Practical Considerations for Family Planning in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic immune-mediated and neurodegenerative disorder that is most often diagnosed in women during their reproductive years.¹ The diagnosis, management, and overall approach to MS care have evolved over time to emphasize evidence-based, comprehensive, patient-centered care. This progress is partially attributable to recent advances in MS disease-modifying therapies (DMTs), which have substantially reduced the risk of relapse and, to a lesser extent, disability.

Similarly, pregnancy rates among women with MS have shifted over time. Over the past 10 years, pregnancy rates in individuals with MS have increased steadily, with recent estimates of up to one-third of women of reproductive age becoming pregnant after disease onset.² Recent studies indicate that most women with stable MS in the prepartum period can navigate the peripartum and postpartum periods without incurring a significant increased risk of postpartum relapse.³ Despite the growing number of pregnancies in women with MS and numerous advances in the field, there is a paucity of robust scientific data on disease management during pregnancy and in the postpartum period.

Family planning should be an integral part of comprehensive patient-centered MS care. We discuss some practical considerations around the prepartum, peripartum, and postpartum periods in individuals with MS.

Contraception

Every woman of childbearing age should be asked about family-building plans at each visit. This question must be open-ended to allow free discussion between the individual and the clinician as opposed to simply asking about plans to get pregnant. Family building includes not only pregnancy but also surrogacy, adoption, and other family building methods and is inclusive of same-sex couples, single individuals, and individuals with fertility issues as well as other people desiring to build their family. The Figure presents an algorithm to assist clinicians with conversing with their patients about family building.

The rate of unintended pregnancies in the US population in 2019 was around 36%.⁴ Because of the potential risks of unintended pregnancies in the MS population, ranging from risks of rebound disease activity with abrupt cessation to teratogenicity, every woman of childbearing age must have effective contraception (except in situations where pregnancy is not possible, such as same-sex relationship, hysterectomy, or partner with a vasectomy) if there are no plans for pregnancy in the next year. Long-acting reversible contraception is the ideal choice, because of the reduced risk of user error. Some symptomatic medications prescribed in those with MS (eg, modafinil used to treat fatigue and sleepiness) may lower the efficacy of oral contraceptives.

Fertility and Fertility Techniques

It has long been thought that MS has no effect on fertility. However, data from more recent large administrative claims database studies have shown that a greater proportion of women with MS have a diagnosis of infertility compared with those without MS (8.5% vs 8.1%; P=.0006). These differences were most notable in people aged 18 to 34 and older than 42 years.⁵ Infertility traditionally is diagnosed after more than 12 months of unsuccessful conception attempts in women younger than 35 and more than 6 months of unsuccessful conception attempts in those older than 35. However, most individuals with MS, because of the delicate balance of disease control as well as time off DMTs, should be referred to a fertility specialist for additional workup after 6 months of unsuccessful conception attempts.

A recent study reported no increase in relapses after a variety of fertility treatments, including in vitro fertilization. Notably, just over 40% of these patients were on DMTs.⁶ If individuals require multiple cycles of fertility treatments, it is beneficial to keep them on DMTs, as long as there are no detrimental oocyte effects. This helps minimize time off DMTs and subsequent risk of relapse.

Pregnancy Planning

Before pregnancy, each woman of childbearing age should have a comprehensive discussion with her practitioner and obstetrician about MS and the use of DMTs in the peripartum and postpartum periods. Obstetrician referral before conception is ideal to allow for the evaluation of symptomatic medication safety during pregnancy and open a line of communication. Disease stability is preferred for 6 to 12 months before conception but not always practical, particularly given the effect of age on fertility and potential family-building plans. Vitamin supplementation (eg, prenatal vitamins, folic acid) does not differ for women with MS.

Pregnancy

Relapses During Pregnancy

Relapses during pregnancy are less common because of hormonal and immunologic changes during pregnancy: a state called immunotolerance.⁷ Results from PRIMS (Pregnancy in Multiple Sclerosis Study) found a drop in annualized relapse rates from 0.7 prepartum to 0.2 in the third trimester—a 70% decrease.^7,8 These findings have since been replicated across numerous modern cohort studies, including populations taking a variety of DMTs.⁹

Despite the lower rates of relapse during pregnancy, relapses can occur. If a relapse does occur, the treating neurologist and patient must determine its severity and decide whether steroid treatment is necessary. Preferred steroids include methylprednisolone, prednisone, and prednisolone rather than dexamethasone, as dexamethasone can cross the placenta.^8,10 The most common treatment is 1000 mg intravenous methylprednisolone for 3 to 5 days.⁸ Historically, the primary concern with steroid use in pregnancy was cleft palate and cleft lip, but this has not been confirmed in more recent studies.¹⁰ Consultation with the individual’s obstetrician can help stratify individual risks further. In theory, the use of steroids after the 10th week of gestation may reduce risks, because this is after the period of organogenesis.^8,10 Repeat courses of high-dose steroids should be avoided, if possible, given potential accumulated risks of preeclampsia and other hypertensive disorders, intrauterine growth restriction, and low birthweight.¹⁰

Plasmapheresis can be used safely during pregnancy, but attention should be paid to minimize rapid fluid shifts.

MRI Use During Pregnancy

Preconception MRI scans should be obtained as well as surveillance MRI scans 4 to 6 weeks postpartum.¹¹ Imaging is not necessary during pregnancy. If there are new symptoms of clinical uncertainty, a noncontrast MRI scan can be obtained in consultation with radiology. MRI with contrast should be avoided unless absolutely necessary, as there have been reports of pregnancy risks with gadolinium (eg, recurrent late decelerations, prolonged fetal bradycardia, preterm labor), as well as fetal risk of rheumatologic and dermatologic conditions, as well as stillbirth.^8,9 If preconception MRI scanning was performed, the presence or absence of new T2-based hyperintensities may help identify new lesions without the risks associated with gadolinium.

Pregnancy Outcomes and Obstetric Management

In general, women with MS do not have higher-risk pregnancies and having MS should not strongly influence the mode of delivery or anesthesia choice.^7,8 Systematic reviews and meta-analyses have shown no increased risk for ectopic pregnancy, placental abnormalities, spontaneous abortions, stillbirth, premature birth, or congenital malformations in women with MS compared with women without MS.^7,8 More severe disease and poor access to care have been associated with higher rates of maternal and fetal complications.⁸

There are conflicting reports about higher rates of cesarean deliveries in women with MS vs healthy controls.^6,7 It has been hypothesized that higher rates of cesarean deliveries may be secondary to neurologic functioning, including severe lower extremity weakness, spasticity, and pelvic weakness; or, alternatively, patient or physician preference.¹¹ Following the guidance of the obstetrician during delivery is recommended.

Conflicting data exist about infant birthweights. One retrospective study showed no significant differences; other studies have reported that women with MS may be more likely to have babies that are small for gestational age.⁸ No long-term adverse pediatric outcomes have been reported in children born to mothers with MS.

Regarding anesthesia choice, spinal, epidural, or spinal-epidural anesthesia have all been shown to be safe in women with MS.^6,10

DMT Use in Pregnancy Planning and During Pregnancy

The majority of DMTs for MS are labeled Food and Drug Administration (FDA) pregnancy category C, except for glatiramer acetate (category B), cladribine (Mavenclad; Merck, Darmstadt, Germany) (category D), and teriflunomide (Aubagio; Sanofi, Bridgewater, NJ) (category X). Some DMTs do not have an assigned FDA pregnancy category because this system is no longer used, with focus shifting toward discussing specific risks and benefits of DMTs with the individual’s health care provider.

Most DMTs should be stopped before conception because of potential risk of passage through the placenta to the fetus, although some DMTs are safe to continue during pregnancy if absolutely necessary.^6-9 The general question each neurologist should ask is whether the individual requires treatment throughout pregnancy.

Prescribing information for specific DMTs may overestimate the period of washout needed before attempting conception, unnecessarily increasing the risk for prepregnancy relapse. Considering the pharmacokinetics of different DMTs can assist in determining the recommended washout periods for clinical practice. Special consideration and planning should be given to drugs that can have rebound disease activity when discontinued (such as natalizumab (Tysabri; Biogen, Cambridge, MA) and sphingosine-1-phosphate receptor modulators), and bridging therapy may be required. Specific information regarding individual DMT use and recommendations for pregnancy can be found in Table 1.

Postpartum Period

Outcomes

Whereas pregnancy has been noted to be protective against relapses in MS, an increased risk for relapses exists in the postpartum period. Results from PRIMS showed a relapse rate increase of 70% in the first 3 months postpartum compared with prepartum risk before returning to prepregnancy levels.¹² Postpartum increases in disability accrual were driven by increased relapse rates in an Italian multicenter cohort study.⁷ The pathophysiology underlying postpartum relapses is poorly understood, but some studies have shown a decline in CD4+ cells, interferon-γ–producing T cells, and CD56 natural killer cells correlating with postpartum relapses.⁷

In PRIMS, a minority of women had an elevated relapse rate. Factors related to increased rate of postpartum relapses included greater prepartum relapse rates, Expanded Disability Status Scale score >2.0, and use of specific DMT (fingolimod and natalizumab) that are associated with high rates of rebound relapses.¹² Because the highest rate of relapses occurs early in the postpartum period, it is essential to begin discussions of timing of resumption of treatment before delivery. Most experts recommend a neurology visit in the third trimester to discuss breastfeeding, timing of resumption of therapy, and surveillance imaging 4 to 6 weeks postpartum (if delaying restarting DMT therapy) or 2 to 3 months after restarting DMT therapy to establish a new baseline.

Increased disease activity and relapse rates can also be seen in the setting of pregnancy loss, and early counseling of risk with individuals considering family planning should be provided.⁷

Postpartum Symptom Management

Differentiating symptoms of postpartum relapses vs pseudorelapses can be challenging. Fatigue, sleep disturbance, cognitive changes, pain, numbness, and bowel or bladder changes can be symptoms of MS or can be secondary to delivery of and caring for a newborn. Fatigue is a common symptom in MS that can worsen in the postpartum period in the setting of hormone changes and the need for frequent feeding and care of an infant. Fatigue, sleep disruption, and cognitive changes are common in the postpartum period. Early discussion of symptoms and strategies for optimizing support available to allow for periods of rest and examination for comorbid causes of fatigue (including checking vitamin D and thyroid-stimulating hormone levels) should be done.

Numbness is another concern that may be confounded by delivery type (cesarean versus vaginal) and whether an epidural was used. Evaluating the timing of onset of numbness, the duration, and the distribution can help to differentiate MS relapse. Bowel or bladder changes are common after childbirth, and differentiation between neurogenic and obstetric causes can be challenging. Preemptive referral to pelvic floor physical therapy can help decrease the risk of severe symptoms in the postpartum period.

Peripartum depression and anxiety are a substantial concern, affecting up to 26% of women with MS in the peripartum period in some studies, higher than in age-matched peers without MS.¹³ Premorbid mood disruption is the greatest risk factor for postpartum depression. The elevated risk of mood disorders in individuals with MS likely increases the risk of peripartum depression, but studies are underrepresented in the MS literature. Formal screening with the Edinburgh Postnatal Depression Scale is recommended; if a score greater than the 13-point cutoff is determined, immediate referral to mental health support is recommended.

Workup and Treatment of Postpartum Relapses

If there is concern for new neurologic symptoms lasting longer than 24 hours that are concerning for a relapse, a workup should be done. MRI scans are safe and well-tolerated in the postpartum period. Gadolinium is detected in miniscule amounts in breastmilk, and recommendations do not suggest a pause in breastfeeding after gadolinium use.¹⁴ If a relapse is confirmed on MRI and is acute on contrast enhancement, treatment with steroids should be initiated. Table 2 delineates the use of steroids and DMT with breastfeeding.

Breastfeeding

Breastfeeding is likely to have a small protective effect in terms of relapse risk. A recent meta-analysis showed 37% lower odds of relapses in women who did vs did not breastfeed, and exclusive breastfeeding showed an up to 48% decrease vs 32% in nonexclusive breastfeeding.¹⁵ There are no definitive guidelines on restarting DMTs after childbirth, which should be decided based on an individualized discussion of risks vs benefits. If the relapse risk is very high or breastfeeding not planned, resumption of DMT is recommended. Most women who had well-controlled MS before pregnancy should be encouraged to breastfeed; some therapies can be restarted safely during breastfeeding (Table 2).¹⁶

Conclusion

A proactive approach to discussion regarding family planning is important for women of childbearing age with MS, and this topic should be addressed at each visit in an open-ended manner. MS alone does not substantially affect pregnancy risk, delivery mode, or anesthesia choices. Ceasing most DMTs before conception is usually advised, acknowledging the relative quiescence of MS during pregnancy, to minimize risk to the fetus. Understanding the pharmacokinetics of different DMTs aids in determining appropriate washout periods. Special considerations should be applied for medications that can have rebound disease activity when discontinued (eg, natalizumab, sphingosine-1-phosphate receptor modulators). Given the postpartum relapse peak, initiating treatment discussions before delivery is essential. If the woman with well-controlled MS wants to breastfeed, this should be encouraged; certain therapies can be reintroduced safely during breastfeeding. Further research is warranted to establish more specific guidelines regarding pregnancy in the setting of MS.