631897 research-article2016

TAN0010.1177/1756285616631897Therapeutic Advances in Neurological DisordersP Coyle

Therapeutic Advances in Neurological Disorders

Management of women with multiple sclerosis through pregnancy and after childbirth

Review

Ther Adv Neurol Disord 2016, Vol. 9(3) 198­–210 DOI: 10.1177/ 1756285616631897 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Patricia K. Coyle

Abstract:  Multiple sclerosis (MS) is a major acquired neurologic disease of young adults. The prototypic patient is a young woman of reproductive age. Gender preference is becoming more pronounced, since MS is increasing specifically among women. Any healthcare provider who deals with MS must be prepared to discuss pregnancy issues, and provide appropriate counseling. This is now complicated by the availability of multiple treatment options. There is growing literature on which to base recommendations, particularly regarding washout periods. After a brief background introduction, this review will discuss state-of-the-art family planning counseling in the treatment era, divided into prepregnancy, pregnancy, and postpartum MS issues.

Keywords:  multiple sclerosis, postpartum relapses, pregnancy, women’s issues

Background Pregnancy is a major concern for many patients with multiple sclerosis (MS) [Bove et  al. 2014; Carvalho et al. 2014; Miller et al. 2014]. MS is the most common acquired neurologic disorder of young adults, short of trauma, with at least 2.5 million individuals affected worldwide. The disease shows a female predominance that now approximates 3 to 1. This gender bias will become more pronounced, because MS is on the rise among young women. The prototypic patient is a woman of reproductive age. Specific management questions and concerns surround the prepregnancy, pregnancy and postpartum periods (Table 1). This is complicated by the fact that MS has entered a treatment era. Unfortunately there are no recognized and implemented guidelines [Borisow et al. 2014; Wundes et al. 2014]. The major current pregnancy issue is pharmacotherapy [Lu et al. 2012; Vukusic and Marignier, 2015]. There are now multiple disease-modifying therapies (DMTs) for relapsing forms of MS, but they are not recommended for use in patients who are pregnant, trying to become pregnant, or who are breastfeeding. Recent articles have called for these initial rules to be liberalized [Coyle, 2014a; Hellwig, 2014]. After a brief introduction

covering the DMTs, this review will discuss management recommendations for MS patients around the prepregnancy, pregnancy, and postpartum periods in the MS treatment era. This is based on an up-to-date review of the literature.

Correspondence to: Patricia K. Coyle, MD Dept. of Neurology HSC, T12 Stony Brook University Medical Center Stony Brook, NY 11794, USA Patricia.Coyle@ stonybrookmedicine.edu

Disease-modifying therapies There are 13 distinct approved DMTs for relapsing forms of MS. They encompass eight different mechanisms of action (Table 2). The European Medicines Agency (EMA) has a rating scale for drug pregnancy risk. The United States Food and Drug Administration (FDA) previously used ratings that involved letters (A, B, C, D, X). For new drugs, this system has been replaced with descriptions of fetal risk summary, clinical considerations and data. The FDA plans to rewrite existing drug ratings over the next several years. The interferon betas have shown dose-dependent first trimester abortofacient effects in primate models at 2.8 to 40 times the recommended human dose; this effect has not been noted in human studies [Bayer HealthCare Pharmaceuticals, Inc. 2012; Coyle et al. 2014; Sandberg-Wollheim et  al. 2011]. After injection, serum levels peak between 8 to 24 hours, then decline [Khan et al.

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P Coyle Table 1.  Pregnancy-related management issues in multiple sclerosis. Prepregnancy • Fertility and fetal development • Impact on the female versus male patient • Genetic risk • Basic counseling • Pregnancy impact on MS prognosis (early and late) • Contraception choice • Impact of MS on ability to care for children • Economic and social burden of having children • DMT use and recommended washout periods • Assisted reproductive technology/in vitro fertilization Pregnancy • Disease activity • DMT use • Evaluation and treatment of relapses and disease symptoms • Delivery and anesthesia choices Postpartum • Disease activity • Breastfeeding • DMT use • Impact on infant/child development MS, multiple sclerosis; DMT, disease-modifying therapies.

1996]. Interferon beta is not believed to cross the placenta; a sister type-1 interferon (alpha) was shown by two assays not to penetrate placental tissue [Waysbort et al. 1993]. Some reports suggest maternal interferon beta exposure is associated with lower infant birth weights and length, and higher incidence of premature births [Amato et al. 2010; Boskovic et  al. 2005; Patti et  al. 2008; Weber-Schoendorfer and Schaefer, 2009]; but other analyses do not confirm these findings [Coyle et  al. 2014; Hellwig et  al. 2012; Romero et  al. 2015]. This could be a disease-specific rather than drug-specific issue, since other studies report lower birth weights and birth lengths with MS pregnancies in general [Dahl et al. 2006, 2008; Ebrahimi et al. 2015]. However, a recent large study found no link between MS and birth weight, or preterm delivery [Van der Kop et al. 2011]. Glatiramer acetate is also not believed to cross the placenta [Cree, 2013]. There are no measurable blood levels, and it is rapidly hydrolyzed at the site of injection [Ziemssen et al. 2001]. Glatiramer

acetate has not been associated with negative pregnancy effects in either animal or human studies, and has the best pregnancy rating among the DMTs. Because the interferon betas and glatiramer acetate have been available for years, they have the largest accumulated pregnancy exposures. No significant issues have been identified. Recent commentaries suggest these DMTs do not require a washout prior to attempting pregnancy [Amato and Portaccio, 2015; Coyle, 2014a]. Glatiramer acetate, and to a lesser extent interferon beta, have been used during pregnancy for women in whom there is concern about extended treatment-free periods [Dung and Panda, 2014; Fragoso et  al. 2010; Hellwig and Gold, 2011; Salminen et  al. 2010]. For the pregnant MS patient, the appropriate counseling remains that the preferred option is no DMT. However, selected pregnant women may choose to continue glatiramer acetate or interferon beta, when they feel this is their best option. Both glatiramer acetate and interferon beta are probably compatible with breastfeeding. They would not be expected to enter breast milk at high levels, due to their negligible or low blood levels and higher molecular weights. Any trace amounts would likely be depolymerized in the neonate’s gastrointestinal tract after oral intake. In a small study, breast milk contained only 0.006% of the maternal dose of intramuscular interferon beta-1a [Hale et al. 2012]. None of the oral DMTs are recommended for use while pregnant or breastfeeding. Teriflunomide has the most profound warning. It shows selected teratogenic and embryo lethal effects in multiple animal species, at doses below those used clinically. Human pregnancy exposures to teriflunomide or leflunomide (its precursor used in rheumatoid arthritis) have not demonstrated teratogenicity, however. A recent teriflunomide series reported on 83 female and 22 male pregnancy exposures, without identified issues [Kieseier and Benamor, 2014]. There is a rapid elimination protocol (using oral cholestyramine over several days) to quickly lower teriflunomide levels to less than 0.02 µg/ml; otherwise it can persist in the body for up to 2 years. Mean halflife is 16–18 days. European product information on teriflunomide does not note any implications for male MS patients. The drug is detected in semen in very low concentrations, and could be inoculated into the female partner if a barrier

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Therapeutic Advances in Neurological Disorders 9(3) Table 2.  Approved multiple sclerosis (MS) disease-modifying therapies (DMTs) and pregnancy, washout, and breastfeeding recommendations. DMT

Dosing and brands

Pregnancy ratings (USA/ Europe)*

Prepregnancy washout

Pregnancy use

Breastfeeding

Interferon beta (IFNβ)

SC IFNβ-1b 250 µg every other day (Betaseron, Extavia) IM IFNβ-1a 30 µg weekly (Avonex) SC PEG IFNβ-1a 125 µg every 2 weeks (Plegridy) SC IFNβ-1a 44 or 22 µg 3 times weekly (Rebif) SC 40 mg 3 times weekly, or SC 20 mg daily (Copaxone, Glatopa) PO 0.5 mg daily (Gilenya)

C/Category 2

Probably not necessary (0–1 month)

Probably acceptable

Probably acceptable (levels 0.006% of maternal dose) [Hale et al. 2012]

B/Category 2

Not necessary

Probably acceptable

Probably acceptable

C/Category 2

2 months

Not used

Accelerated elimination procedure (until blood level < 0.02 µg/ml) Probably not necessary (0–1 month) Probably not necessary (0–1 month) 4 months

Not used

Avoid (no data) Avoid (no data)

Not used

Avoid (no data)

Can be considered for very active patients Not used

Present in breast milk

6 months

Not used

Glatiramer acetate Fingolimod Teriflunomide

PO 14 mg (also 7 mg in USA) daily (Aubagio)

X/Category 1 (pregnancy must be ruled out prior to use)

Dimethyl fumarate

PO 240 mg twice a day (Tecfidera)

C/Category 2

Natalizumab

IV 300 mg monthly (Tysabri)

C/Category 2

Alemtuzumab

IV 12 mg daily for 5 days in the first year, 3 days in the second year (Lemtrada) IV 12 mg/m² every 3 months (lifetime max 140 mg/m²) (Novantrone)

C/Category 1

Mitoxantrone

D/Category 2 (pregnancy must be ruled out prior to use)

Avoid (no data) Avoid (still present in breast milk at 4 weeks)

SC, subcutaneous; IM, intramuscular; PEG, pegylated; IV, intravenous; PO, taken orally. *USA ratings have been replaced by description of animal/human data.

contraceptive technique is not used. Estimated exposure would be over 100 fold less than from direct oral dosing [Kieseier and Benamor, 2014]. Teriflunomide has been detected in rat milk following a single oral dose. In rabbit and rat models, fingolimod is associated with fetal malformations, death, growth retardation, and learning deficits. Depending on the animal model, problems were seen at doses below the clinically used amount, as well as with much higher doses. The S1P receptor is involved in vascular formation during embryogenesis. The Fingolimod Pregnancy Registry reported on 66

human exposure cases, and noted a 7.6% rate of abnormal fetal development [Karlsson et  al. 2014]. Fingolimod has a half-life of 6–9 days [Novartis Pharmaceuticals Corporation, 2015]. It is known to cross the placenta, is present in rat milk, and requires a 2-month washout before attempting pregnancy [Novartis Pharmaceuticals Corporation, 2015]. There is a concern for rare rebound activity when fingolimod is discontinued [Faissner et al. 2015]. In rats, dimethyl fumarate is associated with embryo lethality at doses two times higher than the approved human dose. Testicular toxicity was

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P Coyle noted in mice, rats, and dogs. Male rats showed increase in nonmotile sperm. Human pregnancy exposures to date have not detected any deleterious signal. It is not clear that dimethyl fumarate requires any washout, due to its short half-life (approximately one hour) [Biogen Idec, Inc., 2014]. Currently all the oral agents are avoided in breastfeeding patients. Natalizumab is an IgG4 humanized monoclonal antibody. In guinea pigs it has been associated with decreased pup survival at 7 times the human dose, and in primates with reversible fetal hematologic abnormalities, at doses 2.3 times the human dose. Alpha 4-integrin, its antigen target, is expressed on human uterus epithelia as well as embryonic tissue. This antigen plays a role in fertilization, implantation, placental, and cardiac development [Duquette and Prat, 2015]. However, no human implantation or embryonic defects have been reported, and no cardiac issues have been found [Cree, 2013]. In a recent prospective, controlled, observational study, 101 MS women exposed to natalizumab in the first trimester were compared with 78 pregnant MS women without DMT exposure, and 97 healthy control women [Ebrahimi et al. 2015]. There was no difference in major malformations, low birth weight, or premature births. Higher miscarriage rates and lower birth weights were noted in the two MS groups, which were not significantly different. Natalizumab washout recommendations have ranged from 1 to 3 months, but all agree it should be as short as possible. There is risk not only for return of disease activity, but also rebound activity [De Giglio et al. 2015; Verhaeghe et al. 2014]. A recent report suggested one could justify no washout, since monoclonal antibodies do not cross the placenta until the second trimester [De Giglio et  al. 2015]. IgG is the only antibody isotype to significantly cross the placenta (IgG1, followed by IgG4 and 3). This transfer does not start until week 13, and peaks in the third trimester [Palmeira et al. 2012]. Early on, the theoretic concern is that natalizumab could interfere with implantation. Natalizumab has been detected in human breast milk, with relative infant exposure as high as 5.3% of the maternal dose, and concentrations increasing over time [Baker et al. 2015]. It is not typically used by nursing mothers. Natalizumab has been used during pregnancy without notable teratogenicity, but newborns may experience transient hematologic abnormalities including anemia and thrombocytopenia [Haghikia et  al. 2014]. One study noted an immune disturbance (abnormal

lymphocyte chemotaxis) in two exposed neonates [Schneider et al. 2013]. Alemtuzumab (an IgG1 humanized monoclonal antibody) is a recently approved DMT. It is an induction agent, with prolonged suppression of disease activity after 2 cycles of treatment (5 days in year 1, and 3 days in year 2). Alemtuzumab is embryo lethal in mice, and can lower offspring lymphocyte counts. It is detected in the milk of lactating mice. All pregnant women with exposure should be checked for hypothyroidism. Placental transfer of antithyrotropin receptor antibodies has been associated with neonatal Graves’ disease with thyroid storm, in an infant born 1 year after DMT dosing. Before trying to become pregnant, a 4-month washout is recommended. This may be excessive, since blood levels are negligible or undetectable by 30 days after the last dose, and IgG does not cross the placenta until after the first trimester anyway. However this is a new DMT with limited pregnancy data, and the recommended washout should be followed for now. Mitoxantrone is no longer used to treat MS in the United States. It is associated with growth retardation and premature delivery in animal models, and there is one case of Pierre Robin syndrome in human exposures [Hellwig et  al. 2011]. A 6-month washout has been recommended prior to pregnancy. Mitoxantrone is excreted in human milk with concentrations of 18 ng/ml as late as 28 days after dosing [Azuno et al. 1995]. Drug treatment can produce amenorrhea, typically in those over age 35. Among off-label therapies for MS, anti-CD20 and anti-CD25 monoclonal antibodies may become approved agents in the near future. These IgG antibodies would be actively transported across the placenta beginning during the second trimester. Anti-CD20 monoclonals include chimeric (rituximab) and human (ofatumumab) antibodies, as well as an experimental humanized (ocrelizumab) antibody. The greatest experience is with rituximab. In monkey models, exposure during pregnancy was only linked to decreased lymphoid tissue B cells in the newborn, with immunosuppression that returned to normal by 6 months [Biogen Idec, Inc. and Genentech Inc., 2014]. In humans, preconception or first-trimester exposure has not been associated with negative outcomes; use in the second and third trimester results in detectable cord blood levels

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Therapeutic Advances in Neurological Disorders 9(3) [Østensen, 2014]. With regard to anti-CD25 monoclonal, which is under consideration for MS by the FDA, there are no available data on pregnancy risk. Prepregnancy issues Fertility and fetal development Patients should be counseled that MS has no significant impact on the ability to conceive, on fetal development, or the ability to carry to term. Fertility does not appear to be affected by MS phenotype or DMT use [Roux et  al. 2015]. Definitive data are lacking, although a recent study suggested MS patients showed decreased ovarian reserve [Thöne et al. 2015]. There is no disease-associated increase in spontaneous abortions, stillbirth, cesarean delivery, premature birth, or birth defects [Alwan et  al. 2013; Ramagopalan et al. 2010]. There are conflicting data on whether babies born to MS mothers may be a little bit smaller in weight and length. This is not a definite association, and should not be a major concern. Female versus male patients Pregnancy issues and management concerns are for the most part limited to women. Two recent studies evaluated MS men who fathered children. A British Columbia database of 202 MS men versus 981 matched controls found no impact of paternal MS on birth weight or gestational age [Lu et  al. 2014]. They concluded that paternal MS, and factors such as disease duration and disability, had no impact on birth outcomes. A second, smaller Italian study found no paternal MS association with adverse fetal outcome, even when exposure to DMTs was included as a factor [Pecori et al. 2014]. Analysis of semen quality in MS men is limited, with one study reporting lower total sperm counts, sperm motility, and percent normal sperm morphology [Safarinejad, 2008]. Genetic risk MS is a complex disease involving interactions between environmental and genetic factors, with epigenetic mechanisms likely involved [Harbo et  al. 2013; Küçükali et  al. 2015]. Patients are concerned about risk to their children. One can counsel that MS is not an inherited disease; most patients (80%) have no affected relative, but there are a number of identified risk or susceptibility

genes. Having a first-degree relative with MS increases disease risk from 0.13% to 2–2.5%. Risk is slightly higher when the first-degree relative is a sib versus a parent, supporting the impact of environmental factors [O’Gorman et al. 2013]. Risk is at least 30% in two instances: monozygotic twins, and when both parents have MS. Basic counseling Vitamin D deficiency increases risk for MS, and MS women were shown to have lower vitamin D concentrations during pregnancy and postpartum compared with controls [Jalkanen et  al. 2015]. Vitamin D deficiency should be evaluated and treated prior to pregnancy. Any MS woman seeking to become pregnant should be counseled to take prenatal vitamins and folic acid, avoid alcohol and smoking, and assure good sleep hygiene and diet. Pregnancy impact on prognosis Up until the 1950s MS women were counseled to avoid pregnancy because it would make their disease worse. This turned out to be untrue. Some studies suggest pregnancy conveys a long-term benefit [Keyhanian et  al. 2012; Masera et  al. 2015; Runmarker and Andersen 1995; Verdru et al. 1994], while others find no long-term impact [Karp et al. 2014; Ramagopalan et al. 2012]. The most accurate current counseling would be to inform patients that pregnancy has no negative effect on long-term prognosis. This statement is valid for relapsing MS women, who make up 87– 97% of all pregnancies [Coyle, 2014a]. One study did suggest pregnancy impact might be different for progressive MS women [D’Hooghe et  al. 2012]. However, the number of pregnant progressive MS patients is so limited it would take a multicenter and probably multinational pregnancy registry to evaluate this. For now, progressive pregnant MS patients should be managed like relapsing patients, and if possible entered into an ongoing pregnancy database. With regard to whether pregnancy affects risk for development of MS, a large Australian study looked at clinically isolated syndrome (CIS) patients and matched controls [Ponsonby et  al. 2012]. They reported a cumulative benefit of pregnancies to decrease risk for CIS. Giving birth, or even having a terminated pregnancy seems to protect women against MS over the next 5 years [Hedström et al. 2014; Magyari, 2015]. Another

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P Coyle small study of radiologically isolated syndrome (RIS) patients (n = 60) found that pregnancy (n = 7) was associated with increased risk for subsequent clinical attack in the postpartum period, and MRI disease activity [Lebrun et  al. 2012]. This observation requires verification. For now, patients can be told that the data indicate pregnancy protects against developing MS. RIS patients who become pregnant should have more intense follow up. Contraception choice MS women capable of pregnancy should be counseled on contraception before they initiate a DMT. Failure rates differ based on chosen technique [Coyle, 2014b]. Abstinence is most effective (0% failure rate). Long-acting reversible contraception (subdermal rod or intrauterine devices) and tubal sterilization have failure rates of less than 1%. Oral, patch, injection, ring-hormonal contraceptives (5% failure rate), and barrier methods (11–32% failure rate) are much less effective. Among the DMTs, teriflunomide may increase levels of ethinylestradiol and levonorgestrel contained in oral contraceptives [Genzyme Corporation, 2012]. Of all available contraception techniques, the longacting reversible methods should be encouraged based on efficacy, safety, and convenience [Committee on Gynecologic Practice, 2015]. Ability to care for children; economic and social burden MS patients often have concerns that their disease will have a negative economic and psychosocial impact on bearing and raising children. In a survey of 5949 MS patients diagnosed during their reproductive years, 79% did not become pregnant after diagnosis [Alwan et al. 2013]. In 34.5%, this choice involved MS-related issues, in particular concerns that their disease would interfere with parenting, followed by concerns about burdening their partner and passing MS on to their children. Patients can be told pregnancy does not produce disability, and the modern DMT era appears to be changing the natural history of MS in a positive way. Choosing to have children should not be directed by a diagnosis of MS.

women, and whether they should forego DMT use to start a family. A large study from the MSBase global registry reported that prior DMT use, any time in the 2 years before pregnancy, resulted in a 45% decreased risk for postpartum relapse [Hughes et  al. 2014]. The authors interpreted their study as providing evidence in favor of choosing to delay pregnancy, in order to commit to a DMT to control disease activity first. This would be particularly pertinent for MS women with high disease activity, greater disability, or a poor prognostic profile. The DMT washout period should be as short as possible (Table 2). There is increasing consensus that glatiramer acetate and the interferon betas do not require washouts, and can be continued until pregnancy is confirmed. It is possible that natalizumab and dimethyl fumarate do not need washouts. When a washout is used, one consensus group proposed monthly pulsed corticosteroids until pregnancy is achieved in very active MS women, or those with a history of delayed conception [Bove et al. 2014]. Assisted reproductive technology and in vitro fertilization About 10% of women have difficulties getting or staying pregnant. Assisted reproductive technology or in vitro fertilization can be used, with success rates as high as 39% in those under age 35. Estimates are that at least 1% of live births in developed countries use such technology [Bove et al. 2014]. MS women who undergo in vitro fertilization and do not conceive may be at increased risk for clinical and MRI disease activity in the 3 months post procedure [Correale et  al. 2012; Hellwig and Correale, 2013; Michel et al. 2012]. This appears to be associated with use of gonadotropin-releasing hormone agonists, as opposed to antagonists, to produce multiple eggs. Although the number of patients studied is less than 100, MS patients should be counseled about this possible risk. Fertility experts must be aware of this data as well. One could avoid using an agonist, or elect to continue use of glatiramer acetate or interferon beta during the procedure. Pregnancy issues

DMT use and washout None of the DMTs are approved for use in women who are actively trying to become pregnant. A frequent controversy involves newly diagnosed young

Disease activity Pregnancy is an immunotolerant state. Clinical and MRI disease activity is suppressed, most

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Therapeutic Advances in Neurological Disorders 9(3) clearly during the third trimester. Although precise mechanisms continue to be studied, it is coincident with increasing concentrations of a number of hormones (estrogens, progesterone, prolactin, glucocorticoids, leptin). This observation has fostered investigation of sex hormone therapy as a treatment for MS [Durand-Dubief et  al. 2014; Sicotte et  al. 2002]. In a published phase I open-label study, six relapsing MS patients benefited from oral estriol 8 mg daily, while four secondary progressive MS women did not [Sicotte et  al. 2002]. In a phase II, 2-year combination trial (glatiramer acetate with add-on estriol/progresterone or placebo), confirmed annual relapse rate at 2 years was 0.25 versus 0.37 (p = 0.077), with mixed MRI effects [Voskuhl et al. 2016]. Unfortunately, the associated editorial emphasized that the study must be viewed as negative [Langer-Gould, 2016]. DMT use The current standard of care is to avoid DMT use during pregnancy, and to stop a DMT as soon as pregnancy is recognized. Exposed patients should be encouraged to participate in a formal pregnancy registry. Among the DMTs, glatiramer acetate, interferon beta, and natalizumab have been used in pregnant patients, and there is increasing awareness that extensive glatiramer acetate and interferon beta data suggest they are safe to use [Dung and Panda, 2014; Fragoso et al. 2010; Salminen et al. 2010]. The decision to continue a DMT during pregnancy should involve formal documentation of the conversation involving the risks and benefits, and a clear indication the patient has made this informed decision. Relapse Clinical attacks are less common during pregnancy, but can occur and are more likely in the first two trimesters. There is no conclusive evidence that MRI scans up to 3T are associated with fetal harm [Bove and Klein, 2014]. Contrast should not be used without informed consent from the mother; typically it is avoided because gadolinium compounds cross the placenta and enter the fetal bloodstream. To treat the unusual relapse that occurs during pregnancy, there is no contraindication to conventional short-term corticosteroids (most often 1 g of intravenous methylprednisolone daily, given for several days without an oral taper). There is controversy as to whether first trimester steroid exposure is

associated with cleft lip and palate abnormalities [Gur et  al. 2004; Hviid and Mølgaard-Nielsen, 2011], but obstetricians feel short-term steroids can be used safely in all trimesters. Dexamethasone (which crosses the placenta with minimal metabolism) should always be avoided in favor of prednisone or methylprednisolone. Disease symptoms Pharmacotherapy for MS symptoms should be evaluated carefully and limited during pregnancy [Miller et al. 2014]. Drugs should be used at their minimum effective doses, for as short a time as possible. When there are options, drugs with the most favorable pregnancy ratings should be chosen. Since most pregnant MS patients are not disabled and are relatively early in their disease, they do not typically require significant pharmacologic symptom management. Delivery and anesthesia choices Having MS does not create a high-risk pregnancy, and the birth hospitalization period is not increased [Lu et al. 2013]. Any anesthetic choice or delivery method is acceptable [Pastò et  al. 2012]. These are purely obstetric decisions. The one exception is the rare, more disabled pregnant MS patient, where it may be necessary to consider assisted vaginal delivery or even cesarean section. Postpartum issues Disease activity The first 3 months postpartum are a recognized high-risk period for increased clinical and MRI disease activity. Activity then reverts back to the prepregnancy level [Paavilainen et al. 2007]. This may relate to rapid reversal of late pregnancy hormone levels. Factors associated with postpartum relapses have included higher relapse rate and disability prior to pregnancy, lack of prior DMT use, and relapse during pregnancy [Coyle, 2014b; Hughes et al. 2014; Vukusic et al. 2004]. In the original pregnancy in MS (PRIMS) cohort, almost 30% of MS women experienced a postpartum relapse during this period [Confavreux et al. 1998]. In the more modern MSBase registry, only 14% relapsed [Hughes et al. 2014]. In a recent small study (44 pregnant relapsing MS women and 20 controls), low maternal vitamin D levels were not associated with postpartum relapse risk [Runia et al. 2015]. The authors interpreted

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P Coyle this as not supporting the argument for additional vitamin D supplements in pregnant MS women. As noted earlier, ideally this issue is dealt with before pregnancy occurs. Small-scale studies have evaluated postpartum prophylactic intravenous immune globulin, as well as pulse corticosteroids, to minimize relapses with reported success [De Seze et  al. 2004; Haas and Hommes, 2007]. Hormonal therapy (percutaneous 17-β estradiol 100 µg weekly along with oral nomegestrol acetate 10 mg daily) was evaluated in the POPARTMUS trial, but showed no ability to suppress postpartum relapses or MRI activity [Durand-Dubief et al. 2014]. Breastfeeding Although breastfeeding is considered to offer superior health benefits to using formula, a recent very large analysis comparing healthy sibs (one breastfed, the other bottle fed), did not confirm any advantage [Colen and Ramey, 2014]. MS women should be told it is acceptable to choose not to breastfeed. Typically, the major postpartum issue is whether to breastfeed, or to start, or restart, a DMT. Until recently, these options were considered mutually exclusive. As noted earlier, both glatiramer acetate and the interferon betas can be considered with breastfeeding. This cannot be said for any of the other DMTs. For treated postpartum relapses, methylprednisolone levels in breast milk may be as high as 1.45% of maternal dose, but are much lower with a 2- to 4-hour delay following the intravenous infusion [Cooper et al. 2015]. This should be taken into account when using steroids to treat postpartum attacks in breastfeeding patients. The value of breastfeeding in MS is controversial [Langer-Gould and Hellwig, 2013; Vukusic and Confavreux, 2013]. The literature on breastfeeding and MS has never suggested a deleterious effect. Studies have shown breastfeeding either had no effect, or more commonly was associated with suppression of disease activity [Hutchinson, 2013; Langer-Gould and Beaber, 2013; Langer-Gould and Hellwig, 2013; Langer-Gould et  al. 2009, 2011; Pakpoor et al. 2012; Portaccio et al. 2011; Vukusic and Confavreux, 2013]. These conflicting results have been attributed to mixing patients who exclusively breastfed, with those who did not. Exclusive breastfeeding is defined as no regular formula feedings (less than one bottle a day). This results in a prolonged lactational amenorrhea with

ovarian suppression, high prolactin levels, and low nonpulsatile luteinizing hormone levels. MS patients should be told that if they breastfeed it should be exclusive, because this is more likely associated with decreased MS disease activity. It is not clear if disease suppression equals that of an effective DMT, however. Some studies suggest that breastfeeding, particularly when prolonged (⩾4 months), reduces risk for MS in the child [Conradi et al. 2013; Ragnedda et al. 2015]. DMT use For women at higher risk of postpartum relapse (very active disease, poor prognostic profile, relapse during pregnancy, no prior DMT use), it may be advisable to plan on starting a DMT. Treatment can be instituted very quickly after delivery. In a recent study, natalizumab started within 8 days of delivery was able to prevent postpartum relapses in five of six highly active patients [Vukusic et al. 2015]. Impact on infant/child development Maternal MS is not recognized to have a negative impact on long-term development of the child. There have been limited analyses of development of children exposed to DMTs in utero; to date, no negative impact has been found [Coyle et  al. 2014; Fragoso et al. 2013]. Neuromyelitis optica spectrum disorder For many years neuromyelitis optica spectrum disorder (NMOSD) was considered a variant of MS. It is now recognized as a distinct neuroimmune channelopathy, with most patients showing diagnostic anti-aquaporin 4 IgG. Aquaporin 4 is expressed maximally by the human placenta during midgestation; and in animal models, antibodies are capable of causing placental inflammation and fetal death [Saadoun et  al. 2013]. NMOSD shows a distinct pregnancy impact from MS. The attack rate is not significantly reduced during pregnancy, but then is also elevated during the 3 months postpartum [Shimizu et al. 2015]. NMOSD is also associated with higher risk for miscarriage [Nour et al. 2016]. Unmet needs Pregnancy will continue to be a major focus for MS patients, and the treatment era makes decision making more complex. It would be very

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Therapeutic Advances in Neurological Disorders 9(3) helpful to have accurate biomarkers for disease activity and prognosis, to guide appropriate recommendations. This could help decide whether a young woman with MS should commit to therapy, or attempt to become pregnant. Accumulating accurate data on fetal risks and breast milk exposure should allow the development of better recommendations on when it is possible to: eliminate DMT washouts, treat during pregnancy, and treat while breastfeeding. Finally, identifying why MS disease activity decreases late in pregnancy, then temporarily increases for 3 months postpartum could focus development of novel therapeutic strategies. Acknowledgement The editorial assistance of Dawn Caffrey is greatly appreciated. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Conflict of interest statement The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PKC has received consulting fees from Abbvie, Accordant, Acorda, Bayer, Biogen, Genentech/ Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, Teva and research support from Actelion, Genentech/Roche, Novartis, Opexa. References Alwan, S., Yee, I., Dybalski, M., Guimond, C., Dwosh, E., Greenwood, T. et al. (2013) Reproductive decision making after the diagnosis of multiple sclerosis (MS). Mult Scler 19: 351–358. Amato, M. and Portaccio, E. (2015) Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs 29: 207–220. Amato, M., Portaccio, E., Ghezzi, A., Hakiki, B., Zipoli, V., Martinelli, V. et al. (2010) Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis. Neurology 75: 1794–1802. Azuno, Y., Kaku, K., Fujita, N., Okubo, M., Kaneko, T. and Matsumoto, N. (1995) Mitoxantrone and etoposide in breast milk. Am J Hematol 48: 131–132. Baker, T., Cooper, S., Kessler, L. and Hale, T. (2015) Transfer of natalizumab into breast milk in a mother with multiple sclerosis. J Hum Lact 31: 233–236.

Bayer HealthCare Pharmaceuticals, Inc. (2012) Betaseron® Interferon beta-1b (package insert). New Jersey: Bayer HealthCare Pharmaceuticals, Inc. Biogen Idec, Inc. (2014) Tecfidera® Dimethyl fumarate (package insert). Massachusetts: Biogen Idec, Inc. Biogen Idec, Inc. and Genentech,Inc. (2014) Rituxan® Rituximab (package insert). California: Genentech, Inc. Borisow, N., Friedemann, P., Ohlraun, S., Pach, D., Fischer, F. and Dörr, J. (2014) Pregnancy in multiple sclerosis: a questionnaire study. PLoS One 9: e99106. Boskovic, R., Wide, R., Wolpin, J., Bauer, D. and Koren, G. (2005) The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 65: 807–811. Bove, R., Alwan, S., Friedman, J., Hellwig, K., Houtchens, M., Koren, G. et al. (2014) Management of multiple sclerosis during pregnancy and the reproductive years. Obstet Gynecol 124: 1157–1168. Bove, R. and Klein, J. (2014) Neuroradiology in women of childbearing age. Continuum 20: 23–41. Carvalho, A., Veiga, A., Morgado, J., Tojal, R., Rocha, S., Vale, J. et al. (2014) Multiple sclerosis and motherhood choice: an observational study in Portuguese women patients. Rev Neurol 59: 537–542. Colen, C. and Ramey, D. (2014) Is breast truly best? Estimating the effects of breastfeeding on long-term child health and wellbeing in the United States using sibling comparisons. Soc Sci Med 109: 55–65. Committee on Gynecologic Practice (2015) Committee Opinion No. 642: Increasing access to contraceptive implants and intrauterine devices to reduce unintended pregnancy. Obstet Gynecol 126: e44–e48. Confavreux, C., Hutchinson, M., Hours, M., Cortinovis-Tourniaire, P. and Moreau, T. (1998) Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 339: 285–291. Conradi, S., Malzahn, U., Friedemann, P., Quill, S., Harms, L., Bergh, F. et al. (2013) Breastfeeding is associated with lower risk for multiple sclerosis. MSJ 19: 553–558. Cooper, S., Felkins, K., Baker, T. and Hale, T. (2015) Transfer of methylprednisolone into breast milk in a mother with multiple sclerosis. J Hum Lact 31: 237–239. Correale, J., Farez, M. and Ysrraelit, M. (2012) Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol 72: 682–694. Coyle, P. (2014a) Multiple sclerosis and pregnancy prescriptions. Expert Opin Drug Saf 13: 1565–1568.

206 http://tan.sagepub.com

P Coyle Coyle, P. (2014b) Multiple sclerosis in pregnancy. Continuum 20: 42–59.

fingolimod treatment. Ther Ad Neurol Disord 8: 233–238.

Coyle, P., Sinclair, S., Scheuerle, A., Thorp, J., Jr, Albano, J. and Rametta, M. (2014) Final results from the Betaseron (interferon β-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events. BMJ Open 4: e004536.

Fragoso, Y., Adoni, T., Alves-Leon, S., Azambuja, N., Jr, Barreira, A., Brooks, J. et al. (2013) Longterm effects of exposure to disease-modifying drugs in the offspring of mothers with multiple sclerosis: a retrospective chart review. CNS Drugs 27: 955–961.

Cree, B. (2013) Update on reproductive safety of current and emerging disease-modifying therapies for multiple sclerosis. Mult Scler 19: 835–843. Dahl, J., Myhr, K., Daltveit, A. and Gilhus, N. (2006) Planned vaginal births in women with multiple sclerosis: delivery and birth outcome. Acta Neurol Scand Suppl 183: 51–54. Dahl, J., Myhr, K., Daltveit, A. and Gilhus, N. (2008) Pregnancy, delivery and birth outcome in different stages of maternal multiple sclerosis. J Neurol 255: 623–627. De Giglio, L., Gasperini, C., Tortorella, C., Trojano, M. and Pozzilli, C. (2015) Natalizumab discontinuation and disease restart in pregnancy: a case series. Acta Neurol Scand 131: 336–340. De Seze, J., Chapelotte, M., Delalande, S., Ferriby, D., Stojkovic, T. and Vermersch, P. (2004) Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. MSJ 10: 596–597. D’Hooghe, M., Haentjens, P., Nagels, G., D’Hooghe, T. and Keyser, J. (2012) Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis. J Neurol 259: 855–861. Dung, A. and Panda, A. (2014) Interferon β-1a therapy for multiple sclerosis during pregnancy: an unresolved issue. BMJ Case Rep 2014: bcr2013201273. DOI: 10.1136/bcr-2013-201273. Duquette, P. and Prat, A. (2015) How safe is natalizumab during pregnancy? Mult Scler 21: 121–122. Durand-Dubief, F., El-Etr, M., Ionescu, J., Bracoud, L., Cotton, F., Merle, H. et al. (2014) The POPARTMUS: a French-Italian multicentric trial of postpartum progestin and estradiol in multiple sclerosis – MRI findings. MSJ 20: 95. Ebrahimi, N., Herbstritt, S., Gold, R., Amezcua, L., Koren, G. and Hellwig, K. (2015) Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. MSJ 21: 198–205. Faissner, S., Hoepner, R., Lukas, C., Chan, A., Gold, R. and Ellrichmann, G. (2015) Tumefactive multiple sclerosis lesions in two patients after cessation of

Fragoso, Y., Finkelsztejn, A., Kaimen-Maciel, D., Grzesiuk, A., Gallina, A., Lopes, J. et al. (2010) Longterm use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicenter case series. CNS Drugs 24: 969–976. Genzyme Corporation. (2012) Aubagio® Teriflunomide (package insert). Massachusetts: Genzyme Corporation. Gur, C., Diav-Citrin, O., Shechtman, S., Arnon, J. and Ornoy, A. (2004) Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 18: 93–101. Haas, J. and Hommes, O. (2007) A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. MSJ 13: 900–908. Haghikia, A., Langer-Gould, A., Rellensmaan, G., Schneider, H., Tenenbaum, T., Elias-Hamp, B. et al. (2014). Natalizumab use during the third trimester of pregnancy. JAMA Neurol 71: 891–895. Hale, T., Siddiqui, A. and Baker, T. (2012) Transfer of interferon β-1a into human breast milk. Breastfeed Med 7: 123–125. Harbo, H., Gold, R. and Tintoré, M. (2013) Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord 6: 237–248. Hedström, A., Hillert, J., Olsson, T. and Alfredsson, L. (2014) Reverse causality behind the association between reproductive history and MS. Mult Scler 20: 406–411. Hellwig, K. (2014) Pregnancy in multiple sclerosis. Eur Neurol 72: 39–42. Hellwig, K. and Correale, J. (2013) Artificial reproductive techniques in multiple sclerosis. Clin Immunol 149: 219–224. Hellwig, K. and Gold, R. (2011) Glatiramer acetate and interferon-beta throughout gestation and postpartum in women with multiple sclerosis. J Neurol 258: 502–503. Hellwig, K., Haghikia, A., Rockhoff, M. and Gold, R. (2012) Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord 5: 247–253. Hellwig, L., Schimrigk, S., Chan, A., Epplen, J. and Gold, R. (2011) A newborn with Pierre Robin

http://tan.sagepub.com 207

Therapeutic Advances in Neurological Disorders 9(3) sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis. J Neurol Sci 307: 164–165. Hughes, S., Spelman, T., Gray, O., Boz, C., Trojano, M., Lugaresi, A. et al. (2014) Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 20: 739–746. Hutchinson, M. (2013) One can prevent post-partum relapses by exclusive breast feeding: commentary. MSJ 19: 1569–1570. Hviid, A. and Mølgaard-Nielsen, D. (2011) Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 183: 796–804. Jalkanen, A., Kauko, T., Turpeinen, U., Hämäläinen, E. and Airas, L. (2015) Multiple sclerosis and vitamin D during pregnancy and lactation. Acta Neurol Scand 131: 64–67. Karlsson, G., Francis, G., Koren, G., Heining, P., Zhang, X., Cohen, J. et al. (2014) Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology 82: 674–680. Karp, I., Manganas, A., Sylvestre, M., Ho, A., Roger, E. and Duquette, P. (2014) Does pregnancy alter the long-term course of multiple sclerosis? Ann Epidemiol 24: 504–508. Keyhanian, K., Davoudi, V., Etemadifar, M. and Amin, M. (2012) Better prognosis of multiple sclerosis in patients who experienced a full-term pregnancy. Eur Neurol 68: 150–155. Khan, O., Xia, Q., Bever, C., Jr, Johnson, K., Panitch, H. and Dhib-Jalbut, S. (1996) Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration. Neurology 46: 1639–1643. Kieseier, B. and Benamor, M. (2014) Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurol Ther 3: 133–138. Küçükali, C., Kürtüncü, M., Çoban, A., Çebi, M. and Tüzün, E. (2015) Epigenetics of multiple sclerosis: an updated review. Neuromol Med 17: 83–96. Langer-Gould, A. (2016) Sex hormones and multiple sclerosis: another informative failure. Lancet Neurol 15: 22–23. Langer-Gould, A. and Beaber, B. (2013) Effects of pregnancy and breastfeeding on the multiple sclerosis disease course. Clin Immunol 149: 244–250. Langer-Gould, A. and Hellwig, K. (2013) One can prevent post-partum MS relapses by exclusive breast feeding: Yes. MSJ 19: 1567–1568.

Langer-Gould, A., Huang, S., Gupta, R., Leimpeter, A., Greenwood, E., Albers, K. et al. (2009) Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 66: 958–963. Langer-Gould, A., Huang, S., Van Den Eeden, S., Gupta, R., Leimpeter, A., Albers, K. et al. (2011) Vitamin D, pregnancy, breastfeeding, and postpartum multiple sclerosis relapses. Arch Neurol 68: 310–313. Lebrun, C., Le Page, E., Kantarci, O., Siva, A., Pelletier, D., Okuda, D. et al. (2012) Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler 18: 1297–1302. Lu, E., Dahlgren, L., Sadovnick, A., Sayao, A., Synnes, A. and Tremlett, H. (2012) Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs. Mult Scler 18: 460–467. Lu, E., Zhao, Y., Zhu, F., Van der Kop, M., Synnes, A., Dahlgren, L. et al. (2013) Birth hospitalization in mothers with multiple sclerosis and their newborns. Neurology 80: 447–452. Lu, E., Zhu, F., Zhao, Y., Van der Kop, M., Sadovnick, A., Synnes, A. et al. (2014) Birth outcomes of pregnancies fathered by men with multiple sclerosis. Mult Scler 20: 1260–1264. Magyari, M. (2015) Role of socio-economic and reproductive factors in the risk of multiple sclerosis. Acta Neurol Scand 132: 20–23. Masera, S., Cavalla, P., Prosperini, L., Mattioda, A., Mancinelli, C., Superti, G. et al. (2015) Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. Mult Scler 21: 1291–1297. Michel, L., Foucher, Y., Vukusic, S., Confavreux, C., de Sèze, J., Brassat, D. et al. (2012) Increased risk of multiple sclerosis relapse after in vitro fertilization. J Neurol Neurosurg Psychiatry 83: 796–802. Miller, D., Fazekas, F., Montalban, X., Reingold, S. and Trojano, M. (2014) Pregnancy, sex, and hormonal factors in multiple sclerosis. MSJ 20: 527–536. Nour, M., Nakashima, I., Coutinho, E., Woodhall, M., Sousa, F., Revis, J. et al. (2016) Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder. Neurology 86: 79–87. Novartis Pharmaceuticals Corporation. (2015) Gilenya® Fingolimod (package insert). New Jersey: Novartis Pharmaceuticals Corporation. O’Gorman, C., Lin, R., Stankovich, J. and Broadley, S. (2013) Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology 40: 1–12.

208 http://tan.sagepub.com

P Coyle Østensen, M. (2014) Safety issues of biologics in pregnant patients with rheumatic diseases. Ann NY Acad Sci 1317: 32–38.

Romero, R., Lünzmann, C. and Bugge, J. (2015) Pregnancy outcomes in patients exposed to interferon beta-1b. J Neurol Neurosurg Psychiatry 86: 587–589.

Paavilainen, T., Kurki, T., Parkkola, R., Färkkilä, M., Salonen, O., Dastidar, P. et al. (2007) Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis. Eur J Neurol 14: 1216–1221.

Roux, T., Courtillot, C., Debs, R., Touraine, P., Lubetzki, C. and Papeix, C. (2015) Fecundity in women with multiple sclerosis: an observational mono-centric study. J Neurol 262: 957–960.

Pakpoor, J., Disanto, G., Lacey, M., Hellwig, K., Giovannoni, G. and Ramagopalan, S. (2012) Breastfeeding and multiple sclerosis relapses: a metaanalysis. J Neurol 259: 2246–2248. Palmeira, P., Quinello, C., Silveira-Lessa, A., Zago, C. and Carneiro-Sampaio, M. (2012) IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012: 1–13. Pastò, L., Portaccio, E., Ghezzi, A., Hakiki, B., Giannini, M., Razzolini, L. et al. (2012) Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study. BMC Neurology 12: 165. Patti, F., Cavallaro, T., Lo Fermo, S., Nicoletti, A., Cimino, V., Vecchio, R. et al. (2008) Is in utero early-exposure to interferon beta a risk factor for pregnancy outcomes in multiple sclerosis? J Neurol 255: 1250–1253. Pecori, C., Giannini, M., Portaccio, E., Ghezzi, A., Hakiki, B., Pastò, L. et al. (2014) Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study. BMC Neurol 14: 114. Ponsonby, A., Lucas, R., Van der Mei, I., Dear, K., Valery, P., Pender, M. et al. (2012) Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology 78: 867–874. Portaccio, E., Ghezzi, A., Hakiki, B., Martinelli, V., Moiola, L., Patti, F. et al. (2011) Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 77: 145–150. Ragnedda, G., Leoni, S., Parpinel, M., Casetta, I., Riise, T., Myhr, K. et al. (2015) Reduced duration of breastfeeding is associated with a higher risk of multiple sclerosis in both Italian and Norwegian adult males: the EnvIMS study. J Neurol 262: 1271–1277. Ramagopalan, S., Guimond, C., Criscuoli, M., Dyment, D., Orton, S., Yee, I. et al. (2010) Congenital abnormalities and multiple sclerosis. BMC Neurology 10: 115. Ramagopalan, S., Yee, I., Byrnes, J., Guimond, C., Ebers, B. and Sadovnick, D. (2012) Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study. J Neurol Neurosurg Psychiatry 83: 793–795.

Runia, T., Neuteboom, R., de Groot, C., de Rijke, Y. and Hintzen, R. (2015) The influence of vitamin D on postpartum relapse and quality of life in pregnant multiple sclerosis patients. Eur J Neurol 22: 479–484. Runmarker, B. and Andersen, O. (1995) Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 118: 253–261. Saadoun, S., Waters, P., Leite, M., Bennett, J., Vincent, A. and Papadopoulos, M. (2013) Neuromyelitis optica IgG causes placental inflammation and fetal death. J Immunol 191: 2999–3005. Safarinejad, M. (2008) Evaluation of endocrine profile, hypothalamic-pituitary-testis axis and semen quality in multiple sclerosis. J Neuroendocrinol 20: 1368–1375. Salminen, H., Leggett, H. and Boggild, M. (2010) Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. J Neurol 257: 2020–2023. Sandberg-Wollheim, M., Alteri, E., Moraga, M. and Kornmann, G. (2011) Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler 17: 423–430. Schneider, H., Weber, C., Hellwig, K., Schroten, H. and Tenenbaum, T. (2013) Natalizumab treatment during pregnancy–effects on the neonatal immune system. Acta Neurol Scand 127: e1–4. Shimizu, Y., Fujihara, K., Ohashi, T., Nakashima, I., Yokoyama, K., Ikeguch, R. et al. (2015) Pregnancyrelated relapse risk factors in women with anti-AQP4 antibody positivity and neuromyelitis optica spectrum disorder. MSJ 1–8. Sicotte, N., Liva, S., Klutch, R., Pfieffer, P., Bouvier, S., Odesa, S. et al. (2002) Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 52: 421–428. Thöne, J., Kollar, S., Nousome, D., Ellrichmann, G., Kleiter, I., Gold, R. et al. (2015) Serum anti-Müllerian hormone levels in reproductive-age women with relapsing-remitting multiple sclerosis. MSJ 21: 41–47. Van der Kop, M., Pearce, M., Dahlgren, L., Synnes, A., Sadovnick, D., Sayao, A. et al. (2011) Neonatal and delivery outcomes in women with multiple sclerosis. Ann Neurol 70: 41–50. Verdru, P., Theys, P., D’Hooghe, M. and Carton, H. (1994) Pregnancy and multiple sclerosis: the influence on long-term disability. Clin Neurol Neurosurg 96: 38–41.

http://tan.sagepub.com 209

Therapeutic Advances in Neurological Disorders 9(3) Verhaeghe, A., Deryck, O. and Vanopdenbosch, L. (2014) Pseudotumoral rebound of multiple sclerosis in a pregnant patient after stopping natalizumab. Mult Scler Relat Disord 3: 279–281. Voskuhl, R., Wang, H., Jackson, W., Sicotte, N., Nakamura, K., Kurth, F. et al. (2016) Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomized, placebo-controlled, phase II trial. Lancet Neurol 15: 35–46. Vukusic, S. and Confavreux, C. (2013) One can prevent post-partum MS relapses by exclusive breast feeding: No. MSJ 19: 1565–1566. Vukusic, S., Durand-Dubief, F., Benoit, A., Marignier, R., Frangoulis, B. and Confavreux, C. (2015) Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis. MSJ 21: 953–955. Visit SAGE journals online http://tan.sagepub.com

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Vukusic, S., Hutchinson, M., Hours, M., Moreau, T., Cortinovis-Tourniaire, P., Adeleine, P. et al. (2004) Pregnancy and multiple sclerosis (the PRIMS study):

clinical predictors of post-partum relapse. Brain 127: 1353–1360. Vukusic, S. and Marignier, R. (2015) Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol 11: 280–289. Waysbort, A., Giroux, M., Mansat, V., Teixeira, M., Dumas, J. and Puel, J. (1993) Experimental study of transplacental passage of alpha interferon by two assay techniques. Antimicrob Agents Chemother 37: 1232–1237. Weber-Schoendorfer, C. and Schaefer, C. (2009) Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler 15: 1037–1042. Wundes, A., Pebdani, R. and Amtmann, D. (2014) What do healthcare providers advise women with multiple sclerosis regarding pregnancy? Mult Scler Int 2014: 819216. Ziemssen, T., Neuhaus, O. and Hohfeld, R. (2001) Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 24: 979–990.

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