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Reproductive Issues

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Overview

Multiple sclerosis (MS) is diagnosed most commonly in young adulthood, when individuals are in the process of making important lifestyle, career and family decisions. The following information can help inform conversations between MS patients and their healthcare providers.

MS and contraception

Decisions about contraception in females with MS should be made on gynecologic rather than neurologic grounds; all methods of contraception appear to be safe for females with MS from a neurologic standpoint. Some oral contraceptives may interfere with the effectiveness of other drugs used for symptom management and vice versa. Females 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).

MS and conception

In general, MS does not impact fertility. A few very small studies of females who have received some types of fertility drugs have reported increases in exacerbations and inflammation. More information is needed in this area (Kaisey et al., 2018).

The impact of pregnancy on MS

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 females 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 males. 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 abortion in females with relapsing remitting MS (Landi et al., 2018). An investigation of 188 pregnancies 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. Appropriate counseling and follow up may be warranted for females who experience early pregnancy termination.

Impact of MS on pregnancy

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).

Disease management

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.

Females are advised to stop their DMT for the appropriate period of time specific to that agent (Kaisey et al., 2018). Females of child-bearing potential, females who wish to become pregnant or males who wish to father a child 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.
 
Interferon beta and glatiramer acetate have the largest amount of data on pregnancy exposure and neither have been shown to increase risk of negative pregnancy effects in humans (Coyle et al., 2019). Rituximab has been studied in females with highly active disease who wish to become pregnant. In a retrospective cohort of 74 females 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 females 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.
 
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 females 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.

Females with MS 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 (Langer-Gould et al., 2020). Previous studies have shown the more active a woman’s disease is during pregnancy and the year prior, the higher her risk of postpartum relapse (Coyle, 2016Bove et al., 2014Vukusic et al., 2004Confavreux et al., 1998). Recent data, however, suggest no increase in relapses in the postpartum year and breastfeeding exclusively in the first 6 months was protective from relapse even in those with sub-optimally controlled disease before pregnancy (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).

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).

Symptom and relapse management

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, 2016Bove 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 in pregnant females, though data are limited (Coyle et al., 2019). Methylprednisolone is the preferred drug because it is metabolized before crossing the placenta (Coyle, 2016Bove et al., 2014Ferrero 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, 2016Bove et al., 2014Ferrero et al., 2004Achiron 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).

Additional delivery and postpartum considerations

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

Compared to the general population, females with MS are at significantly-increased risk for depression, which means they may also be at greater risk of depression in the post-partum 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).

Menstrual cycle

Self-report studies suggest that females 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

Menopause has been associated 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 females with MS to use HRT.

Additional resource



Reviewed by Barbara Giesser, MD, June 2020.
 

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