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.

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. 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. Assisted reproductive technology (ART) may increase relapse risk in women of reproductive potential, though prospective studies are needed to investigate possible confounding factors, including MS severity and the effect of location on ART protocols and DMT prescription patterns (Bove et al., 2020).

Pregnancy is characterized by a down-regulation of cellular immune responses and the presence of potentially neuroprotective hormones, both of which protect the developing fetus. The combined anti-inflammatory and neuroprotective effects of pregnancy appear to have a positive impact on MS as well (Voskuhl, R. & Giesser, B. Gender and reproductive issues. In Giesser (ed.) Primer on Multiple Sclerosis - 2nd ed., NY: Oxford University Press, 2016).

A study on the association between past pregnancy, gravidity and first clinical demyelinating event risk in women of reproductive potential indicated a robust, cumulative, and beneficial effect of pregnancy and childbirth, including a permanent additive effect from each birth (Ponsonby et al., 2012). No association was found between the number of offspring and the risk of a first demyelinating event in men of reproductive potential. A subsequent study of parity in reducing the risk of MS suggests that the effect is limited to pregnancies that have occurred within 5 years of onset of MS (Hedstrom et al., 2014).

Clinical and radiological outcomes may be negatively impacted by pregnancy (Houtchens et al., 2020) and abortion (Landi et al., 2018). In one retrospective cohort study of 123 pregnancies in 123 women of reproductive potential, there was a marked increase in postpartum inflammatory activity on MRI that correlated with relapses; however, previous research has shown no effect of postpartum relapses on long-term disability (Houtchens et al., 2020).
 
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).

None of the disease-modifying therapies (DMTs) are approved for use during pregnancy or breastfeeding. The reviews by Coyle et al. (2019), Vaughn et al. (2018), Bove et al. (2014) and Cree (2013) provide comprehensive information for clinicians who are counseling their patients about treatment options.

Women of reproductive potential are advised to stop their DMT for the appropriate period of time specific to that agent (Kaisey et al., 2018). Women and men of reproductive potential who do take or will take teriflunomide or cladribine should be counseled on the teratogenic effects of those medications. Refer to the prescribing information for teriflunomide and cladribine for specific guidance. The Food and Drug Administration (FDA) has retired the A, B, C, D and X pregnancy categories and replaced them with more useful information about a medication’s risk. The prescribing information for each DMT has been updated to reflect that change.
 
There are no data definitively linking interferon beta or glatiramer acetate to adverse fetal outcomes and some clinicians will allow use up until conception (Coyle, 2016). Rituximab has been studied in women of reproductive potential with highly active disease who wish to become pregnant. In a retrospective cohort (n=74) who had received rituximab before conception, holding rituximab during pregnancy was not associated with increased rebound relapse or disease activity (Smith et al., 2020). Rituximab did not increase risk of negative fetal outcomes, including in those who received rituximab infusion within 6 months of conception (n=50) and during the first trimester (n=9). Most babies in this study were breastfed (89%) or exclusively breastfed (35%) and no harm to baby was detected, including babies being breastfed when rituximab infusions were resumed.
 
When suspended within 6 months of conception, rituximab may exert longstanding, beneficial effects on disease activity during pregnancy and the postpartum period compared to suspended natalizumab and no treatment (Razaz et al., 2020). Recent studies reported that stopping natalizumab and/or fingolimod prior to pregnancy is associated with increased risk of relapse during pregnancy, but this observation may be confounded by the possibility that women of reproductive potential with more active disease would be more likely to use these particular medications (Alroughani, et al., 2018). Also stopping these agents has been reported to produce “rebound” disease activity (Das et al., 2018, Smith et al., 2020) which may be contributing to increased relapses seen during pregnancy after stopping natalizumab or fingolimod.

Rituximab, 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).
 
Mothers on other DMTs who wish to breastfeed should be encouraged to do so unless it is judged critical that they resume their DMT as soon as possible after delivery. Previous studies have shown the more active the disease during pregnancy and the year prior, the higher the risk of postpartum relapse (Coyle, 2016; Bove et al., 2014; Vukusic et al., 2004; Confavreux et al., 1998). In a recent study of 466 pregnancies over 8 years, 74% of pregnancies were not followed by relapse in the first postpartum year and there was no rebound effect (i.e., post pregnancy relapse rates where not higher than prepartum relapse rates) (Langer-Gould et al., 2020). High relapse activity prepartum was associated with postpartum relapses throughout the first year, but not within the first 6 months, and lower relapse risk was seen in mothers who breastfed exclusively (Langer-Gould et al., 2020). This study population is noted to have milder disease compared to university-based academic centers, which could contribute to the positive outcomes and complicate comparisons across studies (Houtchens et al., 2020).
                                                                             
The impact of a father’s DMT regimen on spermatogenesis or fetal development has received less study. Data from several population-based clinical and health administrative databases in British Columbia, Canada found no association between paternal MS, disease duration at conception and level of disability with birth outcomes (Lu E et al., 2014).

Many 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). 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; balance problems may worsen with weight gain.

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 be 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). IVIG is safe for use during pregnancy and may provide some benefit when administered postpartum in preventing relapses in patients judged to be at high risk for relapse. (Coyle, 2016; Bove et al., 2014; Ferrero et al., 2004; Achiron et al., 2004). Glucocorticoids are excreted in breast milk, which means that breastfeeding may need delayed for 2-4 hours after receiving glucocorticoid treatment for a relapse (Coyle et al., 2019).

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).

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).

Self-report studies suggest that women of reproductive potential commonly 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).

Menopause has been associated with worsening of MS symptoms (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

Reviewed by Barbara Giesser, MD, October, 2020.