnancy: therapeutic considerations. Nat Rev Neurol. Mar 2020;16(3):154-170. doi:10.1038/s41582-020-0313-y
  18. Wind M, Gaasbeek AGA, Oosten LEM, et al. Therapeutic plasma exchange in pregnancy: A literature review. Eur J Obstet Gynecol Reprod Biol. May 2021;260:29-36. doi:10.1016/j.ejogrb.2021.02.027
  19. Lum M, Tsiouris AJ. MRI safety considerations during pregnancy. Clin Imaging. Jun 2020;62:69-75. doi:10.1016/j.clinimag.2020.02.007
  20. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA. Sep 06 2016;316(9):952-61. doi:10.1001/jama.2016.12126
  21. Media ACoDaC. ACR Manual on Contrast Media. American College of Radiology.
  22. Meek JY, Noble L. Technical Report: Breastfeeding and the Use of Human Milk. Pediatrics. Jul 01 2022;150(1)doi:10.1542/peds.2022-057989
  23. Gynecologists TACoOa. Guidelines for Diagnostic Imaging During Pregnancy and Lactation. https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2017/10/guidelines-for-diagnostic-imaging-during-pregnancy-and-lactation.pdf
  24. Administration FaD. Gammagard (intravenous immunoglobulin G). FDA Drug Label. file:///C:/Users/13208/Downloads/Package%20Insert%20-%20GAMMAGARD%20LIQUID.pdf.
  25. Administration FaD. Methotrexate. FDA Drug Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/040054s015,s016,s017.pdf.
  26. Krysko KM, LaHue SC, Anderson A, et al. Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurological conditions. Neurol Neuroimmunol Neuroinflamm. Jan 2020;7(1)doi:10.1212/NXI.0000000000000637
  27. Boz C, Terzi M, Zengin Karahan S, Sen S, Sarac Y, Emrah Mavis M. Safety of IV pulse methylprednisolone therapy during breastfeeding in patients with multiple sclerosis. Mult Scler. Aug 2018;24(9):1205-1211. doi:10.1177/1352458517717806
  28. Administration FaD. IMURAN (azathioprine). FDA Drug Label.
  29. Administration FaD. CellCept (mycophenolate mofetil). FDA Drug Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf.
  30. Administration FaD. Gammagard (intravenous immunoglobulin G). file:///C:/Users/13208/Downloads/Package%20Insert%20-%20GAMMAGARD%20LIQUID.pdf.
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Table 1: Immunosuppressive / Immunomodulatory Therapies in Pregnancy

Medication

Recommended Washout

Special Considerations

Use in Pregnancy

Azathioprine28

2 weeks

DO NOT USE

Mycophenolate Mofetil29

6 weeks

Male patients should discontinue treatment for 3 months prior to conception

DO NOT USE

IVIg30

None

Use if benefit outweighs risks

Rituximab14

1 - 3 months*

Use if benefit outweighs risks

Satralizumab31

3 months

Use if benefit outweighs risks

Tocilizumab32

3 months

DO NOT USE

This table reflects our clinical practice and our review of combined recommendations, prescribing information, and key articles. Pregnancy testing is recommended before commencement or re-infusion for all therapies in women of childbearing potential.

* See the corresponding paragraph for in-depth discussion regarding anti-CD20 therapies and pregnancy timing.

Table 2. Summary of Risks and Management Recommendations for Fetal Exposure to Immunosuppressive / Immunomodulatory Therapies During Pregnancy

Medication

First Trimester Exposure

Exposure Risks

Pregnancy Registry

Azathioprine28

Early ultrasound for major malformations may be considered

Some animal models have shown teratogenicity with associated skeletal malformations and visceral abnormalities. Neonatal lymphopenia, hypogammaglobulinemia, CMV infection, and decreased thymic shadow have been reported. Human studies have demonstrated possible increased risk of preterm birth and fetal growth restriction.

Contact manufacturer

Mycophenolate Mofetil8

Early ultrasound for major malformations recommended

Known teratogen with risk of first trimester pregnancy loss and congenital malformations including external ear and facial abnormalities, anomalies of distal limbs, heart, esophagus, and kidneys.

1-800-617-8191

IVIg30

No additional fetal or neonatal monitoring

Animal reproduction studies have not been conducted – it is unknown whether IVIg causes fetal harm, including major birth defects or miscarriage. IVIg crosses the placental increasingly after 30 weeks' gestation.

NA

Rituximab14

No additional fetal or neonatal monitoring

Risk of B-cell depletion in fetus/infant with 2nd and 3rd-trimester exposure (typically with normalization within 6 months); risk of neonatal infections. There are no clear teratogenic effects in animal studies.

Contact manufacturer

Satralizumab31

No additional fetal or neonatal monitoring

Limited data have not shown adverse effects on maternal animals or fetal development. Risk of impaired immune function in fetus/infant with 2nd and 3rd trimester exposure; risk of neonatal infections.

1-833-277-9338

Tocilizumab32

No additional fetal or neonatal monitoring

Limited animal data have demonstrated risk of abortion / embryo-fetal death, and prior animal studies have suggested that inhibition of IL-6 signaling may interfere with cervical ripening and dilation. No clear teratogenic effects in animal studies have been demonstrated. Risk of impaired immune function in fetus/infant with 2nd and 3rd trimester exposure; risk of neonatal infections.

Contact manufacturer

This table reflects our clinical practice and our review of combined recommendations, prescribing information, and key articles.