However, MS patients take many disease- and symptom-modifying medications that can affect both fertility and a developing fetus. Patients of both genders who require second-line therapy with chemotherapeutic or immunosuppressant agents such as mitoxantrone, azathioprine, methotrexate, and cyclophosphamide may experience a decrease in fertility and should be counseled about the option of sperm and egg banking if pregnancy is desired following cessation of treatment. The disease-modifying therapies (DMTs) and common symptom medications used in MS are listed in Table 7.1 and Table 7.2 along with their pregnancy safety categories for reference.

Contraceptive issues

Given the potential risk of certain DMTs to the developing fetus, female MS patients may wish to take contraceptive precautions against pregnancy if it is not immediately desired. If pregnancy is immediately desired, it is recommended that patients stop their interferon or glatiramer acetate therapy at least one to two cycles prior to trying to become pregnant (Voskuhl & Giesser 2011) and at least two cycles for the oral therapy fingolimod given its half-life. Natalizumab should be discontinued 3 months prior to conception (Hellwig et al. 2011). Dimethyl fumarate has a short half life and its metabolite does not accumulate, so theoretically no wash out period should be necessary (Lu et al., 2014). Conservative patients may wish to have one normal menstrual cycle off of dimethyl fumarate prior to conception.

The teratogenic potential for terflunomide may be up to 2 years after cessation of administration. The minimum recommended wash out period is at least 8 months. Facilitated elimination may be accomplished with cholestyramine or activated charcoal (Lu et al., 2014).

There are no official guidelines as to the pros and cons of the use of OCPs or HRT in MS patients. Although estrogens may have a protective effect in MS as described earlier, there is no current evidence to suggest that estradiol, in the amounts contained in OCPs, is helpful in treating or preventing MS (Voskuhl & Giesser 2011). It is recommended that individual patients decide what contraceptive method is best for them in consultation with their doctors.

Congenital effects

To date, there is no evidence that babies born to mothers with MS experience congenital malformations or stillbirths at a higher rate than the general population (Argyriou & Makris 2008). A national pregnancy registry of patients with MS, diabetes, and epilepsy showed that MS patients displayed a higher incidence of intrauterine growth restriction and cesarean delivery than controls (Kelly et al. 2009) but that overall patients with MS tend to have healthy, full-term pregnancies.

The main MS-related risk to the developing fetus is the fact that children born to parents with MS have an increased risk of developing MS, roughly 20–50 times that of the general population, depending upon the study cited (Voskuhl & Giesser 2011). A Danish population-based registry study of 8205 MS patients since 1968 found that the lifetime risk of a daughter developing MS born to an MS-affected parent was 2.9%. For sons, the risk was 2.8%. This is compared to the general population risk in Denmark of developing MS of 0.5% for females and 0.3% for males (Nielsen et al. 2005). This data will vary based upon the location and ethnicity of the patients being studied naturally and may be difficult to extrapolate to patients who are not of Northern European descent.

Epidemiology

While pregnancy can be considered a protected state in MS, previously conducted population studies were unclear as to the long-term protective effects of pregnancy in women with MS. There is some evidence that women who have had children take longer to reach an EDSS of six than women who have not had children (Greer & McCombe 2011). But authors note that this may indicate that women who have greater amounts of disability, or perhaps more aggressive MS, may just choose not to get pregnant. Women with MS are more likely to never have children than the general population (Ponsonby et al. 2012). Other previous studies show that there is no effect of parity on disability progression outcome measures in MS (D’hooghe et al. 2010).

The Ausimmune study recently attempted to address this question by examining the age of onset of a first clinical demyelinating event (FCD). They found that per patient an increasing number of offspring was associated with a dose–response trend toward a later age of developing an FCD for women but not men. In fact, there was a 49% reduction in the risk of FCD for each birth. This trend persisted even after adjusting for sun index scores and vitamin D levels, smoking, body mass index, HLA-DR15 gene presence, and other potential risk factors for developing MS. Hence, the presumptive mechanism of this decreased MS risk is thought to be due to the pregnancies themselves (Ponsonby et al. 2012). This study is also important because it studied FCD, not when women were diagnosed with MS. Therefore, these patients were not choosing to be childless because of their diagnosis. Interestingly, the age of first birth for women in Australia has increased to 31.9 years in 2008 as compared to 23.2 years in 1961. During this same time period, the female-to-male ratio of MS has increased significantly, prompting the study authors to wonder if these environmental factors are related (Ponsonby et al. 2012).

Although the 9 months of pregnancy is a protected state for exacerbations in MS patients, as discussed earlier, the effect of multiple pregnancies on the course of the disease and progression in disability had been unclear until now. There is some evidence that pregnancy may increase the time until reaching SPMS, but evidence on pregnancy and its effect on disability progression (EDSS score) is mixed (Voskuhl & Giesser 2011). Longer-term and prospective studies are required to address these specific questions.

Clinical concerns

Women with MS who wish to become pregnant should not be discouraged from doing so as they were in years past. Any patient with a chronic or potentially disabling medical condition is labeled as a high-risk pregnancy. But it is now well known that MS patients experience a decrease in relapses during pregnancy and a potential rebound in relapses in the postpartum time frame. The Pregnancy and Multiple Sclerosis, or PRIMS, study addressed this question by prospectively following 227 pregnancies in women with MS. They found that the mean relapse rate for the women was 0.7 per year before pregnancy, 0.2 during the third trimester of pregnancy, and an uptick to 1.2 during the fourth trimester or postpartum period (Vukusic et al. 2004; Figure 7.1). Even with this increase in relapse activity postpartum, it is important to note that most patients followed did not incur a relapse during this 3-month time period (72% remained relapse-free). Also, keep in mind that only 2.2% of patients went on DMTs in the 6 months following delivery, meaning the majority of these women were medically unprotected against MS during the postpartum trimester. In this study, the predictors for women who would experience a relapse included women with more frequent relapses the year before and during pregnancy and women with higher levels of disability prepregnancy.