Multiple Sclerosis in Women: Impact of Different Life Stages on Treatment Decisions

Abstract

Multiple sclerosis (MS) is a chronic, immune-mediated disorder that predominantly affects women, with an average age of onset between 20 and 50 years. As a result of the early age of onset and increasing life expectancies of women, owing to improvements in disease-modifying treatments (DMTs), recommendations regarding disease and symptom management may vary depending on their life stage and should be tailored to the individual. In addition, in recent years, new data regarding the management of MS from the preconception to postpartum period has led to evolving recommendations from both neuroimmunologists and national drug agencies alike. Similarly, an aging MS population has led to questions regarding the effect of menopause on MS and guidance regarding DMTs as patients age. The purpose of this review is to provide an up-to-date, comprehensive summary of the clinical course and management of the disease and commonly experienced symptoms during puberty, preconception and pregnancy, postpartum, menopause, and life after menopause.

Key Points

Management of multiple sclerosis (MS) is shifting towards a proactive approach with early initiation of high-efficacy treatments, which can be utilized to confer clinical protection throughout the preconception and postpartum period while limiting exposure to the offspring in utero or through breastfeeding. Close management by neurologists and obstetricians is key during this period, highlighting the importance of neurologists staying up to date on this evolving topic.

The menopause transition has been associated with decreased inflammatory activity as well as disability progression; however, it is unclear whether this is related to reproductive aging versus biological aging. Despite evidence of immunosenescence with age, exclusion of patients > 55 in clinical trials for MS has led to uncertainty regarding the use of DMTs after menopause.

Many symptoms of pregnancy, postpartum, and menopause overlap with the symptoms of MS and may exacerbate underlying symptoms related to MS or spark anxiety about disease progression. Understanding these overlapping systems during each stage of life allows neurologists to provide anticipatory guidance and address both MS and non-MS causes of these symptoms.

Background

Multiple sclerosis (MS) is a chronic, immune-mediated disorder that affects the central nervous system (CNS). MS is typically diagnosed between the ages of 20 and 50 years and has a 2:1 female predominance [1, 2]. As a result, for many patients with MS, their diagnosis coincides with their reproductive years, which has important ramifications on their disease course and family planning. In addition, patients with MS are living longer, which introduces new treatment considerations as patients experience biological and reproductive aging.

Given the onset during reproductive years, the influence of hormonal changes on disease activity, and longer lifespans with improved disease modifying treatments (DMT), neurologists require episodic updates on key evidence-based treatment considerations at each stage in a woman’s life with MS.

Puberty and Menarche

While the focus of this review is primarily geared towards adults with MS, 3–5% of patients with MS experience their first clinical attack before age 18 years [3, 4]. Onset of MS before puberty is exceedingly rare, representing < 1% of all cases of pediatric onset MS (POMS) [4, 5]. Most cases of POMS occur after puberty, between the ages of 13 and 16 years [3, 4]. In addition, the female predominance in MS emerges during this period and is higher than that in adulthood [4]. The age of puberty onset also plays a role in risk for MS development, with a later age of menarche associated with a decreased risk of MS [3, 6].

Children were historically excluded from clinical trials for MS treatments, given their age, risk of adverse events, and potentially unknown long-term side effects. Hence, many of the data for outcomes and adverse events in children on DMTs were obtained through observational studies. Here, data are most robust for agents such as interferon beta and glatiramer acetate, which have been available longer than other therapies [7], which led the 2016 consensus statement from the International Pediatric Multiple Sclerosis Study Group to recommend them as first-line agents for POMS [8]. Since these guidelines were published, however, randomized clinical trials were conducted in pediatric patients with MS, demonstrating superior efficacy of fingolimod over interferon beta, leading to its status as the first FDA-approved treatment for POMS [9, 10]. Teriflunomide was also studied in a randomized trial and received approval from the European Medicines Agency (EMA) for use in POMS [11, 12]. As higher-efficacy DMTs gained widespread use for adult-onset MS, their utility and safety in POMS have been increasingly explored. In retrospective studies, rituximab was shown to reduce clinical relapse and prevent radiographic progression with similar rates of adverse events as seen in adult populations [13–15]. Similar results have been seen in observational studies of natalizumab in POMS [13, 16]. As is the case with adult-onset MS, there is an emerging shift towards initiating high-efficacy treatment earlier on in the disease course, given evidence of improved disease control. However, in pediatric populations, concerns remain regarding the long-term safety of more novel agents [14, 17]. The management of pediatric onset MS is a rapidly evolving field with multiple clinical trials for the treatment of POMS ongoing, including for dimethyl fumarate, alemtuzumab, ocrelizumab, ofatumumab, and siponimod [7].

Contraceptive Choices

Family planning is an important consideration for patients with MS, as the decision to conceive has implications regarding the choice of DMT, as will be discussed below. For patients who are not currently planning for pregnancy or do not wish to conceive, contraception is recommended. Altogether, for most women with MS, most forms of contraceptives can be considered [18], and contraceptive selection should be individualized and based on patient and MS-related factors. For women with higher degrees of disability or limited mobility, the small risk of venous thromboembolism with combined hormonal contraceptives could be magnified; therefore, it is recommended that these patients consider progestin-only forms of birth control such as the progestin-only pill, an intrauterine device (IUD), and other implantable forms of contraception [18]. Additional consideration should be given to women with osteopenia or osteoporosis, as certain forms of contraception, such as depot medroxyprogesterone acetate, have been associated with a loss of bone density, although bone density tends to recover once contraception is discontinued [18]. Long-acting forms of contraception, such as IUDs or other implantable forms of birth control, are preferred, given the low failure rates [18]. This is especially true in adolescents and young adults with MS, who overall have low use of contraception [19].

Preconception and Pregnancy Planning

While women with MS were previously counseled to avoid pregnancy, it is now widely recognized that pregnancy does not affect the overall disease course of MS and, conversely, that the disease does not negatively affect pregnancy outcomes [1, 20, 21]. Pregnancy itself is an immunotolerant period; however, it is followed by a period of increased disease activity and elevated risk of relapse postpartum, especially in the first 3–6 months [22–24]. The choice of DMT during the preconception to postpartum period requires balancing multiple considerations, including maternal protection against immune activity during the conception period, limiting fetal exposure to the DMT, and maternal protection and wellness during the postpartum period to support the maternal–infant dyad. In addition to DMTs, consideration should be given to measures available to manage MS-related symptoms throughout this period.

DMT Selection: Shift from Avoidant to Reactive to Proactive Management

When it comes to the selection of a DMT in reproductive-age women, family planning should be addressed early on. Even for patients who have no current plans to conceive, understanding whether they might conceive in the future should help inform the current choice of DMT, as discontinuation of certain DMTs in anticipation of pregnancy is associated with an increased risk for rebound disease activity. In addition, elevated disease activity before conception and during pregnancy is associated with a higher risk of disease activity in the postpartum period, highlighting the importance of active maintenance of disease stability [23, 25, 26]. While prior guidelines emphasized the need for a year of clinical stability before conception, this may not be necessary if utilizing highly effective DMTs preconception and if using DMTs with discontinuation rebound potential (see Sect. 4.1.2). This apparent stability could be followed by severe inflammatory activity pre/during pregnancy upon cessation of DMT. Finally, there is a need to optimize protection against infectious diseases, including through updated vaccines. In particular, vaccines relevant to pregnancy management (covid, influenza, Tdap, and, if indicated, measles, mumps, rubella (MMR), pneumococcal, human papilloma virus (HPV), hepatitis A/B, and meningococcal) should be considered prior to initiating treatment with certain DMTs, such as anti-CD20 monoclonal antibodies, which may impact the immune response to vaccinations and preclude the use of live vaccines once initiated [27].

Management of MS overall has shifted in recent years with the initiation of high-efficacy treatments (HETs) early in the disease course [1]. Use of HET is a special consideration in pregnancy planning in women with MS, given an emerging focus on proactive management—whereby judicious use of medications with limited placental or breastmilk transfer can substantially abrogate the risk of maternal pregnancy-related disease activity and provide freedom from relapses and associated stressors. The field is therefore moving from an avoidant approach (avoiding MS treatment altogether during childbearing, or conversely, avoiding pregnancy) to a reactive approach (monitoring for new injury and treating reactively) to the current proactive approach (judiciously utilizing DMT to prevent injury). Since each DMT carries varying risks of placental transfer and teratogenicity/adverse events, there is a need for additional safety evidence with the approval of newer drugs. Decision-making is further complicated by guidelines from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), which may change over time in response to evolving federal guidelines. Here we will discuss important considerations for commonly used treatments for MS, which are summarized in Table 1.

Table 1.

DMT use during pregnancy

DMT	EMA recommendation	FDA recommendation	Expert opinion	Additional considerations
Anti-CD20 monoclonal antibodies
Ocrelizumab Ofatumumab Rituximab Ublituximab	Discontinuation 4–12 months prior to conception	Discontinuation 6 months prior to conception	Discontinuation 3 months prior to conception
Lymphocyte trafficking therapies
Natalizumab	There are insufficient data regarding use in pregnancy; should be used during pregnancy only if benefit outweighs risk to the fetus	There are insufficient data regarding use in pregnancy; should be used during pregnancy only if benefit outweighs risk to the fetus	Can be used up to 34 weeks gestation with extended interval dosing	High risk for rebound disease activity; consider “bridge therapy” with alternative DMT versus extended interval dosing until 34 weeks gestation Newborns exposed in utero should be screened for hematologic abnormalities at delivery
Fingolimod and other S1P receptor modulators	Contraindicated during pregnancy; discontinuation 2 months prior to conception	Contraindicated during pregnancy; discontinuation 2 months prior to conception	Contraindicated in pregnancy and should be discontinued 2 months prior to conception	High risk for rebound disease activity; consider “bridge therapy” with alternative DMT
Immune reconstitution therapies
Alemtuzumab	Discontinuation 4 months prior to conception	Discontinuation 4 months prior to conception	Discontinuation 3 months prior to conception	Risk of autoimmune thyroiditis with alemtuzumab use which poses separate risk to the fetus
Cladribine	Contraindicated during pregnancy; discontinuation 6 months prior to conception	Contraindicated during pregnancy; discontinuation 6 months prior to conception	Contraindicated during pregnancy; discontinuation 6 months prior to conception	Men exposed to cladribine are recommended to wait 6 months after completion of therapy prior to conceiving
First-line self-injectables
Interferon beta and glatiramer acetate	No need for contraception indicated	No need for contraception indicated	No indication for contraception. Patients who conceive while on IFN-ß could be advised to either continue or stop treatment once pregnancy occurs	Most safety data available is in patients exposed to these agents at the time of conception of in the first trimester
Other oral therapies
Dimethyl fumarate and other fumarates	There are insufficient data regarding use in pregnancy; contraception recommended	There are insufficient data regarding use in pregnancy; no need for contraception	No indication for contraception; can be discontinued at the time of conception attempts or at the time of a positive pregnancy test
Teriflunomide	Contraindicated; use of contraception recommended during treatment and after last dose until serum levels < 0.02 mg/L	Contraindicated; use of contraception recommended during treatment and after last dose until serum levels < 0.02 mg/L	Contraindicated; use of contraception recommended during treatment and after last dose until serum levels < 0.02 mg/L	Given long washout period (8–24 months) with teriflunomide, there is an accelerated elimination program for patients who inadvertently conceive or wish to become pregnant sooner

DMT disease modifying treatment, EMA European Medicines Agency, FDA US Food and Drug Administration

Anti-CD20 Monoclonal Antibodies

Anti-CD20 agents such as ocrelizumab (Ocrevus), rituximab (Rituxan and Truxima), ofatumumab (Kesimpta), and ublituximab (Briumvi) work by depleting B cells. Anti-CD20 monoclonal antibodies have become increasingly popular in recent years as a first-line treatment for MS. Current recommendations from the EMA and FDA have advised various washout periods before attempting to conceive, ranging from 4 to 12 months, and expert consensus guidelines often reflect this heterogeneous approach [1, 28–31].

When the properties of this class of medication are examined more closely, however, a case can be made for shorter wash-out periods before conception. First, immunoglobulin G (IgG) monoclonal antibodies, like endogenous IgG, require active transport via Fc receptors to cross the placenta [32, 33]. Fc receptor expression is limited during the first 20–22 weeks of pregnancy, which results in minimal transfer of IgG across the placenta during this period [32, 33]. Second, the terminal half-life of anti-CD20 monoclonal antibodies in the serum is 19–26 days, such that most of the product, if administered close to conception, would be eliminated by the time it could cross the placenta, on the basis of the five maximal half-lives principle [34]. Third, the effects of treatment (B-cell depletion) last at least 6 months after infusion. The persistent pharmacodynamic impact of the drug long after it is no longer detectable in the serum (pharmacokinetic) is significant. Altogether, these findings suggest that a shorter time period between the last treatment and conception attempts could optimize maternal protection against relapses during the preconception and gestational periods, while minimizing the risk of transfer to the fetus. Along these lines, a recent study examined infant outcomes in 855 women with MS who received ocrelizumab infusions within 3 months of the last menstrual period. In this cohort, maternal treatment with ocrelizumab was not associated with an increased risk for adverse pregnancy or infant outcomes [35]. Updated consensus guidelines therefore recommend a shorter period of discontinuation prior to conception attempts, 3 months and potentially less, in order to limit fetal exposure while providing therapeutic coverage to patients during the conception period/early pregnancy [1, 26, 36, 37]. Emerging trends suggest that the timing of treatments could align with a patient’s menses, and patients should be screened for pregnancy prior to infusion/injection.

Lymphocyte Trafficking Therapies

Natalizumab, a monthly infusion therapy, and fingolimod, a daily oral medication, work by preventing transport of lymphocytes into the CNS. Both of these agents confer a significant risk of rebound inflammatory activity and severe relapses, even during pregnancy, and therefore require careful management [38, 39]. Similar to anti-CD20 agents, natalizumab is a monoclonal antibody with likely limited placental transfer in the first 20 weeks of pregnancy [32, 33]. However, unlike anti-CD20 agents, discontinuation of natalizumab is associated with an increased risk of rebound inflammatory activity, and severe relapses can occur even during pregnancy [38, 39]. When considering whether to discontinue natalizumab in this context, discontinuing after the first trimester versus prior to conception is associated with a lower risk of relapse, and continuation until 30 weeks of gestation confers additional protection [26, 38]. Given the benefit on maternal disease stability with continued use throughout pregnancy, consideration of the effects of in utero exposure on neonatal outcomes is important. While no significant effect on risk of preterm birth or congenital abnormalities has been noted, more than half of exposed infants may have transient anemia and thrombocytopenia, especially with maternal treatment past 30 weeks of gestation [38]. Altogether, to minimize the risk of rebound activity after discontinuation in women on natalizumab who wish to conceive, they could either transition to an alternate “bridge” DMT, such as an anti-CD20 prior to conception or continue with extended interval dosing of natalizumab until 34 weeks gestation, when placental transport of antibodies is the highest [1, 40]. Ideally, anti-CD20 therapy would be initiated about 4 weeks after the last natalizumab dose if bridging were pursued [41, 42]. Given the short therapeutic lag associated with antiCD20 therapy, conception attempts could begin after 6 months on treatment (specifically after the baseline and 6-month infusion cycles) [1]. This clinical scenario highlights the importance of risk–benefit conversations and shared decision-making between the patient, neurologist, and, ideally, the obstetrical team, ensuring that patients understand the risk of rebound associated with discontinuation and the potential neonatal risks.

As is the case with natalizumab, discontinuation of fingolimod, and presumably other S1P receptor modulators, is associated with an increased risk of rebound activity. Up to 31% of women who discontinued this DMT have been reported to experience a relapse during pregnancy and 44% during the first year postpartum [43]. Fingolimod is contraindicated in pregnancy, given preclinical evidence of fetal developmental defects in animals exposed to lower than the recommended human dose of fingolimod and post-marketing data which suggested a twofold increase in congenital malformations when fingolimod was utilized throughout pregnancy [44–46]. Given the risk of fetal toxicity, it is recommended that fingolimod be discontinued at least 2 months prior to conception [45, 46]. In this scenario as well, transitioning to an alternative “bridge” DMT, such as an anti-CD20 monoclonal antibody, prior to conception could help stabilize the disease and reduce the risk of rebound activity before, during, and after pregnancy [47].

Immune Reconstitution Therapies

Alemtuzumab, a monoclonal antibody that targets CD52, and cladribine, a purine analog that targets DNA synthesis and cell death primarily in B and T lymphocytes, are used as immune reconstitution therapies for the treatment of MS. These agents offer the possibility of maternal disease protection during protracted periods without the presence of a circulating drug, such as during conception and gestation.

Regarding the period of time between discontinuation and conception, for alemtuzumab the EMA currently recommends 4 months, even though placental transfer recommendations would be analogous to the other IgG monoclonals, as discussed in Sects. 4.1.1 and 4.1.2 [45, 48]. Safety data regarding neonatal outcomes after in utero exposure are limited [49]. However, while fetal exposure through placental transfer within the first 20–22 weeks of pregnancy is likely low, an additional consideration for alemtuzumab is the risk of developing autoimmune thyroiditis, which, if it occurs, poses additional risks to the fetus [50].

Cladribine is contraindicated during pregnancy by the EMA and FDA owing to its teratogenic effects observed in animal models, and contraception is typically recommended for 6 months after discontinuation [51–53]. Very limited data on live births are available from the period of drug development [52], but more recent real-world data have not identified any difference in pregnancy outcomes or congenital malformations associated with the use of cladribine within 6 months of conception [54, 55]. Cladribine has also been shown to deplete germ cells, spermatids, and spermatozoa, which requires a 3-month period after completion of cladribine therapy to complete a full spermatogenic cycle [52, 56]. The EMA and FDA suggest men exposed to cladribine wait an additional 3 months, for a total of 6 months after completion of therapy, before attempting to conceive [51, 53]. Very limited data are available regarding fetal outcomes from paternal exposure to cladribine; however, each recorded pregnancy resulted in a live birth [52].

First-Line Self-Injectable Therapies

Interferon beta (IFN-B), which was one of the first FDA-approved treatments for MS, modifies the immune system response by modulating antigen presentation and T-cell proliferation. Neither the FDA nor EMA recommends contraception with use [1]. Given that IFN-B is one of the oldest MS treatments on the market and has widespread use, there are robust safety data available regarding its use during pregnancy. No increased risk of adverse effects in pregnancy outcomes or congenital abnormalities has been reported in more than 3500 exposed pregnancies [57, 58]. Of note, most observed patients used IFN-B only until conception or the first trimester and therefore safety data on use later in pregnancy is limited. Patients who conceive while on IFN-B could be advised to either continue or stop treatment once pregnancy occurs.

Glatiramer acetate (GA) is an immune-modulating agent thought to reduce CNS inflammation by inhibiting peripheral T-cell proliferation prior to crossing the blood–brain barrier. As with IFN-B, GA was one of the first FDA-approved treatments for MS and, as a result, has more safety data available compared with other classes of DMTs. Multiple studies have shown no elevated risk of adverse pregnancy events or congenital abnormalities in neonates exposed to GA at the time of conception or during the first trimester [59–61]. Contraception is not indicated while taking GA according to both the EMA and FDA, and patients could be advised to continue or stop treatment once pregnant [62, 63].

Other Oral Therapies

Dimethyl fumarate (DMF) and other fumarates are daily oral agents thought to stimulate an anti-inflammatory immune response, although the exact mechanism of action is unknown. Initial analysis of preclinical safety data for delayed-release DMF did not show evidence of teratogenicity in animal models [64]. Subsequent clinical analyses have not demonstrated an increase in congenital abnormalities or adverse pregnancy outcomes in pregnancies exposed to DMF in the first trimester [65–67]. There are limited data available regarding the safety of prolonged exposure to DMF past the first trimester. At this time, the EMA and FDA do not recommend use during pregnancy due to insufficient safety data [68, 69]. Given their short half-life, fumarates could be discontinued at the time of conception attempts or at the time of a positive pregnancy test.

Teriflunomide is a daily oral agent that inhibits pyrimidine synthesis, leading to a reduction in B- and T-cell proliferation. It is contraindicated during pregnancy owing to evidence of teratogenicity and embryo lethality in animal models at lower doses than the recommended human dose [70]. In addition to recommending the use of contraception while taking the drug, contraception is recommended until serum concentrations reach < 0.02 mg, which can take between 8 and 24 months after discontinuation [70, 71]. Given the long wash-out period, an accelerated elimination process is recommended for patients who wish to conceive sooner or those who inadvertently conceive within 8–24 months after discontinuation. Multiple small studies examining pregnancy and fetal outcomes after teriflunomide exposure have been limited by sample sizes, elective terminations, and use of accelerated elimination protocols [72, 73]. Teriflunomide has also been detected in the sperm of men receiving treatment [71]. The risk of fetal toxicity from sperm of exposed individuals is thought to be low; however, the FDA, but not the EMA, recommends barrier contraception with use [11, 70].

Emerging Therapies

Tolebrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that targets B cells. Phase III clinical trials showed similar efficacy to teriflunomide in relapsing–remitting multiple sclerosis (RRMS), but superior efficacy to placebo in progressive MS [74, 75]. As a result tolebrutinib was recently approved by the United Arab Emirates for the treatment of progressive MS, with FDA regulatory approval pending [76, 77] . While pregnant and lactating patients were excluded from the current clinical trials of the drug, safety data exist for other BTK inhibitors, such as ibrutinib and acalabrutinib, which are approved for the treatment of hematologic malignancies. Both ibrutinib and acalabrutinib were found to be teratogenic in animal models [78]. Given this, combined with limited data available in humans, the FDA and EMA recommend the use of contraception during treatment [79–82]. Recommendations regarding how long to continue contraception after discontinuation vary from 0 to 12 weeks, depending upon the specific agent and regulatory agency [79–82]. Although based on the short half-life of these agents (4–6 and 1–3 hours, respectively), a short washout period would be expected on the basis of the five maximal half-lives principle.

Assistive Reproductive Therapy

Women with MS are more likely to be diagnosed with infertility based on a review of administrative claims [83]. The reason for this is unclear as MS otherwise does not affect pregnancy outcomes and is not associated with a higher rate of other obstetric complications [84, 85]. Some theorize that these higher rates of infertility may be related to delays in pregnancy out of concerns related to their disease. While women with MS are more likely to be diagnosed with infertility, they are less likely to be offered assistive reproductive therapies (ART) such as in vitro fertilization (IVF) and intrauterine insemination (IUI) [83]. Indeed, there have historically been concerns about the risk of relapse with the use of ART owing to the administration of high doses of hormones [86–90]. However, recent studies conducted in the DMT era have shown no elevated risk of relapse with use of ART [91]. As a result, women who are unable to achieve pregnancy after 12 months of trying for women < 35 years or after 6 months for women > 35 years should be referred for ART [1, 85]. The choice of ART method (IVF versus IUI) is not influenced by MS and should be determined on an individual basis [85]. In regard to DMT management during the ART process, clinicians should aim to limit disruptions to DMT as much as possible. With respect to fetal safety, DMTs should be discontinued prior to egg transfer in accordance with recommendations for DMT use during conception and pregnancy as discussed in Sect. 4.1 [1, 84, 92]. DMTs do not need to be discontinued during the oocyte cryopreservation (“egg freezing”) process if no immediate transfer is planned [1].

Management of Acute Relapses During Pregnancy

Treatment of new clinical relapses aims to accelerate recovery and typically involves the use of high-dose steroid therapy. Use of corticosteroids during pregnancy has been shown to have minimal placental transfer and is generally considered to be low risk during pregnancy by the American College of Obstetricians and Gynecologists (ACOG) [93–95]. Previously, there were concerns that steroid use during pregnancy was associated with an increased risk for cleft palate development, low birth weight, and impaired neurocognitive development; however, subsequent studies have not shown a clear association with corticosteroid use at the dose used for treatment of an acute MS relapse [37, 92, 95]. As with nonpregnant patients with MS, steroid use is indicated for treatment of relapses causing moderate to severe symptoms or interfering with functional ability. First-line treatment involves nonfluorinated corticosteroids (prednisone, methylprednisolone, or prednisolone) at the equivalent dose of 500–1000 mg prednisolone per day for 3–5 days [37, 94, 95]. For patients who do not respond to corticosteroid treatment, plasma exchange can be considered [37, 94, 95]. Immunoglobulin (IVIG) therapy is not routinely used to treat relapses during pregnancy given the high thrombotic risk associated with both IVIG and pregnancy [37].

Symptom Management

Management of MS-related symptoms is an important aspect of comprehensive MS care and quality of life. In addition, pregnancy represents a period when common MS-related symptoms may worsen owing to an overlap with symptoms related to pregnancy. For instance, fatigue is a common symptom in pregnancy and may exacerbate baseline levels of fatigue experienced with MS [96, 97]. In addition, frequent urination related to increased bladder pressure from the fetus and greater circulating blood volume may worsen underlying urinary symptoms associated with bladder spasticity. Lastly, mobility can be affected by pregnancy owing to changes in gait, stability, pain, and shortness of breath, which places patients at risk for falls, particularly if mobility was reduced prior to pregnancy [98, 99]. Overall, maintaining maternal emotional and physical wellness is an important component of the management of the maternal–infant dyad throughout the pregnancy period. When possible, pharmacological treatment approaches should minimize potential risks of transfer to the fetus or infant. Below, we discuss important considerations regarding commonly used symptomatic treatments, which are summarized in Table 2.

Table 2.

Symptom management during pregnancy

Symptom	Common pharmacologic intervention	Safety of use during pregnancy	Nonpharmacologic intervention
Depression	SSRIs (sertraline or escitalopram)	Can be used during pregnancy if clinically necessary; use of lowest clinically effective dose recommended	Psychotherapy
Fatigue	Modafinil Amantadine Methylphenidate	No pharmacologic agent for the treatment of fatigue is recommended during pregnancy given insufficient data in humans and potential harm in animal studies	Combined aerobic and strength training Cognitive behavioral therapy Sleep management
Mobility and gait dysfunction	Dalfampridine Baclofen	Contraindicated in pregnancy owing to evidence of fetal toxicity in animal studies Insufficient data regarding use in pregnancy; recommended only if the benefit outweighs risk to fetus	Physical therapy
Urinary symptoms	Oxybutynin Mirabegron	Low probability of adverse effects on fetus based on animal studies; recommended only if the benefit outweighs risk to fetus Insufficient safety data regarding use in pregnancy; not recommended for use during pregnancy	Pelvic floor physical therapy

SSRIs selective serotonin reuptake inhibitors

Peripartum Mood Disorders

The prevalence of peripartum mood disorders in the general population ranges from 10 to 20% [100, 101]. Nonpregnant patients with MS have an increased incidence of mood disorders and results of studies examining the prevalence of peripartum depression (PPD) among patients with MS have revealed an increased risk for peripartum mood disorders with risk factors similar to the general population such as preconception depression, first birth, and older maternal age [100, 102, 103]. Untreated peripartum mood disorders are associated with multiple negative outcomes, including for the newborn (preterm birth, low birth weight, and psychiatric and neurodevelopmental disorders), mother (maternal substance use and suicide), and for mother–infant attachment [100, 101, 103]. These risks underscore the importance of preventing and treating peripartum mood disorders. Management of peripartum mood disorders includes an individualized combination of psychotherapy and/or antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants and have the most data to support their use during pregnancy. In a recently published meta-analysis regarding the safety of SSRIs during pregnancy, while accounting for limitations of prior studies, such as observational protocols and the presence of confounding variables, no increased risk of congenital abnormalities was found with the use of SSRIs as a class [104]. There was, however, a small increase in the risk of postpartum hemorrhage and pre-eclampsia noted with the use of SSRIs [104]. Additional data looking specifically at third-trimester exposure suggest a dose-dependent association between use of SSRIs after 20 weeks of gestation and delayed neonatal adaptation (5-min Apgar score ≤ 5, resuscitation at birth, or admission to a neonatal intensive care unit for respiratory support) [105]. This association was highest with the use of escitalopram and fluoxetine; while low-dose sertraline was also associated with increased risk for delayed adaptation, it conferred the lowest risk when compared with other SSRIs [105].

While the use of SSRIs during pregnancy is not completely risk-free, this must be balanced with the risk of untreated peripartum mood disorders. With this in mind, ACOG guidelines typically recommend the use of SSRIs during pregnancy if clinically necessary, and at the lowest effective dose available. Concerning specific SSRIs, while sertraline has been regarded as the preferred SSRI during pregnancy, given the overall limited data to support this recommendation, the ACOG does not recommend switching from an alternative SSRI to sertraline during pregnancy if mood symptoms have been well-controlled on that alternative SSRI [106]. For patients not previously on treatment, the ACOG considers sertraline and escitalopram as first-line agents [106].

Fatigue

Pharmacologic treatments are often used to treat MS-related fatigue. Modafinil, a nonamphetamine stimulant, is the mostly commonly used agent to treat MS-related fatigue. There is currently insufficient data regarding the safety of modafinil use in pregnant women. A larger multicenter case series did not replicate an earlier case series suggesting an increased risk of congenital abnormalities, but modafinil did appear to be associated with lower birthweight and reduced head circumference [107, 108]. Current recommendations from the FDA state that modafinil should only be used if the benefit outweighs the risk, while the EMA states that it should be avoided during pregnancy [109, 110]. Separately, some data suggest that modafinil can make oral contraceptives less effective, an important counseling topic when discussing family planning [111].

Alternative treatment options, such as amantadine, similarly have limited data regarding the safety of use during pregnancy; however, it is not recommended for use during pregnancy owing to embryo lethality in animal studies [112, 113]. Methylphenidate, a stimulant used in the treatment of fatigue and attention deficit hyperactivity disorder (ADHD), is not currently recommended for use during pregnancy by the FDA and EMA owing to developmental abnormalities in rodents and the potential for neonatal cardiotoxicity [114, 115]. Although recent meta-analysis of in utero exposure to methylphenidate did not show higher rates of congenital anomalies or miscarriages compared with the general population [116].

Of note, recent studies have called into question the general effectiveness of the above-mentioned pharmacologic agents for the treatment of MS-related fatigue [117]. Given these findings, and the limited pharmacologic options that can be safely used during pregnancy, attention should be given to nonpharmacologic interventions to address fatigue during pregnancy. In patients with MS, combined aerobic and strength training, as well as cognitive behavioral therapy (CBT), have been shown to significantly reduce levels of fatigue [117–119]. Similarly, exercise during pregnancy has been associated with lower rates of pregnancy-related fatigue, although these studies were not specific to women with MS [120, 121]. Sleep optimization is also important to promote overall well-being as well as reduce fatigue.

Mobility and Gait

Gait disturbances are common in patients with MS and can be related to a number of factors, including weakness, sensory changes, spasticity, and impaired coordination.

Pregnancy itself is associated with changes in gait and is considered a high-risk fall period, with up to 25% of patients experiencing a fall during their pregnancy [122]. Given the risk of falls at baseline for patients with MS, counseling and proactive interventions such as participation in physical therapy prior to conception and throughout pregnancy should be employed.

Careful review of medications used to improve gait before pregnancy should be performed as well to ensure risks to the fetus are limited. Dalfampridine, a medication used to improve nerve conduction and walking speed by blocking potassium channels, is contraindicated during pregnancy [123, 124]. Animal studies suggest that it has the potential to cause fetal harm, and there is insufficient data on fetal risks in pregnancy [123, 124].

Muscle spasticity poses management challenges during pregnancy. Baclofen is a muscle relaxant that provides benefit for patients with spasticity and can aid in walking. There is limited data on developmental risks for those exposed in utero [125]. However, there is evidence of neonatal withdrawal in those born to mothers taking baclofen throughout their pregnancy [125]. The FDA does not recommend the use of baclofen during pregnancy unless the benefit outweighs the risk [125]. Nonpharmacological approaches can include more frequent stretching and massage with practitioners trained in pregnancy care.

Urinary Symptoms

First-line therapies for urinary symptoms in MS include lifestyle modifications (fluid management), pelvic floor physical therapy, and medications such as oxybutynin and mirabegron [126]. In addition to showing benefits in alleviating urinary symptoms in both women with MS and pregnant women, physical therapy (PT) has advantages over medications as it does not pose a risk to fetal health and development [126–129]. Despite this, referrals to PT are underutilized in women with MS during pregnancy and postpartum, even when patients report symptoms that could benefit from this type of therapy [128].

Regarding medication options, oxybutynin is an antispasmodic agent used to treat bladder spasticity in patients with MS. Animal studies have not shown definitive harm to the fetus exposed in utero; however, there is insufficient safety data available in humans [130]. One observational study examined pregnancy outcomes in women with spinal cord injuries. In women who continued use of oxybutynin throughout their pregnancy there was no evidence of adverse effects on neonatal outcomes; however, the sample size was small (n = 5) [131].Mirabegron is a beta-agonist that can also be used to treat symptoms of overactive bladder in patients with MS. In preclinical development, fetal abnormalities were seen at doses higher than the maximum recommended human dose; however, there is no safety data available from human use [132, 133]. The FDA and EMA do not recommend use during pregnancy, given insufficient safety data [132, 133].

Postpartum as a Critical “Fourth Trimester”

The postpartum period is associated with increased inflammatory activity, both in terms of clinical relapses and new inflammatory lesions on magnetic resonance imaging (MRI), particularly during the first 6 months postpartum [22–24]. While maternal proclivity for immune activation (as reflected by pre-pregnancy relapses, expanded disability status scale (EDSS), and discontinuation of certain DMTs) represents a major predictor of peripartum inflammatory activity, both breastfeeding and resumption of HET with short therapeutic lag early in the postpartum period abrogate this risk [1, 23, 24, 26, 39, 134, 135]. Indeed, emerging data suggest that resumption of HET within 1 month postpartum is associated with a decreased risk of inflammatory activity [23, 24, 47, 134–136]. For anti-CD20 agents specifically, treatment within 6 months of conception followed by postpartum resumption within 1 month, resulted in minimal disease activity throughout the pregnancy and postpartum period [47, 134–136]. Prior studies examining early resumption of lower efficacy treatments such as DMF, IFN-B, and GA in the postpartum period did not find a significant reduction in postpartum disease activity [25, 66], which suggests that both the timing of resumption and choice of DMT can modulate the risk of disease activity in the postpartum period.

DMT Resumption

For patients who do not plan to breastfeed, resumption of DMT within the first few weeks postpartum is recommended.

For patients who plan to breastfeed, the increasing safety data available regarding DMTs for MS are better equipping neurologists to counsel patients on options that allow them to breastfeed while resuming treatment for their disease and promote individualized, evidence-based shared decision-making. Factors to take into consideration include the individual’s degree of disease activity before pregnancy, choice of DMT prior to conception, and potential complications from their pregnancy or delivery. When determining the safety of breastfeeding, an important measure is the relative infant dose (RID) which calculates the percentage of maternal dosage that an infant is exposed to through ingestion of breast milk. An RID of < 10% is typically considered to be compatible with breastfeeding, although safety likely also varies by agent and degree of oral bioavailability (i.e., whether the infant would absorb any product ingested in breastmilk) [137]. It is important to note again that guidelines by regulatory agencies (FDA and EMA) around lactation are lagging and heterogeneous. For example, the EMA now states that ocrelizumab can be used while breastfeeding, while still recommending that breastfeeding be avoided for 6 months after the last dose of rituximab [28, 30]. A summary of current recommendations regarding breastfeeding while on various DMTs is summarized in Table 3.

Table 3.

DMT use during lactation

DMT	RID	EMA recommendation	FDA recommendation	Expert opinion
IgG monoclonal antibodies
Anti-CD20 agents (ocrelizumab, rituximab, ofatumumab, and ublituximab)	< 1%	Breastfeeding can continue while on ocrelizumab therapy Breastfeeding should be avoided while on rituximab and for 6 months after last dose Clinical benefit of ofatumumab and ublituximab should be balanced with potential adverse effects	Clinical benefit should be balanced with potential adverse effects	Avoid treatment during the colostrum/immature milk phases (first 2 weeks postpartum) Breastfeeding can continue after treatment
Natalizumab	< 0.5%	Breastfeeding should be discontinued while on treatment	Clinical benefit should be balanced with potential adverse effects	Breastfeeding can continue after infusions
Alemtuzumab	No data available	Breastfeeding should be avoided while receiving alemtuzumab and for 4 months after last dose	Clinical benefit should be balanced with potential adverse effects	Breastfeeding can continue after infusions unless maternal thyroid complications
First-line self-injectables
Interferon beta	0.0006%	Breastfeeding can continue while on therapy	Clinical benefit should be balanced with potential adverse effects	Breastfeeding can continue while on therapy
Glatiramer acetate	0.2%	Breastfeeding can continue while on therapy	Clinical benefit should be balanced with potential adverse effects	Breastfeeding can continue while on therapy
Oral therapies
Dimethyl fumarate	0.007–0.16%	Clinical benefit should be balanced with potential adverse effects	Clinical benefit should be balanced with potential adverse effects	Clinical benefit should be balanced with potential adverse effects
Cladribine	3.1–4.73%	Breastfeeding is contraindicated during treatment and for 1 week after the last dose	Breastfeeding should be avoided during treatment and for 10 days after the last dose	Patients should wait 10 days after last dose prior to breastfeeding
Fingolimod	No data available	Breastfeeding should be discontinued while on therapy	Clinical benefit should be balanced with potential adverse effects	Breastfeeding should be discontinued during therapy
Teriflunomide	No data available	Breastfeeding is contraindicated while on therapy	Breastfeeding is contraindicated while on therapy	Breastfeeding should be discontinued during therapy
Other therapies
IVIG	Normal component of breastmilk	Given insufficient safety data, should be used with caution; no adverse effects anticipated	Clinical benefit should be balanced with potential adverse effects	Breastfeeding can continue while on therapy

DMT disease modifying treatment, EMA European Medicines Agency, FDA US Food and Drug Administration, IgG immunoglobulin G, IVIG intravenous immunoglobulin G, RID relevant infant dose

IgG Monoclonal Antibodies

A recent analysis of the concentration of anti-CD20 monoclonal antibodies (rituximab and ocrelizumab) in 59 women found that the average concentration of monoclonal antibodies (mAbs) in breast milk was low, with a median average RID of < 1% (ocrelizumab 0.1%, range 0.07–0.7%; rituximab 0.04%, range 0.005–0.3%) [134]. These findings have been replicated in smaller cohorts of women treated with rituximab and ocrelizumab [138–140]. This is consistent with a class effect, where the transfer of endogenous and exogenous IgG1 monoclonal antibodies into breastmilk is very low. Given the low RID, breastfeeding can continue after anti-CD20 infusions, and no period of “pump and discard” is recommended. Ofatumumab, a newer anti-CD20 agent, also has a low RID (< 1%) after a single dose, and while levels could theoretically increase with monthly dosing, these remain low [141].

Natalizumab, an IgG5 monoclonal antibody, also transfers into breastmilk at low levels (RID < 0.5%) based on limited data [142–144]. Owing to insufficient data, the FDA recommends considering the risk versus benefit of continuing natalizumab while breastfeeding [145]. While additional data is necessary, existing data on natalizumab and other monoclonal antibodies suggest that treatment with natalizumab during lactation may be compatible with breastfeeding.

Alemtuzumab has been detected in breastmilk in animal studies; however, no data is available regarding transfer into human breast milk [142]. As alemtuzumab is a monoclonal antibody, data from other mAbs may suggest low transfer of alemtuzumab into breastmilk. In patients who have developed autoimmune thyroiditis as a result of alemtuzumab, abnormal thyroid hormone concentrations, particularly hypothyroidism, can affect milk supply [146]. There is currently limited data available regarding the transfer of thyroid antibodies to breastmilk in alemtuzumab-induced thyroiditis [147].

First-Line Self-Injectable Therapies

Both interferon beta and GA have a large molecular size and limited transfer into breast milk. The RID for interferon beta is extremely low at 0.0006% [147]. Similarly, the RID for GA is particularly low, 0.2%, with poor oral bioavailability [148]. Both are considered compatible with breastfeeding by the EMA [1].

Oral Therapies

In two small case studies, dimethyl fumarate was found to have a low RID, ranging between 0.007 and 0.16% [149]. In addition, in a small cohort of women, normal development was seen in infants breastfed by mothers taking dimethyl fumarate after the first month of life [149]. While the limited data in humans do not suggest adverse events associated with breastfeeding while on DMF, animal studies have shown adverse effects on growth, sexual dysfunction, and neurobehavioral function when administered while breastfeeding [68, 69]. The FDA and EMA recommend that the potential risks of DMF be balanced with the benefits of the medication to the mother and the developmental benefits of breastfeeding for the infant [68, 69].

There are limited data regarding the transfer of cladribine into breastmilk. In two small case studies (n = 1 and n = 2, respectively) the RID ranged from 3.1 to 4.73% depending on the dose of cladribine administered [150]. Furthermore, cladribine is orally bioavailable. Current guidelines from the FDA recommend patients wait 10 days after the last dose before breastfeeding [53].

S1P receptor modulators, such as fingolimod, have been detected in breastmilk in animal studies; however, no data is available regarding transfer into human breastmilk [142, 151]. Since fingolimod is orally bioavailable and considered to be potentially toxic to infants, fingolimod should not be used during lactation [151].

Teriflunomide has been shown to transfer into breastmilk in animal studies; however, no data is currently available regarding its transfer into human breastmilk or the effects on infant development in those breastfed by mothers taking teriflunomide [152]. Given the potential toxicity to infants, both the FDA and EMA recommend that patients not breastfeed while on teriflunomide [11, 70].

Postpartum IVIG

Administration of IVIG postpartum has been previously proposed as an option to reduce risk for postpartum relapse, particularly in patients who did not receive therapy prior to conception. Previous studies have demonstrated a reduction in the annualized relapse rate (ARR) postpartum with IVIG administration during the postpartum period, although doses and timing of administration varied between studies [153–157]. However, in more recent studies, no benefit on ARR was seen with postpartum IVIG [156, 158]. Immunoglobulin G (IgG) is a normal component of breast milk and was found in normal or higher levels in two mothers who received IVIG [159]. Immunoglobulin M was also detected in breast milk at normal and low levels in these patients [159]. No RID is available; however, breastfeeding while on IVIG is generally considered safe [161]. Given the sparsity of data regarding IVIG and breastfeeding, the FDA recommends that the risk be weighed against the benefit of breastfeeding [160]. However, the EMA posits that while insufficient safety data is available, adverse effects are not anticipated [161].

Symptom Management

Management of MS symptoms during the postpartum period must factor in changes related to social, emotional, and physical state, as well as the safety of breastfeeding on symptomatic treatments. Recommendations on postpartum symptom management are summarized in Table 4.

Table 4.

Symptom management during the postpartum period

Symptom	Common pharmacologic intervention	RID	Safety of use during breastfeeding	Nonpharmacologic intervention
Depression	SSRIs (sertraline)	0.5–2%	Breastfeeding can continue while on therapy	Therapy
Fatigue	Modafinil Amantadine Methylphenidate	4.85–5.3% No data available 0.2–0.7%	Clinical benefit of modafinil should be balanced with potential adverse effects Amantadine and methylphenidate are not recommended for use while breastfeeding given the reduction in prolactin levels and possible reduction in milk supply	Exercise Screen for sleep disturbances and mood disorders
Mobility and gait dysfunction	Dalfampridine Baclofen	No data available 3.6%	Breastfeeding should be discontinued while on therapy Insufficient safety data; clinical benefit should be balanced with potential adverse effects	Physical therapy
Urinary symptoms	Oxybutynin Mirabegron	No data available No data available	Clinical benefit of oxybutynin should be balanced with potential adverse effects Clinical benefit of mirabegron should be balanced with potential adverse effects	Pelvic floor physical therapy

RID relevant infant dose, SSRI selective serotonin reuptake inhibitor

Peripartum Depression

Discussion around rates of peripartum mood disorders and the risks associated with untreated depression on both the mother and child were detailed above in Sect. 4.4.1. As is the case during pregnancy, treatment of postpartum depression involves a combination of therapy and/or antidepressants. The ACOG recommends against discontinuing medications for mental health conditions while breastfeeding [106]. In the postpartum period, the safety of breastfeeding should be considered when selecting an antidepressant—among which, SSRIs are the most used. While many SSRIs are available, given that sertraline is commonly prescribed, we will use sertraline as a representative for this class. Low levels of sertraline are detectable in breast milk, with an RID of 0.5–2%, depending on the study [162]. The FDA and EMA recommend that the potential risks of sertraline be balanced with the benefits of the medication to the mother and the developmental benefits of breastfeeding for the infant [62, 163]. In women with MS, counseling around risks and benefits should include the elevated risk of peripartum mood disorders, including depression and anxiety [100, 102, 164].

Fatigue

The postpartum period is associated with higher degrees of fatigue, with up to 68% of mothers endorsing persistent fatigue during the first 3 months postpartum [165]. Fatigue during this period is influenced by multiple factors, including quality and duration of sleep, night-time breastfeeding demands, and mood symptoms [165]. Chronic illness in itself has also been identified as a potential exacerbating factor to severity of postpartum fatigue [165]. As fatigue is a common symptom related to MS, irrespective of pregnancy status, the postpartum period represents an at-risk period for higher degrees of fatigue and should be evaluated for during visits in the postpartum period. As discussed in Sect. 4.4.2, lifestyle and behavioral modifications such as exercise and CBT have shown higher efficacy at addressing MS-related fatigue than pharmacologic treatments [117–119]. Exercise, particularly supervised exercise, has also been shown to be beneficial at reducing postpartum fatigue [120, 121]. In addition, patients should be screened for sleep disturbances and mood disorders, which may be contributing to levels of fatigue. If pharmacologic treatment options are pursued, compatibility with breastfeeding should be considered.

Limited data are available regarding the transfer of modafinil into breast milk. Two case studies of women breastfeeding while on modafinil found low levels in breast milk, with an RID ranging from 4.85 to 5.3% [166–168]. Given the insufficient data surrounding infant safety, the FDA and EMA recommend exercising caution with the use of modafinil during lactation [109, 110]. There are no data available regarding the degree of transmission of amantadine into breastmilk, nor for the potential effects on infants who were breastfed by women taking amantadine [112, 169]. However, amantadine has been shown to reduce levels of prolactin, an important hormone in breastmilk production [169]. While it is not clear whether milk production is affected by amantadine use, it is recommended that amantadine be avoided during lactation owing to the theoretical effects on milk production and insufficient data on transfer into breastmilk [112]. Methylphenidate has been shown to have low transfer into breastmilk, with a RID ranging from 0.2 to 0.7% [170]. However, as is the case with amantadine, methylphenidate reduces prolactin levels, thus posing a theoretical threat to milk production, although no studies have directly evaluated this effect. The EMA and FDA recommend caution regarding the use of methylphenidate while breastfeeding [114, 115].

Mobility and Gait

As discussed in Sect. 4.4.3, pregnancy is associated with changes in gait and balance. These changes can persist into the postpartum period, although balance and mobility overall improve with time after delivery [171–173]. Involvement in physical therapy can thus be beneficial to guide activity and balance modifications throughout this recovery period. Use of medications to improve gait and mobility can also be considered during this period after weighing the risks and benefits of each agent, as well as an individual’s plans for breastfeeding. Dalfampridine, which is associated with improvements in walking speed, has no available data regarding transfer into human breast milk [123, 124]. In animal studies, administration of dalfampridine during lactation resulted in decreased viability and growth of offspring [123, 124]. The EMA recommends that use of dalfampridine be avoided while breastfeeding, while the FDA recommends that the potential risks be balanced with the benefits of the medication to the mother and the developmental benefits of breastfeeding for the infant [123, 124]. Spasticity can also contribute to gait dysfunction and instability in women with MS, which can be treated with agents such as baclofen. Baclofen has been detected in breastmilk in low levels in three women [174]. Current data on the effects of baclofen in the breastfed infant are limited, and most studies are confounded by concurrent exposure to baclofen in utero. However, there have been reports of withdrawal symptoms in breastfed infants when either breastfeeding or maternal use of baclofen is abruptly stopped [174]. The FDA recommends that the potential risks of baclofen be balanced with the benefits of the medication to the mother and the developmental benefits of breastfeeding for the infant [125].

Urinary Symptoms

Urinary symptoms are common in postpartum women, including pelvic floor dysfunction, urinary incontinence, and, in the immediate postpartum period, urinary retention [175, 176]. Despite urinary dysfunction being a common symptom experienced by women with MS, there are limited data regarding how these symptoms change during the postpartum period. One small study suggested that there was no significant change in urinary symptom severity or frequency during the postpartum period in patients with MS; however, similar studies have not been replicated [177]. Pelvic floor physical therapy is recommended for the management of urinary symptoms in patients with MS as well as the general population [126–128, 175, 178]. Medications such as oxybutynin and mirabegron are often used to treat urinary symptoms; however, their use during the postpartum period should consider the safety of use while breastfeeding. There are no data currently available regarding the transfer of oxybutynin into breastmilk [179, 180]. Given the absence of safety data available, the FDA and EMA recommend exercising caution with use during lactation [181, 182]. Similarly, there are no data available currently regarding the transfer of mirabegron into breastmilk; however, in animal studies, mirabegron was excreted in the milk of rodents [132, 133, 183]. Given the absence of safety data, the FDA recommends balancing the potential risks of the medication with its benefits to the mother and the developmental benefits of breastfeeding for the infant, while the EMA recommends avoidance while breastfeeding [132, 133].

Menopause

Menopause represents another life transition of relevance to the care of women with MS. It is defined as the complete cessation of the menstrual cycle for more than 12 months [184]. The typical age of spontaneous menopause ranges from 45 to 56 years old, with a median age of 51, which is consistent between women with MS and the general population [184, 185]. Current estimates suggest that approximately two-thirds of all individuals who develop MS are pre-menopausal women, who will therefore enter menopause after their diagnosis, and at least one-third of all people currently living with MS are perimenopausal or postmenopausal women [186]. Considerations for women with MS include: symptomatic management of the perimenopausal period (which lasts years prior to, and for the first few years after the final menstrual period), guidance regarding prevention of disability worsening in the postmenopausal period, prevention of comorbidity accumulation, and appropriate counseling regarding menopausal hormone therapy use.

Perimenopausal Symptom Management

In clinical practice, many women who experienced excellent disease control after diagnosis and appropriate initiation of DMT, report symptomatic worsening during the perimenopausal period. While this could be related to the progression of MS in some, it is often the result of menopausal symptoms that overlap with and exacerbate preexisting MS symptoms [185]. This clinical overlap can lead to undertreatment of perimenopausal symptoms by internists owing to the concern that they are related to their MS, and by neurologists who assess the MS itself as “stable.” Management of symptoms in the perimenopausal period is summarized in Table 5 and discussed in detail below.

Table 5.

Comprehensive symptom management approaches during the perimenopause and post-menopause period

Concern	Symptoms	Intervention
Therapeutic alignment	Escalation of symptoms, confusion over appropriate clinical team	Begin and document anticipatory guidance at age 45 years, continue at least annually As symptoms arise, increase frequency of visits (e.g., from 6 months to 3 months) Develop a collaborative care model or referral network to ensure multidisciplinary needs are met (physical therapy, pelvic floor rehabilitation, mental health, urogynecology, neuropsychology, endocrinology)
Cognition	Impairment in executive function, attention, verbal memory, multitasking, and word finding ability	Treatment of underlying mood disorders, sleep disturbances and fatigue, cognitive rehabilitation
Mood disorders	Anxiety, depression	Psychotherapy, support groups, antidepressants
Sleep dysfunction	Insomnia, daytime sleepiness, sleep apnea	Treatment of underlying mood disorders, neurogenic bladder, or vasomotor symptoms Screening and treatment of sleep apnea Counseling on sleep hygiene Medications including melatonin and hypnotics (benzodiazepines, mirtazapine, trazodone, doxepin)
Fatigue	Excessive daytime fatigue	Address underlying sleep dysfunction and stimulants (modafinil, amantadine)
Vasomotor Symptoms	Hot flashes, night sweats, heart palpitations	Menopausal hormone therapy, fezolinetant, SSRI/SNRIs, and behavioral modifications
Musculoskeletal pain	Back, neck, and shoulder pain, muscle stiffness, arthralgia	Exercise program that includes stretching and joint flexibility, massage, physical therapy Antispasmodic agents, neuropathic pain agents
Urinary symptoms	Urinary urgency, incontinence, frequency, increased risk of UTIs	Bladder training, pelvic floor PT, vaginal estrogen, antispasmodics (baclofen), antimuscarinics (oxybutynin)
Sexual dysfunction	Decreased libido, decreased vaginal lubrication, pelvic pain	Intravaginal estrogen, water soluble lubricants, pelvic floor rehabilitation, intravaginal botulinum injections for spasms, medications for hypoactive sexual desire

PT physical therapy, SSRI selective serotonin reuptake inhibitor, SNRI serotonin–norepinephrine reuptake inhibitor, UTI urinary tract infection

Vasomotor Symptoms

Vasomotor symptoms (VMS) include hot flashes, night sweats, and heart palpitations. Vasomotor symptoms are one of the most commonly experienced symptoms of perimenopause in Western societies, occurring in an estimated 80% of women [187]. Hot flashes can also trigger recrudescence of or exacerbate neurologic symptoms in women with MS, presumably because of the Uhthoff phenomenon [185]. In addition, the impact of VMS on sleep quality can worsen daytime energy, mood, cognition, and overall emotional well-being [188]. A variety of nonpharmacologic and pharmacologic treatment options exist. Menopausal hormone therapy (HT) is considered one of the most effective pharmacologic treatments for vasomotor symptoms, which is detailed more completely in Sect. 6.3. For women where hormone therapy is contraindicated or who prefer nonhormonal agents, options include the newly approved fezolinetant, SSRIs, SNRIs, and gabapentin [189].

Urinary Symptoms

A variety of urinary symptoms are associated with menopause, including urgency, nocturia, urinary incontinence, and urinary tract infections (UTIs). Treatment options for these symptoms include topical estrogen therapy (which is considered safe when systemic hormone therapy is contraindicated), antimuscarinics (oxybutynin), antispasmodics (baclofen), and nonpharmacologic interventions (bladder training and pelvic floor physical therapy) [185].

Mood Disorders

In the general population, up to 70% of women may experience depression and/or anxiety during perimenopause [187]. While the exact percentage of women with MS who experience new or worsening mood symptoms during this period is unknown, patients with MS experience higher rates of depression and anxiety than the general population [185]. This suggests that perimenopause could represent a period of vulnerability for women with MS and highlights the importance of screening for these symptoms at each visit. Patients experiencing depression or anxiety should be connected to resources for psychotherapy or pharmacologic treatments (SSRIs and SNRIs) if interested.

Fatigue

Fatigue is one of the most common symptoms in patients with MS and often increases in severity during menopause, potentially related to changes in sleep and VMS [185]. Pharmacologic treatment options, which are used clinically but have not shown clear benefit in limited short-term trials on MS-related fatigue, include modafinil, amantadine, methylphenidate, and other stimulants [117]. Nonpharmacologic interventions such as combined aerobic and strength exercises and CBT have been shown to be effective at reducing MS-related fatigue [119]. In addition, addressing underlying sleep quality, including the contribution of VMS, is particularly important for patients going through menopause [190].

Sleep

Disturbances in sleep are common among perimenopausal women and are related to several underlying factors, including vasomotor symptoms, mood disorders, increasing rates of obstructive sleep apnea (OSA), as well as others [185, 191]. Women with MS experience higher rates of sleep dysfunction than the general population, which suggests that they may be particularly vulnerable to sleep disturbances associated with menopause, as demonstrated in one cohort [190, 191]. Chronic disruption in sleep can lead to worsening of mood symptoms, fatigue, and cognition. Management of sleep disturbances is multimodal and includes addressing sleep hygiene, treatment of factors which may fragment sleep (VMS, mood disorders, and bladder dysfunction), and pharmacologic measures [191]. Medication options include melatonin, benzodiazepines, and other hypnotics (trazodone, mirtazapine and doxepin); however, care should be given to the selection of sleep-promoting medications, given the risk of worsening fatigue and cognition with certain agents.

Cognition

Cognitive decline occurs in up to 65% of patients with MS and worsens with age [191]. During menopause, women report a number of cognitive complaints, including changes in attention, executive function, multitasking, word-finding, and verbal memory [185, 191]. As discussed in Sections 6.1.3–5, a number of other perimenopausal symptoms can worsen cognition, highlighting the importance of addressing disturbances in mood and sleep to optimize cognitive function. Perimenopausal women with MS may be particularly concerned about their risk of cognitive decline; management includes reducing contributing factors (sleep, mood, and fatigue) and consideration of neuropsychological evaluation.

Sexual Dysfunction

Changes in sexual function, such as decreased libido, decreased vaginal lubrication, and pelvic pain may occur as a result of the reduced levels of estrogen [185, 187]. These changes may worsen preexisting sexual dysfunction in women with MS. Intravaginal estrogen and water-soluble lubricants can be used to address vaginal dryness and pain. Approaches to addressing hypoactive sexual desire include sex therapy, CBT, as well as pharmacologic agents such as flibanserin, bremelanotide, and testosterone [192].

Musculoskeletal Pain

Musculoskeletal pain, including back pain, neck and shoulder pain, muscle stiffness, and arthralgias, is a common complaint among perimenopausal women, and worsens post-menopause [193]. These changes are often not recognized by clinicians as associated with menopause. Furthermore, changes in hormone levels can affect pain perception and tolerance, which may further exacerbate underlying pain syndromes in women with MS [185, 193]. A holistic approach to pain management is recommended and includes a combination of behavioral changes, such as physical therapy and massage, and pharmacologic management.

Postmenopausal MS Course

An earlier, surgical, menopausal transition (< 45 years) is associated with an increased risk of cognitive decline, brain atrophy, and certain neurologic conditions such as Alzheimer’s disease and Parkinson’s disease [194, 195]. In women with MS, some studies have suggested that menopause is associated with a decrease in inflammatory activity and an increase in disability progression [196–198], but not all have shown this [199, 200]. Onset of the progressive stage of MS also tends to occur around the fifth decade of life, which coincides with the menopause transition [201]; however, not all patients with MS experience substantial progression in their course, and this risk is reduced with DMT use.

Mechanistically, reproductive aging itself (i.e., loss of gonadal steroids) occurs in the context of chronologic and biological aging. Furthermore, reproductive aging likely has both direct (on CNS cell types) and indirect (i.e., effects mediated by comorbidities) effects on brain function. In addition, there may be a lag between loss of gonadal hormones and neurological outcomes.

A recent study utilizing prospectively collected data, identified worsening in measures of neurodegeneration—namely, the multiple sclerosis functional composite (MSFC) and serum neurofilament light chains (sNFL), a marker of axonal injury—after the menopausal transition [198]. Inconsistent findings regarding EDSS point to this being an insensitive and confounded measure of disease worsening in the menopausal setting, as it is in general with aging and highlights the fact that the clinical impact of menopause on MS progression may not be immediately apparent, but could rather accrue over time [202].

Development of MS after menopause also has noticeable differences, with there being fewer sex differences in disease course between women and men who are diagnosed over the age of 50 years [185].

Menopausal Hormone Replacement Therapy

Menopausal hormone replacement therapy (MHT) consists of estrogen therapy or, in women with a preserved uterus, combined estrogen–progesterone therapy. In women with MS, considerations for use include both perimenopausal symptom management and possible postmenopausal protection.

Perimenopausal Management

MHT is considered one of the most effective treatments for perimenopausal vasomotor symptoms associated with menopause, as well as vulvar and vaginal atrophy [185]. MHT also has beneficial effects on quality of life during perimenopause, including effects on sleep, mood, and libido. While there are many potential benefits of MHT on the overall quality of life in women with MS, one consideration in those with increased disability and sedentarism is the potential risk of developing venous thrombosis [203]. In addition, MHT is contraindicated in patients with a history of breast cancer, coronary artery disease, previous venous thromboembolism or stroke, active liver disease, or unexplained vaginal bleeding [204].

Longer-Term Neuroprotection

In addition to symptomatic treatment during perimenopause, MHT also has longer term benefits. It can be effective in the treatment of overactive bladder and the prevention of recurrent UTIs [185, 203]. MHT has also shown benefit in improving bone mineral density, thus reducing the risk of osteoporosis-related fractures [203, 205]. This is particularly important for women with MS, as they are at higher risk for the development of osteoporosis [206]. Reanalysis of the landmark Women’s Health Initiative (WHI) trial also demonstrated benefits of systemic estrogen utilized within 5 years of menopause in women aged 50-59 years on all-cause mortality, cancer risk, hyperlipidemia, and diabetes [207].

With respect to possible effects on neuroprotection, there are extensive data in preclinical models, and some observational studies have suggested that use of MHT in women aged 50–59 years within 5 years of menopause can protect against cognitive impairment [208]. This finding is relevant for women with MS, given the prevalence of cognitive concerns, and since the loss of ovarian hormones is associated with an elevated risk of developing dementia [187]. However, an interventional trial examining the effect of estrogen-only therapy on cognition in postmenopausal women without neurological disease did not find any effect on cognitive ability, regardless of when hormone therapy was initiated after menopause [209]. The ongoing analyses of the KEEPS trial, while suggesting some benefits on related mediators such as sleep and mood disturbances, did not find beneficial effects on cognition [210]. In MS, interventional studies in premenopausal women with MS have shown possible neuroprotective benefit (improved cognition and reduced brain atrophy) with high-dose estrogen [211, 212], but there are no interventional data on MHT for postmenopausal women with MS.

Postmenopausal Management

DMT

Overall, there are no data regarding whether the efficacy of DMTs changes after menopause. In fact, women of menopausal age have typically been entirely excluded from a majority of phase III randomized controlled trials that led to the approval of MS DMTs [213].

When weighing the relative risks and benefits of DMTs in postmenopausal women with MS, it is important to weigh specific DMT factors such as safety concerns, risk of rebound activity, and degree of immune suppression. Individual factors to consider include personal risk tolerance, disability level, MS duration, and age-associated changes in immune activity, neurodegeneration, and comorbidities. It is also important to consider female-specific concerns, such as breast cancer risk, gynecological health (including the impact of immune suppression on risk of HPV-associated cervical cancer), and bone density [214].

Increasing age is associated with immune senescence and a decrease in relapses over time. A retrospective analysis of > 2000 patients with MS found that the annual relapse rate decreased by 17% every 5 years and that this effect was magnified with increasing age [215]. In addition, for most phase III clinical trials for DMTs, the maximum age at randomization was 55 years, yet 46% of adults with MS are over the age of 55 years [215]. Understandably, this had led to an important clinical question: at what age, if ever, should DMTs be discontinued?

Unfortunately, there are no clear guidelines on when to discontinue treatment for those with RRMS, and data regarding this question are limited overall. Studies exploring the risk of relapse and EDSS progression after discontinuation of DMTs have been limited by the inclusion of young (< 55 years old) participants, short interval follow-up, and few patients on HET [216, 217]. A few studies looked specifically at patients over the age of 50 years with inactive disease, including one study which found no associated risk of EDSS progression or risk of relapse with discontinuation of DMTs [218]. However, 35% of patients who initially discontinued therapy ultimately resumed DMTs. In the DiscoMS randomized controlled trial of patients over the age of 55 years with clinically inactive disease (defined as no relapses within 5 years), more participants who discontinued DMTs experienced a relapse or evidence of new inflammatory activity on brain imaging [219]. However, the difference was not statistically significant.

While for many this stage of life can be associated with the question of de-escalating therapy, for some it represents a period where DMT may be initiated for the first time after a new diagnosis of MS. Late onset MS (LOMS) is defined as the onset of MS after the age of 50 years [220]. LOMS is more likely to be characterized by a progressive course and is associated with a higher prevalence of motor disability [220]. Historically, there has been a lack of evidence regarding the efficacy of DMTs in LOMS; however, according to some studies, a majority of patients with LOMS are still started on DMTs, although at lower rates than those with adult-onset MS (74.7% versus 95.6%) [220, 221]. While in some cases this may include medium efficacy therapies, presumably due to a more established safety profile and lower risk of infections, in others, HET is used to target more progressive disease [221–223]. As many cases of LOMS have a progressive course, it is challenging to find an effect of DMT on disability progression, as it is generally in older adults [221, 224–228]. For those with LOMS who present with a relapsing–remitting course, treatment outcomes were similar between those with late-onset and adult-onset relapsing–remitting MS [229].

Preventative Care: Female-Specific Comorbid Conditions and Screening

Comprehensive care of female specific comorbidities is discussed in detail and summarized in Table 6.

Table 6.

Comprehensive sex-specific screening and preventative care recommendations for postmenopausal women

Condition	Screening recommendation
Breast cancer	Annual mammography starting at age 40 years
Osteoporosis	DXA scan in all postmenopausal women with MS, even if < 65 years
Cardiovascular disease	Routine serum screening for hyperlipidemia and diabetes Regular blood pressure monitoring Screening for sleep apnea in all patients with sleep disturbances
Gynecological health	Cervical cancer screening per immunocompromised guidelines which currently entails [247]:  Screening beginning 1 year after onset of sexual activity or at age 21 years  Co-screening (cytology, HPV testing)  Annual screening, which can be increased to every 3 years after 3 consecutive years of normal cotest results
General care	General age-specific guidelines for colon and skin cancer screening

DXA dual-energy X-ray absorptiometry, HPV human papilloma virus, MS multiple sclerosis

Breast Cancer

Breast cancer is the most common cancer affecting women in the USA, with one in eight women being diagnosed with breast cancer during their lifetime [230]. The median age of onset of breast cancer is 62 years. A recent case study found that outcomes related to breast cancer were similar among women with MS than in the general population [231]. Additional counseling considerations include concerns about the potential contribution of immunomodulatory DMTs to the risk of breast cancer, and the continuation of DMT during breast cancer treatment. Longitudinal safety data for rituximab, natalizumab, and ocrelizumab have reassuringly not shown an elevated cancer risk with use (despite earlier phase III trial data for ocrelizumabClick or tap here to enter text.) [229, 232, 233]. During cancer treatment, many MS DMTs can be continued [231]. If the decision is made to discontinue DMTs during chemotherapy, patients on fingolimod and natalizumab should be counseled about the increased risk of rebound activity after discontinuation. In addition, cyclophosphamide, used in many chemotherapy protocols, is associated with a reduction in MS-related immune activity [234–236]. For patients with MS who have an average risk of breast cancer, they should receive annual breast cancer screening with mammography beginning at age 40 years per the most recent ACOG guidelines [237, 238].

Cardiometabolic Health

Cardiovascular disease is the leading cause of death in women [239]. Menopause has been associated with a substantial increase in lipid levels, in particular total cholesterol and low-density lipoprotein [239]. The prevalence of insulin resistance and high blood pressure also increases after menopause [239], as does the incidence of obstructive sleep apnea [240]. In addition to its effects on sleep disturbances, untreated OSA has been associated with the development of cardiovascular disease [240]. After menopause, women with MS should be routinely screened for hyperlipidemia, hypertension, diabetes, and sleep apnea. In addition, counseling should be provided regarding physical activity, well-balanced diets, and tobacco cessation when relevant.

Bone Health

The risk of osteoporosis increases after menopause [205]. Women with MS may be at higher risk for the development of osteoporosis than the general population [185], and given MS-related balance and gait impairment, are at higher risk for falls, increasing the opportunity for fractures that arise with osteoporosis. The US Preventative Task Force (USPTF) recommends bone mineral density assessment with the use of a DXA bone density scan in women beginning at age 65 years, and earlier in postmenopausal women who are at increased risk for osteoporosis [241]. As a result, any postmenopausal woman with MS may be eligible for earlier screening.

Management of osteoporosis includes lifestyle modifications (calcium and vitamin D supplementation, smoking cessation, limiting alcohol use, and regular exercise) as well as pharmacologic treatments (bisphosphonates, parathyroid hormone, denosumab, and calcitonin) depending on bone mineral density [205]. As per above, HT is also associated with improvement in bone mineral density and reduced risk of fracture [185, 206]. In patients with MS who are diagnosed with osteoporosis, home safety evaluations and physical therapy for gait training should also be considered to reduce the risk of falls.

Gynecologic Health

There are emerging concerns about the risk of cervical atypia/dysplasia/cancer resulting from decreased immunosurveillance against HPV in women on DMTs [214, 242–244]. Furthermore, inflammatory and infectious vaginitis has also been reported [211], with inflammatory vaginitis specifically linked to B-cell depleting therapy [214]. Counseling women about these risks when starting DMTs and during routine clinical visits, encouraging HPV vaccination (now indicated until age 45 years) prior to DMT initiation, and recommending cervical cancer screens per immunocompromised guidelines, could all contribute to decreased gynecologic morbidity [214, 245].

Conclusions

The management of women with MS requires an understanding of the complex interplay between individualized needs, reproductive transitions, and female-specific physiology. Proactive management and anticipatory guidance could substantially improve MS disease control and quality of life, as well as optimize healthy aging.

Clinical guidelines for the care of women with MS are continuously evolving in light of accumulating evidence. As such, clinicians require periodic updates to support evidence-based care and to optimize the capacity for patients to participate in shared decision-making.

With the advent of novel DMTs, there has been a profound shift towards early initiation of HET. This shift carries important implications for family planning and pregnancy in reproductive age women, as safety data must continue to be generated and guidelines and recommendations must continue to evolve and be disseminated. However, sex differences in DMT utilization exist, with a recent study demonstrating that women are less likely to be started on DMTs than men, particularly HET [246]. As the use of HETs expands, additional data on their safety and efficacy in specific populations (POMS, postmenopausal patients, and LOMS) will be needed to optimize judicious treatment use and monitoring.

In addition to DMTs, the comprehensive care of women with MS also entails management of MS-related symptoms to optimize quality of life. Given the potential for symptomatic exacerbation peripartum, as well as during perimenopause, management of these symptoms may fall in part to neurologists, given concern from other clinicians that they represent worsening of the underlying disease. Furthermore, care of aging women with MS must be centered in an understanding of postmenopausal changes in general health, as well as potential effects of menopause on neurocognitive changes. Such perspectives will allow clinicians to provide comprehensive care to women with MS across their lifespan.

Funding

No specific funding was provided for the preparation of this manuscript.

Declarations

Conflict of Interest

Riley Bove has received research support from Alexion, Biogen, EMD Serono, Novartis, Roche/Genentech, Sanofi Genzyme, and TG Therapeutics. Riley Bove has served on advisory boards and/or steering committees for Alexion, Biogen, EMD Serono, Novartis, Roche/Genentech, Sanofi Genzyme, and TG Therapeutics. Kylie McConville has no conflicts of interest.

Ethics Approval

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Consent to Publish

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Availability of Data and Materials

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Code Availability

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Author’s Contributions

Kylie McConville—idea origination, literature review and analysis, manuscript drafting and editing. Riley Bove—idea origination, literature review and analysis, manuscript drafting and revision. Both authors have read and approved the final submitted manuscript and agree to be held accountable for the work.