Multiple sclerosis: Pregnancy and postpartum care

INTRODUCTION — 

Pregnancy has a favorable effect multiple sclerosis (MS) disease activity: relapse rates generally decrease, and the third trimester of pregnancy appears to have similar potency of effect as most high-efficacy MS immune therapies. Thus, some patients can discontinue disease-modifying therapies (DMTs) during pregnancy. If DMTs are required, those with the best fetal safety profile should be used. Postpartum, there is an increased risk of disease exacerbation, which is treated with glucocorticoids.

Most reports suggest that MS does not increase the risk of adverse pregnancy outcomes so routine prenatal and postpartum care from obstetric providers is reasonable. (See "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters" and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs" and "Overview of the postpartum period: Normal physiology and routine maternal care".)

This topic will review the medical 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:

●(See "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)

●(See "Evaluation and diagnosis of multiple sclerosis in adults".)

●(See "Manifestations of multiple sclerosis in adults".)

●(See "Symptom management of multiple sclerosis in adults".)

●(See "Treatment of acute exacerbations of multiple sclerosis in adults".)

●(See "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

Unplanned pregnancy — Ideally, patients with MS will have consulted with their neurologist before attempting to conceive to receive counseling about the effects of MS on pregnancy, the effects of pregnancy on MS, the need to discontinue teratogenic medications and switch to medications with the best fetal safety profile, and timing conception when symptoms are stable. (See "Multiple sclerosis: Pregnancy planning".)

However, some patients become pregnant without preconception care. Management of these patients is based on clinical judgment of individual circumstances.

●For patients receiving older injectable therapies (eg, beta interferons, glatiramer acetate), there is no significant concern of harm as these medications have a good fetal safety profile in registries.

●For patients on oral DMTs, the medication should be discontinued immediately because of evidence of fetotoxicity in animal reproduction studies. The risk of fetal harm in humans is unknown but thought to be low. The routine fetal anatomic ultrasound examination at 18 to 20 weeks of gestation is a reasonable assessment. Ultrasound examination at 11 to 14 weeks will detect some anomalies, but overall sensitivity is lower. Ultrasound examination at 32 weeks may be performed to screen for growth restriction. (See "Prenatal care: Initial assessment", section on 'Ultrasound examination' and "Fetal growth restriction: Screening and diagnosis".)

●For patients receiving natalizumab, a recombinant IgG4 monoclonal antibody, infusions can be continued at least until the third trimester. IgG is poorly transported across the placenta early in pregnancy, but by the middle of the second trimester placental transfer substantially increases so ideally the medication is discontinued by the third trimester [1].

●For patients receiving B cell depleting agents, the agent is discontinued because these agents can cause fetal B cell depletion. Neonatal B cell counts should be checked.

Monitoring — Patients should be monitored during pregnancy 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 [2].

●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 [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.

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 [3]. Although data are scarce, one retrospective study suggested that gadolinium-enhanced MRI during the first trimester was associated with an increased risk of stillbirth, neonatal death, and rheumatologic, inflammatory, or infiltrative skin conditions [4]. This study involved a previous generation of gadolinium-based contrast agents; the newer generation is more stable and may have a lower potential for fetal toxicity, but no data are available.

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 [5]. (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 MS 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 [6].

The mainstay of MS relapse treatment in the second or third trimester 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. In the first trimester, management of MS flares depends on location and severity. As an example, plasma exchange (PLEX) could be considered for severe motor or brainstem attack; acute treatment of relapse helps to hasten recovery but may not change long term outcome.

●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 substantially enter the fetal circulation. Therefore, they are preferred in pregnancy [6,7]. 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 pregnancy-induced hypertension, weight gain, hyperglycemia, gestational diabetes, gastrointestinal ulcers, and preterm prelabor rupture of membranes. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

Limited data suggest that it is uncommon for glucocorticoid therapy to cause hypothalamic-pituitary-adrenal (HPA) axis suppression in neonates [8,9]. In a case series of 56 neonates born to mothers receiving glucocorticoids during pregnancy, adrenal suppression determined by measurement of cortisol levels was detected in only three [10]. These neonates were treated with hydrocortisone and did not have permanent HPA suppression on follow-up.

●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 [7,11-13]. However, subsequent large studies have found no association of congenital abnormalities or low birth weight with early use of glucocorticoids [14-16]. 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 [7].

●Plasma exchange (PLEX) – There are few data for treating refractory MS relapses in pregnancy. There is anecdotal evidence supporting therapeutic PLEX as a possible choice for relapses refractory to glucocorticoid treatment [17-19]. Limited clinical trial and observational data in nonpregnant patients also suggest that PLEX is beneficial for MS relapse. PLEX is thought to be safe in pregnancy [19]. PLEX could be considered as an alternative therapy in first-trimester relapses, though there are no published data on this. 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'.)

●Immune reconstitution inflammatory syndrome (IRIS) and PLEX – Note that patients with MS who are treated with natalizumab are at risk for developing 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 IRIS also may occur with discontinuation of natalizumab without PML and, in this case, is often described as a severe rebound of MS disease activity [20]. There is some concern that PLEX may accelerate IRIS in this setting [21,22]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Inflammatory PML (PML-IRIS)' and "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

Symptom management — As relapses naturally decrease in pregnancy, often more challenging is the management of chronic MS symptoms in pregnancy (see "Manifestations of multiple sclerosis in adults" and "Symptom management of multiple sclerosis in adults"). Bladder symptoms (eg, urinary frequency, urgency, nocturia) and fatigue may worsen with pregnancy, and some medications used for chronic symptoms such as analgesics, antispasticity medications, and antidepressants may have contraindications in different trimesters of pregnancy. Furthermore, some symptoms of a normal pregnancy (eg, maternal fatigue and leg spasms) may be difficult to differentiate from symptoms of an MS exacerbation.

Management of prenatal and postpartum depression may be challenging, though resources on how to counsel prenatally and postpartum have been defined in the United Kingdom by the National Institute of Health and Care Excellence (NICE) [23,24].

As part of prenatal counseling in MS, it is important to review plans for symptom management during pregnancy, and to review again in third trimester to prepare for management in the postpartum period (see 'Postpartum care' below). The neurologist and obstetrician should work together to help the patient understand and balance maternal and fetal risks and benefits. These decisions should be made on a case-by-case and individual drug basis; however, a general rule of thumb is to suspend any small molecule drugs with impact on organogenesis for at least the first trimester; most women can tolerate a brief holiday from most symptomatic medications.

LABOR AND DELIVERY

●Labor recognition – Patients with spinal involvement from T11 inferiorly may not recognize the increase in contraction frequency, strength, and duration that marks the onset of labor. Thus, they should be counseled on alternative signs that should prompt a labor check: bloody show (vaginal discharge of a small amount of blood and mucus), increased spasticity, gastrointestinal dysregulation, flushing, and/or back pain.

●Route of delivery – The choice of route of delivery for patients with MS is similar to that for those in the general population. Rates of forceps- or vacuum-assisted vaginal delivery and cesarean birth were not significantly different in patients with MS compared with those without MS in a systematic review [25]. Although some studies report that assisted vaginal delivery and cesarean birth rates are higher in patients with more severe disability, these conclusions are subject to bias of the obstetrician's perception [26].

Nevertheless, some patients may benefit from operative birth. Patients with significant paraparesis may be at risk for significant pelvic muscle weakness, limiting their ability to push. Assisted vaginal delivery to shorten the second stage of labor is an option for these patients and for any patient with maternal exhaustion during this stage. (See "Assisted (operative) vaginal birth: Overview".)

Significant disability such as spasticity refractory to medications can make labor positioning difficult, and spasticity may increase in labor. These patients may choose to have a planned cesarean birth after discussion with the obstetric, neurology, and anesthesia teams. However, these cases are very rare during the childbearing years.

●Analgesia/anesthesia – The choice of analgesia/anesthesia should be based upon patient preferences and standard obstetric issues (eg, probable operative birth) [27,28]. 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 despite concern about pain increasing rate of relapse [29-31]. (See "Obstetric and nonobstetric anesthesia for patients with neurologic disorders", section on 'Multiple sclerosis'.)

●Autonomic dysreflexia – Patients with severe spinal cord disease as determined by a neurologist are at risk for autonomic dysreflexia during labor [32]. Prevention, clinical findings, and management are discussed in detail separately. (See "Chronic complications of spinal cord injury and disease", section on 'Autonomic dysreflexia'.)

POSTPARTUM CARE

Routine — Postpartum patients are encouraged to obtain support from family and other caregivers to decrease stress and sleep deprivation, particularly those with active neurologic symptoms.

They should be monitored by their obstetrical clinician and neurologist four to six weeks postpartum for potential MS flare, new or worsening depression, or worsening of other chronic MS symptoms and then seen again by their neurologist at four to six months postpartum [6]. (See "Overview of the postpartum period: Normal physiology and routine maternal care".)

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 [6]. Patients with MS have an increased risk of mood disorders and should be screened for the presence of postpartum depression. (See "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Screening'.)

MRI postpartum — Surveillance MRI to establish a new baseline is recommended within the first few months postpartum, particularly for patients who have not yet resumed disease-modifying therapy (DMT), to look for evidence of silent MS disease activity [2,6]. Specific recommendations vary based on the individual patient, but imaging could be repeated four to six weeks postpartum for those at increased risk of postpartum relapse (had a prior postpartum relapse, high prepregnancy relapse rate, or not exclusively breastfeeding) or at minimum at four to six months postpartum. 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 [2].

Breastfeeding should not be interrupted with gadolinium administration [5]. 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 [33]. If the patient prefers to completely avoid exposing the infant to gadolinium, they should "pump and dump" (ie, discard) breast milk for 24 hours following gadolinium infusion. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Use of gadolinium'.)

As an alternative, some experts obtain an MRI 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.

Relapse risk and prevention — The protective effect of pregnancy against relapse is lost in the postpartum period, with an increased risk of relapse in the first six months postpartum compared with the preconception period [34]. Predictors for early postpartum relapse include poor prognostic profile, higher annualized relapse rate in the two years prior to conception, relapses occurring in pregnancy, higher EDSS score at conception, and lack of DMT in the two years prior to conception [35,36]. Patients with DMT use for at least eight weeks during pregnancy had lower risk of postpartum relapse compared with those without DMT use in pregnancy or the 3 months prior in one study [37]. These issues are reviewed in detail separately. (See "Multiple sclerosis: Pregnancy planning", section on 'MS activity in pregnancy and postpartum'.)

Resumption of DMT 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 [38]. Breastfeeding should be encouraged for its maternal and infant benefits, exclusive breastfeeding (see 'Breastfeeding and MS' below) may also reduce the risk of relapse. Resumption of DMTs in patients who wish to breastfeed is discussed below. (See 'Use of DMTs during breastfeeding' below.)

If the patient does not wish to breastfeed, then DMT treatment should be restarted within 10 days of delivery to reduce the risk for relapse. This is especially important for patients with high level of preconception MS disease activity. Limited data suggest that DMT with glatiramer acetate or natalizumab is associated with a lower risk of disease reactivation when administered within three months of delivery [39,40].

Contraception — Highly effective reversible contraception methods that are long-acting (eg, intrauterine devices, implants) are probably the best option for contraception, especially for patients who resume or will resume taking potentially teratogenic medications. These contraceptive options do not interfere with DMT and are compatible with breastfeeding [41]. (See "Contraception: Postpartum counseling and methods".)

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 [42,43].

Limited retrospective data suggest that pulsed IV glucocorticoid treatment reduces the postpartum relapse rate, but high-quality data are lacking [44,45]. Studies have shown no consistent benefit of intravenous immunoglobulin (IVIG) for relapse prevention in the postpartum period [46-48].

BREASTFEEDING AND MS

MS relapse rate — Exclusive breastfeeding for at least two months appears to be associated with a reduction in postpartum MS relapse rates [49-51]. A 2020 meta-analysis of observational data found that breastfeeding was associated with a 37 percent reduced risk of postpartum MS relapse (pooled odds ratio [OR] 0.63, 95% CI 0.45-0.88) [52]. A subsequent observational study of 1998 pregnancies from 1619 patients with MS also found that breastfeeding was associated with a 39 percent 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 [53]. The biologic mechanism of this association is not yet clear, but authors have speculated that it may be related to lactational suppression of menses during exclusive breastfeeding.

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, patients with milder forms of MS were more likely to breastfeed and forego DMTs, which are generally avoided during lactation, whereas those with more active MS avoided lactation because of the need to resume DMTs [29,54-57]. However, this likely led to confounding by indication, since women with more active MS on DMT were usually not included [57,58].

Use of DMTs during breastfeeding — The effects of most DMTs on development of breastfed infants is uncertain. For patients who choose to breastfeed, one option is to defer DMT while breastfeeding, followed by a rapid wean and resumption of a high-efficacy DMT [6]. 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 patient counseling about what is known and not known about short and long term infant effects [59].

IFN-beta is secreted at minimal levels in breast milk (the levels are below the level of detection), and no side effects have been observed in breastfed infants [60]. It is unknown if glatiramer acetate is secreted in breast milk, but no adverse effects have been reported in breastfed infants [59]. Although data are limited, the B-cell depleting monoclonal antibody DMTs are probably compatible with breastfeeding (table 1).

DMTs best avoided during breastfeeding include the fumarates (eg, dimethyl fumarate), mitoxantrone, sphingosine 1-phosphate receptor modulators (fingolimod, siponimod, ozanimod, and ponesimod), teriflunomide, alemtuzumab, and cladribine [6,61-63]. Alemtuzumab has been detected in the offspring of lactating mice, but data for human breast milk are lacking [64,65].

Use of 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 [42,66].

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 patient preference and obstetric concerns (eg, likelihood of forceps- or vacuum-assisted vaginal delivery because of maternal fatigue during the second stage of labor). (See 'Labor and delivery' above.)

Patients with severe spinal cord disease as determined by a neurologist are at risk for autonomic dysreflexia during labor. Prevention, clinical findings, and management are discussed in detail separately. (See "Chronic complications of spinal cord injury and disease", section on 'Autonomic dysreflexia'.)

●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 'Routine' above.)

●Breastfeeding – Since breastfeeding is known to provide beneficial health effects for the newborn and mother, patients with MS should be encouraged and supported to breastfeed. Exclusive breastfeeding has been associated with a reduction in postpartum MS relapse rates. Many patients 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 patients 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 10 days of delivery (per consensus opinion), balancing any risks of infection or clotting for the mother. (See 'Relapse risk and prevention' above.)

●Contraception – Highly effective reversible contraception methods that are long-acting (eg, intrauterine devices, implants) are probably the best option for contraception. These contraceptive options do not interfere with DMT and are compatible with breastfeeding. (See 'Contraception' above.)