Sage Journals: Discover world-class research

Abstract

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

Keywords

breastfeeding multiple sclerosis pregnancy sex differences sex hormones women

Introduction

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Several factors implicate chromosomal sex and hormones in susceptibility and disease course in MS. MS is more common in women, with a female to male sex ratio of 3:1,¹ whereas before puberty and after menopause the sex ratio approaches 1:1.^2–4 MS most commonly begins between 20 years and 40 years of age, and thus women of reproductive age are most commonly affected.

Whereas relapse rate decreases during pregnancy, there tends to be an increased relapse rate postpartum,⁵ and relapse rate decreases after menopause.⁶ Management of women with MS throughout their reproductive lifespan requires consideration of effects of pregnancy and breastfeeding, including understanding disease-modifying therapy (DMT) effects on children of women with MS. Hormonal factors may influence disability progression, as progression tends to occur earlier in men,⁷ and later during the perimenopausal period in women.^8,9

In this review, we discuss effects of sex on disease susceptibility, implications of MS on fertility and pregnancy, including peripartum DMT and other management considerations, the impact of pregnancy on the course of MS, the interaction between reproductive aging and MS, and sexual dysfunction in women with MS.

Susceptibility to MS

It has long been recognized that MS is more common in women, but recent observations suggest the sex ratio may be increasing due to a rise in cases in women over the last century.¹⁰ An increasing sex ratio has been reported in several countries (e.g., in Canada the sex ratio increased from 1.9 to 3.2, and in Sweden from 1.7 to 2.7 for patients born in the 1930s compared with the 1980s).^1,11 However, there appear to be regional differences in the changing sex ratio as this has not been observed in New Zealand,¹² and may differ by latitude.¹³ More recently, the sex ratio was stable in Ontario, Canada for MS onset from 1996 to 2013.¹⁴ A rise in incidence over the last century is too short for a genetic cause and suggests a sex by environmental factor interaction. While some question whether the rising incidence is confounded by better diagnostics, others urge searching for an environmental cause of the observed increased incidence in women. There have been many changes in women’s lifestyles in recent decades: a later age at first pregnancy, increased availability and use of hormonal contraception, a lower rate of childbirth, and higher rates of employment and smoking.

Many of these factors have been examined in the Danish MS Registry.¹⁵ Having children reduced the risk of MS in women (but not in men) by about 46% during the following 5 years. This may be due to temporary immunosuppression during pregnancy, although reverse causation secondary to an “MS prodrome” resulting in fewer pregnancies in women with subclinical MS cannot be excluded.¹⁶

It is likely that the increased susceptibility of women towards MS is influenced by genetic, hormonal, and environmental factors.

Genetics and epigenetics

The genetic predisposition of MS is approximately 25%, based on monozygotic twin studies.¹⁷ With the success of genome wide association studies (GWAS) over the last decade, 48% of this heritability has been explained with 233 statistically independent loci (32 in the MHC region).¹⁸ Carrying HLA-DRB1*15:01 accounts for 10.5% of the genetic risk for MS.

Leveraging the largest GWAS of nearly 50,000 MS cases, one single nucleotide polymorphism (SNP rs2807267, closest gene VGLL1) on the X chromosome has been associated with MS.¹⁸ The SNP lies within an enhancer peak specific for T cells, and additional study is required to understand its functional consequence in MS. No susceptibility alleles have been identified on the Y chromosome.

Interaction between the genome and sex-specific biological and environmental factors may underlie at least part of the possible increase in MS incidence in women. One aspect of this may be sex-specific epigenetic changes. Maternal imprinting of the X chromosome or X dosage effects may contribute to autoimmunity in women.¹⁹ Voskuhl et al. demonstrated differential methylation and expression of genes on the X chromosome in T lymphocytes from females versus males.^20,21 In addition, an X chromosome gene (Kdm6a) that escapes X inactivation, with two copies expressed in females and one in males, is a histone demethylase that influences autosomal genome wide expression and is proinflammatory in T lymphocytes.²² It is thus conceivable that a key environmental factor, which has changed over the last century, may interact with genes on either sex chromosomes or autosomes to create increased risk in women.

Hormones

The effects of puberty, pregnancy, and menopause – periods during which sex hormone levels change dramatically – have been the subject of several studies. Puberty represents a risk factor for MS; earlier age of menarche has been associated with increased risk of MS and younger onset of MS symptoms in women.^23,24 In pediatric MS, girls largely present 2 years after menarche²⁵; the immune system may be stimulated by sex steroid hormones during puberty.²⁶ Additional work is needed to parse out the specific biological mechanism of the epidemiologic association of puberty with MS risk. As mentioned previously, nulliparous women may have higher risk of MS than those who had several pregnancies.¹⁵ To reconcile this increased risk with female puberty onset and decreased risk with multiparity, estrogens have been shown to have a biphasic dose effect, being immunostimulatory at low levels consistent with menstrual cycling, while being immunosuppressive at high levels of pregnancy.^27,28

Environmental

Environmental factors likely play a large role in MS risk given the 75% discordance rate amongst identical twins.¹⁷ The most replicated environmental risk factors for MS include: active and passive smoking, Epstein Barr virus (EBV) seropositivity, low serum levels of vitamin D, and low sunlight exposure. Biological sex may interact with some of these factors to increase MS risk.

Smoking

Smokers of both sexes have increased risk of developing MS (odds ratio 1.4); risk increases with cumulative smoking dose.^29,30 Data from The Swedish National Institute of Public Health showed that, at the beginning of the 21st century, 20–25% women smoked (compared with 15–17% men). United Kingdom (UK) smoking prevalence has been increasing in women throughout the 20th century, which has been hypothesized to contribute to increasing MS risk.³¹

EBV

EBV is a ubiquitous gamma herpes virus. In adulthood, ~95% of the general population have evidence of prior EBV exposure; this proportion approaches 100% in MS.³² While, on average, men seroconvert to positive EBV status at a slightly later age than women, there is no clear evidence that EBV plays a role in driving the unequal sex ratio of MS.

Vitamin D/sunlight exposure

The move away from outdoor-based lifestyles may be driving a reduction in serum vitamin D levels in the population. It is not known if women are more susceptible to downstream effects of low vitamin D,³³ but a study in an animal model demonstrated protection from experimental autoimmune encephalitis (EAE) with vitamin D only in female mice.³⁴ Low sunlight exposure is also associated with MS risk, with potential sex-specific effects of ultraviolet radiation exposure.³⁵

More data are needed to identify hormonal and environmental risk factors for MS, which act preferentially in women.

Fertility and contraception

Fertility and assisted reproductive technology

There are no studies that directly assess pregnancy success rates in MS,^36,37 though some epidemiological studies have shown that women with MS may have fewer children than the general population.^36,38,39 Potential underlying reasons for this could include the effect of autoimmune disease on fertility, the contributions of symptoms such as fatigue, sexual dysfunction, and bladder impairment on attempting pregnancy, or the individual’s decision to conceive being influenced by her disease.^36,37,40 Certain older DMTs, particularly cyclophosphamide and mitoxantrone,^41,42 may also impair fertility. Rigorous analyses for newer drugs are limited. More recent studies have assessed markers of ovarian reserve and function in women with MS, including levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), and antral follicle count.^9,43,44 In one study of 76 women with relapsing MS (most of whom were not taking DMT) and 58 controls, women with MS had reduced ovarian reserve (lower AMH level) compared with healthy controls.⁴³ Another study showed those with higher disease activity had lower AMH levels than those with lower disease activity.⁴⁴ However, in a study of 412 women with MS [mostly relapsing remitting (RRMS) and using injectable therapies] and 180 healthy controls, there was no difference in AMH level for women with MS compared with controls after adjustment for chronological age, birth control/hormonal therapy use, body mass index (BMI), and smoking.⁹

Regardless of any potential impact of MS on fertility, 12% of women in the general population confront infertility and may turn to assisted reproductive technologies (ART).⁴⁵ ART involves administration of hormonal medications, and may include several procedures in vitro on oocytes and sperm, or on embryos, to establish a pregnancy. Artificial insemination (INSE) may be performed either with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).⁴⁶ Although the effect of ART on the immune system in women with MS requires further study, there are reports of increased MS activity after ART (Table 1).^47–50 Hellwig et al. observed that 12 of 23 women with MS relapsed within 3 months after ART, and the difference in relapse rate pre- and post-ART was correlated with INSE procedure.⁵¹ A small study of women treated with GnRH (gonadotropin releasing hormone) agonists and recombinant FSH observed increased clinical relapses and enhancing magnetic resonance imaging (MRI) lesions after ART.⁵² Similarly, another study, wherein women with MS received GnRH agonist or antagonist, followed by FSH, found that the annualized relapse rate (ARR) increased during 3 months following ART, with correlation to GnRH agonist use and IVF failure.⁵³ A recent meta-analysis by Bove et al.⁵⁰ combined five published studies and reported a case series (n = 12).^51–55 Whereas the Boston case series did not have higher ARR after ART compared with before, the overall meta-analysis including this cohort confirmed increased ARR after ART, with a mean ARR increase of 0.92 [95% confidence interval (CI) 0.33–1.51].⁵⁰ On the other hand, Guzman-Soto et al. reported that leuprolide acetate, a synthetic analogue of GnRH used in IVF, has a neurotrophic effect on neurofilament, myelin basic protein expression, and axonal morphometry in EAE, thus opening horizons for studying protocols of ART in MS.⁵⁶

Table 1.

Summarized data from articles reporting on ART in women with MS.

Authors	Year	Type of article	Main findings
Cavalla et al.³⁶	2006	Review	Review on fertility in women with MS
D’Hooge et al.⁵⁷	2013		Review on reproductive factors in women with MS
Hellwig and Correale⁵⁸	2013		Immunological changes induced by ART can increase pro-inflammatory factors in MS
Laplaud et al.⁵⁴	2006	Case series	GnRH agonists correlated to relapses
Laplaud et al.⁵⁹	2007		GnRH agonists correlated to relapses
Hellwig et al.⁵⁵	2008		GnRH agonists correlated to relapses
Hellwig et al.⁵¹	2009		Hormonal approach did not correlate to relapses
Correale et al.⁵²	2012		GnRH agonists correlated to relapses
Michel et al.⁵³	2012		GnRH agonists correlated to relapses
Bove et al.⁵⁰	2019	Meta-analysis	Meta-analysis of above studies confirmed increased ARR after ART versus prior
Vaknin-Dembinsky et al.⁴⁷	2015	Case reports	Relapse and tumefactive lesion shortly after an IVF cycle
Ladwig et al.⁴⁸	2016		Onset of MS after IVF
Torkildsen et al.⁴⁹	2018		Severe reactivation of MS following IVF
Voskuhl et al.60	2012	Editorial	Hormonal manipulation in ART is complex and may induce changes in immunomodulation

ARR, annualized relapse rate; ART, assisted reproductive technology; GnRH, gonadotropin releasing hormone; IVF, in vitro fertilization; MS, multiple sclerosis.

In summary, ART, particularly the use of GnRH agonists, may increase MS disease activity in the short term, though further work is necessary to elucidate how induced hormonal changes may affect MS course.

Contraception

Contraception is an important topic in MS, particularly as women are often of childbearing age at disease onset and some DMTs are potential teratogens.⁶¹ Multiple dimensions should be considered, including contraception effect on risk of MS and related disability, family planning, type of contraception available, and concurrent use with DMTs.

Prior studies have reported mixed effects of hormonal contraception on risk of developing MS.^62–67 Different population-based, case-control, or cohort studies concluded a protective,^65,66 neutral,⁶⁴ or even negative effect of oral contraceptive (OC) exposure on MS risk.⁶⁷ While the Nurses’ Health Study showed no effect of past or current use of OC on risk of MS,⁶⁴ a case-control study demonstrated decreased risk of MS in those using OC in the 3 years prior to MS onset,⁶⁵ and the Swedish MS registrar demonstrated that OC use before first MS symptoms was associated with an older age of MS onset.⁶⁶ On the other hand, a nested case-control study suggested a slightly increased risk of MS or clinically isolated syndrome (CIS) with former or current OC exposure, although this could have been due to an unmeasured confounder.⁶⁷ Limitations of most of these studies include observational design, small sample size, self-reported data on OC use, lack of information about OC hormonal composition and duration of exposure, and the potential for residual confounding. As such, definitive conclusions on the effect of OC on MS risk remains unclear.

There is scarce information about the effect of OC on long-term prognosis of MS, although, reassuringly, hormonal contraception does not seem to negatively affect disease progression or disability.⁶⁸ Two studies reported decreased risk of disability accumulation and conversion to secondary progressive MS (SPMS) in relapsing onset patients who had ever used OC.^69,70 No significant differences in ARR between OC ever and never users were found. In contrast, D’Hooghe et al. described a shorter time from first symptom to reach Expanded Disability Status Scale (EDSS) 6.0 in OC users with primary progressive MS (PPMS).⁷¹ The lack of consistency between studies could be partially explained by the influence of potential confounders that affect disease evolution and also determine the patient’s decision to take OC. Recently, a multivariable and time-dependent analysis applied to the Barcelona CIS cohort reported that OC use before or after CIS did not significantly influence the risk of MS or time to confirmed EDSS 3.0.⁷² However, OC may have an impact in patients with established MS distinct to any effect on ARR due to transition from the more inflammatory early stage of disease to the more neurodegenerative stage, which may be more sensitive to neuroprotective effects of estrogens in OC.⁷³

Optimal contraceptive methods should be individualized, as women with MS may suffer from symptoms that make use of some methods difficult (such as using vaginal rings).⁷⁴ The US Medical Eligibility Criteria for Contraceptive Use, published by the United States (US) Centers for Disease Control and Prevention, outlines the safety of contraception in women with MS, and generally, the majority are felt to be safe in MS. Caution should be exercised in the use of combined hormonal contraceptives in individuals with prolonged immobility, due to increased thromboembolic risk.⁷⁵ Current DMTs do not appear to alter effectiveness of hormonal contraceptives,^74,76 but there are limited formal drug–drug interaction studies, and symptomatic medications such as modafinil can decrease effectiveness of hormonal contraceptives.⁷⁴

Immunology of pregnancy: effects in MS

Immunological changes at the maternal–fetal interface

The maternal–fetal interface refers to the collocation between the uterus and extra-embryonic tissue.⁷⁷ On the fetal side, the blastocyst differentiates into an inner cell mass, the future fetus, and the outer extra-embryonic trophoblast. The trophoblast further separates into villous and non-villous cytotrophoblast and syncytiotrophoblast.⁷⁷ In preparation for potential conception, the endometrium undergoes a series of changes, or decidualization, that continue into pregnancy.⁷⁸ Decidualization requires a number of immune cells allowing trophoblast invasion (resulting in maternal–fetal interface), remodeling of spiral arteries, and placentation.⁷⁷ Decidualization is also important in the development of anti-microbial immunity.⁷⁹

Immunological changes in pregnancy and MS

Pregnancy affords protection from relapses in EAE and MS.^5,80,81 Hormonal changes induced by pregnancy modulate immune response toward a state of tolerance to allow the semi-allogenic fetus to grow within the maternal uterus. Estrogen, progesterone, and human chorionic gonadotropin (hCG) modulate cells of the innate and adaptive immune system to adopt fetal-friendly phenotypes.⁸² A shift from Th1 to Th2 response has been observed consistently in MS pregnancies,^83–85 based on studies between 13 weeks and 27 weeks gestation. More recent data suggests active pro-inflammatory Th1 immunity before and after this period.⁷⁹ Regulatory T cells (Tregs) have been found to be increased,^86,87 decreased,⁸⁸ or unchanged,^89,90 probably due to different definitions of Tregs used across studies. The Th17 compartment seems unaffected by pregnancy,⁸⁸ whereas CD56^bright natural killer (NK) cells were increased peripherally in one study.⁸⁸

In MS, pregnancy also alters the clonal composition of T cells toward a more uniformly distributed repertoire.⁹¹ It induces a contraction of relapse-associated T cell clones, potentially contributing to reduced relapse rate from the first to third trimester.⁹¹ Such clones re-expand after delivery in an individualized fashion.⁹¹ Women gradually recover pre-pregnancy immunity along with decreased pregnancy hormones postpartum, which may lead to disease rebound, although immunological mechanisms are unclear. Tregs changed functionally in the early postpartum period in MS in one study,⁸⁹ and decreased numerically in another study.⁸⁸ Decline in CD4+, interferon-γ producing T cells, as well as in CD56^bright NK cells,⁸⁹ has been correlated with postpartum MS relapses.⁹² Although the immunopathogenic role of B cells is increasingly recognized, and these cells are sensitive to stimulation by female sex hormones,⁹³ there is a paucity of studies exploring whether they are modulated by pregnancy. Further studies investigating functional changes of immune cell subtypes are required to clarify complex relationships between pregnancy and immunomodulation. Indeed, the immune system during pregnancy is dynamic and responsive, promoting tolerance to fetal proteins and allowing fetal growth.^79,89,94 Table 2 summarizes immunological changes by pregnancy trimester and effects on MS.

Table 2.

Immunological changes by pregnancy trimester and effects on MS.

	First trimester of pregnancy (post-ovulation to <13 weeks GA)	Second trimester of pregnancy (13–27 weeks GA)	Third trimester of pregnancy (>27–40 weeks GA)
Main event	Implantation and placentation^77,79	Symbiotic relationship between mother, placenta, and fetus allowing fetal tolerance and growth^79,94	Preparation for labor and delivery by induction of uterine contractions, delivery of the infant, and placental separation⁷⁹
Direction of immune changes	Pro-inflammatory milieu⁷⁹	Anti-inflammatory milieu with Th2 deviation based on several studies investigating the immunology of pregnancy during this period⁷⁹	Pro-inflammatory milieu^79,89
Immune mechanisms	u-NK (70%): weakly cytotoxic unlike peripheral NK; source of cytokines, MMPs and angiogenetic factors.MP (20%) and u-NK are involved in vascular and tissue remodeling, angiogenesis, trophoblast invasion and cytokine production. MP digest apoptotic cells secondary to remodeling.T cells (10–20%): 2/3 CD8+ and 1/3 CD4+.- Exact function yet to be defined- Might regulate trophoblast invasionu-DC (rare): weak APC; role in early pregnancy unclear but might prime naïve CD4 to become Th2; crucial role in presenting fetal antigens to T cells leading to tolerance.^77,95 Paucity of information on B cells, despite newer data on the evolving role for B cells in different phases of pregnancy.^96,97	MP, M2-phenotype promotes tissue renewal and placental growth.u-NK interacts with MP-M2 phenotype and generated Tregs.Tregs expand early in pregnancy and promote tolerance to paternal antigens.Th17 cells are present on maternal-fetal interface and prevent from infections.Imbalance in Tregs/Th17 ratio results in spontaneous abortion, pre-term birth and pre-eclampsia.^77,79,95 Increasing role of B-cells in suppression of pro-inflammatory milieu.⁹⁷ Paucity of information on B cells, although newer data on the evolving role for B cells in different phases of pregnancy.^96,97	Activation of inflammation NF-kappa B pathway signaling such as:^79,98 - MP-M1 polarization- Production of inflammatory cytokines, chemokines and adhesion molecules- Regulation of cell proliferation, apoptosis, morphogenesis and differentiationPaucity of information on B cells, despite newer data on the evolving role for B cells in different phases of pregnancy.⁹⁷
Impact on MS	Pro-inflammatory milieu potentially increases risk of post-abortion ARR and gadolinium enhancing lesion accumulation in case of early pregnancy termination.⁹⁹	M2 polarization and Tregs expansion may be associated with the reduction of ARR in full term pregnancies.^5,100,101	Activation of NF-kappa B pathway pre-delivery may contribute to risk of postpartum MS rebound disease activity.¹⁰²

APC, antigen presenting cells; ARR, annualized relapse rate; B cell, B lymphocyte; CD4 T lymphocytes, helper and regulatory type; CD8 T lymphocytes, cytotoxic type; GA, gestational age; MMP, matrix metalloproteinase; MP, macrophage; NF, nuclear factor; Tregs regulatory T lymphocytes; u-DC, uterine dendritic cells; u-NK, uterine natural killer cells.

Recommendations on planning a pregnancy in MS

Pregnancy planning is an important consideration for many women with MS.¹⁰³ Discussing DMT in the context of pregnancy and breastfeeding considerations is essential. It is generally recommended to establish pre-pregnancy baseline, through a clinical neurology visit and an MRI before pregnancy, and to choose a pregnancy-compatible DMT. Visits during the first and third trimester can be helpful, and, during the latter, breastfeeding and postpartum plans can be confirmed. Recommendations for postpartum management are outlined later in this review.

Ideally, women should aim for a period of disease and treatment stability prior to conception. When women receive maintenance DMT, care should be taken to proactively discuss future plans following conception – including whether or not to continue DMT during pregnancy and plans around breastfeeding. Such discussions are particularly pertinent in women with more active disease. DMTs with potential teratogenicity or contraindicated in pregnancy should be discontinued and replaced with acceptable alternatives prior to conception, or, in case of unintended pregnancy, changed as soon as able. In addition, the tendency for rebound activity after discontinuation of certain DMTs (fingolimod and natalizumab, as discussed later in the review) should be considered prior to initiating therapy in women with plans for pregnancy in the near future. The use of highly effective therapies without rebound risk, such as depleting antibodies, in women with more active disease prior to pregnancy may be preferable, as these may enable a balance between disease control and low potential exposure and risk to the fetus. In women with less active disease, continuing injectable therapies until conception, or even through pregnancy, appears safe, and may offer a favorable risk–benefit ratio.¹⁰⁴ Key recommendations are included in Box 1.

Box 1.

Key expert opinion recommendations for women planning pregnancy and postpartum.

Planning prior to pregnancy • Preconception counselling should be provided to all women with MS of childbearing age from the time of initial diagnosis and DMT discussion.• Take an individualized approach to pregnancy timing, incorporating the need to minimize MS activity with a suitable DMT where required, along with obstetric factors such as maternal age.• Pregnancy planning involves deciding whether to stop or continue the current DMT. Washout periods differ between DMTs (see Table 3).○ Injectables (glatiramer acetate, interferon-β) can be safely continued to conception and stopped upon a positive pregnancy test, and could be considered to continue throughout pregnancy after discussion of risks and benefits.○ Oral DMTs should not be continued during pregnancy, with varying washout depending on the DMT, as outlined in Table 3.○ Cell-depleting DMTs can be given before pregnancy to women with active MS with timing before conception to limit fetal exposure while providing longer-lasting benefit on disease activity (see Table 3).○ Special consideration should be made for DMTs with risk of disease reactivation upon discontinuation (e.g., fingolimod, natalizumab), and one may transition to a cell-depleting DMT before pregnancy, or natalizumab may be continued every 8 weeks until approximately 34 weeks gestation to prevent rebound, with evaluation for neonatal risks.• If anticipating prolonged periods of attempted conception and not on an injectable DMT or natalizumab, use of B-cell depleting therapies can be considered in women at higher risk of relapse, with an appropriate time before conception is attempted after each infusion. During pregnancy and postpartum • In the case of unintended pregnancy on a DMT not suitable for use in pregnancy (see Table 3), the DMT should be stopped and an organ screening ultrasound considered, with the accelerated elimination protocol administered for teriflunomide. Caution should be taken if stopping a DMT with risk of rebound.• Many women could consider stopping DMT during pregnancy, although this should be discussed according to individual risks and benefits.• A visit during the third trimester of pregnancy is recommended to plan for the postpartum period.○ Most women should be encouraged to breastfeed, exclusively, if possible.○ Women with active MS could consider use of certain DMTs, such as injectable or monoclonal antibody therapies, while breastfeeding (see Table 4).○ If not breastfeeding, DMT should be resumed within 2–4 weeks postpartum.

Adequate vitamin D supplementation prior to conception and during pregnancy (up to 4000 IU/day) is important.¹⁰⁵ Timely commencement of folate-containing pre-natal vitamins, avoidance of active or passive smoking, pelvic floor exercises, and proactive diagnosis and treatment of urinary tract infections (UTIs) are also important. UTIs are associated with both worsening of MS symptoms and adverse pregnancy outcomes, and are of particular concern in this patient group.¹⁰⁶ Routine pre-natal and pregnancy care can be utilized, unless pregnancy is deemed to be high-risk due to specific obstetrical concerns. Women should be counselled about the risk of postpartum depression. Non-pharmacologic management of fatigue, insomnia, spasticity, and other symptoms during and after pregnancy should be pre-emptively discussed. Use of symptomatic therapies with potential fetal risk should be discussed with the neurologist and maternal fetal medicine specialist.

Pregnancy and DMTs

DMT safety before and during pregnancy

In the past decade, there has been an enormous increase in disease modifying treatment options in MS. Fortunately, most women with mild disease will remain relapse-free during pregnancy, and treatment can be safely stopped during pregnancy. At least 300 first-trimester pregnancy exposures, and preferably 1000 total exposures, are needed to assess the possible risk and safety of medication use during pregnancy.¹⁰⁷ However, rare events may only be captured with even more exposed pregnancies. Injectable therapies (glatiramer acetate and interferon-β) have the most comprehensive safety data available, and they are safe to continue at least up to conception.^108–122 Many women stop treatment when they become aware of their pregnancy, most commonly during the first trimester. Therefore, very few data on entire pregnancy exposure exist, with the most data available for glatiramer acetate (Table 3).¹²³

Table 3.

DMT use in pregnancy and recommendations.

DMT	Animal data	First trimester exposure	Exposure throughout pregnancy	Recommendation*
Injectables
Glatiramer acetate¹²⁴	No embryolethality or teratogenic effects seen¹²⁴	No increased risk for SA or CAn > 2500^108–120	Limited data shows no increased risk of adverse pregnancy outcomes in n < 250^{110,113,115,116,120,121,123}	- Can be safely continued until positive pregnancy test- Active approach: continue during pregnancy
Interferon-β^125–129	Abortifacient effects seen at very high dosesNo teratogenic effects or effects on fetal development^125–129	No increased risk for SA or CA in n = 1550^{108–110,113,115,118–120,122}	No increased risk of adverse pregnancy outcomes in n < 100^{113,120–122}	- Can be safely continued until positive pregnancy test- Active approach: continue during pregnancy
Oral
Dimethyl fumarate^130,131	No embryolethalityNo teratogenicityAt very high dose: low birth weight, delayed ossification and SA	Risk of SA and CA not elevated to daten = 263, 214 known pregnancy outcomesRisk of SA: 16/214 (7%)Risk of CA: 7/214 (4%)Hellwig ECTRIMS 2019¹³²	Single cases, so risk unclear	- Stop with contraception or with positive pregnancy test- In case of accidental exposure during pregnancy: stop- EMA: may be used during pregnancy only if the potential benefit justifies potential risk to the fetus
Diroximel fumarate¹³³	Embryolethality in one species (rabbit) and teratogenicity in one species (rabbit) At very high dose: low birth weight, skeletal variation	Risk of SA and CA still unknown but likely similar to dimethyl fumarate	–	- Stop with contraception or with positive pregnancy test- In case of accidental exposure during pregnancy: stop
Fingolimod^134,135	Embryolethality in one species (rabbit) and teratogenicity in one species (rat)	2-Fold increased risk of major congenital malformations (congenital heart disease, renal and musculoskeletal abnormalities) according to a registryRegistry with n = 113 live births with seven major malformations (6.2%)Novartis safety database: 3.7% (25/678)Pregnancy outcomes intensive monitoring (PRIM) program: 2% (8/393)Hellwig ECTRIMS 2019¹³⁶ EMA alert in September 2019	-	- EMA: contraindicated without effective contraception and during pregnancy- FDA: use effective contraception and avoid pregnancy during and for 2 months after stopping- Stop 2 months before conception and discuss bridging with another DMT- In case of accidental exposure during pregnancy: stop and recommend organ screening ultrasound
Siponimod¹³⁷	Embryolethality in one species (rabbit) and teratogenicity in one species (rat)	Risk of CA still unknown, but likely similar to fingolimod	–	- FDA: use effective contraception and avoid pregnancy during and for 10 days after stopping- Stop 10 days before conception- In case of accidental exposure during pregnancy: stop and recommend organ screening ultrasound
Cladribine^138,139	Embryolethality in one species (mice) and teratogenicity in two species (rabbit and mice)	Risk of CA unknown, but report of 16 pregnancies within 6 months of cladribine (10 elective terminations; 3 healthy newborns; 2 SA; 1 ectopic) Galazka ECTRIMS 2017¹⁴⁰	–	- Pregnancy safe 6 months after the last administration- Risk of interaction between cladribine and oral contraception: women must also use mechanical contraception during the days of treatment and at least 4 weeks after the last dose
Teriflunomide^141,142	Embryolethality and teratogenicity in two species (rabbit and rat)	No increased risk of CA n = 437, 222 known pregnancy outcomes (risk of major malformation: 3.6% (1/28) in clinical trials, 0% (0/51) in post-marketing data)¹⁴³	–	- FDA/EMA: contraindicated in pregnant women or women of reproductive potential not using effective contraception- Stop before conception with accelerated elimination procedure (serum level <0.02 mg/l twice, 2 weeks apart)- In case of accidental exposure during pregnancy: stop, accelerated elimination procedure and recommend organ screening ultrasound
Infusion
Natalizumab^144,145	No abortifacient or teratogenic effects, but immunological and hematologic effects¹⁴⁶	Risk for SA and CA most likely not elevated¹⁴⁷ n = 369, 355 known outcomes with 9.0% SA and 5.05% CA¹⁴⁸ n = 92, 17.4% SA and 3.7% CA¹⁴⁷ n = 98, 17.3% SA and 5.2% CA¹⁴⁹	Hematologic abnormalities^150,151 Possible increased risk of malformation (4/31) and anemia (5/31)¹⁵²	- Case-by-case decision- Consider switch to depleting agents- Semi-active: stop with positive pregnancy test but risk of rebound relapse- Active: maintain during pregnancy (can give every 8 weeks and last dose at approximately 34 weeks),⁷⁶ evaluate neonate for hematological abnormalities
Rituximab^153,154	Transient peripheral B cell depletion¹⁵⁵	Reduced B cell count in newborns^156,157 if treated during pregnancyRisk for SA and CA likely not elevated n = 102 with 12% SA and 4.5% CA or medical conditions¹⁵⁷	Reduced B cell count in newborns^156,157	- Attempt conception 1–3 months after the last dose¹⁵⁸ - Discontinue in case of pregnancy- Re-dose if not pregnant after 6–9 months- Pregnancy test before each infusion
Ocrelizumab^159,160	B cell depletion observedIn monkeys, increased perinatal mortality, renal, bone marrow and testicular toxicity^159,160	Risk for SA likely not elevated n = 118, 54 known outcomes with 7.4% (4/54) SA and 3% (1/32 at risk) stillbirth^161,162	Limited^161,162	- Attempt conception 1–3 months after the last dose- Discontinue in case of pregnancy- Re-dose if not pregnant after 6–9 months- Pregnancy test before each infusion
Alemtuzumab^163,164	Embryolethal when administered during organogenesis^163,164 and decreased B and T lymphocyte populations	Slightly elevated risk for SA cannot be excluded n = 193, 167 known outcomes with 22% SA, 0% CA, 0.6% stillbirth¹⁶⁵	–	- Conception 4 months after last infusion may be attempted- Pregnancy test prior to each course- Monitor thyroid function and antithyroid antibodies (placental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves’ disease observed)¹⁶³

Some recommendations for timing of DMT use around pregnancy are off-label and represent expert opinion based on available data.

CA, congenital abnormality; DMT, disease-modifying therapy; EMA, European Medicines Agency; FDA, Food and Drug Administration; SA, spontaneous abortion.

Immunological changes during pregnancy may not be sufficient to protect women with active disease from relapses or rebound, especially after withdrawal from fingolimod or natalizumab.^166–168 The continuation of natalizumab, or bridging with the use of depleting antibodies or cladribine prior to conception should be considered in these patients. Oral DMTs should not be continued in pregnancy, whereas depleting antibody therapies can potentially be used in women with active MS, ideally prior to pregnancy, but with biological effects that may persist after drug elimination.

More data are necessary to fully address this challenging clinical topic, especially for women with more aggressive MS who wish to have children. Current knowledge of the safety of MS DMTs during pregnancy is outlined in Table 3.

DMT safety in breastfeeding

Although breastfeeding may reduce risk,¹⁶⁹ individuals at high risk for postpartum relapse may require additional strategies to decrease relapse risk, such as restarting DMT. Interferon-beta preparations were recently approved by the European Medicines Association (EMA) for use while breastfeeding,¹²⁵ but the US Food and Drug Administration (FDA) has not done so. Mothers have historically faced a choice about whether to breastfeed – which has significant benefits to both the mother and infant – or treat their MS.¹⁷⁰ However, some DMTs are unlikely to pass in relevant or harmful quantifies to breastmilk, underscoring the importance of designing studies to support the ability for women to both safely breastfeed while treating their disease.

Transfer of drugs to breastmilk depends on several factors, including molecular weight, protein binding, lipid solubility, volume of distribution, and transport mechanisms, as well as the stage of breastmilk, with less transfer into mature milk than colostrum.¹⁷¹ Lactation studies are required to determine breastmilk transfer, and a commonly used measure is the relative infant dose (RID), which represents the percent of the weight-adjusted maternal dose consumed in breastmilk over 24 h. RID of <10% is generally considered acceptable for breastfeeding, although the toxicity of each drug should be considered.¹⁷² Based on these considerations, an overview of data on excretion of DMTs to breastmilk, and recommendations for DMT use while breastfeeding are listed in Table 4.

Table 4.

DMT use during lactation and recommendations.

DMT	Animal data excretion into breastmilk	Human data excretion into breastmilk	Relative infant dose in human	Recommendation*
Injectables
Glatiramer acetate^121,124,173	Limited data	Unknown, but low likelihood due to large MW (4700–13,000 Da) but broken rapidly into its amino acid components	–	Probably compatible with breastfeeding
Interferon-β^121,125,173	Limited data	Negligible in 6 women¹⁷⁴ Low likelihood due to large MW (22,500 Da)	0.006%¹⁷⁴	Compatible with breastfeedingEMA: IFN-beta can be used while breastfeeding¹²⁵
Oral
Dimethyl fumarate^130,131	Limited data	Unknown, but likely due to low MW (129 Da) of active metabolite (MMF), although rapid metabolism and high volume of distribution may decrease transfer	–	Breastfeeding not recommended
Diroximel fumarate¹³³	Limited data	Unknown, but likely due to low MW (129 Da) of active metabolite (MMF), although rapid metabolism and high volume of distribution may decrease transfer	–	Breastfeeding not recommended
Fingolimod^134,135	Excreted in milk of treated rats (2–3-fold higher in milk than maternal plasma)	Unknown, but likely due to low MW (344 Da) and long t_1/2 although high protein binding could decrease transfer	–	Breastfeeding not recommended
Siponimod¹³⁷	Excreted in milk of treated rats	Unknown, but likely due to long t_1/2 although moderate MW (1149 Da) and high protein binding could decrease transfer	–	Breastfeeding not recommended
Cladribine^138,139	Limited data	Unknown, but likely due to low MW (286 Da) and low protein binding, although high volume of distribution may decrease transfer	–	Breastfeeding not recommended (contraindicated - FDA for 10 days and EMA 7 days after last dose)
Teriflunomide^141,142	Detected in rat milk after single oral dose	Unknown, but likely due to low MW (270 Da) and long t_1/2 although high protein binding could decrease transfer	–	Breastfeeding not recommended (contraindicated by EMA and not recommended by FDA)
Infusion
Natalizumab^144,145	Low levels of natalizumab in breastmilk in cynomolgus monkeys treated until parturition¹⁴⁵	Low in seven women^175–177	5.30% (based on peak concentration) and 1.74% (based on average concentration),¹⁷⁵ but cumulative effects of monthly dosing possible	Probably compatible with breastfeeding but further study needed
Rituximab^153,154	Detected in cynomolgus monkey milk^153,154	Low in nine women¹⁷⁸	0.08% (range 0.06–0.10)¹⁷⁸	Probably compatible with breastfeeding
Ocrelizumab^159,160	Detected in milk of treated monkeys,¹⁵⁹ with levels about 0.2% of steady state trough serum levels during lactation¹⁶⁰	Unknown, but likely low given large MW and limited known IgG1 transfer into breastmilk	–	Probably compatible with breastfeeding
Alemtuzumab^163,164	Detected in milk and offspring of lactating mice treated postpartum; ^163,164 Serum levels similar in lactating mice and offspring, and associated with decrease in offspring lymphocyte counts¹⁶³	Unknown, but likely to be low given large MW and limited known IgG1 transfer into breastmilk	–	Probably compatible with breastfeedingEMA: breastfeeding 4 months after the last dose safe (specific timing not advised by FDA)

Some recommendations for DMT use while breastfeeding are off-label and represent expert opinion based on available data.

DMT, disease-modifying therapy; EMA, European Medicines Agency; FDA, Food and Drug Administration; MMF, monomethyl fumarate; MW, molecular weight; t_1/2, half life.

While additional study of DMT use during lactation is required, when deciding whether to breastfeed while using DMTs, patients and clinicians should consider the risk of postpartum relapse balanced with potential adverse effects to the infant. In patients with high risk of postpartum disease activity, the benefits of breastfeeding despite DMT may outweigh risks for the injectable and monoclonal antibody therapies, while breastfeeding is not suggested while on oral DMTs. A recent review similarly suggested breastfeeding while on monoclonal antibody therapies can be considered in neuromyelitis optica spectrum disorders.¹⁷⁹ It is important to note that data are lacking regarding the long-term immunological and infectious profile of children of women with MS exposed to DMTs in breastmilk.

Obstetric management

Management of women with MS during labor and delivery is relevant to obstetricians, neurologists, anesthesiologists, and patients. Concern regarding associations between spinal anesthesia and MS relapses emerged almost 70 years ago.¹⁸⁰ Since then, prospective studies and a meta-analysis have demonstrated the safety of spinal anaesthesia in MS.^5,81,181,182 The American Society of Regional Anesthesia and Pain Medicine states in its 2015 guidelines that epidural anesthesia is considered safer than spinal anesthesia because it does not deposit local anesthetic directly adjacent to the CNS.¹⁸³ However, choice of analgesia in labor is best left to discretion of the obstetrician and anesthesiologist in discussion with the woman.

Disease-related factors such as fatigue, lower limb weakness, and spasticity need to be considered when developing a birth plan, and should be discussed during prenatal care.¹⁸⁴ As commonly used symptomatic treatments such as baclofen and dalfampridine are contraindicated in pregnancy, a greater emphasis on physical therapy may be needed to manage symptoms. Clinicians’ apprehension may lead to an increase in cesarean section or instrumental interventions during delivery. However, reports of increased cesarean section deliveries in women with MS may be confounded by cultural and geographical influences on cesarean rates.¹⁸⁵ In many countries, obstetrical care during labor is managed by midwives, and it is important that education on management of women with MS during labor extends to all involved medical professionals.

A systematic review and meta-analysis of women with MS and their pregnancies concluded that women with MS do not have a significantly increased risk of obstetrical or neonatal complications such as prematurity or neonatal death.¹⁸⁶ Management of women with MS during labor and delivery is therefore generally left to the discretion of the obstetrician (or midwife) and anesthesiologist. Clear communication from the neurologist to outline the disease state of the woman with MS, any relevant functional impairments, as well as optimization of MS-related symptom management, remains an important part of holistic care during pregnancy and should be a key focus of the neurologist’s involvement.

Pregnancy and disease course: short-term outcomes and postpartum relapse risk

In the early 20th century, pregnancy was believed to promote poorer outcomes for women with MS, and was discouraged. This perception changed with the landmark Pregnancy in Multiple Sclerosis (PRIMS) study, published in 1998.⁵ This prospective multicenter study, including data from 269 pregnancies across 12 European countries, revealed a ~70% decrease in relapse rate in the third trimester, relative to the 12 months pre-conception, and a postpartum relapse rate increase of ~170%. Subsequently, Vukusic showed that following the initial postpartum increase in relapses,⁸¹ ARR returned to pre-pregnancy levels. The findings of the seminal PRIMS,⁵ and its extension,⁸¹ have been replicated across numerous cohorts in subsequent decades,^39,187–191 and confirmed in a meta-analysis.¹⁸⁶ The seemingly high postpartum relapse rate is driven by a minority of women. Various studies estimate that relapses occur in 14–31% within the first 3 months postpartum.^5,190,191 In women with mild MS, the trend for postpartum relapse has generally diminished in the two decades following the PRIMS study.¹⁹² A contemporary population-based cohort of women with MS and CIS did not find rebound disease activity postpartum, attributed to inclusion of women with milder disease and high rates of exclusive breastfeeding.¹⁹² However, recent studies have demonstrated that women treated with highly effective therapies, specifically fingolimod and natalizumab, are at increased risk of rebound relapse activity in pregnancy and the postpartum period once therapy is withdrawn, with rebound relapses associated with longer duration of wash-out.^{166–168,187,193–196}

In terms of short-term MS outcomes beyond relapse activity, the PRIMS study reported a mean increase of 0.9 points on the Kurtzke disability scale over a 24-month period, without an apparent acceleration in disability worsening.^5,81 Sixteen years later, a study of 338 women from an Italian multicenter cohort demonstrated that short-term increases in disability accrual (6-month confirmed disability progression) postpartum were driven primarily by relapse activity in the year after delivery.¹⁹⁷

Postpartum outcomes are not limited to women with live births. A recent Italian multicenter study of 188 abortions (17 elective) in RRMS reported that women were at increased risk of clinical and radiological inflammatory activity in the 12 months post-abortion compared with pre-abortion, and risk of inflammatory activity was higher in those with elective compared with spontaneous abortion.⁹⁹ Similarly, a smaller study reported a trend towards increased MS activity after pregnancy loss compared with before.¹⁹⁸ The relative risk of inflammatory activity in women who have had abortions relative to women with live births remains unknown.

Various studies have proposed predictors of postpartum relapses,^{5,81,166,187,189–191,196,199–201} summarized in Table 5. Beyond withdrawal of highly effective therapies,^166,193 these studies have consistently demonstrated that patients with higher relapse activity pre-conception and during pregnancy, as well as EDSS scores of >2.0 at conception are the key independent predictors of postpartum relapses.^81,191,197 Potentially modifiable risk factors of postpartum relapse such as resuming DMT, vitamin D status, diet, smoking, alcohol, and stress have not been adequately studied.²⁰² On the other hand, breastfeeding has received substantial interest, and is discussed in detail in the following section.

Table 5.

Proposed predictors of postpartum relapses.

Protective against postpartum relapse	Risk factors associated with postpartum relapse	No consistent effect on postpartum relapse
- Pre-conception disease modifying therapy use- Lower disease activity pre-conception- Early re-initiation of disease modifying therapy- Potentially breastfeeding, particularly exclusive	- Higher disease activity pre-conception (preceding 12 months)- Higher disease activity during pregnancy- Higher disability level at onset of pregnancy- Longer wash out period after discontinuation of high-efficacy disease-modifying therapy	- Age (neither at the onset of MS or pregnancy)- Number of prior pregnancies- Infant sex- Cesarean section- Use of epidural anesthesia- Postpartum use of IVIG or IV steroids

IV, intravenous; IVIG, intravenous immune globulin; MS, multiple sclerosis.

Breastfeeding and postpartum relapses

The effect of breastfeeding on postpartum relapse risk has been controversial, with some studies supporting a protective effect,^{192,200,201,203,204} while others have not.^{5,119,199,205–212} There is no evidence to suggest a harmful effect of breastfeeding on MS relapse risk, which is important given the many benefits of breastfeeding to the infant and mother.¹⁷⁰ A recent systematic review and meta-analysis included 24 studies evaluating the association between breastfeeding and postpartum MS relapses, of which 16 had data available to pool.¹⁶⁹ Overall, breastfeeding was associated with 37% lower odds of postpartum relapse compared with nonbreastfeeding. This association was stronger in studies of exclusive breastfeeding (no regular formula supplementation for ⩾2 months) with 48% lower odds of postpartum relapse, compared with 32% lower odds in studies of nonexclusive breastfeeding. One study reported that women who partially breastfed had similar relapse risk to those who did not breastfeed,²⁰¹ supporting benefit primarily of exclusive breastfeeding. Confounding and other sources of bias remain a concern given the observational design of these studies, although pooling four well-designed studies was supportive of a protective effect with 43% lower rate of postpartum relapse in breastfeeding compared with nonbreastfeeding groups.¹⁶⁹ The potentially protective effect of breastfeeding may be due to breastfeeding-associated hormonal changes including suppression of pulsatile release of GnRH and LH, as well as high prolactin.²¹³

Management of MS during the postpartum period should be individualized based on postpartum relapse risk. In those with particularly high risk of postpartum relapse, breastfeeding may be deferred to resume MS therapies. However, the majority of women with MS should be encouraged to breastfeed, and some therapies may be safe to use while breastfeeding. A better understanding of additional strategies to prevent postpartum relapses is urgently needed, including better understanding of the safety of breastfeeding during treatment with DMTs, to allow both the benefit of breastfeeding and treatment of MS.

Postpartum management

In the postpartum period, there are three treatment goals: to prevent inflammatory activity, to provide holistic care, and to optimize psychosocial functioning. Whenever possible, anticipatory guidance should be initiated prior to delivery to minimize delays in care. Care should be in collaboration with the mother, other family members, and, when necessary (e.g., concerns about maternal medications in breastmilk), other healthcare providers.

To prevent inflammatory activity, individualized decisions should be made regarding when to resume DMT, choice of DMT, breastfeeding plans, and use of bridge therapies if indicated. A surveillance MRI 4–6 weeks postpartum may assist in monitoring for subclinical disease activity, particularly in women who delay early DMT initiation. Most women with MS should be encouraged to breastfeed, but those who cannot, or do not wish to, breastfeed should be advised to resume DMT within 2–4 weeks postpartum. For those breastfeeding with higher risk of relapse, certain DMTs could be considered while breastfeeding, as outlined elsewhere in this review.

The second goal is to comprehensively evaluate the woman’s function. There are limited data to guide care. In our clinical experience, monitoring includes evaluating and treating the following functions and when warranted multidisciplinary referrals (e.g., psychologist, psychiatrist, physical therapist, pelvic floor therapist, and/or urologist).

Screening for peripartum depression (PPD), anxiety or milder “baby blues.” PPD is present in 7–19% of all women in the peripartum period (final weeks of pregnancy through 1 year postpartum), and a major risk factor is prior history of depression.^214–216 For the general population, screening with the Edinburgh Postnatal Depression Scale with a cutoff of 13 is acceptable, and “screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up.”²¹⁷ PPD in MS is under-explored.²¹⁸

Fatigue may worsen postpartum as a result of sleep disruption (newborn needs, mood, or bladder changes) or hormonal changes. Contributing factors should be assessed prior to initiation of medications.

Strength and gait optimization including screening for weakness, loss of balance, or cardiopulmonary deconditioning.

Evaluation of bladder and bowel function, which could be disrupted from neurogenic and/or obstetrical causes but is understudied,^219,220 and consideration of pre-emptive referral to pelvic floor physical therapy.

Screening for endocrine changes may include vitamin D level,^211,221 which in some, but not all, studies has been associated with inflammatory activity in MS,^211,222 as well as thyroid function.²²³

The third goal is to optimize the patient’s psychosocial functioning, minimizing as possible disruption caused by postpartum recovery and care of the newborn, and optimizing support available to her. This support may include assistance (from the partner, other family members or a professional) with management of the newborn to enable periods of rest. A social worker may provide advice regarding short-term disability leave and/or financial resources when needed.

Pregnancy and disease course: long-term outcomes

Despite the potential increased relapse risk postpartum, the majority of individuals do not experience relapses in the postpartum period, and pregnancy does not appear to alter long-term relapse rate or disease progression.^5,81,166 However, the impact of pregnancy on long-term outcomes remains less clear. Studies up to the mid-2010s demonstrated either a slower rate of disability progression in women becoming pregnant after MS onset,^{38,71,224–227} or failed to demonstrate an association between pregnancy and long-term disability.^228–230 One notable exception found weak evidence for increased risk of converting to SPMS over 10-years in a parous cohort (on injectable or no DMT).²³¹

More recently, a protective effect of pregnancy on long-term outcomes was reported in a large real-world cohort (MSBase). Females with at least one pregnancy had lower EDSS scores over 10 years, after adjustment for relapse rate, therapy use, and other covariates.²³² Interestingly, when comparing proportion of time spent pregnant with proportion of time on first-line therapy, the protective effect of pregnancy was greater. While the possibility of reverse causality (women with milder disease more likely to attempt pregnancy) cannot be excluded, this is challenged by the fact that approximately half of pregnancies were conceived while on therapy. In the Barcelona CIS cohort, pregnancy after CIS was protective against risk of MS, and time to EDSS 3.0 if pregnancy was modelled as a baseline variable. However, these protective effects were lost when pregnancy was analyzed as a time-dependent variable.²³³ Notably, 32% of this cohort did not fulfill Barkhof criteria, potentially limiting generalizability.

Overall, there is little-to-no evidence that pregnancy has a negative impact on long-term outcomes at the group level, with most studies demonstrating a neutral or protective effect. MS does not preclude parenthood or pregnancy.²³⁴ Nonetheless, the effect of pregnancy on disease outcomes, a woman’s ability to care for her child, and future financial stress are key concerns of women with MS considering family planning.^235–238 Relapses are the greatest independent driver of long-term disability accrual.²³² Therefore, careful pregnancy planning and monitoring including appropriate use/withdrawal of DMTs is paramount to ensuring positive long-term outcomes for women with MS.^239,240

Further studies are needed to evaluate effects of pregnancy in PPMS, address issues of reverse causality, and understand the long-term impact of pregnancy in heterogeneous cohorts to allow pregnancy planning advice tailored to the individual.

Stigma around family planning

Stigma means mark of inferiority.^241–243 People with MS or their partners who want to procreate may be questioned about wishing to have children despite a neurodegenerative condition. They may be judged by their family, society, the healthcare team, and even their partners. Moreover, they may feel guilty and fearful of unforeseen consequences,^244,245 even though MS has negligible impact on pregnancy and vice versa.²⁴⁰ They may conceal their desires and their condition,^242,246 or discontinue treatment. This fear and stigma may have greater impact on quality of life of prospective parents than the actual disease.^240,247

While it is not implied that every couple should procreate, expert support and multidisciplinary guidance could help patients structure their lives and manage their condition, to allow them to have a positive reproductive experience.^241,248

Exogenous hormones as a DMT with impact on long-term prognosis of MS

High doses of estrogen seem to be protective by decreasing MS disease activity in the EAE animal model and women during pregnancy.²⁴⁹ Observational studies of potential effects of oral contraceptives and ART are discussed earlier in this review. To solve the inherent limitations of retrospective and observational studies, two randomized-controlled, phase II, clinical trials have assessed the impact of exogenous hormones on disease course.^249,250 They suggest that the addition of ethinyl estradiol 40 µg and desogestrel 125 µg to interferon-β-1a,²⁵⁰ and estriol to glatiramer acetate,²⁴⁹ are associated with fewer lesions on brain MRI (26.5% reduction of cumulative number of combined unique active lesions, p = 0.04), and lower ARR (0.25 versus 0.48, p = 0.016 at 12 months), respectively. In addition, both studies showed promising effects of estrogen on cognitive disability as exploratory outcomes. Estriol treatment-induced cognitive improvement was correlated with less cerebral cortex gray matter atrophy,²⁴⁹ which was mapped to sparing of frontal cerebral cortex.²⁵¹ Further research is needed to understand the effect of exogenous hormones on long-term MS prognosis in women.

Menopause and reproductive aging

Like puberty and pregnancy, perimenopause leads to widespread changes in biology. Changes in the immune and nervous systems, fluctuations in gonadal hormones, and symptoms that overlap with those caused by MS may contribute to changes in clinical phenotype to a progressive disease course over the fifth decade.²⁵² Challenges in understanding the role of perimenopause in MS include distinguishing effects of somatic versus reproductive aging and the potential confounding from comorbid illnesses that become more frequent with older age.

Ovarian aging and disease course

The mean age of onset of secondary progressive MS, characterized by a change from a relapsing remitting phenotype to a continuously progressive form of disease, conspicuously occurs for most women during the perimenopausal period. Several studies have aimed to determine if the menopausal transition affects disease course. Some have reported clinical worsening when patients were asked about their disease perception during menopausal transition,^253–255 possibly due to the additive effect of menopause and MS overlapping symptoms. On the other hand, others have focused on the search for an inflection point in MS course centered on menopause. Bove et al. described an inflection point in EDSS worsening at menopause (difference of 0.076 units; 95% CI 0.010–0.14, p = 0.024) in 124 women followed longitudinally (mean follow up 10.4 years).⁸ This was replicated by Baroncini et al., who also reported a significant annual EDSS increase in the post-menopausal period (3 years) as compared with the pre-menopausal period (3 years) (0.4 ± 0.7 versus 0.2 ± 0.6 points, p = 0.014) in 108 women.²⁵⁶ In a smaller cohort (n = 37), Ladeira et al. detected stable EDSS variation across the menopausal transition.⁶ Ladeira et al. and Baroncini et al. also reported significant decrease in annual relapse rate after menopause.^6,256 On the other hand, Otero et al. found that menopause did not influence the risk of disability accumulation when trajectories of EDSS over the complete disease course (from CIS through menopause) were accounted for, and once adjusting for age and disease duration.⁷²

Much of the ovarian aging biology accumulates years before the final menstrual cycle, highlighting a continuum of physiological changes, rather than any abrupt change arising at the final menstrual period that could influence MS course. To study the prolonged period of ovarian decline, Graves et al. used AMH as a marker of ovarian function.⁹ AMH is produced by ovarian follicles, and levels decline exponentially during the peri-menopausal period. Within a 10-year longitudinal cohort, declines in AMH level were associated with clinically and statistically significant increases in disability and gray matter atrophy, even with adjustment for chronological age, BMI, and disease duration.⁹

Mechanistically, the loss of ovarian estrogen around menopause could potentiate several aging-associated phenomena, including decrease in brain repair mechanisms, decrease in immune activation, and, ultimately, a loss of neuro-homeostasis leading to accelerated neurodegeneration and subsequent disease progression.^257–259 The subsequent results of these potential changes include increased levels of senescent immune cells and neurons as well as increased CNS atrophy and disability. Notably, cognition is one disability in MS that may be particularly sensitive to loss of estrogens during menopause in light of the well-documented “brain fog” described in otherwise healthy women during natural menopause with aging and surgical menopause not due to aging.^260–265 However, estrogen may not be the only culprit as there are also substantial changes in androgen production, and it is difficult to tease apart the effects of somatic aging processes that are linked with perimenopause in women.

Symptom management in perimenopause

Few studies have addressed management of MS symptoms at menopause. Symptom management and choice of DMT should be tailored to account for fatigue and pseudo-exacerbations triggered by hot flashes, which can become more prominent at menopause.^266,267 Co-management with primary or women’s health providers may be beneficial. Bladder symptoms may also worsen and urology assessment may be needed.

Prospective, randomized studies on the effect of hormone therapy in patients with MS during menopause are needed, as prior studies reported improved quality of life in post-menopausal women with MS.²⁶⁶ Wellness approaches, attention to co-morbidities, as well as adding a neuroprotective agent may be appropriate when these are substantiated and become available for women living with MS at menopause and beyond.

Female sexual dysfunction in MS

Sexual dysfunction affects up to 95% of women with MS,^268,269 but it is rarely discussed in the office setting. Many patients are embarrassed to bring up the topic, while many physicians feel that they have little to offer and do not ask. Nevertheless, sexual satisfaction is heavily linked to quality of life for women with MS,²⁷⁰ and it is important for care providers to help manage this.

Female sexuality is multifaceted, and MS can impact it at every level. Direct damage to the brain and spinal cord can impede desire, decrease vaginal sensation and lubrication, and impair orgasm, as well as contribute to pain with sex. Indirect factors impacting sexual function can include physical problems like bladder/bowel dysfunction, fatigue, weakness, and spasticity, as well as emotional problems like cognitive dysfunction or depression.²⁷¹

“Invisible” psychologic and emotional factors may also negatively impact sexuality. Desire, for women, is heavily correlated with stress levels, fatigue, relationship quality, and many other intangibles that are vulnerable in settings of chronic neurologic disease. Women with MS often struggle with body image. Many couples struggle as they cope with the physical, emotional, and financial stressors imposed by the disease, and subsequently experience deterioration of their sexual relationship.

Sexual problems may develop early in the course of MS, and tend to persist or worsen over time.^268,272 Nevertheless, many factors contributing to sexual dysfunction in MS can be effectively modified (Table 6).²⁷³

Table 6.

Contributors to sexual dysfunction in MS and management options.

Contributing factors	Management options
Pain	Vaginal lubricant/moisturizersLow-dose vaginal estrogenIntra-vaginal DHEALaser treatment for vaginal atrophyPelvic floor physical therapy
Comorbid medical problems (e.g., diabetes, obesity)	Treatment of gynecologic disorders, bladder and bowel incontinenceDiagnosis and management of sleep disordersDepression managementWeight lossSystemic hormones for menopause, when appropriate
Medication side effects	Manage anti-depressant associated sexual dysfunctionBehavioral (exercise, vibratory stimulation, scheduling sexual activity)AcupuncturePharmacologic (bupropion, sildenafil, cyproheptadine)Modification of medications
Psychologic factors	Psychotherapy, CBT, individual/couples therapyStress management
Hypoactive desire	EducationBooks: “Better Sex through Mindfulness” (Lori Brotto), “Mating inCaptivity” (Esther Perel), “Come As You Are” (Emily Nagoski)Apps: Meet Rosy, OMGYesSex therapy (may include behavioral, CBT, mindfulness therapy)CNS medications (flibanserin, bupropion^†, buspirone^†)Hormone therapy (transdermal testosterone^{†, ‡})Behavioral modifications (exercise, erotica, vibratory or clitoral vacuum stimulation)

†

Limited evidence exists to support these treatment options; these medications are not FDA-approved for hypoactive sexual desire in women.

‡

Safety is incompletely understood in this population so risks and benefits should be considered.

CBT, cognitive behavioral therapy; DHEA, dehydroepiandrosterone; MS, multiple sclerosis.

Conclusion

Sex hormones play a significant role in the risk and course of MS. Dramatic hormonal fluctuations can influence clinical, radiographic, and disability-related disease parameters. The role of sex chromosomes on sex differences in MS risk and disease progression represents a new frontier for exploration. More research efforts are needed to fully understand unique questions related to MS and fertility, contraception, pregnancy, and reproductive aging.

Footnotes

Acknowledgements

We would like to thank the Executive Committee and members of the International Women in MS (iWiMS) group.

Conflict of interest statement

Kristen M. Krysko is funded by a Sylvia Lawry Physician Fellowship through the National Multiple Sclerosis Society [FP-1605-08753 (Krysko)]. She also had fellowship funding through Biogen.

Jennifer S. Graves has received recent grant and clinical trial support from the National MS Society, Race to Erase MS, UCSF CTSI RAP program, Biogen, and Genentech. She has received honoraria from Biogen and Genzyme for non-promotional trainee education events. She has received personal fees from Novartis and Celgene.

Ruth Dobson works within the PNU, which is funded by Barts Charity. She receives grant support from the UK MS Society, Horne Family Charitable Trust, Biogen, Celgene, and Merck. She has received honoraria for Advisory boards and/or educational actives from Biogen, Teva, Sanofi, Merck, and Roche.

Ayse Altintas has received speaker honoraria for non-promotional education events and travel grants from Merck, TEVA, and Novartis.

Maria Pia Amato has received research grants and honoraria as a speaker and member of advisory boards by Biogen, Merck, Roche, Teva, Sanofi Genzyme, and Novartis.

Jacqueline Bernard has served as a Consultant for Biogen.

Simona Bonavita has received speaker honoraria and/or Advisory Board fees from Novartis, Teva, Sanofi-Genzyme, Biogen-Idec, and Merck-Serono.

Riley Bove is funded by a Harry Weaver Scholarship through the National Multiple Sclerosis Society. She has received recent research support from the National Multiple Sclerosis Society, the California Initiative to Advance Precision Medicine, the Hilton Foundation, the Sherak Foundation, the Weill Innovation Fund, and the UCSF CTSI RAP program. She has received consulting fees from Alexion, Biogen, EMD Serono, Genzyme Sanofi, Novartis, and Roche Genentech.

Paola Cavalla has received recent grants and clinical trial support from Biogen and Sanofi-Genzyme. She has received honoraria from Almirall, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, and Teva for non-promotional trainee education events.

Marinella Clerico has received personal compensation for speaking/advising/consulting from Merck, Sanofi-Genzyme, Biogen, Novartis, and Teva; was supported in travelling expenses for congresses from Merck, Sanofi-Genzyme, Biogen, Novartis, Teva, and Almirall; has received research grants from Italian MS Foundation (FISM), Italian Ministry of Research, Merck, Sanofi-Genzyme, Biogen, and Novartis.

Teresa Corona declares no conflicts of interest.

Anisha Doshi declares no conflicts of interest.

Yara Fragoso declares no conflicts of interest.

Dina Jacobs has clinical research trial support from Genentech/Roche, Biogen, Novartis, and Medimmune, and has received consulting/advisory board honoraria from Celgene, Biogen, Novartis, EMD Serono, and Sanofi Genzyme.

Vilija Jokubaitis is funded by an MS Research Australia Fellowship (16-0206). She receives project grant support from the National Health and Medical Research Council (NHMRC) of Australia (GNT1156519) and MS Research Australia (18-0424; 19-0665). She has received honoraria from Biogen and Roche for non-promotional educational activities, and conference travel support from Merck and Roche.

Doriana Landi has received travel funding from Roche, Biogen, Merck-Serono, Sanofi-Genzyme, and Teva; speaking or consultations fees from Bayer-Schering, Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche, Mylan, and Almirall.

Gloria Llamosa declares no conflicts of interest.

Erin E. Longbrake has received honoraria from Genentech, Genzyme, Alexion, Biogen, EMD Serono, and Celgene. She has grant support from NIH K23NS107624 and Race to Erase MS.

Elisabeth Maillart has received grant support from Biogen, Novartis, and Roche. She has also received consultant honoraria from Biogen, Celgene, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva.

Monica Marta has received honoraria and travel costs from Genzyme, AbbVie, Roche, and Novartis.

Luciana Midaglia declares no conflicts of interest.

Suma Shah has received honoraria from Biogen.

Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck-Serono, Biogen Idec, Teva Pharmaceuticals, Sanofi-Aventis, Novartis, Almirall, Genzyme, Viela Bio, and Roche.

Anneke van der Walt has served on scientific advisory boards, received travel support and speaker’s honoraria from Biogen, Merck, Novartis, and Roche. She is supported by funding from the National Health and Medical Research Council of Australia.

Rhonda Voskuhl declares no conflicts of interest.

Yujie Wang declares no conflicts of interest.

Rana K. Zabad has been a site investigator or site PI for clinical trials funded by Adamas, Biogen, Genentech, Novartis, Sunpharma, and PCORI. In the last 5 years, she has served as a consultant for Bayer, Biogen, Genentech, Celgene, Genzyme, TEVA Neuroscience, and TG therapeutics, and has given unbranded lectures sponsored by TEVA, Novartis, and Genentech. She is a member of the Adjudication Committee for a clinical trial of biotin in primary and secondary progressive multiple sclerosis sponsored by PAREXEL and medDay pharmaceutical.

Burcu Zeydan reports funding from NIH (NIA: U54 AG44170).

Maria Houtchens has received grant support from Biogen, Serono, Sanofi Genzyme, and Genentech/Roche. She also received consultant honoraria from Biogen, Serono, Sanofi Genzyme, Roche, and Celgene.

Kerstin Hellwig receives grant support from the Innovation Fund of the Federal Joint Committee. She has also received consultant and speaker honoraria and grant support from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Roche, and Teva.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Kristen M. Krysko is funded by a Sylvia Lawry Physician Fellowship through the National Multiple Sclerosis Society [FP-1605-08753 (Krysko)].

ORCID iDs

Kristen M. Krysko

Anneke van der Walt

Kerstin Hellwig

References

Orton

Herrera

Yee

, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006; 5: 932–936.

Tintoré

Arrambide

. Early onset multiple sclerosis: the role of gender. J Neurol Sci 2009; 286: 31–34.

Bove

Healy

Augustine

, et al. Effect of gender on late-onset multiple sclerosis. Mult Scler 2012; 18: 1472–1479.

Polliack

Barak

Achiron

. Late-onset multiple sclerosis. J Am Geriatr Soc 2001; 49: 168–171.

Confavreux

Hutchinson

Hours

, et al. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 1998; 339: 285–291.

Ladeira

Salavisa

Caetano

, et al. The influence of menopause in multiple sclerosis course: a longitudinal cohort study. Eur Neurol 2018; 80: 223–227.

Damasceno

Von Glehn

Brandão

, et al. Prognostic indicators for long-term disability in multiple sclerosis patients. J Neurol Sci 2013; 324: 29–33.

Bove

Healy

Musallam

, et al. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort. Mult Scler 2016; 22: 935–943.

Graves

Henry

Cree

BAC

, et al. Ovarian aging is associated with gray matter volume and disability in women with MS. Neurology 2018; 90: e254–e260.

10.

Koch-Henriksen

Sorensen

. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9: 520–532.

11.

Westerlind

Bostrom

Stawiarz

, et al. New data identify an increasing sex ratio of multiple sclerosis in Sweden. Mult Scler 2014; 20: 1578–1583.

12.

Taylor

Pearson

Clarke

, et al. MS prevalence in New Zealand, an ethnically and latitudinally diverse country. Mult Scler 2010; 16: 1422–1431.

13.

Trojano

Lucchese

Graziano

, et al. Geographical variations in sex ratio trends over time in multiple sclerosis. PLoS One 2012; 7: e48078.

14.

Rotstein

Chen

Wilton

, et al. Temporal trends in multiple sclerosis prevalence and incidence in a large population. Neurology 2018; 90: e1435–e1441.

15.

Magyari

. Role of socio-economic and reproductive factors in the risk of multiple sclerosis. Acta Neurol Scand 2015; 132: 20–23.

16.

Wijnands

JMA

Kingwell

Zhu

, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol 2017; 16: 445–451.

17.

Hawkes

Macgregor

. Twin studies and the heritability of MS: a conclusion. Mult Scler 2009; 15: 661–667.

18.

IMSGC. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019; 365: eaav7188.

19.

Voskuhl

. The effect of sex on multiple sclerosis risk and disease progression. Mult Scler 2020; 26: 554–560.

20.

Voskuhl

Sawalha

Itoh

. Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression. Mult Scler 2018; 24: 22–31.

21.

Golden

Itoh

, et al. Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes. Proc Natl Acad Sci USA 2019; 116: 26779–26787.

22.

Itoh

Golden

Itoh

, et al. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J Clin Invest 2019; 130: 3852–3863.

23.

Ramagopalan

Valdar

Criscuoli

, et al. Age of puberty and the risk of multiple sclerosis: a population based study. Eur J Neurol 2009; 16: 342–347.

24.

Sloka

Pryse-Phillips

WEM

Stefanelli

. The relation between menarche and the age of first symptoms in a multiple sclerosis cohort. Mult Scler 2006; 12: 333–339.

25.

Boesen

Magyari

Koch-Henriksen

, et al. Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977–2015: a nationwide population-based incidence study. Mult Scler 2018; 24: 1077–1086.

26.

Lulu

Graves

Waubant

. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler 2016; 22: 193–200.

27.

Correale

Arias

Gilmore

. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1998; 161: 3365–3374.

28.

Soldan

Alvarez Retuerto

Sicotte

, et al. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol 2003; 171: 6267–6274.

29.

Hedstrom

Baarnhielm

Olsson

, et al. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009; 73: 696–701.

30.

Poorolajal

Bahrami

Karami

, et al. Effect of smoking on multiple sclerosis: a meta-analysis. J Public Health (Oxf) 2017; 39: 312–320.

31.

Bostrom

Landtblom

. Does the changing sex ratio of multiple sclerosis give opportunities for intervention? Acta Neurol Scand 2015; 132: 42–45.

32.

Dobson

Kuhle

Middeldorp

, et al. Epstein-Barr-negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm 2017; 4: e318.

33.

Krementsov

Asarian

Fang

, et al. Sex-specific gene-by-vitamin D interactions regulate susceptibility to central nervous system autoimmunity. Front Immunol 2018; 9: 1622.

34.

Spach

Hayes

. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol 2005; 175: 4119–4126.

35.

Orton

Wald

Confavreux

, et al. Association of UV radiation with multiple sclerosis prevalence and sex ratio in France. Neurology 2011; 76: 425–431.

36.

Cavalla

Rovei

Masera

, et al. Fertility in patients with multiple sclerosis: current knowledge and future perspectives. Neurol Sci 2006; 27: 231–239.

37.

McCombe

Stenager

. Female infertility and multiple sclerosis: is this an issue? Mult Scler 2015; 21: 5–7.

38.

Runmarker

Andersen

. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 1995; 118 (Pt. 1): 253–261.

39.

Jalkanen

Alanen

Airas

, et al. Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland. Mult Scler 2010; 16: 950–955.

40.

Lavorgna

Esposito

Lanzillo

, et al. Factors interfering with parenthood decision-making in an Italian sample of people with multiple sclerosis: an exploratory online survey. J Neurol 2019; 266: 707–716.

41.

Boumpas

Austin

III Vaughan

, et al. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993; 119: 366–369.

42.

Cocco

Sardu

Gallo

, et al. Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study. Mult Scler 2008; 14: 1225–1233.

43.

Thöne

Kollar

Nousome

, et al. Serum anti-Müllerian hormone levels in reproductive-age women with relapsing-remitting multiple sclerosis. Mult Scler 2015; 21: 41–47.

44.

Sepúlveda

Ros

Martínez-Lapiscina

, et al. Pituitary-ovary axis and ovarian reserve in fertile women with multiple sclerosis: a pilot study. Mult Scler 2016; 22: 564–568.

45.

Centers for Disease Control and Prevention (CDC). Infertility, https://www.cdc.gov/reproductivehealth/infertility/index.htm (2019, accessed 8 March 2020).

46.

Farquhar

Marjoribanks

. Assisted reproductive technology: an overview of Cochrane reviews. Cochrane Database Syst Rev 2018; 8: CD010537.

47.

Vaknin-Dembinsky

Bdolah

Karussis

, et al. Tumefactive demyelination following in vitro fertilization (IVF). J Neurol Sci 2015; 348: 256–258.

48.

Ladwig

Dunkl

Richter

, et al. Two cases of multiple sclerosis manifesting after in vitro fertilization procedures. J Neurol 2016; 263: 603–605.

49.

Torkildsen

Holmøy

Myhr

K-M

. Severe multiple sclerosis reactivation after gonadotropin treatment. Mult Scler Relat Disord 2018; 22: 38–40.

50.

Bove

Rankin

Lin

, et al. Effect of assisted reproductive technology on multiple sclerosis relapses: case series and meta-analysis. Mult Scler. Epub ahead of print 1 August 2019. DOI: 10.1177/1352458519865118.

51.

Hellwig

Schimrigk

Beste

, et al. Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis. Eur Neurol 2009; 61: 65–68.

52.

Correale

Farez

Ysrraelit

. Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol 2012; 72: 682–694.

53.

Michel

Foucher

Vukusic

, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry 2012; 83: 796–802.

54.

Laplaud

Leray

Barrière

, et al. Increase in multiple sclerosis relapse rate following in vitro fertilization. Neurology 2006; 66: 1280–1281.

55.

Hellwig

Beste

Brune

, et al. Increased MS relapse rate during assisted reproduction technique. J Neurol 2008; 255: 592–593.

56.

Guzmán-Soto

Salinas

Hernández-Jasso

, et al. Leuprolide acetate, a GnRH agonist, improves experimental autoimmune encephalomyelitis: a possible therapy for multiple sclerosis. Neurochem Res 2012; 37: 2190–2197.

57.

D’Hooghe

De Keyser

. Female gender and reproductive factors affecting risk, relapses and progression in multiple sclerosis. Gynecol Obstet Invest 2013; 75: 73–84.

58.

Hellwig

Correale

. Artificial reproductive techniques in multiple sclerosis. Clin Immunol 2013; 149: 219–224.

59.

Laplaud

Lefrère

Leray

, et al. Increased risk of relapse in multiple sclerosis patients after ovarian stimulation for in vitro fertilization. Gynecol Obstet Fertil 2007; 35: 1047–1050.

60.

Voskuhl

. Assisted reproduction technology in multiple sclerosis: giving birth to a new avenue of research in hormones and autoimmunity. Ann Neurol 2012; 72: 631–632.

61.

Bove

Chitnis

. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler 2014; 20: 520–526.

62.

Alonso

Clark

. Oral contraceptives and the risk of multiple sclerosis: a review of the epidemiologic evidence. J Neurol Sci 2009; 286: 73–75.

63.

Villard-Mackintosh

Vessey

. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 1993; 47: 161–168.

64.

Hernán

Hohol

Olek

, et al. Oral contraceptives and the incidence of multiple sclerosis. Neurology 2000; 55: 848–854.

65.

Alonso

Jick

Olek

, et al. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol 2005; 62: 1362–1365.

66.

Holmqvist

Hammar

Landtblom

, et al. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis. Fertil Steril 2010; 94: 2835–2837.

67.

Hellwig

Chen

Stancyzk

, et al. Oral contraceptives and multiple sclerosis/clinically isolated syndrome susceptibility. PLoS One 2016; 11: e0149094.

68.

Zapata

Oduyebo

Whiteman

, et al. Contraceptive use among women with multiple sclerosis: a systematic review. Contraception 2016; 94: 612–620.

69.

Sena

Couderc

Vasconcelos

, et al. Oral contraceptive use and clinical outcomes in patients with multiple sclerosis. J Neurol Sci 2012; 317: 47–51.

70.

Gava

Bartolomei

Costantino

, et al. Long-term influence of combined oral contraceptive use on the clinical course of relapsing-remitting multiple sclerosis. Fertil Steril 2014; 102: 116–122.

71.

D’Hooghe

Haentjens

Nagels

, et al. Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis. J Neurol 2012; 259: 855–861.

72.

Otero-Romero

Rovira

Zuluaga

, et al. Impact of oral contraceptives and menopause on MS risk and prognosis: results from the Barcelona CIS cohort. Paris: ECTRIMS-ACTRIMS, 2017.

73.

Voskuhl

Gold

. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 2012; 8: 255–263.

74.

Houtchens

Zapata

Curtis

, et al. Contraception for women with multiple sclerosis: guidance for healthcare providers. Mult Scler 2017; 23: 757–764.

75.

Curtis

Tepper

Jatlaoui

, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep 2016; 65: 1–103.

76.

Dobson

Dassan

Roberts

, et al. UK consensus on pregnancy in multiple sclerosis: ‘Association of British Neurologists’ guidelines. Pract Neurol 2019; 19: 106–114.

77.

Morelli

Mandal

Goldsmith

, et al. The maternal immune system during pregnancy and its influence on fetal development. Res Rep Biol 2015; 6: 171–189.

78.

Dunn

Kelly

Critchley

. Decidualization of the human endometrial stromal cell: an enigmatic transformation. Reprod Biomed Online 2003; 7: 151–161.

79.

Mor

Aldo

Alvero

. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017; 17: 469–482.

80.

Gatson

Williams

Powell

, et al. Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. J Neuroimmunol 2011; 230: 105–113.

81.

Vukusic

Hutchinson

Hours

, et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 2004; 127: 1353–1360.

82.

Nair

Verma

Singh

. Immune-endocrine crosstalk during pregnancy. Gen Comp Endocrinol 2017; 242: 18–23.

83.

Al-Shammri

Rawoot

Azizieh

, et al. Th1/Th2 cytokine patterns and clinical profiles during and after pregnancy in women with multiple sclerosis. J Neurol Sci 2004; 222: 21–27.

84.

Gilmore

Arias

Stroud

, et al. Preliminary studies of cytokine secretion patterns associated with pregnancy in MS patients. J Neurol Sci 2004; 224: 69–76.

85.

Lopez

Comabella

Tintore

, et al. Variations in chemokine receptor and cytokine expression during pregnancy in multiple sclerosis patients. Mult Scler 2006; 12: 421–427.

86.

Sanchez-Ramon

Navarro

Aristimuno

, et al. Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity. Immunol Lett 2005; 96: 195–201.

87.

Iorio

Frisullo

Nociti

, et al. T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis. Clin Immunol 2009; 131: 70–83.

88.

Neuteboom

Verbraak

Wierenga-Wolf

, et al. Pregnancy-induced fluctuations in functional T-cell subsets in multiple sclerosis patients. Mult Scler 2010; 16: 1073–1078.

89.

Airas

Saraste

Rinta

, et al. Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol 2008; 151: 235–243.

90.

Spadaro

Martire

Marozio

, et al. Immunomodulatory effect of pregnancy on leukocyte populations in patients with multiple sclerosis: a comparison of peripheral blood and decidual placental tissue. Front Immunol 2019; 10: 1935.

91.

Ramien

Yusko

Engler

, et al. T cell repertoire dynamics during pregnancy in multiple sclerosis. Cell Rep 2019; 29: 810–815.e4.

92.

Langer-Gould

Gupta

Huang

, et al. Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch Neurol 2010; 67: 51–57.

93.

Asaba

Bandyopadhyay

Kindy

, et al. Estrogen receptor signal in regulation of B cell activation during diverse immune responses. Int J Biochem Cell Biol 2015; 68: 42–47.

94.

Mor

Cardenas

Abrahams

, et al. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann NY Acad Sci 2011; 1221: 80–87.

95.

Yang

Zheng

Jin

. Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front Immunol 2019; 10: 2317.

96.

Lima

Martins

Leandro

, et al. Characterization of B cells in healthy pregnant women from late pregnancy to post-partum: a prospective observational study. BMC Pregnancy Childbirth 2016; 16: 139.

97.

Dutta

Sengupta

Haque

. Reproductive immunomodulatory functions of B cells in pregnancy. Int Rev Immunol 2020; 39: 53–66.

98.

Liu

Zhang

Joo

, et al. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017; 2: 17023.

99.

Landi

Ragonese

Prosperini

, et al. Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2018; 89: 1272–1278.

100.

Chu

Shi

Zheng

, et al. The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 2018; 318: 1–7.

101.

Vasileiadis

Dardiotis

Mavropoulos

, et al. Regulatory B and T lymphocytes in multiple sclerosis: friends or foes? Auto Immun Highlights 2018; 9: 9.

102.

Leibowitz

Yan

. NF-kappaB pathways in the pathogenesis of multiple sclerosis and the therapeutic implications. Front Mol Neurosci 2016; 9: 84.

103.

Houtchens

Edwards

Schneider

, et al. Pregnancy rates and outcomes in women with and without MS in the United States. Neurology 2018; 91: e1559–e1569.

104.

Gyllensten

Juuti

Hakkarainen

, et al. Pregnancy outcomes in multiple sclerosis populations exposed and unexposed to interferon β: a register-based study in the Nordic countries. EU PAS Register, 2019.

105.

Munger

Aivo

Hongell

, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the finnish maternity cohort. JAMA Neurol 2016; 73: 515–519.

106.

Mazor-Dray

Levy

Schlaeffer

, et al. Maternal urinary tract infection: is it independently associated with adverse pregnancy outcome? J Matern Fetal Neonatal Med 2009; 22: 124–128.

107.

European Medicines Agency (EMA). Evaluation of medicines for human use. Guidelines on risk assessment of medical products on human reproduction and lactation: from data to labeling, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003307.pdf (2008, accessed 1 January 2020).

108.

Finkelsztejn

Fragoso

Ferreira

, et al. The Brazilian database on pregnancy in multiple sclerosis. Clin Neurol Neurosurg 2011; 113: 277–280.

109.

Fragoso

Boggild

Macias-Islas

, et al. The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis. Clin Neurol Neurosurg 2013; 115: 154–159.

110.

Fragoso

Finkelsztejn

Comini-Frota

, et al. Pregnancy and multiple sclerosis: the initial results from a Brazilian database. Arq Neuropsiquiatr 2009; 67: 657–660.

111.

Fragoso

Finkelsztejn

Kaimen-Maciel

, et al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series. CNS Drugs 2010; 24: 969–976.

112.

Giannini

Portaccio

Ghezzi

, et al. Pregnancy and fetal outcomes after glatiramer acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol 2012; 12: 124.

113.

Hellwig

Haghikia

Rockhoff

, et al. Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord 2012; 5: 247–253.

114.

Herbstritt

Langer-Gould

Rockhoff

, et al. Glatiramer acetate during early pregnancy: a prospective cohort study. Mult Scler 2016; 22: 810–816.

115.

Wang

Guimond

, et al. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology 2012; 79: 1130–1135.

116.

Salminen

Leggett

Boggild

. Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. J Neurol 2010; 257: 2020–2023.

117.

Sandberg-Wollheim

Neudorfer

Grinspan

, et al. Pregnancy outcomes from the branded glatiramer acetate pregnancy database. Int J MS Care 2018; 20: 9–14.

118.

Weber-Schoendorfer

Schaefer

. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler 2009; 15: 1037–1042.

119.

Fernández Liguori

Klajn

Acion

, et al. Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study). Mult Scler 2009; 15: 555–562.

120.

Thöne

Thiel

Gold

, et al. Treatment of multiple sclerosis during pregnancy: safety considerations. Expert Opin Drug Saf 2017; 16: 523–534.

121.

Hellwig

Gold

. Glatiramer acetate and interferon-beta throughout gestation and postpartum in women with multiple sclerosis. J Neurol 2011; 258: 502–503.

122.

Sandberg-Wollheim

Alteri

Moraga

, et al. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler 2011; 17: 423–430.

123.

Hellwig

Neudorfer

Melamed-Gal

, et al. Pregnancy outcomes in patients with multiple sclerosis and exposure to branded glatiramer acetate during all three trimesters. Paris: ECTRIMS-ACTRIMS, 2017.

124.

Teva Pharms USA. Copaxone (glatiramer acetate) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020622 (2019, accessed 4 December 2019).

125.

EMA. Avonex (interferon beta-1A): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/avonex-epar-product-information_en.pdf (2019, accessed 4 December 2019).

126.

Biogen. Avonex (interferon beta-1A) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103628s5264lbl.pdf (2019, accessed 1 January 2020).

127.

Serono Inc. Rebif (interferon beta-1A) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103780s5204lbl.pdf (2019, accessed 1 January 2020).

128.

Bayer Healthcare. Betaseron (interferon beta-1B) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103471s5195lbl.pdf (2019, accessed 1 January 2020).

129.

Biogen Idec. Plegridy (peginterferon beta-1A) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125499s019lbl.pdf (2019, accessed 1 January 2020).

130.

EMA. Tecfidera (dimethyl fumarate): EPAR summary of product characteristics, https://www.ema.europa.eu/en/medicines/human/EPAR/tecfidera (2019, accessed 4 December 2019).

131.

Biogen. Tecfidera (dimethyl fumarate) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204063s024lbl.pdf (2019, accessed 4 December 2019).

132.

Hellwig

. An international registry tracking pregnancy outcomes in women treated with dimethyl fumarate. Stockholm: ECTRIMS, 2019.

133.

Alkermes. Vumerity (diroximel fumarate) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211855s000lbl.pdf (2019, accessed 4 December 2019).

134.

EMA. Gilenya (fingolimod): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf (2019, accessed 4 December 2019).

135.

Novartis. Gilenya (fingolimod) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022527s029s030lbl.pdf (2019, accessed 4 December 2019).

136.

Hellwig

. Effect of fingolimod on pregnancy outcomes in patients with multiple sclerosis. Stockholm: ECTRIMS, 2019.

137.

Novartis. Mayzent (siponimod) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022527s029s030lbl.pdf (2019, accessed 4 December 2019).

138.

EMA. Mavenclad (cladribine): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf (2019, accessed 4 December 2019).

139.

EMD Serono. Mavenclad (cladribine) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf (2019, accessed 4 December 2019).

140.

Galazka

Nolting

Cook

, et al. Pregnancy outcomes during the clinical development programme of cladribine in multiple sclerosis (MS): an integrated analysis of safety for all exposed patients. Paris: ECTRIMS-ACTRIMS, 2017.

141.

EMA. Aubagio (teriflunomide): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_en.pdf (2019, accessed 4 December 2019).

142.

Sanofi Aventis US. Aubagio (teriflunomide) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s008lbl.pdf (2019, accessed 4 December 2019).

143.

Vukusic

Coyle

Jurgensen

, et al. Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: clinical study data and 5 years of post-marketing experience. Mult Scler. Epub ahead of print 10 April 2019. DOI: 10.1177/1352458519843055.

144.

Biogen. Tysabri (natalizumab) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125104s966lbl.pdf (2019, accessed 10 December 2019).

145.

EMA. Tysabri (natalizumab): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/tysabri-epar-product-information_en.pdf (2019, accessed 10 December 2019).

146.

Wehner

Shopp

Oneda

, et al. Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009; 86: 117–130.

147.

Portaccio

Annovazzi

Ghezzi

, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: fetal risks. Neurology 2018; 90: e823–e831.

148.

Friend

Richman

Bloomgren

, et al. Evaluation of pregnancy outcomes from the Tysabri(R) (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol 2016; 16: 150.

149.

Ebrahimi

Herbstritt

Gold

, et al. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler 2015; 21: 198–205.

150.

Ciron

Hautecoeur

Mathis

, et al. Natalizumab throughout pregnancy: risk of low platelet count in the newborn at delivery. Rev Neurol 2016; 172: 165–166.

151.

Haghikia

Langer-Gould

Rellensmann

, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol 2014; 71: 891–895.

152.

Landi

Portaccio

Bovis

, et al. Continuation of natalizumab versus interruption is associated with lower risk of relapses during pregnancy and postpartum in women with MS. Mult Scler 2019; 25: 890–938.

153.

Genentech. Rituxan (rituximab) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103705 (2019, accessed 10 December 2019).

154.

EMA. Rixathon (rituximab): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/rixathon-epar-product-information_en.pdf (2019, accessed 10 December 2019).

155.

Vaidyanathan

McKeever

Anand

, et al. Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys. Toxicol Sci 2011; 119: 116–125.

156.

Chakravarty

Murray

Kelman

, et al. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011; 117: 1499–1506.

157.

Das

Damotte

Gelfand

, et al. Rituximab before and during pregnancy: a systematic review, and a case series in MS and NMOSD. Neurol Neuroimmunol Neuroinflamm 2018; 5: e453.

158.

Shah

Eckstein

. B cell depletion and pregnancy: review and applications for MS treatment. Mult Scler Relat Disord 2019; 33: 153–157.

159.

Genentech. Ocrevus (ocrelizumab) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761053s018lbl.pdf (2019, accessed 10 December 2019).

160.

EMA. Ocrevus (ocrelizumab): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf (2019, accessed 10 December 2019).

161.

Oreja-Guevara

Wray

Buffels

, et al. Pregnancy outcomes in patients treated with ocrelizumab. Stockholm: ECTRIMS, 2019.

162.

Vukusic

SKL

Wray

Bader-Weder

, et al. An update on pregnancy outcomes following ocrelizumab treatment in patients with multiple sclerosis and other autoimmune diseases. Paris: ECTRIMS-ACTRIMS, 2017.

163.

Genzyme. Lemtrada (alemtuzumab) [package insert]. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103948s5169s5170lbl.pdf (2019, accessed 10 December 2019).

164.

EMA. Lemtrada (alemtuzumab): EPAR summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/lemtrada-epar-product-information_en.pdf (2019, accessed 10 December 2019).

165.

Achiron

Chambers

, et al. Pregnancy outcomes in patients with RRMS who received alemtuzumab in the clinical development program (S24.008). Neurology 2016; 86: S24.008.

166.

Alroughani

Alowayesh

Ahmed

, et al. Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology 2018; 90: e840–e846.

167.

Sepulveda

Montejo

Llufriu

, et al. Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors. Mult Scler Relat Disord 2019; 38: 101483.

168.

De Giglio

Gasperini

Tortorella

, et al. Natalizumab discontinuation and disease restart in pregnancy: a case series. Acta Neurol Scand 2015; 131: 336–340.

169.

Krysko

Rutatangwa

Graves

, et al. Association between breastfeeding and postpartum multiple sclerosis relapses: a systematic review and meta-analysis. JAMA Neurol 2020; 77: 327–338.

170.

Breastfeeding

. Breastfeeding and the use of human milk. Pediatrics 2012; 129: e827–e841.

171.

Wang

Johnson

Sahin

, et al. Evaluation of the safety of drugs and biological products used during lactation: workshop summary. Clin Pharmacol Ther 2017; 101: 736–744.

172.

Bennett

. Drugs and human lactation: a comprehensive guide to the content and consequences of drugs, micronutrients, radiopharmaceuticals and environmental and occupational chemicals in human milk. 2nd ed. Amsterdam: Elsevier, 1996.

173.

Voskuhl

Momtazee

. Pregnancy: effect on multiple sclerosis, treatment considerations, and breastfeeding. Neurotherapeutics 2017; 14: 974–984.

174.

Hale

Siddiqui

Baker

. Transfer of interferon beta-1a into human breastmilk. Breastfeed Med 2012; 7: 123–125.

175.

Baker

Cooper

Kessler

, et al. Transfer of natalizumab into breast milk in a mother with multiple sclerosis. J Hum Lact 2015; 31: 233–236.

176.

Proschmann

Thomas

Thiel

, et al. Natalizumab during pregnancy and lactation. Mult Scler 2018; 24: 1627–1634.

177.

Matro

Martin

Wolf

, et al. Exposure concentrations of infants breastfed by women receiving biologic therapies for inflammatory bowel diseases and effects of breastfeeding on infections and development. Gastroenterology 2018; 155: 696–704.

178.

Krysko

LaHue

Anderson

, et al. Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurological conditions. Neurol Neuroimmunol Neuroinflamm 2020; 7: e637.

179.

Mao-Draayer

Thiel

Mills

, et al. Neuromyelitis optica spectrum disorders and pregnancy: therapeutic considerations. Nat Rev Neurol 2020; 16: 154–170.

180.

Kytta

Rosenberg

. Anaesthesia for patients with multiple sclerosis. Ann Chir Gynaecol 1984; 73: 299–303.

181.

Pastò

Portaccio

Ghezzi

, et al. Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study. BMC Neurol 2012; 12: 165.

182.

Bornemann-Cimenti

Sivro

Toft

, et al. Neuraxial anesthesia in patients with multiple sclerosis: a systematic review. Rev Bras Anestesiol 2017; 67: 404–410.

183.

Neal

Barrington

Brull

, et al. The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine: executive summary 2015. Reg Anesth Pain Med 2015; 40: 401–430.

184.

Van Der Walt

Nguyen

Jokubaitis

. Family planning, antenatal and post partum care in multiple sclerosis: a review and update. Med J Aust 2019; 211: 230–236.

185.

Kelly

Nelson

Chakravarty

. Obstetric outcomes in women with multiple sclerosis and epilepsy. Neurology 2009; 73: 1831–1836.

186.

Finkelsztejn

Brooks

Paschoal

Jr , et al. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011; 118: 790–797.

187.

Bsteh

Algrang

Hegen

, et al. Pregnancy and multiple sclerosis in the DMT era: a cohort study in Western Austria. Mult Scler 2020; 26: 69–78.

188.

De Las Heras

De Andrés

Téllez

, et al. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler 2007; 13: 981–984.

189.

Hellwig

Beste

Schimrigk

, et al. Immunomodulation and postpartum relapses in patients with multiple sclerosis. Ther Adv Neurol Disord 2009; 2: 7–11.

190.

Houtchens

Edwards

Phillips

. Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS. Neurology 2018; 91: e1570–e1578.

191.

Hughes

Spelman

Gray

, et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 2014; 20: 739–746.

192.

Langer-Gould

Smith

Albers

, et al. Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort. Neurology 2020; 94: e1939–e1949.

193.

Portaccio

Moiola

Martinelli

, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: maternal risks. Neurology 2018; 90: e832–e839.

194.

Hatcher

Waubant

Nourbakhsh

, et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol 2016; 73: 790–794.

195.

Frau

Sormani

Signori

, et al. Clinical activity after fingolimod cessation: disease reactivation or rebound? Eur J Neurol 2018; 25: 1270–1275.

196.

Berenguer-Ruiz

Gimenez-Martinez

Palazon-Bru

, et al. Relapses and obstetric outcomes in women with multiple sclerosis planning pregnancy. J Neurol 2019; 266: 2512–2517.

197.

Portaccio

Ghezzi

Hakiki

, et al. Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs. J Neurol Neurosurg Psychiatry 2014; 85: 845–850.

198.

Kaplan

Bove

Galetta

, et al. Effect of pregnancy loss on MS disease activity. J Neurol Sci 2019; 397: 58–60.

199.

Benoit

Durand-Dubief

Amato

M-P

, et al. History of multiple sclerosis in 2 successive pregnancies: a French and Italian cohort. Neurology 2016; 87: 1360–1367.

200.

Langer-Gould

Huang

Gupta

, et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 2009; 66: 958–963.

201.

Hellwig

Rockhoff

Herbstritt

, et al. Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol 2015; 72: 1132–1138.

202.

Langer-Gould

Beaber

. Effects of pregnancy and breastfeeding on the multiple sclerosis disease course. Clin Immunol 2013; 149: 244–250.

203.

Gulick

Halper

. Influence of infant feeding method on postpartum relapse of mothers with MS. Int J MS Care 2002; 4: 183–191.

204.

Hellwig

Haghikia

Agne

, et al. Protective effect of breastfeeding in postpartum relapse rate of mothers with multiple sclerosis. Arch Neurol 2009; 66: 1580–1581.

205.

Airas

Jalkanen

Alanen

, et al. Breast-feeding, postpartum and prepregnancy disease activity in multiple sclerosis. Neurology 2010; 75: 474–476.

206.

Hanulíková

Vlk

Meluzínová

, et al. Pregnant women with multiple sclerosis at the Motol Hospital Prague 2007–2011: outcomes analysis. Aktual Gynekol Porodnictvi 2013; 5: 27–32.

207.

Iorio

Nociti

Frisullo

, et al. Breastfeeding and multiple sclerosis. Arch Neurol 2009; 66: 1580.

208.

Jesus-Ribeiro

Correia

Martins

, et al. Pregnancy in multiple sclerosis: a Portuguese cohort study. Mult Scler Relat Disord 2017; 17: 63–68.

209.

Nelson

Franklin

Jones

. Risk of multiple sclerosis exacerbation during pregnancy and breast-feeding. JAMA 1988; 259: 3441–3443.

210.

Worthington

Jones

Crawford

, et al. Pregnancy and multiple sclerosis: a 3-year prospective study. J Neurol 1994; 241: 228–233.

211.

Runia

Neuteboom

de Groot

CJM

, et al. The influence of vitamin D on postpartum relapse and quality of life in pregnant multiple sclerosis patients. Eur J Neurol 2015; 22: 479–484.

212.

Portaccio

Ghezzi

Hakiki

, et al. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 2011; 77: 145–150.

213.

Howie

McNeilly

. Breast-feeding and postpartum ovulation. IPPF Med Bull 1982; 16: 1–3.

214.

Williams

Koleva

. Identification and treatment of peripartum anxiety disorders. Obstet Gynecol Clin North Am 2018; 45: 469–481.

215.

Jones

Shakespeare

. Postnatal depression. BMJ 2014; 349: g4500.

216.

Langan

Goodbred

. Identification and management of peripartum depression. Am Fam Physician 2016; 93: 852–858.

217.

Siu

Bibbins-Domingo

Grossman

, et al. Screening for depression in adults: US preventive services task force recommendation statement. JAMA 2016; 315: 380–387.

218.

Razaz

Tremlett

Marrie

, et al. Peripartum depression in parents with multiple sclerosis and psychiatric disorders in children. Mult Scler 2016; 22: 1830–1840.

219.

de Sèze

Gamé

. Multiple sclerosis and pelviperineology: urinary and sexual dysfunctions and pregnancy. Prog Urol 2014; 24: 483–494.

220.

Durufle

Petrilli

Nicolas

, et al. Effects of pregnancy and child birth on urinary symptoms and urodynamics in women with multiple sclerosis. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17: 352–355.

221.

Jalkanen

Kauko

Turpeinen

, et al. Multiple sclerosis and vitamin D during pregnancy and lactation. Acta Neurol Scand 2015; 131: 64–67.

222.

Mowry

Waubant

McCulloch

, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012; 72: 234–240.

223.

Jalkanen

Saraste

Gfeller

, et al. Increased thyroid autoimmunity among women with multiple sclerosis in the postpartum setting. Mult Scler 2013; 19: 1734–1742.

224.

Verdru

Theys

D’Hooghe

, et al. Pregnancy and multiple sclerosis: the influence on long term disability. Clin Neurol Neurosurg 1994; 96: 38–41.

225.

Stenager

Jensen

. Effect of pregnancy on the prognosis for multiple sclerosis. A 5-year follow up investigation. Acta Neurol Scand 1994; 90: 305–308.

226.

D’Hooghe

Nagels

Uitdehaag

. Long-term effects of childbirth in MS. J Neurol Neurosurg Psychiatry 2010; 81: 38–41.

227.

Masera

Cavalla

Prosperini

, et al. Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. Mult Scler 2015; 21: 1291–1297.

228.

Ramagopalan

Yee

Byrnes

, et al. Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study. J Neurol Neurosurg Psychiatry 2012; 83: 793–795.

229.

Koch

Uyttenboogaart

Heersema

, et al. Parity and secondary progression in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80: 676–678.

230.

Thompson

Nelson

Burns

, et al. The effects of pregnancy in multiple sclerosis: a retrospective study. Neurology 1986; 36: 1097–1099.

231.

Karp

Manganas

Sylvestre

, et al. Does pregnancy alter the long-term course of multiple sclerosis? Ann Epidemiol 2014; 24: 504–508.e2.

232.

Jokubaitis

Spelman

Kalincik

, et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol 2016; 80: 89–100.

233.

Zuluaga

Otero-Romero

Rovira

, et al. Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis. Neurology 2019; 92: e1507–e1516.

234.

Bove

Alwan

Friedman

, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol 2014; 124: 1157–1168.

235.

Ferraro

Simone

Adani

, et al. Definitive childlessness in women with multiple sclerosis: a multicenter study. Neurol Sci 2017; 38: 1453–1459.

236.

Alwan

Yee

Dybalski

, et al. Reproductive decision making after the diagnosis of multiple sclerosis (MS). Mult Scler 2013; 19: 351–358.

237.

Prunty

Sharpe

Butow

, et al. The motherhood choice: themes arising in the decision-making process for women with multiple sclerosis. Mult Scler 2008; 14: 701–704.

238.

Smeltzer

. Reproductive decision making in women with multiple sclerosis. J Neurosci Nurs 2002; 34: 145–157.

239.

Vukusic

Marignier

. Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol 2015; 11: 280–289.

240.

Amato

Bertolotto

Brunelli

, et al. Management of pregnancy-related issues in multiple sclerosis patients: the need for an interdisciplinary approach. Neurol Sci 2017; 38: 1849–1858.

241.

Cook

. Guest editorial: stigma and identity in multiple sclerosis. Int J MS Care 2019; 21: iv.

242.

Grytten

Maseide

. ‘What is expressed is not always what is felt’: coping with stigma and the embodiment of perceived illegitimacy of multiple sclerosis. Chronic Illn 2005; 1: 231–243.

243.

Stevens

Thompson

Sullivan

. Prevalence and correlates of body image dissatisfaction in patients with multiple sclerosis. Int J MS Care 2019; 21: 207–213.

244.

Wilkinson

Nair

. The psychological impact of the unpredictability of multiple sclerosis: a qualitative literature meta-synthesis. Br J Neurosci Nurs 2013; 9: 172–178.

245.

Mendibe Bilbao

Boyero Duran

Barcena Llona

, et al. Multiple sclerosis: pregnancy and women’s health issues. Neurologia 2019; 34: 259–269.

246.

Barker

Smale

Hunt

, et al. Experience of identity change in people who reported a diagnosis of multiple sclerosis: a qualitative inquiry. Int J MS Care 2019; 21: 235–242.

247.

Willson

Tetley

Lloyd

, et al. The impact of multiple sclerosis on the identity of mothers in Italy. Disabil Rehabil 2018; 40: 1456–1467.

248.

Spencer

Silverman

Cook

. Adapting to multiple sclerosis stigma across the life span. Int J MS Care 2019; 21: 227–234.

249.

Voskuhl

Wang

, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 35–46.

250.

Pozzilli

De Giglio

Barletta

, et al. Oral contraceptives combined with interferon beta in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2015; 2: e120.

251.

MacKenzie-Graham

Brook

Kurth

, et al. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav 2018; 8: e01086.

252.

Tutuncu

Tang

Zeid

, et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 2013; 19: 188–198.

253.

Smith

Studd

. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med 1992; 85: 612–613.

254.

Holmqvist

Wallberg

Hammar

, et al. Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas 2006; 54: 149–153.

255.

Bove

Healy

Secor

, et al. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord 2015; 4: 18–24.

256.

Baroncini

Annovazzi

De Rossi

, et al. Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurol Neurosurg Psychiatry 2019; 90: 1201–1206.

257.

Dhandapani

Brann

. Role of astrocytes in estrogen-mediated neuroprotection. Exp Gerontol 2007; 42: 70–75.

258.

Nilsen

Chen

Irwin

, et al. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci 2006; 7: 74.

259.

Christianson

Mensah

Shen

. Multiple sclerosis at menopause: potential neuroprotective effects of estrogen. Maturitas 2015; 80: 133–139.

260.

Dumas

Hancur-Bucci

Naylor

, et al. Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Horm Behav 2008; 53: 159–169.

261.

Rasgon

Silverman

Siddarth

, et al. Estrogen use and brain metabolic change in postmenopausal women. Neurobiol Aging 2005; 26: 229–235.

262.

Engler-Chiurazzi

Brown

Povroznik

, et al. Estrogens as neuroprotectants: estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 2017; 157: 188–211.

263.

Sherwin

. Estrogen therapy: is time of initiation critical for neuroprotection? Nat Rev Endocrinol 2009; 5: 620–627.

264.

Kurita

Henderson

Gatz

, et al. Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women. Fertil Steril 2016; 106: 749–756.e742.

265.

Verghese

Kuslansky

Katz

, et al. Cognitive performance in surgically menopausal women on estrogen. Neurology 2000; 55: 872–874.

266.

Bove

White

Fitzgerald

, et al. Hormone therapy use and physical quality of life in postmenopausal women with multiple sclerosis. Neurology 2016; 87: 1457–1463.

267.

Boulware

Kent

Frick

. The impact of age-related ovarian hormone loss on cognitive and neural function. Curr Top Behav Neurosci 2012; 10: 165–184.

268.

Zorzon

Zivadinov

Bosco

, et al. Sexual dysfunction in multiple sclerosis: a case-control study. 1. Frequency and comparison of groups. Mult Scler 1999; 5: 418–427.

269.

Polat Dunya

Tulek

Uchiyama

, et al. Systematic review of the prevalence, symptomatology and management options of sexual dysfunction in women with multiple sclerosis. Neurourol Urodyn 2020; 39: 83–95.

270.

Tepavcevic

Kostic

Basuroski

, et al. The impact of sexual dysfunction on the quality of life measured by MSQoL-54 in patients with multiple sclerosis. Mult Scler 2008; 14: 1131–1136.

271.

Ashtari

Rezvani

Afshar

. Sexual dysfunction in women with multiple sclerosis: dimensions and contributory factors. J Res Med Sci 2014; 19: 228–233.

272.

Kisic-Tepavcevic

Pekmezovic

Trajkovic

, et al. Sexual dysfunction in multiple sclerosis: a 6-year follow-up study. J Neurol Sci 2015; 358: 317–323.

273.

Clayton

Goldstein

Kim

, et al. The International Society for the Study of Women’s Sexual Health process of care for management of hypoactive sexual desire disorder in women. Mayo Clin Proc 2018; 93: 467–487.

Sex effects across the lifespan in women with multiple sclerosis

Abstract

Keywords

Introduction

Susceptibility to MS

Genetics and epigenetics

Hormones

Environmental

Smoking

EBV

Vitamin D/sunlight exposure

Fertility and contraception

Fertility and assisted reproductive technology

Contraception

Immunology of pregnancy: effects in MS

Immunological changes at the maternal–fetal interface

Immunological changes in pregnancy and MS

Recommendations on planning a pregnancy in MS

Pregnancy and DMTs

DMT safety before and during pregnancy

DMT safety in breastfeeding

Obstetric management

Pregnancy and disease course: short-term outcomes and postpartum relapse risk

Breastfeeding and postpartum relapses

Postpartum management

Pregnancy and disease course: long-term outcomes

Stigma around family planning

Exogenous hormones as a DMT with impact on long-term prognosis of MS

Menopause and reproductive aging

Ovarian aging and disease course

Symptom management in perimenopause

Female sexual dysfunction in MS

Conclusion

Footnotes

Acknowledgements

Conflict of interest statement

Funding

ORCID iDs

References