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Pregnancy and childbirth, Women's health

Planning for pregnancy

This article discusses the effects of MS on fertility, decisions about starting or stopping a DMT, the use and safety of oral contraceptives and the possible impact of in vitro fertilisation on MS disease course.

Does MS affect my fertility?

No, MS does not affect fertility. Women and men with MS are as fertile as people without MS. However, MS does not protect women and men from other causes of infertility. Fertility treatment may impact MS (see below). Please be aware that mitoxantrone, AHSCT (autologous haemopoietic stem cell treatment) and other chemotherapy treatments, such as cyclophosphamide used off-label to treat MS, may be toxic to ovarian and testicular function and require egg and sperm banking before treatment.

Should I go onto a DMT and get my MS under control before starting a family or first start my family?

In general, I recommend that women with active MS delay pregnancy until their disease is under control, optimise their general health and prepare properly for becoming a parent. There is no point in having active MS, not starting a DMT and having a catastrophic relapse in the period during which you are trying to fall pregnant.

However, a desire to start or extend your family should not change the way you want your MS managed. Early effective treatment, treating to a target of NEIDA, potentially flipping the pyramid, preventing end-organ damage and the holistic management of MS are all compatible with pregnancy. There are no rules for implementing this strategy in pregnancy because all decisions should be personalised. For example, a woman with rapidly evolving severe MS may choose natalizumab and stay on it throughout pregnancy and while breastfeeding because her MS was so active and potentially devastating. Another woman who is young, risk adverse and with a very good prognosis may choose to delay starting a DMT until she has had a child. Yet another woman, diagnosed at 40, may not want to delay falling pregnant and may opt for a DMT that is safe during pregnancy.

It is up to the person with MS, their partner and sometimes their extended family to make the final decisions about how to manage their MS during pregnancy. The healthcare professional (HCP) is there to provide information and guidance in this process.

Are oral contraceptives safe in people with MS?

To my knowledge, contraceptives are safe and effective in women with MS. The same contraindications and relative contraindications to specific contraceptives apply to women with MS as to the general population. Hormonal contraceptives are associated with an increased risk of thrombosis; women with MS who are immobile thus have a higher risk of deep vein thrombosis than those who are mobile.

Which contraceptive would you recommend?

MS should not be the deciding factor around the choice of contraceptive unless the degree of MS-related disability makes managing menstrual hygiene difficult. In this case, contraceptives that suppress menstruation have advantages, for example, continuous hormonal contraceptives or the progestin-tipped intrauterine contraceptive device (Mirena).

Inclusion criteria for participation in specific drug trials sometimes mandate double contraception, for example, a hormonal contraceptive and a barrier method. This is to try and avoid accidental pregnancies while taking an investigational compound without a safety track record in humans.

How long before I fall pregnant must I stop my DMT?

It depends on which DMT you are taking. Only the DMTs that are teratogenic or potentially teratogenic (i.e., may cause foetal malformations) need to be stopped before you fall pregnant. It is essential to allow sufficient time for these agents to be eliminated from the body.

Teriflunomide

Teriflunomide has the potential to cause birth defects; therefore, patients must have effective contraception whilst on this treatment. It has a very long half-life because it is reabsorbed in the intestine and is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes up to 8 months to reach plasma concentrations of less than 0.02 mg/l, which are considered safe. Remarkably, due to individual variations in teriflunomide clearance, it may take up to 2 years to fall to acceptable levels. An accelerated elimination procedure with cholestyramine or activated charcoal can be used at any time after the discontinuation of teriflunomide.

Teriflunomide accelerated elimination procedure

After stopping treatment with teriflunomide:

• Cholestyramine 8 g is administered three times daily for 11 days, or cholestyramine 4 g three times a day can be used if cholestyramine 8 g three times a day is not well tolerated.

• Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

Following either of the accelerated elimination procedures, it is recommended to verify elimination by checking teriflunomide blood levels and allow a waiting period of 1.5 months between the first occurrence of a plasma concentration below 0.02 mg/l and planned fertilisation.

S1P modulators

S1P modulators are contraindicated during pregnancy, owing to the risk to the foetus. Before starting treatment in women of childbearing potential, we do a urine pregnancy test. Women taking an S1P modulator must use effective contraception during treatment and then continue for:

  • 2 months after stopping treatment with fingolimod (Gilenya)
  • 10 days after stopping treatment with siponimod (Mayzent)
  • 3 months after stopping treatment with ozanimod (Zeposia)
  • 7 days after stopping treatment with ponesimod (Ponvory).

Stopping the S1P modulators brings the potential for rebound disease activity, so most neurologists now prefer to transition women on one of these therapies to another class of DMT that is considered safer in pregnancy.

Safer options

Safer options during pregnancy include an injectable (interferon-beta or glatiramer acetate), a fumarate, an anti-CD20 therapy, natalizumab or an immune reconstitution therapy (cladribine or alemtuzumab). I cover some of the issues related to anti-CD20 therapies in the MS-Selfie case study ‘Wait to fall pregnant or start a DMT now?’.

The good news is that several DMT options are now available to women with MS wanting to fall pregnant.

Can I have IVF, and what will IVF do to my MS?

There is no reason why a person with MS cannot have IVF (in vitro fertilisation). However, there appears to be a slightly increased risk of relapse after IVF and egg harvesting. Whether this is due to stopping DMTs before undergoing IVF or due to the drugs used to stimulate ovulation is unknown. Studies reporting an increase in disease activity after IVF are more likely to be published than studies not showing such an increase so that publication bias may affect the findings. I recommend viewing IVF as a planned pregnancy and giving women with MS the option of receiving a DMT that is relatively safe in pregnancy or treating their MS with immune reconstitution therapy before IVF.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth:
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

Causes and prevention of MS

What is multiple sclerosis?

This is the first of a series of basic lessons to help you understand multiple sclerosis (MS).

Key points

  • MS is an autoimmune disease in which the immune system attacks the central nervous system.
  • Its exact cause is unknown; some contributory environmental factors are outlined.
  • Common manifestations of MS include lesions, relapses and intermittent symptoms, which often worsen with fatigue.
  • Early treatment is important to help prevent the damage that occurs with MS.

Multiple sclerosis (MS) is an organ-specific autoimmune disease. Autoimmune simply means that the immune system, whose primary role is to fight infections and cancers, goes awry and attacks itself. Organ-specific means that a disease is limited to one organ. So, in the case of MS, the immune system attacks the central nervous system (CNS), which consists of the brain, spinal cord and optic nerves.

Every organ in the body has its specific autoimmune disease. For example:

  • joints: rheumatoid arthritis
  • skin: psoriasis 
  • insulin-producing cells of the pancreas: type 1 diabetes
  • intestines: inflammatory bowel disease
  • kidneys: autoimmune nephritis (interstitial or glomerulonephritis).

The cause of MS

At present, the exact cause of MS is unproven. MS is a complex disease that occurs due to the environment’s interaction with inherited or genetic factors.1 Some of the main environmental factors are:

  • low vitamin D levels or a lack of sunshine
  • smoking 
  • Epstein–Barr virus (EBV), the virus that causes infectious mononucleosis (glandular fever) 
  • obesity, particularly in adolescence.

What we don’t know is how these genetic and environmental factors interact to cause MS. There are many genetic variants that predispose someone to get MS, but only a minority of people who have these variants will get the disease. Similarly, only a minority of people exposed to environmental risk factors get the disease.

Mechanisms that underlie the common manifestations of MS

Lesions

MS is characterised by inflammatory lesions – areas of damage or scarring (sclerosis) in the CNS – that come and go. The clinical manifestations of MS depend on where these inflammatory lesions occur. If, for example, a lesion involves the optic nerve, it will cause impaired vision; if it involves the brain stem, it causes double vision, vertigo or unsteadiness of gait; a spinal cord lesion leads to loss of feeling, limb weakness or bladder and bowel problems.  

Relapses

A new MS lesion in a site that is eloquent will cause symptoms and neurological signs; if these last for at least a day, they are called an attack or a relapse. If a lesion occurs in a site not associated with overt symptoms, this is often referred to as a subclinical or asymptomatic relapse. Subclinical relapses can be detected using magnetic resonance imaging (MRI). It is said that for every clinical attack there are 10 or more sub-clinical attacks (new MRI lesions).2 

Damage frequently occurs at the site of MS lesions. The inflammation strips the myelin covering the nerve processes and may cut through axons. Axons are the nerve processes that transmit electrical impulses or signals. When the axons are stripped of their myelin sheath, and/or are cut, they can’t transmit electrical signals. This causes loss of function, which manifests with specific symptoms.

Demyelination: loss of the myelin sheath that insulates nerves, leading to disruption of electrical signals. Image courtesy of Timonina/shutterstock.com. 

Intermittent symptoms

Surviving axons that pass through the lesion are able to recover function, by synthesising and distributing so-called ion channels across the demyelinated segment or by being remyelinated. Both these processes are not perfect. For example, the new sodium channels may not function normally, so they sometimes fire spontaneously. The spontaneous firing of axons may cause positive symptoms, for example, pins and needles, pain or spasms. The new myelin is typically thinner and shorter than normal and is temperature, fatigue and stretch sensitive. 

Stretch sensitivity

If someone with MS has a lesion in their spinal cord, electric shock-like sensations may occur when they stretch the spinal cord by bending or flexing their neck; this is known as Lhermitte’s sign.  

Temperature sensitivity

Recurrent symptoms may occur when body temperature rises, for example following fever, exercise or a hot bath. The MS symptoms (which may vary among individuals) disappear when the fever resolves or the body cools down. The temperature sensitivity is often referred to as Uhtoff’s phenomenon. 

Fatigue

Symptoms tend to worsen with physical and/or mental fatigue; for example, someone with MS may begin dragging a leg or dropping their foot after 20–30 minutes of walking. This is because the transmission in the functioning nerves, which have been previously damaged, begins to fail. This failure may be related to a lack of energy and/or to temperature changes that occur with exercise. 

Worsening MS (also called progressive MS)

If the axons, or nerve processes, above and below an MS lesion die off, the surviving axons may sprout to take over the function of the axons below the lesion. This puts an unnecessary strain on the surviving axons, which makes them vulnerable to die off in the future. A reduction in the number of nerves in a neuronal system reduces the neurological reserve of that system, making it more vulnerable to future attacks. In other words, the ability to recover from future attacks is reduced, and the neuronal pathway is susceptible to delayed degeneration and premature ageing. Clearly, if no treatment is given and focal inflammatory lesions continue to come and go, this will cause worsening of the disease. If enough damage is allowed to accrue, even switching off new inflammatory lesions may not prevent the so-called delayed neurodegeneration. This is why one of the primary principles of managing MS is early treatment to prevent damage from occurring in the first place. We have also discovered that the neuronal systems with the longest nerve fibres, in particular the bladder and legs, are much more susceptible to damage. We think this is simply because the longest pathways provide the greatest scope to be hit by multiple MS lesions.

Ageing and MS

As we get older our nervous systems degenerate. If we live long enough, we will all develop age-related neurological problems, such as unsteadiness of gait, loss of memory, reduced vision, loss of hearing, and poor coordination. 

What protects people with MS from becoming disabled and developing age-related neurodegeneration are brain reserve and cognitive reserve. Brain reserve is simply the size of your brain or the number of nerve cells you have. Cognitive reserve, in comparison, relates to how well these nerves function; it is associated with your level of education and how well you enrich your life by using your brain. From about 35 years of age, our brains start to shrink. In MS, this brain shrinkage is in general much greater than normal, and the resulting reduction in brain and cognitive reserve almost certainly primes the nervous system to age earlier. This is one of the reasons why people with MS continue to develop worsening disability later in the course of their disease. This insight is one of the main reasons why we promote early effective treatment of MS to protect and maintain brain and cognitive reserves.  

References

  1. Olsson T, et al. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017;13:25–36.
  2. Gafson A, et al. The diagnostic criteria for multiple sclerosis: From Charcot to McDonald. Mult Scler Relat Disord 2012;1:9–14

DMTs, Treatment strategy

How do I want my MS to be treated?

What is the difference between a maintenance ̶ escalation DMT and an immune reconstitution therapy (IRT)? Why is it important to understand the distinction?

Key points

  • Maintenance–escalation and immune reconstitution therapy (IRT) are two approaches to MS treatment currently favoured.
  • IRT is a one-off, short course which acts on immune system cells in three stages: reduction, repopulation and reconstitution.
  • Maintenance–escalation is given continuously without interruption. If it does not work well, the treatment is changed to a more effective DMT (known as ‘escalation’).
  • Additional future approaches are likely to include induction ̶ maintenance and/or combination therapy.

If I had MS, how would I want to be treated? This is a difficult question, and one that many of my patients ask me. The answer depends on your life stage, what risks you are prepared to take, personal factors such as family planning considerations and the extent of your understanding of MS and how we approach its treatment.

Currently, there are two main philosophies regarding the treatment of MS with DMTs: maintenance/escalation versus immune reconstitution therapies (IRTs). 

What is an immune reconstitution therapy?

By definition, an IRT is given as a short course, i.e. as a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently in the case of alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses of the therapy are given only if there is a recurrence of MS inflammatory activity. IRTs can induce long-term remission and, arguably, in some cases a potential cure.

IRTs have three phases to their mode of action, which I refer to as the ‘three Rs’.

  1. Reduction, or depletion, when we try to kill the autoimmune cells that cause MS.
  2. Repopulation, when the immune system recovers from stem cell transplantation and, hopefully, the autoimmune cells don’t return.
  3. Reconstitution, when the immune system is recovered and fully competent. The recovered immune system following treatment with an IRT is different from what was there before. Some people like to think of an IRT as a reboot of the immune system, but without MS.
Slide1

The three Rs of immune reconstitution therapy: reduction, repopulation and reconstitution. From Giovannoni, Curr Opin Neurol.1 

What is an MS ’cure’?

One attempt at a definition describes an MS cure as no evidence of disease activity (NEDA) 15 years after the administration of an IRT. I justify using 15 years because it is the time-point most accepted for defining ‘benign MS‘ and is also beyond the average time to onset of secondary progressive MS in natural history studies.

What is a maintenance therapy?

A maintenance therapy is given continuously without an interruption in dosing. Although maintenance therapies can induce long-term remission (i.e. NEDA), they cannot result in a cure. The recurrence or continuation of inflammatory disease activity with maintenance therapies is an indication of a suboptimal response to treatment and typically results in a treatment switch. Ideally, this switch should be to a more effective class of DMTs – hence the term ‘escalation’. 

What would I recommend?

I can’t choose for you. The debate is complex and depends on many factors. One important consideration is vaccine readiness: will I be able to mount an adequate immune response to a vaccine? IRTs have the advantage that they allow reconstitution of the immune system; once it recovers, vaccine responses are restored, and even live vaccines can be given.

The table below highlights key differentiators. Further, detailed information about most of the products listed in the Table can be accessed through the DMT comparison tool available at ClinicSpeak or via the Multiple Sclerosis Trust MS Decisions aid.

Similarities and differences between maintenance treatments and immune reconstitution therapies. Registered trade names (UK market) of the generic drugs listed are shown in brackets. *How to define a ‘cure’ in MS is controversial. Modified from Giovannoni, Curr Opin Neurol.1
DMT, disease-modifying therapy; HSCT, haematopoietic stem cell transplant; IRT, immune reconstitution therapy.

The future

I envisage two more treatment strategies emerging.

  • One approach is induction ̶ maintenance therapy, using an IRT followed by an immunomodulatory therapy rather than an immunosuppressive DMT (which is a safer option) the aim is to keep MS in long-term remission. This approach is used in oncology, where the cancer is hit hard with induction chemotherapy and then kept at bay with a well-tolerated maintenance therapy (e.g. antihormonal therapies in breast cancer).
  • Another approach is combination maintenance therapy; the aim would be to combine an anti-inflammatory therapy with, say, neuroprotective therapies to target smouldering MS.

The diagram below illustrates the scheduling of the four approaches discussed in this section. You may like to try out the DMT comparison tool to find out how some of the drugs listed in the comparison Table above align with your personal life choices and priorities.

Slide5

Four approaches discussed in this section. The white panels illustrate the two approaches currently available; the shaded panels illustrate two strategies that may emerge in the future. Modified from Giovannoni, Curr Opin Neurol.1

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
DMTs, Treatment strategy

Am I eligible for an MS disease-modifying therapy?

Key points

Do you know the eligibility criteria for MS disease-modifying therapies? And who decides what drugs can be prescribed for your MS?

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system from further damage.
  • Regulators such as the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) decide in which group(s) of patients a particular drug can be used, based on the results of clinical trials.
  • Once a drug has been licensed in your region, local payers decide whether to make it available within your country, based on cost-effective assessments.
  • If you have active MS, your level of disease activity, its severity and speed of development will determine which DMTs you can be offered.
  • In some countries, ocrelizumab has been approved for the treatment of active primary progressive MS (PPMS) and siponimod has been approved for the treatment of active secondary progressive MS.
  • Protecting upper limb function has been a neglected area; studies are now ongoing, however, with a view to finding DMTs that limit the progression of upper limb disability.

What do disease-modifying drugs do?

Disease-modifying therapies (DMTs) are treatments that change the natural history – that is, the long-term trajectory – of the disease. They reduce the rate of disability worsening and so protect the end-organ (in the case of MS, this is the central nervous system). To simplify, let’s say that a person with MS on no treatment may manage for an average of 18-20 years before needing to use a walking stick (corresponding to Expanded Disability Status Scale [EDSS] 6.0), while someone on treatment might manage without aid for 24 years, i.e. a 4-6-year delay, then the treatment can be called disease-modifying. (Please note, the treatment effect or 4-6-year delay in reaching EDSS 6.0 is an average and some people with MS will do better than others. Conversely, some will do worse than average.) 

Is interferon a DMT?

In the early days of interferon therapy, there was debate about whether simply reducing the relapse rate by 30% relative to placebo treatment, without slowing down the worsening of the disease over 2 years, was disease-modification. However, subsequent trials and follow-up of people with MS treated with interferon-beta showed a slowing down of disease worsening, delays in developing secondary progressive MS and a favourable impact on survival.1 

Do symptomatic treatments modify the disease?

Symptomatic treatments improve the symptoms associated with MS without affecting the natural history. Treatments are classified as symptomatic in relation to their mode of action; but some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying. 

Who decides on eligibility for a licensed DMT?

Regulators decide in which group of people with MS the DMT can be used, and they grant a licence for its use. Regulators include the EMA, the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA in the UK).

Payers hold the purse strings and decide which licensed drugs to make available. They makecost-effectiveness assessments to try and optimise the use of the drug in clinical practice. Payers include medical insurance companies and the NHS in the UK. 

Guidelines are formulated to help healthcare professionals use DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers, in that they try to address potential ambiguities in the prescribing of DMTs. National, regional or local guidelines that provide expert clinical guidance include the UK NICE (National Institute for Health and Care Excellence) MS management guidelines and the Association of British Neurologists guidelines. 

In the NHS in England, we must abide by NHS England’s algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is. 

How does disease activity affect my treatment options?

To be eligible for DMTs, you must have active MS. A summary of the four categories of disease activity is given below. Further details can be found in the section entitled Do I have active MS?

  1. Inactive MS – you are not currently eligible for DMTs.
  2. Active MS – you should be eligible for a so-called platform therapy (interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate or ponesimod) and ocrelizumab or ofatumumab.
  3. Highly active MS – you are eligible for all therapies except natalizumab. Please note in England fingolimod can only be used as a second-line therapy (after another DMT has failed).
  4. Rapidly evolving severe MS – you should be eligible for all DMTs.

Advanced or progressive MS

Ocrelizumab and siponimod are now approved in several countries for the treatment of active PPMS and active SPMS, respectively. A classification of active PPMS requires recent MRI evidence of disease activity, that is, the formation of new T2 lesions and/or the presence of gadolinium-enhancing lesions in the last 3 years. Active SPMS is confirmed by the occurrence of superimposed relapses and/or the presence of new T2 lesions and/or gadolinium-enhancing lesions in the last 2 years. Based on these very narrow definitions, most patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod, respectively. The differences between the MRI criteria for active PPMS and active SPMS reflect the reality that people with PPMS are less likely to be having regular monitoring MRI scans.

Stages of MS currently not eligible for treatment

In the UK, people with MS who are wheelchair users are not eligible for DMTs. The reason for this is that patients with more advanced MS have generally been excluded from phase 3 clinical trials; hence there are no data to show whether licensed DMTs are effective in this group.

There is a long-held view that inflammation is reduced or absent in advanced MS. However, clinical, imaging and pathological data show that inflammation still plays a large, and possibly a major, role in advanced MS. Therefore, not targeting more advanced MS with an anti-inflammatory is counterintuitive.

The importance of upper limb function

In 2016, the #ThinkHand campaign was launched to raise awareness of the importance of hand and arm function in people with MS and the need for clinical trials in this population. Studies currently ongoing that focus on limiting upper limb disability progression include ChariotMS (oral cladribine)2 in people with advanced MS (UK only) and the global, multicentre O’HAND trial  (ocrelizumab)3 in participants with PPMS. 

Once someone with MS becomes a wheelchair user, they still have neuronal systems that are potentially modifiable – for example, upper limb, bulbar (speech and swallowing), cognition and visual function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials. 

References

  1. Goodin DS, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012;78:1315 ̶ 22.
  2. National Institute for Health and Care Research (NIHR). MS clinical trial to focus on people who can’t walk. November 2020. Available at https://www.nihr.ac.uk/news/ms-clinical-trial-to-focus-on-people-who-cant-walk/26227 (accessed June 2022).
  3. US National Library of Medicine. A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (O’HAND). First posted July 2019. Available at https://clinicaltrials.gov/ct2/show/NCT04035005 (accessed June 2022).