Many studies have demonstrated important hormonal changes in women with MS. These changes affect the pattern of the menstrual cycle and, subsequently, fertility and sexual functioning. Patients with MS have significantly higher follicle-stimulating hormone and luteinizing hormone levels but lower estrogen levels in the early follicle phase of the menstrual cycle.¹,² These hormonal changes can cause menstrual cycle irregularities. Additionally, some studies have found that about half of women with MS have worsened symptoms or relapse onset during the premenstrual or menstrual period.³ Hormonal changes observed in women with MS may account for this exacerbation of symptoms. Specifically, progesterone increases nerve conduction speed by reducing sodium/potassium ATPase,⁴ and elevated estrogen and progesterone levels after ovulation cause increased Th-2 anti-inflammatory cytokine production.⁵ It has been theorized that the precipitous decline in estrogen and progesterone levels after ovulation, in the premenstrual period, may account for worsening of symptoms and symptom onset.⁶ Of note, medications such as cyclophosphamide can cause premature ovarian failure and bring about early menopause in these patients.⁷

Women with MS can have complex issues involving psychosocial, sexual, and family relationships, which often happens with chronic illness. They often are taking multiple medications, with side effects that can affect mood and libido and incite physical symptoms such as decreased vaginal lubrication.¹,²,⁸ One study utilizing a Multiple Sclerosis Intimacy and Sexuality Questionnaire found that 80.4% of the 35 patients with relapsing-remitting MS experienced primary sexual dysfunction, with decreased libido being the most frequent complaint.⁸ Another study using the Female Sexual Function Index questionnaire analyzed both hormone levels in relation to sexual dysfunction in patients with MS. Of the 54 women with MS, more than half (57.4%) manifested at least one sexual dysfunction and 36.4% exhibited abnormal hormone alterations, the most common being low 17 beta-estradiol (40%). The study could not find any statistical significance between hormone abnormalities and sexual dysfunction.²

Sexual dysfunction among patients with MS can be considered multifactorial, and therefore, it can be very challenging to treat. Sadly, studies have shown that only a small percentage of patients with MS seek treatment for sexual dysfunction.⁹ Possible interventions include counseling, psychotherapy, lubricants, and medications. It is important
to emphasize that sexual dysfunction can be an inciting cause of, or occur in conjunction with, depression and associated mood disorders. Treatment for mood disorders can also have a side effect of decreasing libido and lubrication, which only exacerbates the problem. Providers should carefully screen for symptoms of sexual dysfunction in patients with MS, because few patients will come forward asking for treatment for this issue, and it can have a major impact on mental health and psychosocial functioning.¹⁰

Fertility does not appear to be decreased in women with MS.¹¹ This is evidenced by the fact that pregnant patients with MS, which is an illness typically diagnosed during a woman’s reproductive years, are well represented in MS clinical trials.¹² However, international studies have shown that patients with MS have fewer children and are more likely to seek assisted reproductive technology (ART) services.¹³,¹⁴ This may be at least partially due to higher rates of hyperprolactinemia, decreased estrogen levels, and thyroid disorders, which patients with MS are at increased risk for because these disorders are also typically autoimmune in nature.¹,¹⁵,¹⁶ Sexual dysfunction, such as decreased libido, vaginal sensory abnormalities, and insufficient lubrication, which can occur early in the course of MS, can also interfere with fertility. Some treatments for MS, such as interferon beta and mitoxantrone, have been associated with menstrual irregularities, which can impact fertility.⁸,¹⁵,¹⁷

Several studies have shown that ART has been associated with an increased risk of MS relapse, especially in the first 12 weeks after unsuccessful cycle attempts.¹⁷,¹⁸,¹⁹ Some studies have shown that the risk of relapse is greater when using gonadotropin-releasing hormone (GnRH) agonists for hormonal downregulation. This may be because GnRH can stimulate the proliferation of immune cells and increase cytokine and endothelial-growth factor production.²⁰ Rapid hormonal fluctuations, the stress of undergoing fertility treatment, and possibly an interruption in MS therapy owing to the risk of teratogenicity also predispose patients with MS undergoing ART to relapse.¹² One study by Correale et al followed 16 women with relapsing-remitting MS prospectively during 26 ART cycles. There was a ninefold increase in the risk of new brain lesions on magnetic resonance imaging (MRI) and a sevenfold increase in the risk of new brain lesions on MRI in the 3 months after ART.²¹ All of the patients in this study were taking GNRH agonists. However, studies analyzing different hormonal treatments during ART cycles have not consistently shown that GNRH agonists have increased rates of MS relapse compared with other hormonal treatments. For example, retrospective case series in Germany did not find a higher rate of relapse in GNRH-agonist ART cycles vs the
use of other hormonal treatments,²⁰,²² whereas reproductive case series performed in France showed increased rates of relapse in the 3 months following ART in patients with MS treated with GNRH-agonists.²¹,²³

There is no consensus among ART providers and neurologists as to what hormonal treatments to use and what disease-modifying therapies should be employed or stopped during fertility treatment. Patients with MS should be thoroughly counseled about the risk of relapse with ART treatment, and as with most chronic medical illnesses, disease stabilization before initiating fertility treatment is advisable.¹²

As of June 2015, the US Food and Drug Administration (FDA) has removed the categorization of medications in pregnancy and instituted a system of prescription labeling that includes more about the evidenced-based risks of the medication (FDA). Most studies about the safety of disease-modifying treatments in pregnancy are animal studies that use higher doses of medications than are typically used in humans. Medications that have positive safety profiles in pregnancy are interferon beta and glatiramer, which are immunomodulators that are used to prevent the occurrence of relapses and to delay disability.³,¹² These medications, if used before pregnancy, may be continued in pregnancy; however, owing to lack of data with regards their safety in pregnancy, these medications are only used up until the time of conception and then stopped once the patient is pregnant. Natalizumab is a monoclonal antibody that is often used for the treatment of relapsing forms of MS. Current recommendations are that it be discontinued before pregnancy, although it has been used to treat patients during pregnancy in special circumstances.³,¹²

Although there are several disease-modifying drugs for MS, most clinicians recommend discontinuing these medications, if possible, when planning for pregnancy. These medications are discussed in the next section.

It is not surprising that the marked hormonal transition and transient immunological tolerance of pregnancy modifies the course and disease activity of MS.

Many animal studies have evaluated the hormonal effects of estrogens (17β-estradiol-E2 and estriol-E3), progesterone, and testosterone in MS. These hormones are thought to provide anti-inflammatory and neuroprotective effects on experimental allergic encephalomyelitis.²⁴,²⁵ The anti-inflammatory effects appear to be mediated by estrogen nuclear receptors
alpha (ERα) and beta (ERβ), which are expressed by regulatory CD4+CD25+ T cells, regulatory B cells, and dendritic cells. E2 neuroprotective effects on experimental allergic encephalomyelitis seem to be mediated by binding to the membrane G-protein-coupled receptor 30 (GPR30). Progesterone appears to play a role in axonal protection and remyelination. Testosterone is thought to work by either binding to androgen receptors or after its conversion to estrogen, through estrogen receptors or GPR30. It can restore synaptic transmission deficits in the hippocampus. Additionally, androgens may induce remyelination by acting on neural androgen receptors.²⁶,²⁷,²⁸ As a result, current research efforts are aimed at studying hormones as therapeutic agents, which may have implications for add-on therapy.

MRI is widely used for the diagnosis and monitoring of MS. It significantly surpasses other imaging modalities with respect to its positive predictive value.²⁹,³⁰,³¹ MRI is also used in pregnancy for maternal assessment and fetal prenatal diagnosis. Its use is often times avoided in the first trimester because of theoretical risks associated with an increase in body temperature and acoustic noise exposure to a developing fetus. However, when indicated and necessary, MRI should be used regardless of gestational age. The use of gadolinium-contrast agents is generally avoided in pregnancy, mainly because of a lack of safety data in humans.³⁰

Vitamin D deficiency has been linked to the development of MS in offspring by two distinct mechanisms—autoimmunity with an increase in proinflammatory T cell populations and lipid effect on myelinogenesis.³² In a recent Finnish study, Munger et al compared maternal vitamin D levels during pregnancy with those of controls. The authors found that offspring of mothers with hypovitaminosis D during their pregnancy had a nearly twofold increase in risk of developing MS when compared with children born to mothers with nondeficient levels. One limitation of this study was the relatively young cohort of children, ranging from 18 to 27 years of age, which may have contributed to an inflated relative risk because the average age of MS diagnosis is 30 years.³³ A dietary study performed in the United States found a similar association, although two smaller Swedish studies did not.³⁴,³⁵,³⁶

Fortunately, relapse, which is defined as a worsening of neurologic symptoms lasting more than 24 hours,¹² is less likely to occur in pregnancy.
However, glucocorticoids can be used to reduce the severity and duration of relapses during pregnancy. Corticosteroids, which are often used in pregnancy to treat other autoimmune diseases such as systemic lupus nephritis and rheumatoid arthritis, are generally considered safe in pregnancy. Short-term, high-dose regimens are recommended, because prolonged glucocorticoid exposure can cause neonatal adrenal suppression and maternal glucose intolerance and increase the risk of preterm delivery and premature rupture of membranes.⁷ If a relapse occurs in the first trimester, the preferred treatment is prednisolone, as it is inactivated in the placenta and therefore fetal passage is much less than with dexamethasone. Primary or secondary progressive MS was previously treated with immunosuppressants such as cyclophosphamide or methotrexate. These medications are contraindicated in pregnancy because of their teratogenicity and associated adverse pregnancy outcomes and are not commonly used. The only FDA-approved treatment for primary progressive MS is ocrelizumab, which is a monoclonal antibody with limited safety data in pregnancy.³⁷

Medications that are not recommended in pregnancy owing to teratogenicity concerns include fingolimod, alemtuzumab, mitoxantrone, ocrelizumab, and teriflunomide. Most physicians recommend that women discontinue treatment with these disease-modifying drugs for MS before attempting to conceive, and often times a “washout” period is recommended before attempting conception. The length of time recommended for these medications to wash out before attempting conception differs according to the medication type. For example, most providers recommend that a patient wait 4 months after alemtuzumab and a 6-month washout period is recommended for rituximab and ocrelizumab. For teriflunomide, patients who are attempting to conceive undergo an elimination procedure, which involves taking cholestyramine or activated charcoal for up to 2 weeks. Of note, men taking teriflunomide and attempting to conceive with a partner are advised not to be on this medication during that period. See Table 15.1 for the washout periods for commonly used medications.

A systematic review of disease-modifying MS therapies during pregnancy, by Lu et al, found associated pregnancy outcomes with several commonly used medications. The study found that interferon beta exposure was associated with lower birthweight and preterm delivery but not with any congenital anomalies. Glatiramer acetate exposure did not have any adverse effects on birthweight or gestational age at delivery and also did not have any associated congenital anomalies. Natalizumab was also not found to have any associated adverse effects on neonates.⁴¹ See Table 15.1 for a list of the most common MS medications and their current pregnancy-related advisories. Importantly, in 2015, the FDA discontinued the use of pregnancy risk categories (A, B, C, D, X) and it has been replaced by the
FDA Pregnancy and Lactation Labeling Rule (PLLR). This rule requires narrative text to describe risk information, clinical considerations, and background data for the drug. Examples of these narratives are included in Table 15.2.⁴²