Management of Multiple Sclerosis During Pregnancy and the Reproductive Years

Management of Multiple Sclerosis During Pregnancy and the Reproductive Years

A Systematic Review

Obstetrics & Gynecology

Bove, Riley MD, MMSc; Alwan, Sura PhD; Friedman, Jan M. MD, PhD; Hellwig, Kerstin MD; Houtchens, Maria MD, MMSc; Koren, Gideon MD; Lu, Ellen PhD; McElrath, Thomas F. MD, PhD; Smyth, Penelope MD; Tremlett, Helen PhD; Sadovnick, A. Dessa PhD

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Abstract

OBJECTIVE: To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women.

DATA SOURCES: We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: “multiple sclerosis” and “pregnancy.” We manually searched the reference lists of identified studies.

METHODS OF STUDY SELECTION: Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team.

TABULATION, INTEGRATION, AND RESULTS: The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be an increased risk of MS relapses after use of assisted reproductive techniques. There does not appear to be a major increase in adverse outcomes in newborns of mothers with MS.

CONCLUSION: Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mother's reproductive outcomes and MS course.

 

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, primarily affecting white matter in the brain and spinal cord. The principal pathologic features of MS are autoimmune destruction of myelin and subsequent axonal degeneration. Clinical deficits are manifested in a number of functional systems (fatigue, cognition, mood, vision, ambulation, dexterity, sensation, bladder and bowel function). Initially, MS is often characterized by a relapsing-remitting course with over time a decline in relapses but an accelerated progression of disability (secondary progressive).

Multiple sclerosis preferentially affects females, with clinical onset often during childbearing years; hence, reproduction is an important consideration for many women with MS. Although MS specialists often advised against childbearing previously, today health care professionals are supporting young adults with MS in raising families. The Multiple Sclerosis Centre of Excellence on Reproduction and Child Health (MS-CERCH) is an international collaborative multidisciplinary research consortium that emerged in response to an increasing need for evidence-based, up-to-date information around childbearing in MS. Our mandate is to provide evidence-based strategies in reproductive decision-making to individuals with MS and their health care providers. We review and evaluate the available literature, highlight knowledge gaps, and provide consensus recommendations on the management of reproduction in MS.

 

SOURCES

We performed a comprehensive literature review around management of MS in women before, during, and after pregnancy. Evidence was gathered primarily through a search of PubMed, Embase, ClinicalTrials.gov, and other resources with the final search completed on August 12, 2014.

 

STUDY SELECTION

Study selection included all English-language papers combining the keywords “pregnancy” and “multiple sclerosis” for all years available from each database. Reference lists of identified articles were searched for further manuscripts. Two reviewers categorized studies by management topic (Table 1) and strength of evidence. Most studies were observational; few were prospective, and fewer were randomized interventional studies. We also included meta-analyses and systematic studies. The entire MS-CERCH team then discussed individual study merits and limitations and made consensus recommendations, evidenced-based where possible, but primarily consisting of expert opinion.

 

 

RESULTS

When planning a pregnancy, important counseling and management considerations for women with MS include both effects of pregnancy on MS and effects of MS on fertility, genetic counseling, and preconception care including discontinuation of MS therapies. Because up to 50% of pregnancies may be unintentional, all women with MS of reproductive age should be counseled at each clinical encounter to ensure adequate reproductive planning. Whenever possible, we advise face-to-face, individualized preconception counseling; online childbearing resources are underexplored in MS.

The best studied aspect of childbearing in MS is the effect of pregnancy on relapse risk. According to the American Academy of Neurology's criteria for prognostic questions, the evidence is “moderate” for a decreased relapse rate during pregnancy (notably during the third trimester) and “moderate to strong” for an increased relapse rate postpartum relative to prepregnancy rates. In the first 3 months postpartum, up to 30% of women may relapse, and relapses may worsen long-term disability. Over the whole prepregnancy to postpregnancy period, the relapse risk appears to be similar to the nonpregnant state. Small observational imaging studies demonstrating increased inflammatory activity corroborate clinical reports. The increase in relapses postpartum coincides with dramatic hormonal shifts and loss of the immunotolerant state of pregnancy; the most studied of these is the rapid postpartum decline of estriol levels. Factors associated with but not necessarily predictive of postpartum relapses include high relapse rate in the prepregnancy year and during pregnancy and a higher disability level at conception.

Pregnancy reportedly has either no adverse effects on maternal MS progression and disability or a beneficial effect. Important confounders often overlooked in studies include reverse causation, whereby women with more severe disease are less likely to have children, and age at MS onset. Maternal age appeared to fully explain delay in disability progression in one large study but not in three others.

Fertility in women with MS could be affected by reproductive decision-making, decreased libido or sexual function, lower estrogen levels, thyroid autoimmunity, temporary therapy-related amenorrhea, or premature ovarian failure. Nevertheless, no reliable studies have demonstrated altered rates of fertility or use of assisted reproductive technology in women with MS. We encourage women to consider strategies (eg, ovulation predictors, fertility consultations) to increase the chance of conceiving while they are relatively healthy and not on any disease-modifying treatment.

Assistive reproductive technology accounts for at least 1% of live births in developed countries, and an increased MS relapse risk has been reported after assisted reproductive technology; this was most tied to unsuccessful cycles, and to ovulation stimulation with gonadotropin-releasing hormone agonists rather than antagonists. Confounding from timing of MS treatment interruption and emotional stressors has not been assessed. Dialogue between obstetric and neurologic teams is essential before assisted reproductive technology cycles.

Oral contraceptive use may be mildly protective for MS onset or course, but studies are conflicting  and may be confounded by the effect of oral contraceptives on delaying childbearing. Interaction studies between oral contraceptives and disease-modifying treatments are limited, and no MS-specific considerations in the choice of oral contraceptive are reported. Women discontinuing oral contraceptives for a pregnancy may be advised to use mechanical contraception and continue on their MS treatment until fully ovulatory to avoid prolonged treatment interruption.

In addition to routinely recommended prenatal vitamins and 0.4–1.0 g daily of folic acid,74 MS-specific preconception considerations include smoking cessation as a result of a possible role in disease progression, sleep hygiene counseling, and vitamin D supplementation. Optimal dosing of vitamin D during pregnancy remains unknown: supranormal serum levels should be avoided, and 1,000–2,000 IU daily is believed to be safe.

Women may be concerned about risk of transmission of MS to their children. Multiple sclerosis is associated with environmental and genetic risk factors with a complex genetic pattern with more than 100 genetic susceptibility loci identified.88 Children born to a woman with MS have a 20–50 times increased risk of developing MS compared with the general population, but the absolute risk is relatively low (3–5%). Children born to parents who both have MS have a greater than 20% risk of developing MS later in life. Predictive testing is not available for MS.

Opinions vary on disease-modifying treatment use while trying to conceive, but most clinicians recommend discontinuation. Disease-modifying treatments reduce the frequency of exacerbations in relapsing forms of MS but are not effective for treating acute relapses. The currently approved first-line disease-modifying treatments are listed in Table 1. Alemtuzumab has also been approved in some jurisdictions. Because disease-modifying treatments are biologically and chemically diverse, it is unlikely that they would all affect the developing embryo or fetus in the same way. Although the results of limited studies in pregnant women to date have generally been reassuring, and no disease-modifying treatment is known to be teratogenic in humans (Appendix 1, available online at http://links.lww.com/AOG/A570), larger studies are needed to assess the reproductive toxicity of individual treatments. The large molecular size of some biologic therapies may limit transfer across the placenta before 20 weeks of gestation, although active transport may occur after that time. Other effects of gestational exposure including on the placenta are possible; long-term sequelae have not been evaluated. Table 2 summarizes our recommendations for use of disease-modifying treatments during pregnancy. In general, five maximal half-lives is the commonly accepted timeframe for drug discontinuation before conception based on exponential decay. Typically, this represents a 2- to 6-week timeframe.

 

Other immunologic treatments, not always licensed for but which are occasionally used in MS, are contraindicated during pregnancy and should be discontinued before conception (Appendix 2, available online at http://links.lww.com/AOG/A570). Among these, rituximab is an anti-CD20 monoclonal antibody whose use in MS is increasing; its teratogenic risk is undetermined.

A pregnancy test should be considered before prescribing any MS treatment (including infusions). Some symptomatic medications may be continued while trying to conceive, following standard guidelines for safety in pregnancy.

For pregnant women with severe or highly active MS, the benefit of MS treatment may outweigh the (unknown) risk to the fetus. If such treatment is necessary, clinicians may consider switching to a different drug such as glatiramer acetate U.S. Food and Drug Administration Category B (Appendix 1, http://links.lww.com/AOG/A570).

Achieving a pregnancy may take some time so discontinuation of disease-modifying treatment during this period may increase relapse risk. Women who are perceived to be at high risk for a relapse (eg, rebound relapse after discontinuation of certain treatments) or those who have a history of delayed conception may need monthly intravenous corticosteroids, usually at the start of menses with a negative pregnancy test, until conception occurs.

Once a woman with MS is pregnant, prevention of relapses can be an overriding consideration if there was high disease activity before pregnancy. Either monthly intravenous immunoglobulin (IVIG) or monthly steroids after the first trimester can be considered, but safety data are limited. Corticosteroid use should be limited if possible throughout pregnancy. An increased risk of cleft lip and palate among the neonates was reported in several older studies with corticosteroid use in the first trimester, but not in a more recent study. In the second and third trimesters, use has been associated with low birth weight and possibly premature delivery, although these findings may be confounded by the underlying disease. Less than 10% of the maternal dose of prednisone, prednisolone, and methylprednisolone reaches the fetus as a result of metabolism to inactive forms by the placenta; unfortunately, the potential teratogenic effect of these inactive forms is uncertain. In contrast, betamethasone and dexamethasone do cross the placenta with minimal metabolism. Thus, the full adult dose likely reaches the fetus, and these should never be used outside of the brief obstetric indication of promoting fetal lung maturity. Treatment of a serious MS relapse typically consists of either IVIG or intravenous corticosteroids with the same risks outlined previously.

There is no evidence that magnetic resonance imaging exposure up to 3 Tesla is associated with fetal harm during pregnancy, but gadolinium should only be used if it is likely to change management and benefit the patient or fetus. Written informed consent is recommended by the American College of Radiologists to document patients' understanding of risk. With respect to lactation, the excretion of both gadolinium-based and iodinated contrast agents into breast milk is low, as is their absorption from the infant gut. Thus, the use of contrast agents in the mother is considered safe during lactation without the need to interrupt breastfeeding.

At delivery, obstetric indications guide the mode of delivery for patients with most MS. Mothers with MS are often older than mothers in the general population because the typical age of MS onset is 30 years. Even when studies took into consideration maternal age, mothers with MS were reported as having a slightly increased risk of induction (which may be associated with higher disease severity), slower progression of second stage of labor, and increased use of forceps or operative delivery in comparison with women in the general population in most studies but not all. Rarely, severely disabled patients may be unable to push in the second stage of labor. A trend for increased cesarean or assisted vaginal delivery has been reported with increased MS disability as well as in some geographic regions.vWhether this is an effect of the disease, of women with severe disease choosing not to deliver vaginally, or of physicians' propensity to deliver patients with MS perceived as being at “high risk” in a more conservative fashion has not been adequately assessed.

The choice of obstetric anesthesia for women with MS typically depends on the mode of delivery. Multiparous women with MS were found to be more likely to receive epidural rather than spinal anesthesia compared with multiparous women in the general population. In addition, an increased duration of hospitalization for delivery and newborn care for women with MS, noted in previous studies, was not confirmed in a more recent one.

There is no measurable negative effect of obstetric anesthesia or of anesthesia type during delivery on postpartum relapses or disability progression  despite anecdotal reports and historical opinion.

In terms of fetal outcomes, MS does not appear to increase the risk of early trimester pregnancy loss, stillbirth, or fetal malformation in most studies. There are some reports that mothers with MS may be more likely to have fetuses with reduced birth weight for gestational age  but not specifically fetal growth restriction. The finding of reduced birth weight remains controversial, and potential causes are unknown.For instance, a study that reported significantly lower mean birth weight at term in mothers with an MS diagnosis compared with mothers who gave birth before MS onset failed to adjust for potential confounders. The largest study to date to assess the effect of MS on birth weights and on preterm birth rates (less than 37 weeks of gestation) was also the only to adjust for confounders (eg, multiple births to individual mothers, parity, hypertension, and prior preterm births). In contrast to smaller studies, no association was noted between MS status and either newborn birth weight or gestational age.

The biggest management question in the postpartum period is whether women with MS should resume their MS treatment or breastfeed. In addition to the known benefits of lactation for both infants and mothers, reflected in the World Health Organization recommendations of exclusive breastfeeding for 6 months,additional considerations in MS include the relative protection against postpartum relapses afforded by breastfeeding compared with early resumption of disease-modifying treatments.

Studies of exclusive breastfeeding have reported a protective effect of lactation on risk of postpartum relapses, whereas studies collapsing exclusive and nonexclusive breastfeeding have found no apparent protective effect. In a meta-analysis of these small studies, any breastfeeding reduced the risk of postpartum relapses by half. Disease activity, which can alter a patient's decision to breastfeed or restart disease-modifying treatment, may confound the association between breastfeeding and postpartum relapses. At least in a pilot study, vitamin D levels associated with breastfeeding did not appear to be a confounder.

The information available on the safety of disease-modifying treatments during lactation is limited. Breastfeeding is considered “moderately safe” for glatiramer acetate and interferon-[beta], where high molecular weight limits transfer into breast milk, and for natalizumab, despite reports that it is excreted into human breast milk. Information on breastfeeding during maternal use of other disease-modifying treatments is lacking.In light of limited evidence, women should resume MS treatments only after their infant is weaned from breast milk. In these patients, exclusive breastfeeding for 6 months should be supported if disease activity and fatigue permit, and postpartum surveillance magnetic resonance imaging with gadolinium should be used to monitor subclinical MS activity and guide earlier treatment resumption.

For breastfeeding mothers, options for relapse prevention or treatment include corticosteroids or IVIG. Monthly intravenous corticosteroids have been used to reduce the risk of postpartum relapses. Maternal corticosteroid treatment is generally believed to be safe for the infant ; small to moderate doses of corticosteroids ingested from milk add, at most, 10% to the infant's endogenous corticosteroid production and may be of little clinical significance. Nonetheless, because corticosteroids could lead to adverse events (eg, growth restriction) in children, combined with the much larger maternal doses used to treat relapses, suspending breastfeeding for 4 hours after infusion with a “pump and dump” approach is prudent. Prophylactic IVIG use during lactation has been examined in several studies and found to decrease the postpartum relapse rate in mothers. Differing protocols have been implemented, but an optimal dosing regimen that maximizes maternal MS benefit while moderating the high expense of IVIG has not been established; these include a double-blind, randomized trial (n=168 100) and a case series of IVIG (n=43) given within 3 days of delivery and then monthly. Maternal IVIG treatment does not seem to have adverse effects on the infant 100,101,103,136 with only a transient rash possibly caused by IVIG reported.

Multiple sclerosis-specific postpartum counseling should include discussion of potential triggers for MS exacerbations or symptom worsening. Strategies include minimization of sleep disruption (eg, scheduled naps during the day, pumping and storing breast milk on a schedule for others to feed to the baby while the mother naps) and help with household duties when available. Physical therapy may assist with resuming activity. Urologic symptoms may require evaluation to distinguish demyelinating from obstetric etiologies. Although of uncertain significance, thyroid antibodies appear to be elevated in mothers with MS postpartum.

It is estimated that 13–19% of all women experience depression in the first 6 months after delivery with the strongest risk factors being prior depression, stressful life events, and poor marital or social support. Women with MS would be expected to experience some exacerbation of affective symptoms peripartum given their increased baseline risk of mood disorders compounded by MS symptoms. Strategies to prepare the mother should be discussed early (with continuation of antidepressant drug therapy during pregnancy weighed against the known risks, like in pregnant women without MS ). We recommend that any health care professional caring for postpartum women with MS screen for depression. The use of screening tools (eg, Edinburgh Postnatal Depression Scale ) and the relative therapeutic benefits of antidepressant medications and nonpharmacologic interventions  have not been assessed in MS.

 

CONCLUSIONS

Our recommendations for medical management of pregnant and other reproductive-aged women with MS are summarized in Table 1. Because the rate of MS appears to be increasing among women and diagnosis is occurring earlier, it becomes imperative to understand and optimize reproductive outcomes in this population. Our review provides reassurance that, in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Treatments and clinical interventions can be individualized for both the mother's MS and the reproductive course. The many unmet research needs identified in this review include the teratogenic risks (or safety) of most agents used to treat MS, better understanding of postpartum depression in mothers with MS, and the use and improvement of resources to support reproductive decision-making for women with MS.

 

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AUTHOR INFORMATION

Harvard Medical School and the Departments of Neurology and Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts; the Departments of Medical Genetics and Neurology, University of British Columbia, Vancouver, British Columbia, the Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, and the Department of Neurology, University of Alberta, Edmonton, Alberta, Canada; and St. Joseph Hospital Neurology Clinic, Ruhr University, Bochum, Germany.

Corresponding author: A. Dessa Sadovnick, PhD, S113-2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada; e-mail: [email protected].

The launch of MS-CERCH was funded by the Canadian Institutes of Health Research, Teva Neurosciences, and Biogen-Idec.

The authors thank members of MS-CERCH, who contributed comments to the sections specific to their area of expertise: Dr. V. Armenti (disease-specific registries), Dr. P. Duquette (neurology, pregnancy course after MS onset), Dr. A. Pupco (Motherisk, Teratology), Ms. C. Guimond (reproductive and genetic counseling for MS), and Ms. N. Razaz (children of MS parents).

Financial Disclosure The authors did not report any potential conflicts of interest.

 

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