Multiple sclerosis: Pregnancy planning

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system that is a leading cause of neurologic disability. MS disproportionally affects women more than men by a ratio of approximately 2:1 to 3:1, and the mean age of onset of MS is approximately 30 years. In general, the prevalence of MS is highest in North America and European nations and lowest in Asia, Oceania, and South America. The symptoms of MS are commonly present in women of reproductive age, who need special considerations for pregnancy. (See "Pathogenesis and epidemiology of multiple sclerosis".)

This topic will include reproductive goals and fertility planning, assessment of MS disease activity, the need for disease-modifying therapies (DMTs), the effect of MS on pregnancy, the effect of pregnancy on changing the course of MS, DMT washout, and the use of DMTs in pregnancy. Care during pregnancy and the postpartum period is reviewed separately. (See "Multiple sclerosis: Pregnancy and postpartum care".)

Other aspects of MS are discussed elsewhere:

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

PRECONCEPTION PLANNING AND CARE

Counseling — Counseling for women with MS is an important aspect of optimizing pregnancy outcomes [1]. Ideally, preconception counseling should take place with the reproductive partner soon after the diagnosis of MS. Preconception counseling should include reassurance that, in general, pregnancy does not negatively affect MS disease progression.

●Timing of pregnancy – The optimal time for pregnancy is when MS symptoms are stable, since MS disease stability is associated with better intrapartum and postpartum outcomes. Unless premature ovarian failure is a concern, conception is generally not recommended until one to two years after MS diagnosis to allow the disease to be adequately controlled. However, older women or women who have other reasons to conceive shortly after the diagnosis of MS can be readily supported through this process.

●Contraception – Patients should be informed that contraception has not been shown to negatively affect MS course and that the disease itself does not interact with hormonal contraception [2]. In fact, the use of high-dose estrogen, as found in oral contraceptive pills, with interferon (IFN)-beta has been shown to reduce the rate of formation of new T2 magnetic resonance imaging (MRI) lesions, which are thought to work synergistically to promote an anti-inflammatory effect [3].

●Preconception and prenatal care – Preconception recommendations are to avoid alcohol and smoking, eat a balanced diet, take vitamin D supplementation, and prioritize sleep hygiene. Vitamin D levels less than 12 ng/mL (30 nmol/L) in early pregnancy have been associated with two times the risk of MS in the child [4]. Approximately 1000 to 2000 units/day of vitamin D supplementation prior to pregnancy would result in optimal vitamin D levels of 40 to 60 ng/mL during pregnancy [5,6]. (See "Nutrition in pregnancy: Assessment and counseling" and "Nutrition in pregnancy: Dietary requirements and supplements".)

Live vaccines should be avoided in pregnant women with MS. Inactivated vaccines can be used safely. Polysaccharide pneumococcal and hepatitis B vaccines are safe in pregnancy if needed. Bacterial vaccines (Bacillus Calmette-Guerin and typhoid) and attenuated virus vaccines (measles, mumps, rubella [MMR]; varicella-zoster; and rotavirus) are safe in preconception and the third trimester of pregnancy [7]. (See "Immunizations during pregnancy".)

●Risk of MS transmission to offspring – Some parents are concerned that their children might inherit MS [8]. While MS is not a genetically inherited disease, it is believed to be caused by the interaction of genetic susceptibility factors and environmental triggers. The overall risk of developing MS in the general population is low (0.1 to 0.3 percent) [9,10]. Having a first-degree relative (eg, parent) with MS is associated with an increased risk of 2 to 4 percent [11,12]. Thus, mothers and fathers with MS should be aware of the increased genetic risk.

The strongest genetic factor for MS is human leukocyte antigen (HLA) DRB1*15, and this gene explains approximately 10 percent of the genetic risk of the disease. An analysis of genetic data from over 47,000 individuals with MS and 68,000 control subjects found 200 autosomal susceptibility variants for MS outside the major histocompatibility complex (MHC), 31 susceptibility variants within the MHC, and one susceptibility locus on the X chromosome X [13]. Altogether, genetic variants explain approximately 49 percent of MS heritability [13].

Known environmental risk factors for MS are smoking tobacco, low vitamin D, and the Epstein-Barr virus [14]. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Epidemiology and risk factors'.)

Use of disease-modifying therapies (DMTs) — Women of reproductive age with severe MS symptoms should be encouraged to use DMTs [9]. However, given beneficial effects of pregnancy on relapse rate, DMTs may be stopped in pregnancy for some women. For women who desire to become pregnant (or for men who are using teriflunomide), the risk of possible adverse effects of DMTs on the fetus must be weighed against DMT discontinuation and increased risk of maternal disease relapses. Practitioners should discuss the benefits and risks of DMTs commonly used to treat MS, including the effects of DMTs before, during, and after pregnancy.

The overall goal should be to minimize risk of the reactivation of MS by shortening the "washout period" (the time without any DMT to allow the levels of the drug to be eliminated from the maternal system) as much as possible in preconception and managing any risk of rebound relapse associated with stopping a lymphocyte sequestering agent (eg, natalizumab, sphingosine 1-phosphate receptor [S1PR] drugs). (See 'DMT washout' below.)

Forty-nine percent of women surveyed responded they felt "inadequately informed" about DMT in pregnancy [15].

●Guidance for women – Most experts advise that women discontinue treatment with DMTs for MS if possible when they are planning a pregnancy and during pregnancy [16-19]. Ideally, pregnancy would be scheduled for a time when MS activity has been quiescent for a year [19]. Prior to attempting pregnancy, a washout period is advised for some DMTs (table 1). (See 'DMT washout' below.)

To minimize the time off DMT, it may be helpful to use menstrual cycle charting, basal body temperature monitoring, and ovulation predictor kit or ultrasound measurement of follicle size to improve the odds of conception [20]. Referral to a fertility specialist is suggested for women with demyelinating disease if conception is not achieved within six months [20]. (See "Evaluation of the menstrual cycle and timing of ovulation" and "Natural fertility and impact of lifestyle factors", section on 'How do I know if I am in my fertile period?' and "Overview of infertility" and "Female infertility: Evaluation".)

Most MS experts agree, supported by registry data, that the older injectable DMTs (ie, beta interferons and glatiramer acetate) can be continued while trying to conceive with careful planning and counseling. Otherwise, the approach to DMT use in pregnancy varies among MS clinicians. Those who favor stopping DMTs argue that only limited evidence is available concerning their safety during pregnancy, that the MS relapse rate is much reduced in pregnancy regardless (see 'MS activity in pregnancy and postpartum' below), and that DMTs can be started or restarted in the immediate postpartum period. Other experts argue that the decision must weigh uncertain risks to the fetus posed by DMTs for MS against clear benefits to the mother. The available data do not support aborting pregnancy because of concerns regarding DMT exposure, even with exposure to DMTs with the highest theoretical risk [21-23].

●Risk of DMT use during pregnancy – Some drugs used to treat MS are known teratogens, including teriflunomide and mitoxantrone; others are potential teratogens, including fingolimod, siponimod, and cladribine. Such drugs are contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception.

In addition, oral DMTs are relatively contraindicated during pregnancy and breastfeeding, related to the mechanism of delivery (bioavailable to the fetus in the blood stream) and mechanism of action (table 2).

A systematic review searched the literature through February 2012 and identified 15 studies (four prospective cohort, five retrospective cohort, and six case series) that evaluated pregnancies exposed to IFN-beta drugs (n = 761), glatiramer acetate (n = 97), and natalizumab (n = 35) [21]. IFN-beta exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks) but was not associated with spontaneous abortion, cesarean delivery, birth weight <2500 g, lower mean gestational age, or congenital anomaly. Glatiramer acetate exposure was not associated with lower mean birth weight, lower mean gestational age, preterm birth (<37 weeks), congenital anomaly, or spontaneous abortion. Natalizumab exposure was not associated with lower mean birth weight, shorter mean birth length, or lower mean gestational age. There were no studies reporting exposure to alemtuzumab, dimethyl fumarate, mitoxantrone, fingolimod, or teriflunomide during pregnancy.

●Risk of DMT discontinuation – An analysis of data from the observational MSBase Registry, with 1998 pregnancies from 1619 women with MS treated in the time period after 2011, found that discontinuation of natalizumab or fingolimod was associated with an increased intrapartum and postpartum relapse rate [24]; continuation of natalizumab during pregnancy was associated with reduced odds of relapse. Postpartum resumption of high-efficacy DMTs (eg, natalizumab) was associated with a reduced hazard of postpartum relapse. This observational study did not include women treated with anti-CD20 monoclonal antibodies.

An earlier series of women with MS found that exposure to DMTs for at least eight weeks during pregnancy (n = 61) was associated with a significantly lower postpartum MS relapse rate and a lower postpartum risk of disease progression compared with pregnancies not exposed (n = 89) [25]. The MS relapse rate was significantly lower for both the exposed and unexposed groups during pregnancy compared with the baseline relapse rate prior to pregnancy. These findings are limited by the retrospective, nonrandomized nature and small size of this study.

●Highly active disease – For patients with highly active MS, the benefit of continuing DMT up to conception or throughout pregnancy to prevent relapses may be greater than the risk of fetal harm. Among the DMTs, glatiramer acetate may be used during conception and pregnancy, as extensive safety data suggest it is not associated with fetal harm [20,21,26,27]. IFN-beta preparations are also considered relatively safe during pregnancy and are not associated with an increased risk of congenital anomalies [21,28].

If required, natalizumab can continue throughout pregnancy with a reduced infusion regimen of every six to eight weeks [20]. Natalizumab has not been associated with significant fetal harm when continued through pregnancy [29-31] but does cross the placenta; natalizumab use during the second or third trimester, primarily after 25 weeks, is associated with a risk of transient thrombocytopenia and anemia.

However, since most women stop DMT prior to pregnancy or in the first trimester, available data for DMT exposure through pregnancy are limited [32]; more data are awaited from ongoing registries.

DMT washout — A "washout period" refers to the estimated length of time the DMT should be stopped before pregnancy to reduce the risk of fetal harm (table 1) [17,20]. The goal is to time the washout period to end as close as possible to conception. Minimizing the total time off therapy before a positive pregnancy test makes relapse during pregnancy less likely. It is imperative to counsel patients on the length of washout and to establish when the medication was stopped. DMT washout applies to breastfeeding as well as pregnancy. In addition, counseling about the risk of rebound relapse, which is higher for certain medications such as natalizumab and the S1PR modulators, should be weighed against fetal teratogenicity in a shared decision-making model with the patient.

The length of the washout period varies among therapies based upon the half-life of the medication (table 1), although the optimal length of washout is not firmly established for the different DMTs [17,20,33]. The FDA prescription labels recommend the following washout periods:

●Glatiramer acetate, none

●Interferons, none

●Fumarates (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), none; regardless, some experts use a two-week washout

●S1PR modulators:

•Fingolimod, two months

•Siponimod, 10 days

•Ozanimod, three months

•Ponesimod, one week

●Natalizumab, three months

●Alemtuzumab, four months

●Ocrelizumab, six months

●Ofatumumab, six months

●Rituximab, six months

●Cladribine, six months

These washouts may be longer than necessary or practical for natalizumab and certain B-cell depleting monoclonal antibodies (eg, ocrelizumab, rituximab) (table 1) [20,34].

Teriflunomide requires an active elimination protocol using oral cholestyramine or activated charcoal to reduce the plasma level to <0.02 mg/L [35,36].

Infertility

●Infertility risk and MS – Most women with MS have normal fertility. Observational cohort data suggest that MS is not associated with infertility [9,20,37]. Population-based studies have found that the rates of spontaneous pregnancy and time to pregnancy for patients with MS are similar to the general population [38-40]. As an example, an observational cohort study of 216 pregnancies (n = 84 pregnant patients) reported that the rates of spontaneous pregnancy, time to pregnancy, and miscarriage in women with MS were similar to rates in the general population [38]. This study also found that pregnancy rates may be increasing in the MS population over time. Other studies, limited by small sample sizes, reported factors associated with reduced fertility in women with MS, including altered levels of sex hormones and gonadotrophins, and reduced ovarian reserve characterized by various factors, including lower levels of anti-müllerian hormone [41,42]. However, the data are inconsistent; a large case-control study found that levels of anti-müllerian hormone were similar in women with MS (n = 412) compared with healthy controls (n = 180) [43].

Likewise, there are few data on potential outcomes of pregnancies fathered by men with MS undergoing treatment with DMTs. A large population-based study showed that men with MS on either IFN-beta or glatiramer acetate fathered full-term pregnancies that were appropriate for gestational age [44]. The clinical severity of paternal MS did not correlate with birth outcomes.

Immunosuppressants sometimes used in MS, such as mitoxantrone and cyclophosphamide, have been associated with female infertility and may also affect the male spermatozoa [45].

●Sexual dysfunction – MS may be associated with female and male sexual dysfunction, which could impair family planning, as reviewed elsewhere. (See "Manifestations of multiple sclerosis in adults", section on 'Sexual dysfunction'.)

●Infertility treatment – Patients with MS who do not achieve pregnancy after six months of optimal attempts to conceive should be offered referral to a fertility clinic to reduce time off DMT and thereby minimize the risk of MS relapse [20].

Patients should be counseled about the increased risk of relapse (if off DMT) with assisted reproductive technology (ART), even if the ART cycle is not successful. It is reasonable to continue DMT in the form of IFN-beta, glatiramer acetate, or monoclonal antibodies until the ART cycle is over to decrease risk of relapse [40].

ART, especially in the form of gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of MS relapse and the number or size of T2/gadolinium-enhancing lesions [39,46,47]. GnRH is known to stimulate immune cell proliferation and production of cytokines, chemokines, endothelial growth factors, and estrogen. As an example, a prospective study of 16 women with relapsing-remitting MS (RRMS) treated with 26 ART cycles total showed a sevenfold increased risk of MS exacerbation and a nearly ninefold increased risk of new T2 MRI brain lesions three months after ART [46]. Of note, this and similar studies evaluated mainly women on low-efficacy DMT (glatiramer acetate or IFN-beta) that was stopped before the use of ART [20]. Patients receiving glatiramer acetate or IFN-beta during ART therapy until conception may have a lower relapse rate [8]. Data are needed for relapse rates in patients who were treated with higher-efficacy DMTs (eg, ocrelizumab, rituximab, alemtuzumab, cladribine) before undergoing ART [20].

EFFECT OF MS ON PREGNANCY OUTCOMES

Maternal outcomes — MS does not increase the risk of complications of pregnancy, such as ectopic pregnancy, abnormal placentation, spontaneous miscarriage, antepartum bleeding, pre-eclampsia, stillbirth, premature birth, or congenital malformations. A 2002 population-based cohort study showed that women with MS (n = 1980) were not more likely to have pregnancy or delivery complications compared with the general population of patients without MS [48]. A 2021 cross-sectional study also found no differences in pregnancy-related outcomes among women with MS compared with the general population [49]. There was no difference in pre-eclampsia, gestational diabetes, placenta complications, emergency cesarean section, instrumental delivery, low Apgar score, stillbirth, preterm birth, or congenital malformations. Another study analyzed an inpatient database with an estimated 15 million deliveries in the United States from 2003 to 2006, including 4730 in women with MS [50]. MS was associated with a small increase in the rate of cesarean delivery (42.4 percent versus 32.8 percent for controls, absolute risk difference approximately 9.6 percent, odds ratio [OR] 1.3, 95% CI 1.1-1.4).

Fetal development — Fetal anomalies have not been associated with maternal MS in large prospective studies and cross-sectional registries [49,51].

In data from the United States inpatient database cited above, MS was associated with only a small increase in the risk of intrauterine growth restriction (2.7 percent versus 1.9 percent for controls, absolute risk difference approximately 0.8 percent, OR 1.7, 95% CI 1.2-3.3) [50]. An earlier report from Norway evaluated a nationwide registry of over two million births from 1967 through 2002 and identified 649 births among 461 mothers with MS [52]. Mothers with MS had a higher proportion of infants who were small for gestational age (13.5 versus 11.3 percent, absolute risk difference approximately 2.2 percent, OR 1.45, 95% CI 1.14-1.84).

The potential risks for teratogenicity in fetal development associated with disease-modifying therapies are reviewed above. (See 'Use of disease-modifying therapies (DMTs)' above.)

EFFECT OF PREGNANCY ON MS DISEASE ACTIVITY

MS phenotypes — The core MS phenotypes are those of relapsing-remitting and progressive disease. The pattern and course of MS is further categorized into several clinical subtypes as follows:

●Clinically isolated syndrome (CIS), often representing the first attack of MS

●Relapsing-remitting MS (RRMS)

●Secondary progressive MS (SPMS)

●Primary progressive MS (PPMS)

RRMS is the most common type of MS, and it accounts for 85 to 95 percent of MS at disease onset [9]. Most women planning pregnancies will have CIS and RRMS phenotypes. The different MS phenotypes are discussed in detail elsewhere. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)

In addition, these phenotypes are modified by assessments of disease activity and disease progression over time. Disease activity is determined by clinical relapses or MRI evidence of contrast-enhancing lesions and/or new or unequivocally enlarging lesions on T2-weighted images.

MS activity in pregnancy and postpartum — Pregnancy itself is not detrimental for women with MS but rather has a beneficial impact on relapses. Most women with MS have normal fertility, but sexual dysfunction due to MS and fear of getting pregnant may be major obstacles in certain cases. (See "Manifestations of multiple sclerosis in adults", section on 'Sexual dysfunction'.)

The third trimester of pregnancy can have the same potency of effect as most high-efficacy MS disease-modifying therapies. The underlying mechanism is likely related to estriol and progesterone production, a shift from T helper cell 1 phenotype to T helper cell 2 phenotype, and large shifts in gene expression profiles [53]. Thus, for some women with mild to moderate disease, it may be possible to discontinue disease-modifying therapies (DMTs), at least in the second and third trimester, with careful planning in the antepartum period.

A meta-analysis of 13 studies with 1221 pregnancies published in 2011 concluded that pregnancy is associated with a decrease in MS disease activity, while the postpartum period is associated with an increase in MS activity [54]. Data from the prospective Pregnancy in Multiple Sclerosis (PRIMS) studies illustrate this conclusion [55,56]. In the first (1998) report of the PRIMS studies, 254 women with MS were followed during 269 pregnancies and for 12 months postpartum [55]. The mean annualized relapse rate (ARR) decreased from 0.7 in the year prior to pregnancy to 0.2 in the third trimester; the ARR then increased to 1.2 in the first three months postpartum, followed by a return to the prepregnancy rate (figure 1).

Subsequent reports have also found a decrease in MS activity during pregnancy and an increase in MS activity during the early postpartum period [57-59].

The second (2004) PRIMS report, with a two-year postpartum follow-up, analyzed 227 live-born pregnancies from the first report to elucidate any predictors of relapse in the postpartum period [56]. Relapse in the first three months postpartum was most likely in women with an increased relapse rate in the prepregnancy year or an increased relapse rate during pregnancy. However, these factors correctly predicted presence or absence of early postpartum relapse in only 72 percent of women. In this and other studies, predictors for early postpartum relapse included the following [25,56,58,60]:

●Higher ARR in the two years prior to conception

●Relapses occurring in pregnancy

●Higher Expanded Disability Status Scale (EDSS) score at conception

●Lack of DMT in the two years prior to conception

However, discontinuation of certain DMTs (particularly natalizumab and fingolimod) has been associated with an overall increased risk of MS relapses, including during pregnancy and postpartum [61-65]. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Risk of rebound of MS activity'.)

Immunology — MS is considered a T helper type 1 (Th1)-dominant disorder, while normal pregnancy is considered a T helper type 2 (Th2)-dominant immune state to allow for maternal immune tolerance of the fetus [66]. During normal pregnancy, the differentiation of CD4+ T cells favors Th2 instead of Th1 dominance of the immune system [67,68]. Th2 cytokine production increases and subsequently decreases the production of the proinflammatory Th1/Th17 cells. The placenta and fetus also secrete cytokines into the maternal bloodstream, which downregulates other cytokine-like substances involved in cell-mediated immunity. The change in immunity may explain the reduced relapse rate during pregnancy.

MS disease progression — Despite the reduced MS relapse rate during pregnancy, the cumulative lifetime disability of MS appears to be largely unchanged by pregnancy. For this reason, women may want to consider DMT in the peripartum period to reduce the risk of long-term disability.

Several epidemiologic investigations have found that long-term disability due to MS is not altered by pregnancy [69-74]. In the PRIMS study, there was no acceleration in the rate of disability or disease progression postpartum [55]. In other reports, women with pregnancies after disease onset show slower progression compared with nulliparous women, based upon the EDSS score [51,75,76].

The available evidence suggests that pregnancy does not increase the risk of developing MS [69,77-81]. A Danish case-control study found that childbirth within five years before clinical onset was associated with a reduced risk of MS both for one childbirth (OR 0.54, 95% CI 0.41-0.70) and for more than one childbirth (OR 0.68, 95% CI 0.53-0.87) [82].

SUMMARY AND RECOMMENDATIONS

●Pregnancy planning and preconception care – With careful planning, women with multiple sclerosis (MS) can have successful pregnancies without known deleterious effects of pregnancy on mother or infant. Pregnancy has a protective effect against relapse in MS. Counseling during the reproductive years for women with MS is an important aspect of optimizing pregnancy outcomes. The optimal time for pregnancy is when MS symptoms are stable, since MS disease stability is associated with better intrapartum and postpartum outcomes.

Women planning pregnancy should avoid alcohol and smoking, eat a balanced diet, take vitamin D supplementation and prenatal vitamins, and prioritize sleep hygiene. Live vaccines should be avoided in pregnant women with MS and given if needed before pregnancy and before certain disease-modifying therapies (DMTs). Preconception planning should also include any adjustment in symptom management medications to avoid potential risks in the first trimester. (See 'Preconception planning and care' above.)

●DMT considerations – Most experts advise that women may be able to discontinue treatment with DMTs for MS during pregnancy, but it is important to gain control of disease with DMTs before pregnancy, if possible, and to protect women while trying to conceive. Some drugs used to treat MS are clearly contraindicated for use in pregnancy, including most of the oral agents. DMTs that are known teratogens (teriflunomide and mitoxantrone) and others that are potential teratogens (fingolimod, siponimod, and cladribine) are contraindicated for use while pregnant or for women of childbearing potential who are not using reliable contraception. However, DMT discontinuation may lead to an increased intrapartum and postpartum relapse rate, particularly for natalizumab and fingolimod.

For women with highly active MS, the benefit of continuing DMT up to conception or throughout pregnancy may be greater than the risk of fetal harm; reasonable DMT choices in this setting are glatiramer acetate, beta interferons, and natalizumab. B-cell depleting therapies can also be given prior to conception, with lasting B-cell depletion long after the drug has cleared the maternal bloodstream. (See 'Use of disease-modifying therapies (DMTs)' above.)

●DMT washout – For patients who plan to stop DMT before pregnancy, a washout period for DMTs is advised prior to attempting pregnancy to avoid fetal exposure (table 1). (See 'DMT washout' above.)

●Infertility – Limited data suggest that MS is not associated with infertility. However, certain medication exposures with assisted reproductive technology have been associated with an increased risk of MS relapse, particularly for women who are off DMT during treatment. (See 'Infertility' above.)

●MS and pregnancy outcomes – Most reports suggest that maternal MS does not increase the risk of pregnancy complications or fetal anomalies. (See 'Effect of MS on pregnancy outcomes' above.)

●Pregnancy and MS activity – Pregnancy appears to have a protective effect against MS relapses, but there is an increased risk of disease exacerbation in the early postpartum period. (See 'Effect of pregnancy on MS disease activity' above.)