Multiple sclerosis: Pregnancy and postpartum care

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system that is a leading cause of neurologic disability. MS proportionally affects women more than men by a ratio of approximately 2:1 to 3:1, and the mean age of onset of MS is approximately 30 years. Thus, the symptoms of MS commonly present in women of reproductive age, who need special considerations for pregnancy. (See "Pathogenesis and epidemiology of multiple sclerosis".)

This topic will review the care of patients with MS during pregnancy and the postpartum period. Pregnancy planning is reviewed separately. (See "Multiple sclerosis: Pregnancy planning".)

Other aspects of MS are discussed elsewhere:

Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis
Clinical presentation, course, and prognosis of multiple sclerosis in adults
Evaluation and diagnosis of multiple sclerosis in adults
Manifestations of multiple sclerosis in adults
Symptom management of multiple sclerosis in adults
Treatment of acute exacerbations of multiple sclerosis in adults
Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults
Indications for switching or stopping disease-modifying therapy for multiple sclerosis
Treatment of secondary progressive multiple sclerosis in adults
Treatment of primary progressive multiple sclerosis in adults
Overview of disease-modifying therapies for multiple sclerosis

MANAGEMENT IN PREGNANCY — There are multiple aspects of management to be considered during pregnancy:

●Use of preventive disease-modifying therapies (DMTs)

●Monitoring

●Treatment of breakthrough acute attacks/relapses

●Chronic MS symptom management

●Mental and physical wellness measures

Effect of pregnancy on MS disease course — Pregnancy does not have a deleterious impact on MS course. Rather, pregnancy is associated with a decrease in MS relapse rate, with the third trimester of pregnancy having the same potency of effect as most high-efficacy MS immune therapies. These issues are discussed in detail separately. (See "Multiple sclerosis: Pregnancy planning".)

Use of DMTs — As noted above, the MS relapse rate is generally decreased with pregnancy. For many women with mild to moderate disease, DMTs can be discontinued altogether with careful preconception planning. DMTs that are known or potential teratogens should be discontinued before pregnancy, if possible. However, DMT discontinuation may lead to an increased intrapartum and postpartum relapse rate, particularly for natalizumab and fingolimod. Decisions should be guided by age, severity and frequency of previous relapses, magnetic resonance imaging (MRI) activity, disease progression, disability, and risk of treatment discontinuation. Relapse prevention should be the primary goal, with careful planning for what treatments might be required if relapse does occur. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)

Monitoring — Patients should be monitored during pregnancy by clinical follow-up, with careful attention to possible manifestations of MS disease activity including acute attacks (relapses), development of new MS lesions (particularly more than one) on brain or spine MRI, and possibly the onset or progression of sustained disability.

MRI in pregnancy

●Use without contrast – If MS reactivation is suspected during pregnancy and the findings could affect treatment course, then 1.5 Tesla low-field strength MRI without gadolinium contrast should be performed. Consensus recommendations published in 2021 from the Magnetic Resonance Imaging in Multiple Sclerosis, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative (MAGNIMS-CMSC-NAIMS) state that the use of MRI is not contraindicated during pregnancy, but its use should be decided on a case-by-case basis for clinical presentations that suggest MS disease activity or comorbid conditions [1].

●Concerns with gadolinium – The 2021 MAGNIMS-CMSC-NAIMS guidelines consider gadolinium to be strictly contraindicated in pregnancy, despite the absence of convincing evidence of clinical harm [1]. While inadvertent use during pregnancy has not been associated with adverse effects, gadolinium exposure in any trimester may have risks to the fetus that can continue into early childhood [2]. In the absence of gadolinium contrast, new or enlarged T2 lesions on MRI are used as the radiologic marker of increased MS disease activity.

The 2017 guidelines from the American College of Obstetricians and Gynecologists state that the use of gadolinium contrast should be limited in pregnancy but may be considered only if it significantly improves diagnostic performance and is expected to improve fetal or maternal outcome [3]. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Use of gadolinium'.)

Lumbar puncture — Although seldom necessary, lumbar puncture can be performed safely in pregnancy if needed to exclude an infectious or inflammatory condition other than MS (eg, to look for JC virus in a patient who had been receiving a high-efficacy DMT such as natalizumab) or if needed for evaluation of an undiagnosed patient with symptoms suggestive of MS during pregnancy. Diagnostic testing to distinguish MS from other autoimmune encephalopathies should not be delayed due to pregnancy, especially if management may be affected.

Treatment of acute relapse — During pregnancy, it is reasonable to treat MS relapse (also known as MS exacerbation or MS attack) if associated with functionally disabling symptoms in the second or third trimester [4].

The mainstay of MS relapse treatment is intravenous (IV) methylprednisolone. As with all medications used in pregnancy, glucocorticoid use should be guided by patient education and shared decision-making. Treatment of relapse with glucocorticoids during pregnancy needs to account for the trimester of pregnancy.

●Glucocorticoids in the second and third trimester – Short-term, high-dose IV glucocorticoids are first-line treatment for MS relapse, typically given as 1 gram of IV methylprednisolone daily for three to five days. Methylprednisolone, prednisone, and prednisolone are inactivated by placental 11-beta-hydroxysteroid dehydrogenase and do not enter the fetal circulation. Therefore, they are preferred in pregnancy [4,5]. By contrast, dexamethasone and betamethasone are not preferred, given minimal metabolism at the placental interface resulting in increased amounts directed to the fetus. Ideally, oral glucocorticoids should be avoided in pregnancy due to high bioavailability to the fetus. However, this is not always feasible, since outpatient access to IV methylprednisolone may be limited in some settings. In such cases, the patient can be treated with the lowest therapeutic dose of oral methylprednisolone sufficient to manage the relapse symptoms, along with appropriate counseling on the risks of oral glucocorticoids. These risks include preeclampsia, pregnancy-induced hypertension, weight gain, hyperglycemia, gestational diabetes, gastrointestinal ulcers, and premature rupture of membranes. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

●Glucocorticoids in the first trimester – Glucocorticoid use in the first trimester is controversial, given evidence in older studies of an increased risk of craniofacial abnormalities (such as cleft lip and palate) and low birth weight [5-8]. However, subsequent large studies have found no association of congenital abnormalities or low birth weight with early use of glucocorticoids [9-11]. Given the controversy, some experts avoid glucocorticoid use in the first trimester, while other experts will treat relapse in the first trimester with IV methylprednisolone or prednisolone in a shared decision-making process with patients who are counseled about the possible small risk of craniofacial abnormalities and intrauterine growth restriction [5].

●Plasma exchange – There are few data for treating refractory MS relapses in pregnancy. There is anecdotal evidence supporting therapeutic plasma exchange (PLEX) as a possible choice for relapses refractory to glucocorticoid treatment [12-14]. Limited clinical trial and observational data in nonpregnant patients also suggest that PLEX is beneficial for MS relapse. The treatment of refractory MS relapse with PLEX in the general population is reviewed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Treatment of refractory relapse'.)

Note that patients with MS who are treated with natalizumab are at risk for developing an immune reconstitution inflammatory syndrome (IRIS) after withdrawal of natalizumab and restoration of immune response. This may occur in patients who develop progressive multifocal leukoencephalopathy (PML) as a complication of natalizumab treatment, but discontinuation of natalizumab can be associated with a severe rebound of MS disease activity, sometimes leading to a severe reaction similar to IRIS in the absence of PML [15]. There is some concern that PLEX may accelerate IRIS in this setting [16,17]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Inflammatory PML (PML-IRIS)' and "Overview of disease-modifying therapies for multiple sclerosis".)

Symptom management — As relapses naturally decrease in pregnancy, often more challenging is the management of chronic MS symptoms in pregnancy. Bladder and fatigue symptoms may worsen with pregnancy, and some symptoms from medications may have certain contraindications in different trimesters of pregnancy. Management of depression and pain may also be challenging. (See "Manifestations of multiple sclerosis in adults" and "Symptom management of multiple sclerosis in adults".)

DELIVERY — The route of delivery for pregnant patients with MS is similar to delivery for pregnant patients in the general population, unless significant disability is present. Duration of hospital stay, rates of assisted vaginal delivery, and cesarean deliveries were not significantly different in women with MS than in women without MS [18,19]. Other studies indicate that assisted vaginal delivery and cesarean section rates are higher in patients with more severe disability, but these are subject to bias of the obstetrician's perception [19].

The choice of anesthesia should be based upon obstetric concerns [20,21]. Epidural and single-shot spinal anesthesia techniques can be utilized in patients with MS. There is no evidence of harm with epidural anesthesia in patients with MS. Rates of epidural anesthesia are lower in patients with MS, but several studies show regional anesthesia use does not correlate with rate of postpartum relapse or disability progression [22-24]. (See "Obstetric and nonobstetric anesthesia for patients with neurologic disorders", section on 'Multiple sclerosis'.)

POSTPARTUM CARE — Postpartum patients are encouraged to have family and caregiver support to decrease stress and sleep deprivation, particularly those with active neurologic symptoms. They should continue their postpartum care with a maternal-fetal medicine specialist and neurologist to be attuned to potential MS flare, worsening depression, or worsening of other chronic MS symptoms.

Relapse risk — The protective effect of pregnancy against relapse is lost in the postpartum period, and 20 to 30 percent of women may experience a relapse in this period. This risk is reviewed in detail separately. (See "Multiple sclerosis: Pregnancy planning", section on 'MS activity in pregnancy and postpartum'.)

Exclusive breastfeeding (see 'Breastfeeding and MS' below) may reduce this risk, but it is important to make a careful postpartum management plan with women in the third trimester in anticipation of the increased relapse risk.

Clinical evaluation — As already mentioned, the rate of MS relapses may increase in the first one to six months postpartum. Symptoms and need for neuroimaging should be addressed in a visit four to six weeks postdelivery [4]. If a patient has not already been counseled about the increased risk of relapse (and potential signs and symptoms) during the postpartum period or is uncertain, it is reasonable to follow up within one week of delivery.

The postpartum evaluation should cover the major manifestations of MS, including cognition, weakness, fatigue, gait and balance, bladder and bowel symptoms, pain, and social supports [4]. Patients with MS have an increased risk of mood disorders and should be screened for the presence of postpartum depression. (See "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis".)

MRI postpartum — Surveillance MRI to establish a new baseline is recommended within the first two to three months postpartum, particularly for women who have not yet resumed disease-modifying therapy (DMT), to look for evidence of silent MS disease activity [1,4]. While there is no restriction for the use of MRI postpartum, consensus recommendations state that gadolinium should be used during lactation only if essential for patient management, despite lack of evidence associating gadolinium exposure with neonatal harm [1]. Gadolinium administration does not require a washout period during lactation, as less than 1 percent is excreted in breast milk and less than 1 percent is absorbed from the neonatal gut [25]. Therefore, breastfeeding should not be interrupted with gadolinium administration [3]. If the patient prefers to completely avoid exposing the infant to gadolinium, the patient should "pump and dump" (ie, discard) breast milk for 24 hours following gadolinium infusion.

Some experts obtain an MRI also when the infant starts taking some solid food, as they are not as reliant on calories from breast milk and may tolerate 24 hours of formula better than the solely breastfed infant.

Postpartum relapse treatment — Glucocorticoids are first-line treatment for postpartum relapses. Methylprednisolone (typically 1 gram by intravenous [IV] infusion daily for three to five days) is preferred since it has very low transfer to breastmilk [26,27].

Limited retrospective data suggest that pulsed IV glucocorticoid treatment reduces the postpartum relapse rate, but high-quality data are lacking [28,29]. Studies have shown no consistent benefit of intravenous immunoglobulin (IVIG) for relapse prevention in the postpartum period [30-32].

BREASTFEEDING AND MS

Most women with MS can successfully breastfeed — Since breastfeeding is known to provide beneficial health effects for the newborn and mother, women with MS should be encouraged and supported to breastfeed. Exclusive breastfeeding has been associated with a reduction in postpartum MS relapse rates (see 'Breastfeeding and MS relapse rate' below). Medications must be accounted for, such as glucocorticoid use and disease-modifying therapies (DMTs).

Breastfeeding and DMTs — For patients who choose to breastfeed, one option is to defer DMT while maintaining breastfeeding, followed by a rapid breastfeeding wean and resumption of a high-efficacy DMT [4]. Alternatively, it is reasonable to continue breastfeeding while using a DMT compatible with lactation (eg, glatiramer acetate, interferon [IFN]-beta formulation, or monoclonal antibody such as ocrelizumab or rituximab), with counseling to the patient about what is known and not known about DMT use in breastfeeding.

Many women choose to forgo DMTs while breastfeeding, as the effect of most DMTs on neonatal development is uncertain. Resumption of DMTs postpartum has to be measured against DMT excretion in breast milk and effect on the neonate (table 1), so this requires a shared decision-making model of care [33]. (See 'Restarting DMT' below.)

The use of IFN-beta or glatiramer acetate is probably safe during breastfeeding [34]. IFN-beta is secreted at minimal levels in breast milk, as the levels are below the level of detection, and no side effects have been observed in breastfed infants [35]. It is unknown if glatiramer acetate is secreted in breast milk, but no adverse effects have been reported in breastfed infants [34]. Although data are limited, the B-cell depleting monoclonal antibody DMTs are probably compatible with breastfeeding (table 1), while DMTs best avoided during breastfeeding (table 1) include the fumarates (eg, dimethyl fumarate), mitoxantrone, sphingosine 1-phosphate receptor modulators (fingolimod, siponimod, ozanimod, and ponesimod), teriflunomide, alemtuzumab, and cladribine [4,36]. Alemtuzumab has been detected in the offspring of lactating mice, but data for human breast milk are lacking [37,38].

Breastfeeding and glucocorticoids — Glucocorticoids are minimally excreted in breast milk. Patients on doses as high as 80 mg daily were seen to have less than a 10 percent increase in the neonate's overall endogenous steroid levels. If patient preference is to completely avoid glucocorticoid effect on the neonate, this can be accomplished by "pumping and dumping" for 24 to 48 hours after glucocorticoid infusion [26,39].

Breastfeeding and MS relapse rate — Several reports have found that exclusive breastfeeding is associated with a reduction in postpartum MS relapse rates [40-42]. In two prospective cohort studies, exclusive breastfeeding for at least two months postpartum was associated with a reduced rate of MS relapses [40,41]; the biologic mechanism of this association is not yet clear, but the authors speculated that lactational suppression of menses during exclusive breastfeeding led to a reduced risk of postpartum relapses. Similarly, a 2020 systematic review and meta-analysis of observational data found that breastfeeding was associated with a reduced risk of postpartum MS relapse (pooled odds ratio [OR] 0.63, 95% CI 0.45-0.88) [43]. A subsequent observational study of 1998 pregnancies from 1619 women with MS also found that breastfeeding was associated with a reduced risk of relapse (hazard ratio [HR] 0.61, 95% CI 0.41-0.91); the study adjusted for potential confounders including prior disease activity and resumption of DMT [44].

Earlier data suggested that postpartum relapse rates primarily reflected the severity of prepartum MS disease activity and that the rate of breastfeeding was inversely proportional to the underlying disease severity; that is, women with milder forms of MS were more likely to breastfeed and forego DMTs, which are generally avoided during lactation, whereas women with more active MS avoided lactation because of the need to resume DMTs [22,45-48]. However, this likely led to confounding by indication, since women with more active MS on DMT were usually not included [48,49].

RESTARTING DMT

●Patients not breastfeeding – If the patient does not wish to breastfeed, then disease-modifying therapy (DMT) treatment should be restarted within three weeks of delivery. This is especially impactful on patients with high preconception disease activity. Interferon (IFN)-beta and glatiramer acetate decrease reactivation of disease by 50 percent when given within three months and decrease risk of relapse for at least one year [50,51].

●Patients who are breastfeeding – The use of DMTs with breastfeeding is reviewed above. (See 'Breastfeeding and DMTs' above.)

SUMMARY AND RECOMMENDATIONS

●Management during pregnancy

•Use of DMTs – Pregnancy is associated with a decrease in multiple sclerosis (MS) relapse rate. The approach to use of disease-modifying therapies (DMTs) in pregnancy is discussed separately. (See "Multiple sclerosis: Pregnancy planning", section on 'Use of disease-modifying therapies (DMTs)'.)

•Monitoring – Patients should be monitored for MS disease activity including acute attacks (relapses) and development of new MS lesions. MRI should be used sparingly for clinical presentations that suggest MS disease activity or comorbid conditions. Gadolinium contrast is contraindicated during pregnancy. (See 'Monitoring' above and 'MRI in pregnancy' above.)

•Treatment of acute relapse – Acute MS attacks (relapses) causing disabling symptoms during the second and third trimesters of pregnancy are treated with intravenous glucocorticoids. (See 'Management in pregnancy' above.)

●Delivery – The route of delivery for pregnant patients with MS is similar to delivery for pregnant patients in the general population. The choice of anesthesia should be based upon obstetric concerns. (See 'Delivery' above.)

●Postpartum care – The rate of MS relapses may increase in the first one to six months postpartum. Patients with MS should have a comprehensive postpartum evaluation, including imaging to establish a new MRI baseline. Gadolinium contrast should be used during lactation only if essential for patient management; to avoid exposing the infant to gadolinium, the patient should "pump and dump" (ie, discard) breast milk for 24 hours following gadolinium infusion. Only a tiny fraction of gadolinium is excreted into breast milk; thus, with consent, a patient can receive gadolinium and continue to breastfeed if no other food source is available. Glucocorticoids are first-line treatment for postpartum relapses. (See "Multiple sclerosis: Pregnancy planning", section on 'MS activity in pregnancy and postpartum' and 'Clinical evaluation' above.)

●Breastfeeding – Since breastfeeding is known to provide beneficial health effects for the newborn and mother, women with MS should be encouraged and supported to breastfeed. Exclusive breastfeeding has been associated with a reduction in postpartum MS relapse rates. Many women thus choose to forgo DMTs while breastfeeding if MS symptoms can be managed without them. However, breastfeeding is not as protective as pregnancy, and for women with more aggressive disease, DMTs that are likely safe for breastfeeding include the interferon (IFN)-beta, glatiramer acetate, and possibly the B-cell depleting monoclonal antibodies (table 1). (See 'Breastfeeding and MS' above.)

●Restarting DMT – For patients who do not breastfeed, DMT should be restarted within three weeks of delivery (per consensus opinion), balancing any risks of infection or clotting for the mother. (See 'Restarting DMT' above.)