Multiple sclerosis management and reproductive changes

Abstract

Purpose of review

Multiple sclerosis (MS) disease activity and symptoms are tied to hormonal changes. This review explains the current standard of care in MS at various stages of a woman's reproductive life and helps neurologists answer patients' most common questions surrounding MS care and fertility, pregnancy, and menopause.

Recent findings

Recent work has focused on MS risk and exacerbation with variables related to reproductive health. Management of disease-modifying therapies prenatally and postnatally is also a focus.

Summary

This review is a concise, practical guide for general neurologists caring for women with MS. MS is a disease that requires adaptation of management as a woman moves through reproductive stages. With proper planning and management, pregnancy is safe for women with MS. We describe the current standard of care based on trials, when available, and on expert opinion.

A 25-year-old woman with multiple sclerosis (MS) presents to your neurology clinic. She first had symptoms 2 years ago when she presented with optic neuritis. Brain MRI showed evidence of old white matter plaques. She had an episode of right lower extremity numbness 2 months after her initial attack but is now stable on disease-modifying therapy (DMT).

Menstrual cycle

The patient's symptoms of fatigue and urinary urgency are generally well-controlled, but she describes worsening of both in the 2 days preceding her menstrual cycle.

A majority of women with MS report premenstrual worsening of MS symptoms,^1,2 and those who do not are more likely to be using oral contraceptive pills (OCP).³ MRI studies have not shown a consistent correlation between menstrual cycle phase and number of enhancing lesions,^4,5 and the mechanism for premenstrual symptom exacerbation is unknown.

Frequency and regularity of menses do not vary between patients on different DMTs.⁶ You advise your patient to discuss an extended form of birth control that reduces frequency of menses with her primary care physician or gynecologist.

Oral contraceptives

The patient returns for her follow-up visit 6 months later. She has no new symptoms, her examination is unchanged, and she is up to date with laboratory studies and MRIs. She asks whether taking OCP will make her MS worse or may have even caused her MS.

You reassure your patient that OCP use does not increase risk of developing MS and is not putting her at risk for an MS relapse.^7–10 High levels of estrogen, such as levels during pregnancy, may be protective in MS.¹¹ Low doses of estrogen associated with OCP use may reduce risk of developing MS,¹² delay onset of symptoms,¹³ and protect from progression of disability.¹⁴

The patient is also concerned about the interaction of her OCP and DMT.

There is no evidence that OCPs lower the efficacy of DMTs or vice versa; this has been shown recently with fingolimod and dimethyl fumarate.^15,16 Gabapentin and benzodiazepines, medications commonly used to treat symptoms of MS, also do not interact with OCP.¹⁷ However, modafinil—a medication commonly used to treat fatigue in MS—may reduce the efficacy of OCP.¹⁸ Teriflunomide increases some OCP hormone levels.¹⁹

The patient's mother, who accompanies her on this clinic visit, fears that not having children puts her daughter at risk for future relapses.

Women who are older at the birth of their first child are not at higher risk for developing MS.^10,20,21 A handful of studies show reduced risk with higher parity,^20-22 including a study that evaluated parity at first clinical attack and so controlled for increased disability precluding pregnancy.²⁰ However, a recent study finds no association between parity and MS risk and proposes that the supposed protective effect of higher parity may come from subclinical MS lowering fertility rates in the few years prior to diagnosis.¹⁰

Pregnancy planning

On a follow-up visit 5 years later, the patient tells you that she would like to have a child. She asks if pregnancy is safe for women with MS.

Until the latter half of the 20th century, physicians advised women with MS to avoid pregnancy, believing that pregnancy increases disease severity. The Pregnancy in Multiple Sclerosis study showed a decrease in relapse rate during pregnancy and an increase in the first 3 months postpartum.²³ You now counsel your patient that for patients with relapsing-remitting MS, pregnancy does not worsen prognosis long-term. Women with MS are now encouraged to have children if they wish.

The patient would like to know your plan for her DMT during pregnancy.

No MS disease-modifying medications are proven safe during pregnancy in humans. Consider a pregnancy test prior to starting a new DMT and discuss the importance of contraception with female patients on DMT. Long-acting reversible contraception methods (e.g., intrauterine devices) are preferred due to reliability and lack of compliance issues.²⁴ Combined contraceptive use in women with prolonged immobility is sometimes avoided due to increased risk of venous thromboembolism.

Unless a patient has highly active disease, she should discontinue her DMT a few months prior to trying to conceive (table). Those with active disease are sometimes maintained on glatiramer acetate therapy until pregnancy is confirmed or even throughout pregnancy; however, this is not based on any recommendation by manufacturers and there are no prospective studies evaluating safety. Small registries of pregnancies with exposure to glatiramer acetate (drug discontinued less than 4 weeks prior to conception) showed no increase in spontaneous abortion or other negative fetal outcomes,^25–27 pattern of adverse neonatal outcomes, or developmental issues.²⁸ Interferons are likely safe^29–31 but some data hint at an increased spontaneous abortion rate and lower birthweight.^27,32,33 Natalizumab increases risk of spontaneous abortion and low birthweight when discontinued less than 10 weeks prior to conception.³³

Table.

Disease-modifying therapy safety during pregnancy and breastfeeding

Because DMTs take weeks to months to take full effect—and, in the case of glatiramer acetate, up to 6 months³⁴—a newly diagnosed patient is generally not started on DMT if she is planning on conceiving within the next year. The exception is patients with highly active disease, in which case disease activity is ideally controlled prior to conception. Offer women considering pregnancy in the next 2 years a DMT other than teriflunomide due to its teratogenic effect in animal studies and slow elimination³⁵; women on teriflunomide who wish to become pregnant should undergo rapid elimination. Longer-acting monoclonal antibodies such as ocrelizumab provide sustained disease control even after elimination.

Fertility

One year later, the patient is still not pregnant. Her obstetrician recommends assisted reproductive therapy (ART). She comes to you before starting treatment to make sure it is safe.

Women with MS generally do not have more difficulty conceiving than their healthy counterparts^36,37 but a small study found a 5-fold increase in the need for artificial insemination in women with MS.³⁸ There are several reasons a woman with MS may have more difficulty conceiving: purposeful delay of pregnancy due to a new MS diagnosis, sexual dysfunction, an association of MS with endometriosis,³⁹ and lower levels of anti-Müllerian hormone and thus lower ovarian reserve.⁴⁰

Length of time between stopping DMT and pregnancy should be minimized. Your patient can discuss ovulation tracking with her gynecologist. Generally, reproductive endocrinology and infertility (REI) specialists recommend a referral to REI clinic if a couple has not conceived after 12 months of regular intercourse without contraception, but consider an earlier referral if a patient with MS is off DMT and has not conceived after a few months.

ART cycles, specifically utilizing gonadotropin-releasing hormone (GnRH) agonists, increase risk of MS exacerbation.^41–44 GnRH antagonists did not increase relapse rate in 2 small studies^42,43 but did in a third, larger cohort.⁴⁴ You advise your patient and her obstetrician that if a hormone treatment is required, from an MS perspective, a GnRH antagonist may be safer than an agonist.⁴⁵

Pregnancy

The patient's next visit brings good news: she is in the first trimester of pregnancy. She worries about her baby's health, as does any expectant mother. She also worries that she will pass MS on to her child.

Rates of miscarriage and fetal malformation in pregnancies of women with MS are the same as in the general population.^46–48 Babies born to mothers with MS are often found to be smaller,^46,47,49,50 but other studies show birthweights to be equal to the general population.^48,51 You reassure her that her child's risk of having MS is only 1%–5%, though this is higher than the 0.1%–0.2% risk of the general population.^52,53

The patient asks how you plan to manage a relapse during pregnancy and what she should do with the medications she is taking for symptom management.

Relapse rates decrease during pregnancy, especially during the third trimester.⁵⁴ Though MRI without contrast is likely safe, especially after the first trimester, avoid imaging during pregnancy unless it will substantially change management.⁵⁵ Gadolinium contrast, which crosses into the placenta, is a teratogen in animal studies and thus is contraindicated.⁵⁶ For a severe flare during pregnancy, a brief course of steroids (prednisone or methylprednisolone, not dexamethasone) is generally safe except during the first trimester, when it can cause cleft palate,⁵⁷ and with caution towards the end of pregnancy, when it can cause transient neonatal immunosuppression. IV immunoglobulin (IVIg) is safe throughout pregnancy.⁵⁸ Both steroids and IVIg can be used in place of DMT preconception and during pregnancy to prevent relapses.

As most symptomatic treatments used for MS are not proven safe during pregnancy, the patient will use nonpharmacologic strategies to treat her symptoms of MS. You suggest timed voiding for urinary urgency and energy conservation techniques to mitigate fatigue.

The patient may continue her vitamin D supplement up to a dose of 2,000–4,000 IU daily while pregnant.^59,60

Delivery

The patient's obstetrician calls you at her request. She asks if there are any special precautions her team should take to ensure a safe delivery.

Both general and epidural anesthesia are safe in women with MS. Postpartum relapse rate is not affected by epidural anesthesia^23,e1,e2 (links.lww.com/CPJ/A15). Patients with sensory loss or weakness may not be able to feel contractions or push and so may require mechanical assistance.^e3 Instrumental or operative delivery is more common in women with MS,^38,46,49 though this is a small increased risk that was not demonstrated in other studies.^48,51,e4 There is no MS-specific contraindication to cesarean section^e2; the decision of vaginal vs cesarean delivery should be based on obstetric factors except in the rare cases of women with pelvic floor weakness. Two studies demonstrated an increased rate of cesarean section in patients with MS^47,50 but one that excluded planned cesareans did not demonstrate an increased risk of emergency cesareans.⁴⁹

Breastfeeding and the postpartum period

The patient gives birth to a healthy baby girl. She would like to breastfeed her child and wonders if this will affect her MS.

An important decision for patients with MS in the postpartum period is whether to breastfeed or resume DMT. This decision can be fraught with guilt for some mothers, so you counsel your patient that if she chooses not to breastfeed, she will not be harming her child^e5 (links.lww.com/CPJ/A15). No DMT is approved for use during breastfeeding (table), as there are no large prospective trials to demonstrate safety of these medications.⁵⁷ Some DMTs are detected in breastmilk, specifically natalizumab.^e6

Relapse rates increase within 3 months postpartum,²³ and up to one-third of women not on DMT relapse in the postpartum period^54,e7 (links.lww.com/CPJ/A15), leading many women to restart DMT as soon as possible after delivery. Relapse risk correlates with prepregnancy relapse rate for a patient.^23,e7 Consider increasing frequency of screening MRIs for postpartum women who remain off DMT.

Regular IVIg infusion is an alternative to DMT in breastfeeding mothers with MS who are at high risk for postpartum relapses^{58,e8, e9} (links.lww.com/CPJ/A15), as are monthly IV corticosteroids.^e10 Patients on steroids may resume breastfeeding 2–8 hours after high-dose IV steroid infusion^e11–e13 and 4 hours after oral steroid ingestion.^e14 Immunoglobulin is a normal component of breastmilk and studies using this treatment have not demonstrated adverse outcomes in infants.⁵⁸

Breastfeeding may itself prevent relapses^e15–e17 (links.lww.com/CPJ/A15), but women with milder disease more often choosing to breastfeed may confound this observation. Duration of breastfeeding lowers the mother's risk of developing MS,¹⁰ and breastfeeding may even reduce risk of MS in the child.^e18,e19

The patient chooses to breastfeed and remains off DMT. Three months postpartum, she has recurrence of tingling in her right hand. Urinalysis is normal. You are concerned this is a new MS flare and would like to confirm this with MRI.

MRI, generally avoided during pregnancy, is now safe. The American College of Obstetricians and Gynecologists recommends that breastfeeding should not be interrupted after administration of gadolinium contrast,⁵⁵ but patients often feel safer if they “pump and dump” for 24 hours after administration of gadolinium.

You take time at the patient’s follow-up visit to screen her for postpartum depression, as women with disabilities are at increased risk^e20 (links.lww.com/CPJ/A15).

Menopause

The patient has another healthy child and her MS remains relatively stable on DMT. She returns for a follow-up visit at age 52 and shares that she is going through menopause. She wonders how this is different in women with MS. She complains of worsening fatigue and bladder symptoms.

MS does not change average age at menopause^e21 (links.lww.com/CPJ/A15), with the exception of iatrogenically induced menopause.^e22 MS symptoms, however, worsen during menopause in about half of patients,^1,e23 and hot flashes intensify or bring on MS symptoms. The combination of MS and menopause specifically has an additive effect on mood, sleep, and bladder issues.^e24 A proposed explanation is that MS worsens due to withdrawal of estrogen, and women treated with hormone replacement therapy (HRT) noted their MS symptoms improved.¹ The decision to start a patient on HRT is still based on gynecologic status, but there is a suggestion that this treatment may be beneficial to patients with MS going through menopause. Your patient will discuss HRT with her gynecologist.

At this point, you screen your patient for thyroid issues, sleep apnea, depression, and restless leg syndrome. A sleep hygiene discussion may reveal strategies for improved sleep. Stimulants should be used with caution in older patients. Several pharmacologic treatments may help with urinary urgency, but older patients often have intolerable side effects. Bladder training and timed voiding may provide some relief without risks.

While there are little data on disease activity in postmenopausal women with MS, menopause does appear to be a time of more rapid disability accumulation^e25 (links.lww.com/CPJ/A15).

Preventive care

At the patient's next visit, you take the opportunity to discuss general preventive care.

Women with MS receive less preventive care than their counterparts; only half of women with MS have regular checkups^e26,e27 (links.lww.com/CPJ/A15). This can be due to physical barriers such as difficulty getting on an examination table or up to a mammography machine. A diagnosis of MS often changes the primary care physician's practice of preventive care, and misperceptions are common. Women with MS can be viewed as asexual and not offered contraceptives, when the majority are in fact sexually active and degree of disability is not predictive of whether someone is sexually active.^e27

Women with MS have a higher incidence of heart disease, likely due to relative inactivity, and vascular comorbidities lead to worse neurologic outcomes in those with MS^e28 (links.lww.com/CPJ/A15). They also have higher rates of osteopenia and osteoporosis.^e29 Those previously treated with cyclophosphamide or azathioprine have higher risk of cervical dysplasia.

Patients with MS are also at risk for psychosocial issues and have higher divorce rates^e30 (links.lww.com/CPJ/A15). Patients with MS have 2 or 3 times the rate of depression of the general population¹⁹; this effect is at least partially due to structural brain changes from MS.^e31 Those with physical limitations are also at increased risk of long-term abuse compared to their healthy counterparts due to reliance upon a caregiver.^e32

TAKE-HOME POINTS

• → Multiple sclerosis disease activity and symptoms are tied to hormonal changes. This presents several challenges to managing MS throughout a woman's life.

• → Pregnancy is possible and safe for women with MS but should be planned to avoid fetal exposure to potentially harmful medications.

• → Babies born to mothers with MS are not at increased risk for prematurity or deformities.

• → The postpartum period is a time of increased relapse risk, but no MS disease modifying therapy is known to be safe for use while breastfeeding.

• → Menopause is often a time of MS symptom worsening and may even be a time of disease progression.

Author contributions

M. Kaisey: research, writing, editing, revision, submission of manuscript. N. Sicotte: critical revision of manuscript for accuracy and clarity. B. Giesser: concept, critical revision of manuscript for accuracy and clarity.

Study funding

No targeted funding reported.

Disclosure

M. Kaisey has received a speaker honorarium from the American Academy of Neurology; received a fellowship grant from National Multiple Sclerosis Society; and received an unrestricted educational grant from Biogen. N.L. Sicotte receives research support from Novartis, National MS Society, and Guthy Jackson Charitable Foundation. B.S. Giesser serves on the editorial board of Neurology Now; receives publishing royalties for Primer on MS, 2nd Ed (Oxford University Press, 2016); and has served as an expert witness in pharmaceutical patent litigation. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.