Reproductive Health

Multiple sclerosis (MS) is commonly diagnosed in young adulthood, when individuals are in the process of making important lifestyle, career and family decisions. Routinely discussing family planning is important to determine if adjustments to disease modifying medications or other health or lifestyle modifications are needed. The following information can help inform conversations between MS patients and their healthcare providers.

Self-report studies suggest that women who are menstruating experience transient worsening of their neurologic symptoms during the premenstrual phase of their cycle (Voskuhl, R. & Giesser, B. Gender and reproductive issues. In Giesser (ed.) Primer on Multiple Sclerosis - 2nd ed., NY: Oxford University Press, 2016). Use of continuous oral contraceptives (i.e. stable dose for 3 months vs. for 3 weeks with cyclic contraceptives) could help stabilize menstrual fluctuations in  symptoms (Chen et al., 2020).

Decisions about contraception in women of reproductive potential with MS should be made on gynecologic rather than neurologic grounds, as all methods of contraception appear to be safe from a neurologic standpoint. Some oral contraceptives may interfere with the effectiveness of other drugs used for symptom management and vice versa. Long-acting reversible contraceptives (LARCs) are particularly effective as contraceptives and ovulatory cycles resume rapidly after removal. Women of reproductive potential with MS with decreased upper extremity dexterity may have difficulty using barrier methods of contraception (Voskuhl, R. & Giesser, B. Gender and reproductive issues. In Giesser (ed.) Primer on Multiple Sclerosis - 2nd ed., NY: Oxford University Press, 2016).

In general, MS does not impact fertility. After assisted reproductive technology (ART) cycles, some small historic studies suggested elevated relapse risk but, this has not shown to be the case in larger modern studies where women are more actively managed with DMTs (Bove et al., 2020) and (Graham et al., 2023).

During pregnancy

Pregnancy is characterized by an immunotolerant state designed to support the developing fetus. During pregnancy, these shifts seem to reduce the risk of relapses. (Voskuhl, R. & Giesser, B. Gender and reproductive issues. In Giesser (ed.) Primer on Multiple Sclerosis - 2nd ed., NY: Oxford University Press, 2016).

Postpartum

However, in the postpartum period, there can be a risk of elevated inflammatory activity, both clinical and radiological. Two retrospective studies showed that over half of all patients with postpartum MRIs showed new lesions (Houtchens et al., 2020; Anderson et al., 2021). These new lesions correlated with relapses and even occurred in asymptomatic patients. Risk of postpartum inflammatory activity is reduced with MS stability before conception Coyle, 2016; Bove et al., 2014; Vukusic et al., 2004; Confavreux et al., 1998)., exclusive breastfeeding (Langer-Gould et al., 2020) and with initiation of highly effective medications with low therapeutic lag.

Pregnancy Loss

Relapses can also be elevated after pregnancy loss and abortion (Kaplan et al., 2019) (Landi et al., 2018).  An investigation of 188 pregnancies ending with early termination (spontaneous and elective) found an increased rate of relapses and inflammatory lesions on MRI, with the effects being more pronounced in those with more active disease and more inflammatory lesions prior to conception (Landi et al., 2018). Appropriate counseling and follow up may be warranted for those who experience early pregnancy termination.

In general, MS does not impact miscarriage rates, congenital malformations or stillbirths. Several studies have found children born to women with MS have lower birth weights (Dahl et al., 2005; Kelly et al., 2009; Dahl et al., 2006; and Chen et al., 2009) while others found infant birthweight to be the same as the general population (Mueller et al., 2002; van der Kop et al., 2011).

Despite the fact that there are no DMTs approved by the US Food and Drug Administration (FDA) for use during pregnancy, there is evolving guidance in the literature on use of disease-modifying therapies (DMTs) during pregnancy or breastfeeding. The reviews by Coyle et al. (2019), Vaughn et al. (2018), Bove et al. (2014), Cree (2013), Krysko et al. (2023), and Bove and Houtchens (2022) offer evolving guidance for clinicians who are counseling their patients about treatment options.

Oftentimes, DMTs are not required by individuals living with MS who become pregnant. The decision whether to discontinue DMT depends on the safety of the product, risk of MS reactivation in the patient/MS stability and patient preferences. Typically, to ensure no effect of DMT at the time of conception, a DMT should be stopped 5 maximal half-lives before conception (Kaisey et al., 2018). The exception is teriflunomide which has known teratogenic effects, and specific prescribing information guidance including a pregnancy registry. If discontinued, natalizumab and S1P receptor modulators such as fingolimod, can be associated with severe rebound relapses before, during and after a pregnancy (Alroughani, et al., 2018; Das et al., 2018, Smith et al., 2020). In addition, dimethyl fumarate and alemtuzumab have been shown to have unclear but likely risks and, therefore, these medications should be avoided if pregnancy is desired (Langer-Gould, 2019).

While there is not enough human data available for the FDA to support the use of injectable DMTs leading up to or during pregnancy, observational studies support the relative safety of injectable DMTs (glatiramer acetate, interferon-beta) for use in pregnancy and some clinicians will allow use of these agents up until conception (Coyle, 2016). The FDA cautions that pregnancy should be avoided during treatment with B-cell depleting therapies and for 6 months after stopping therapy.

The use of B-cell–depleting therapies during pregnancy remains understudied and definitive safety data are lacking. B-cell depleting agents are large IgG1 monoclonal antibodies, which are minimally transferred across the placenta. During the first trimester, maternal transfer of immunoglobulin is negligible. Highest exposure occurs after week 32, during fetal growth, and exposure to these therapies at this time can lead to neonatal hematological abnormalities. B-cell–depleting therapies have long lasting effects and have the potential to reduce the risk of inflammatory activity during pregnancy despite treatment discontinuation prior to conception. Therefore, some clinicians will allow use of these agents up until conception.

Counseling on the risks of stopping a DMT (i.e. potential for disease activity) or continuing it during pregnancy (i.e. potential for fetal harm) should be personalized and include FDA guidance and real-world data. (Galati et al., 2022).

Relapse management during pregnancy

Relapses severe enough to warrant treatment can be safely managed with a short course of corticosteroids after the first trimester. Plasma exchange for severe relapses may also be safe during pregnancy, though data are limited (Coyle et al., 2019). Methylprednisolone is the preferred drug because it is metabolized before crossing the placenta (Coyle, 2016; Bove et al., 2014; Ferrero et al., 2004).

Some of the medications used to manage MS symptoms may cause fetal harm (e.g., antidepressants, anti-spasticity agents, bladder control agents), and if used, should be implemented for the shortest period of time at the minimal effective dose (Coyle et al., 2019; Iyer and Dobson, 2023). Other management strategies (e.g., rehabilitative) should be considered (Coyle, 2016; Bove et al., 2014).

MS-related fatigue may augment the normal fatigue of pregnancy; bladder and bowel symptoms may increase, including a higher risk of urinary tract infections and increased constipation; and, balance problems may worsen with weight gain.

Anesthesia

All forms of anesthesia are considered safe for women of reproductive potential with MS; anesthesia management does not need to be altered. Epidural anesthesia does not affect the likelihood of post-partum relapse (Vukusic & Confavreux, 2006; Makris et al, 2014; Bornemann-Cimenti et al., 2017). This information should be discussed with the anesthesia team during the early weeks of pregnancy.

Breastfeeding

For patients intending to breastfeed for both general benefits to mother and infant and for specific effects on relapse risk reduction, support should be provided including early referral to lactation experts if needed. In individuals with MS, breastfeeding is associated with 37% lower odds of postpartum relapse compared with those who do not breastfeed. Exclusive breastfeeding has shown even greater benefit with a 48% reduction in odds (Krysko et al. 2020). For individuals with higher relapse risk who intend to breastfeed, injectables or monoclonal antibodies could be considered. Monoclonal antibodies, interferon beta and glatiramer acetate are considered compatible with breastfeeding by some clinicians (Langer-Gould et al., 2020). In a prospective cohort study, first year infant outcomes were not negatively impacted by maternal exposure to interferon beta or glatiramer acetate during breastfeeding, though investigators were unable to rule out rare adverse events due to small sample size (Ciplea et al., 2020). Gastroenterologists and rheumatologists consider monoclonal antibodies to be compatible with breastfeeding (Ciplea et al., 2020) and there have been recent efforts to improve safety data on monoclonal antibody transfer to breastmilk in mothers with MS (Krysko et al., 2020). A small prospective cohort study of 9 mothers with MS demonstrated limited transfer of rituximab to breastmilk at levels that would likely degrade in the newborn gastrointestinal tract, though minimal newborn exposure cannot be excluded (Krysko et al., 2020).

Comprehensive care postpartum

Compared to the general population, individuals with MS are at significantly-increased risk for depression, and women of reproductive potential may be at greater risk of depression in the postpartum period. Patients and their healthcare providers need to be alert to mood changes during pregnancy and the postpartum period, since these can affect self-care and care of the baby. Antidepressant medications should be used with caution during pregnancy (Patil et al., 2011).
 
The comprehensive MS care team should carefully attend to and support a holistic, whole-person approach to the postpartum period, including mood and fatigue management, physical therapy, pelvic floor therapy, MRIs and treatment resumption. The decisions associated with the above areas of consideration are often neglected and pose competing needs for patients with newborns.

Relapse management

Methylprednisolone transfer into breast milk is very low and, therefore, can be used even with breastfeeding 1 hour after infusion. To limit infant exposure still further, individuals can wait 2-4 hours after infusion before resuming breastfeeding (Boz et al. 2018).

Menopause has been associated with worsening of MS symptoms, and in some cases vasomotor symptoms such as hot flashes can worsen patient function and quality of life (Bove et al., 2014). Many symptoms of MS and menopause may overlap, e.g. fatigue, bladder dysfunction, cognitive difficulties, depression and sleep disorders, and should be addressed accordingly. There are no known neurologic contraindications for women of reproductive potential with MS to use HRT.

• Current Topics- Reproductive Care of Patients with MS- webinar