Management of pregnancy in patients with multiple sclerosis

In recent years, the problem of pregnancy management in multiple sclerosis (MS) has received increasing attention. This is due to several reasons. Firstly, the disease itself, MS, is of great medical and social importance, since it often develops in people of young working age and can quickly lead to disability. Secondly, this disease predominantly affects people of childbearing age, with women much more likely (2-4 times) than men. Thirdly, questions of planning, tactics for managing pregnancy, childbirth and the postpartum period, the possibility of breastfeeding with MS, the likelihood of developing this disease in children are quite reasonably asked by patients in each case. Fourthly, improving diagnostic capabilities and expanding the range of therapeutic approaches (primarily the widely used various drugs that modify the course of MS - DMTs, as well as symptomatic drugs) require constant improvement of knowledge by practicing neurologists. It is important for doctors to be informed about the possibility of prescribing certain diagnostic procedures and medications before, during pregnancy and after childbirth to ensure competent, most effective treatment of patients and at the same time safe management of pregnancy for the mother and child. Finally, fifthly, a comprehensive study of the role of hormonal factors and the causes of changes in the course of the disease during pregnancy can serve to clarify the pathogenetic mechanisms of MS and develop new therapeutic approaches.

This review summarizes data from recent publications concerning the most frequently asked questions regarding pregnancy in MS.

So, at the stage of pregnancy planning

key questions relate to the impact of MS on fertility;
risk of developing MS in children; influence of pregnancy on the course of MS. It is the neurological symptoms of MS that can interfere with the care of a child, his upbringing, concern about burdening a spouse, the possibility of developing MS in children, as has been shown by a number of researchers, that are among the main reasons associated with MS, on the basis of which doubts about childbearing arise [9] . At the stage of pregnancy,
the main problems relate to the possibility of using certain pharmacological drugs, monitoring the course of the disease, as well as labor management tactics.
Finally, in the postpartum period,
questions about breastfeeding, including in relation to the prescription of pathogenetic drugs, require solutions.

The impact of MS on fertility, the use of assisted reproductive technologies

To date, no comprehensive research has been carried out on this issue. According to some authors, epidemiological data suggest that spontaneous fertility may be reduced, since a number of endocrine and sexual disorders can potentially affect reproductive function in patients of both sexes [15]. Other data suggest that fertility does not appear to be significantly affected in patients with MS. However, infertility and MS can occur simultaneously [37].

In this situation, assisted reproductive technologies can be used. However, similar technologies using gonadotropin-releasing hormone (both agonists and antagonists) and gonadotropins can increase both the clinical activity of MS and the activity of demyelination foci according to MRI [18, 40]. Also, an increase in the frequency of exacerbations was noted within 3 months after in vitro fertilization (IVF) compared to the same period 1 year before the procedure [49]. According to the authors, a significant increase in MS activity occurs both with the use of gonadotropin-releasing hormone agonists and in cases where the IVF procedure is not accompanied by pregnancy. Possible mechanisms for such deterioration may include hormone-induced immunological changes: proliferation of immune cells with increased production of cytokines and endothelial growth factor; rapid phase changes in estrogen levels under the influence of gonadotropin-releasing hormone agonists; a break in taking DMTs, as well as a stressful situation due to infertility [37, 50].

Of course, further research is needed to understand this phenomenon, but already at this stage, such information should be provided to interested parties in the case of planning the use of assisted reproductive technologies in order to make an informed decision [50].

Risk of developing MS in children (familial incidence)

To date, evidence from numerous population-based, genealogical and twin studies indicates a hereditary predisposition to MS. Thus, if one of the parents has MS and there were no other patients in the family, then the risk of developing MS in a child throughout life is 3-5% [62]. Moreover, these figures are approximately equal to the average population risk of any other birth defect being detected in a child [25]. If both parents have MS, then the risk of developing MS in a child throughout life is, according to various authors, from 6 [59] to 30% [26]. If both parents are healthy, but the marriage is consanguineous, and one of the relatives had MS, then the risk of developing MS in a child can reach 9% [62].

It should be noted that the observed type of inheritance in MS is characteristic of polygenic diseases that arise as a result of the joint contribution of many independently acting or interacting polymorphic genes [12]. Perhaps further work to identify genetic markers of MS in the future will make it possible to more accurately determine the individual risk of developing the disease in children whose parents suffer from MS, and to individualize their treatment.

The effect of pregnancy on the frequency of MS exacerbations

The fact that the frequency of exacerbations during pregnancy decreases is well known. Thus, during pregnancy in women with MS, the number of exacerbations decreases by approximately half, especially in the third trimester, and, conversely, increases in the first 3-6 months after birth [17, 50]. According to the PRIMS (Pregnancy In Multiple Sclerosis) prospective study, which included 227 patients with MS, the rate of exacerbations before delivery was 0.7 (95% CI 0.6-0.8); in the first trimester of pregnancy - 0.5 (95% CI 0.4-0.6), in the second - 0.6 (95% CI 0.5-0.7), in the third - 0.2 (95% CI 0.2-0.3); in the first trimester after childbirth - 1.2 (95% CI 1.1-1.4), followed by a gradual decrease, while already 3 months after birth there were no significant differences in the frequency of exacerbations with the prenatal period [72]. Despite the increased risk of exacerbations in the first 3 months after birth, 72% of patients did not experience exacerbation of the disease during this period. Three parameters (increased number of exacerbations in the 1 year before pregnancy, increased number of exacerbations during pregnancy, and higher EDSS score at the time of pregnancy) were correlated with the onset of exacerbation in the postpartum period.

Preparing for pregnancy with multiple sclerosis

If you have time to prepare for pregnancy, we will carry out a number of preparatory activities:

• Blood test (immunogram, antibodies to infections, PCR studies). We need to accurately understand the state of your immune system and the characteristics of its interaction with infections. If there are significant deviations from the norm, we carry out a course of treatment. By the time pregnancy occurs, the immune system should be able to cope well with infections, but not be too aggressive .
• MRI of the brain with contrast . It is desirable that by the time of pregnancy the disease is in an inactive phase (when foci of demyelination do not accumulate contrast). If necessary, we will relieve the aggravation.
• Standard gynecological examinations and preparatory measures before pregnancy.

The influence of pregnancy on the course of MS and disability

According to a number of authors, a decrease in the risk of developing MS in women who have given birth has been shown compared to nulliparous women [61], which is consistent with the results of A. Ponsonby et al., according to which pregnancy can have a protective effect on the risk of developing the first demyelinating episode [57].

In the case of an established diagnosis of MS, data on the effect of pregnancy on the course of the disease are sparse and ambiguous. According to some data, the risk of progressive disease is significantly lower in women who gave birth after the onset of MS [5, 61]. Other researchers, when analyzing childbirth and secondary progression, did not find their connection [45].

According to S. Ramagopalan et al., pregnancy does not have any delayed effect on disability [58]. On the contrary, M. D'hooghe et al. do not exclude the possibility of a beneficial long-term effect of childbirth on the course of MS [22]. According to B. Weinshenker et al., no associations were identified between disability and the total number of pregnancies, as well as the timing of pregnancy relative to the onset of MS [75]. At the same time, according to P. Verdu et al., the time before the need to use a wheelchair is approximately 50% longer in women who have had at least 1 pregnancy after the development of the disease, compared with non-pregnant patients [70].

Thus, there is currently no clear reliable data on the effect of pregnancy on the course of MS. However, this aspect, according to a number of authors, has a small impact on family planning [50].

Multiple sclerosis is rapidly becoming younger

— Alexey Nikolaevich, is anything known about the causes of multiple sclerosis?

— MS occurs under the influence of trigger factors in people predisposed to it. Genetic predisposition is formed by more than 250 genes, certain sets of allelic variants of which are associated with an increased risk of developing this disease. Among external factors, infections, especially viral ones, come first. For example, Epstein-Barr virus, endogenous retroviruses and others. In addition, psycho-emotional stress (especially chronic), lack of vitamin D, smoking, changes in the intestinal microbiome and a number of other factors can play a big role in the development of the disease. In general, the development of MS requires a polygenic predisposition and a strong influence of an external factor.

— How common is this disease today?

— The prevalence of MS in the world ranges from 250–300 cases per 100,000 population (Northern European countries, Canada, some US states) to 0.5–1 case per 100,000 population in African countries and some Asian countries. But the widespread prevalence and incidence of MS are increasing, which is associated both with better diagnosis and treatment (which extends the lives of these patients and they “accumulate” in the population) and with a real increase in incidence. Therefore, multiple sclerosis is now called a disease of civilization - wherever modern civilization comes, the number of new cases of this disease increases.

— Who is at risk and are there any ways to prevent the disease?

— The main risk groups are families of patients with multiple sclerosis; unfortunately, in all populations there are repeated cases in the family. There is so-called familial multiple sclerosis, which is most often transmitted through the female line. The number of such cases ranges from 5 to 10% of all MS cases in the population. Unfortunately, there are no developed preventive measures yet, although a number of countries have programs to monitor vitamin D levels and other measures designed to reduce the risk of developing this disease. In addition, its early detection allows early initiation of specific treatment and prevention of disease progression.

— What symptoms can be used to suspect the onset of multiple sclerosis and what should be the priority actions in this case?

— Traditionally, MS is called an “organic chameleon.” At the very beginning of the disease, its symptoms can resemble many brain diseases. This is why careful differential diagnosis is necessary at the earliest stages, when there are changes on MRI or minimal clinical abnormalities. These symptoms should be assessed exclusively by a doctor, a neurologist. And if a general neurologist suspects MS, he must send the patient to a specialized center (department, office) to confirm the diagnosis. Sometimes this requires repeat MRIs, lumbar punctures, cerebrospinal fluid studies, and other special tests. The diagnosis is made by excluding other causes of such damage to the central nervous system. In other words, multiple sclerosis is a “diagnosis of exclusion”; it is made last, when other causes have been excluded. Self-diagnosis of MS is ineffective and dangerous; if you have any complaints about disturbances in movement, vision, or sensitivity, you should contact neurologists, who must make a correct differential diagnosis. The basis for diagnosing MS is the clinical picture of the disease. They help in making a diagnosis and excluding other causes of diseases - MRI of the brain and spinal cord with contrast, studies of evoked potentials, cerebrospinal fluid, specific antibodies and many others.

— They often say that MS is a disease of creative people. Why do you think?

— Yes, many creative people have this diagnosis, since they are more vulnerable and susceptible to psycho-emotional stress, which is one of the triggers of MS in the presence of a hereditary polygenic predisposition.

— Under what conditions does MS begin to progress rapidly?

— Progression of the disease is observed with increasing duration of MS, when the neurodegenerative process begins to prevail over the relapsing course (instead of a change in exacerbations and remissions, disability gradually increases). This type of course is called secondary progressive (SPMS), it can occur with or without exacerbations. In 10–15% of patients, progression is observed from the very beginning of MS, without remissions; in such cases, primary progressive MS (PPMS) is diagnosed. As MS progresses, the prognosis for MS worsens significantly.

— Some patients are looking for unconventional methods of treatment. How promising is this?

— We must first select a method of pathogenetic treatment with drugs that modify the course of MS (DMS), then a complex of symptomatic treatment and rehabilitation if there are residual disorders. All non-drug and “non-traditional” methods of treatment should act only as auxiliary, when pathogenetic and symptomatic therapy has already been selected based on the principles of evidence-based medicine. Due to the undulating course of MS at the onset of the disease, many try to treat MS in various unconventional ways, passing off natural remission as a “cure,” but this is not the case. At the same time, it has now been proven through clinical studies and meta-analysis of these studies that, for example, active aerobic physical therapy significantly reduces some manifestations of MS, especially chronic fatigue, depression, and movement disorders. But while there are no cases of complete “cure” of MS, it is possible to achieve stable remission, when the pathological process does not affect the quality of life of patients.

— How has MS therapy changed over the years?

— At the beginning of the century, we had only two drugs with proven effectiveness in preventing exacerbations and progression of MS, in the 2010s there were already about 10, now by 2021 there are more than 15. It is possible to individually select therapy for each patient depending on the severity and activity of the pathological process. There are DMTs for the treatment of PPMS and SPMS, and the first positive studies have been conducted on the treatment of MS in children. But even now there are more than 20 studies of new drugs that can help MS patients at different stages of the disease.

— Are there any chances that such diseases will ever become curable?

— As soon as they learn to “cure” old age, they will quickly begin to “cure” MS, diabetes, rheumatoid arthritis and many other chronic human diseases. Now he considers a result a success if for many years the existing disease does not affect people’s lives in any way. Therefore, in a number of countries it is already customary to call them not “patients with MS”, but “people with MS”. The presence of MS does not in any way affect their quality of life, social activity or ability to work. This is the goal of modern MS treatment.

HELP "MK"

Today, multiple sclerosis has become one of the leading causes of non-traumatic disability in young people: the lion's share of patients receive this diagnosis between the ages of 20 and 40. The disease, which damages the membranes of the nerve fibers of the brain and spinal cord, remains in the category of incurable. Its symptoms are painful - patients suffer from fatigue, muscle weakness, and their vision deteriorates. As time goes on, things get worse and worse, and in the long term, many will find themselves in a wheelchair. In the absence of therapy, after 10 years, about 50% of patients cannot work or do housework; after 15 years, they cannot move independently; after 25 years, they cannot walk even with support. It has been noted that the disease often affects smart, intelligent people, representatives of creative professions: artists, musicians, poets. In approximately 15% of patients, the disease proceeds according to the most severe scenario (primary progressive multiple sclerosis), in which disability occurs rapidly, in a matter of years.

Mechanisms of natural immunosuppression during pregnancy in MS

Endocrine immunoregulation during pregnancy

Previous concepts largely attributed the positive effect of pregnancy on MS activity to increased blood levels of circulating hormones such as estrogen, progesterone, or glucocorticoids. These hormones have powerful immunomodulatory properties, including changes in the production of cytokines, suppression of the expression of adhesion molecules and matrix metalloproteinases, reduction in the presentation of antigens, and the migratory ability of T cells [60, 71]. Most of these hormones peak in the third trimester of pregnancy, which coincides with the maximum decrease in MS activity. However, despite the obvious regulatory role of sex hormones in MS, the lack of correlations with the level of at least one specific hormone allows us to make only assumptions regarding the underlying mechanisms [21].

To date, in order to explain the mechanism of remission that occurs during pregnancy in women with MS, there is a theory based on the supposed shift of the pro-inflammatory Th1 response towards the anti-inflammatory Th2 response in the peripheral blood [8, 34, 47]. However, this paradigm is overly simplistic and does not reflect the complex immunomodulation that occurs in the mother and the mother-placenta-fetus system [16, 66]. It is likely that immunomodulatory mechanisms in MS during pregnancy go beyond the anti-inflammatory Th2 effect.

Currently, much attention is paid to regulatory T cells (Treg) and natural killer (NK) cells, as these cells are believed to be responsible for the development of immunosuppression during pregnancy [55]. Moreover, the role of Tregs in the pathogenesis of MS is currently being actively studied [2].

In the decidua during the first trimester of pregnancy, the most abundant immune cells are dNK (decidua natural killer cells) [43, 52]. Compared to peripheral NKs, dNKs are characterized as CD56 bright CD16-CD3- and have low cytotoxic properties [43, 52]. CD56bright CD16- CD3- originate from CD34+ already present in decidual tissue, rather than migrating here from the periphery. dNK secrete cytokines and chemokines (IL8, VEGF, SDF-1, IT-10), which control the process of blastocyst implantation, growth, development and permeability of the trophoblast, neoangiogenesis and placental remodeling [64]. It has been established that in patients with MS, the number of dNK increases by the third trimester of pregnancy compared to the postpartum period, while the total number of peripheral cytotoxic CD56dim (CD3-CD56dimCD16+) decreases [7].

Also, during the first trimester, a local increase in the number of Tregs (CD4+CD25+Foxp+) and a low content of Th17 cells is observed in the decidua [51, 63]. Normally, Tregs have the ability to suppress autoantigen-specific proliferation and effector functions of autoreactive lymphocytes [19]. During pregnancy, they play a key role in the formation of immune tolerance to the fetus. CD4+CD25+Foxp+ ensure blastocyst implantation into decidual tissue and fetal survival in the uterus. Tregs act by suppressing the proliferation and cytokine production of CD4+ and CD8+ cells, cytotoxic NK, B cells and immunoglobulins [48, 56] and inhibit the activity of dendritic cells and macrophages. Studies in mice have shown that in the blood, lymph nodes and thymus, an increase in Tregs occurs as early as day 2 of pregnancy, followed by a gradual decrease starting in mid-pregnancy [68, 76]. A trend towards an increase in circulating Tregs in early pregnancy, reaching a maximum in the second trimester and their gradual decrease in the postpartum period, is also observed in humans [68].

Thus, both hormonal and immunological changes in the maternal-fetal-placental axis likely contribute to immunosuppression during MS pregnancy. However, of course, these mechanisms have not been sufficiently studied to date.

Relieving exacerbations of MS during pregnancy

It is well known that glucocorticosteroids cross the placenta and can affect the fetus. In experimental studies conducted on animals, it was found that corticosteroid hormones lead to intrauterine death with fetal resorption, miscarriages, non-viability of newborns, deformities and growth deficiency [20, 24]. In this case, developmental disorders are more pronounced the shorter the gestational age and the greater the dose of administered hormones [53]. There is evidence indicating an increased risk of placental insufficiency, malnutrition at birth, decreased height and weight, and sometimes fetal death in women with long-term use of corticosteroid hormones during pregnancy [32, 46]. Their use is especially dangerous in the first trimester. In the case of their short-term exposure during the second and third trimesters of pregnancy, no negative effect on the human fetus was detected [32, 46]. Thus, in women at risk of developing premature birth, who are administered dexamethasone in the third trimester in order to stimulate lung maturation in the fetus, healthy children are born, with normal weight and body length. A general blood test of infants reveals leukocytosis, which persists for a short time [28]. The use of methylprednisolone in the first trimester of pregnancy is also unsafe: there are reports of the possible development of immunosuppression in newborns [28]. Since methylprednisolone is metabolized before passing through the placental barrier, its use is preferable to dexamethasone if it is necessary to prescribe glucocorticosteroids during pregnancy.

In general, the main publications of recent years discuss the possibility of using short courses of methylprednisolone in the second and third trimesters of pregnancy in cases of severe exacerbations of MS [28, 32].

According to a therapeutic opinion published in 2014 by experts in the field of MS, the use of intravenous methylprednisolone to treat exacerbations of the disease during pregnancy is associated with potential risks to the fetus and the development of side effects for the mother; It is best to avoid its use, especially in the first trimester of pregnancy, and limit its use during pregnancy to only those exacerbations that have a significant impact on the patient’s daily activities [50].

Taking DMTs when planning and during pregnancy

The currently fairly large selection of DMTs implies the need for their individual prescription, and various treatment regimens are being discussed [3]. When using DMTs at the stage of pregnancy planning, an individual approach is also, of course, necessary. There is a tactic for canceling DMTs when planning pregnancy in advance. Another opinion has been expressed - about the advisability of canceling DMTs not before, but after the onset of pregnancy, which makes it possible to control the disease [4]. In general, it is best to discontinue the use of both DMTs and symptomatic therapy, both during the planning stage (if possible) and during pregnancy, unless the benefit-to-risk ratio favors continued treatment [50]. To date, certain data have already been accumulated on the use of both first and second line DMTs during pregnancy.

Interferon-β (IFN-β)

Animal studies of IFN-β have reported higher rates of spontaneous abortion [28]. However, in these studies, the dose of IFN-β administered was 3-5 times higher than the recommended weekly dose for humans (while 2 times the excess did not contribute to spontaneous miscarriage) [14, 41].

At the same time, recent prospective studies published from 2005 to 2013 showed that after exposure to IFN-β up to 45 days of gestation, the percentage of pregnancies ending in spontaneous abortion corresponded to the percentage in the general population [65]. Also, no association was found between IFN-β use and the incidence of congenital anomalies [13, 14, 23, 65, 69]. However, a number of authors describe cases in which a decrease in body weight and a decrease in fetal length at birth was observed [10, 30, 73]. This is believed to be related to the mechanism of action of this drug. Although IFN-β is a macromolecule [54] that cannot cross the fetoplacental barrier [54], it can indirectly stimulate the production of maternal cytokines, which freely cross the placenta and affect the fetus [54].

A course of IFN-β is not started during pregnancy. If the patient is already receiving drugs from this group, standard practice is to stop the course before the planned pregnancy. It is also possible to continue treatment immediately until pregnancy occurs if it is necessary to avoid a gap between cessation of therapy and the onset of pregnancy [50].

Glatiramer acetate (GA)

Recent studies have shown that after exposure to GA before 6 weeks of gestation, no significant association was found between its use and an increased risk of spontaneous abortion [31, 33, 73]. The risk of spontaneous abortion was comparable to that in the general population [31, 33, 73]. When prescribing GA, there was no significant reduction in body weight or reduction in fetal length at birth [33, 73]. Also, no anomalies or developmental delays were observed in children during a follow-up period of up to 2.1 years [33]. The low risk of teratogenic effects of GA on the fetus is associated with its mechanism of action - like IFN-β, it is a macromolecule [54] that does not penetrate the fetoplacental barrier, and, unlike the latter, does not contribute to the launch of the production of maternal cytokines.

According to the therapeutic opinion of experts in the field of MS published in 2014, the following provisions have been adopted regarding the use of IFN-β and GA during pregnancy in MS.

Sufficient experience has been accumulated, but the number of published data on the effects of IFN-β and GA on pregnancy is limited. Most likely, there is no increase in the risk of spontaneous abortion. Subcutaneous administration of IFN-β does not currently suggest a precise effect on the development of fetal anomalies, but published information on IFN-β for intramuscular administration and GA is more limited on this issue. Overall, the available data are not sufficient to rule out rare adverse effects on the fetus. It is standard practice to discontinue therapy with these drugs before and during pregnancy unless there is a significant risk to the pregnant woman of increased MS activity without appropriate therapy and the benefits of treatment outweigh the potential (albeit uncertain) risks to the fetus.

Natalizumab

Animal experiments have shown that natalizumab penetrates the fetoplacental barrier, which leads to a decrease in the number of platelets and decreased survival of offspring [74].

There have been no large studies in pregnant women. However, in 2013, an article was published reporting on two newborns whose mothers were treated with natalizumab (a total course of 1200 mg) due to severe neurological deficits between 21 and 34 weeks of gestation [67]. . In both cases, live, full-term children were born, with normal weight and body length. At the age of 12 weeks, psychomotor and somatic development corresponded to the age norm. An ultrasound examination of the brain did not reveal any pathology. However, in the immunogram, as at birth, there was an increase in the number of B-lymphocytes and the CD4/CD8 immunoregulatory index compared to healthy children.

A therapeutic opinion from MS experts published in 2014 recommends discontinuation of natalizumab therapy during pregnancy, but the decision should be made on a case-by-case basis based on benefit and risk, bearing in mind the possibility of relapse into highly active MS after discontinuation of therapy.

Fingolimod

When using the drug in experimental studies, reproductive toxicity was identified, including fetal death and organ malformations, mainly patent ductus arteriosus and ventricular septal defects [44]. To date, recommendations have been published, according to which pregnancy should be avoided until the drug is removed from the body - about 2 months after stopping treatment [27, 50].

Intravenous immunoglobulins (IVIG)

In relapsing-remitting MS, a reduction in the frequency of exacerbations has been described when IVIG is prescribed during pregnancy and after childbirth without serious side effects in newborns [6]. Another study of two doses of IVIG in the postnatal period showed a positive therapeutic effect without increasing the risk of exacerbations [35].

According to a therapeutic opinion from MS experts published in 2014, although the use of IVIG is probably safe, it is not currently recommended due to insufficient evidence of effectiveness.

Mitoxantrone

First of all, when prescribing mitoxantrone, it is necessary to take into account the possibility of developing amenorrhea. In addition, mitoxantrone has also been shown to contribute to the development of premature birth in animals, and also leads to retardation of fetal growth and development. Spontaneous abortion and fetal growth restriction have also been observed in women who were given mitoxantrone during pregnancy for the treatment of breast cancer. The drug is not prescribed during pregnancy, given the potential teratogenic effect.

Regarding the effect of DMTs on fertility in men and the pregnancy of the spouse of a patient suffering from MS, at the moment there is very little information on this issue. One study compared pregnancy outcomes from paternal treatment (mainly IFN-β or GA) with outcomes from a maternal cohort with or without DMT. At the same time, the average body weight of newborns from fathers suffering from MS did not differ from the control group. Despite the small number of observations, the data obtained, according to the authors, suggest safe parenthood for patients suffering from MS [38]. Although some men stop treatment with GA or IFN-β before their spouse becomes pregnant, there is limited justification for this approach [50].

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The disease most often affects young people aged 20 to 45 years; if treatment is prescribed on time, patients with multiple sclerosis live only 7 years less compared to people from the corresponding age group without a similar disease. However, there is a fulminant form of the disease, in which irreversible changes occur within a few years.

CAUSES OF MULTIPLE SCLEROSIS

Reliable data on the main causes of the disease have not been established. Numerous studies have allowed scientists to suggest that multiple sclerosis occurs when the immune system is adversely affected by external and internal factors. External causes of the disease include:

• Bacterial infections.
• Viral infections - measles, rubella, rabies.
• Poisoning with toxic substances, exposure to radiation.
• Injuries.
• Features of the diet.
• Psycho-emotional disorders.

Race and geo-ecological place of residence. Near the equator, the prevalence of multiple sclerosis is lowest, with the number of patients increasing in the north and south.

There is also some genetic predisposition to the disease, that is, multiple sclerosis can be inherited. If one parent is more likely to have multiple sclerosis, then the probability of developing it in children is about 5%, which is considered a low indicator of hereditary predisposition.

Viruses can live in nerve cells for years, gradually destroying their membrane and replacing myelin with a prion, a foreign protein. A prion is an antigen to the body, and the immune system produces antibodies in response to it, leading to a severe autoimmune reaction.

The result of this reaction is the formation of multiple sclerosis plaques, they are located in any part of the white matter of the spinal cord or brain - in the cerebral hemispheres, cerebellum, optic nerves, hypothalamus, brain stem. Damage to the myelin sheath leads to disruption of nerve impulses.

Viruses in the body can act for a long time without causing much concern, but when several provoking factors are combined, the disease begins to progress sharply.

INITIAL SYMPTOMS AND SIGNS

Multiple sclerosis is characterized by a long latent period. When a small number of nerve fibers are damaged, their function is partially compensated by healthy fibers; focal symptoms begin to appear when the percentage of damage approaches 40%. The first signs of the disease may appear suddenly after a trauma, difficult childbirth, or prolonged stress. Symptoms of multiple sclerosis can be transient, and therefore the patient does not immediately pay attention to changes in his health.

Early signs of the disease include:

• Increased fatigue of the lower extremities, their weakness.
• Such lesions of the upper extremities are detected only in 6% of cases.
• Feeling of periodic numbness of the arms and legs, crawling “goosebumps”.
• Hot flashes or, conversely, sudden coldness of the body.
• Some patients with multiple sclerosis experience pain in the abdomen, lower back, and a feeling of tightness.
• The functioning of the optic nerve is disrupted - a short-term, predominantly unilateral decrease in visual acuity.
• Dizziness accompanied by nausea and vomiting.
• Urinary disorders - urge or, conversely, delay.
• In 80% of patients in the early stages, emotional instability is noted - the mood can change several times in one hour.
• The interval between the first signs of the disease and its sudden development can range from several months to several years.

In advanced stages the disease manifests itself:

• Paresis (paresis), impaired muscle tone.
• Impaired coordination in movements - unsteadiness of gait, instability of the body in an upright position, trembling of the limbs.
• Impaired sensitivity - tingling, numbness, pain.
• Decreased visual acuity, nystagmus, narrowing of visual fields.
• Slowing down speech.
• Emotional instability - euphoria, depression.
• Decreased intellectual activity and concentration.
• Disinhibition of behavior.
• In the final stages, dysfunction of the pelvic organs is observed - urinary and fecal incontinence, and in men, impotence.

With multiple sclerosis, there is no specific symptom characteristic of this particular disease, and therefore the disease must be differentiated from other pathologies.

MULTIPLE SCLEROSIS AND PREGNANCY

During pregnancy, there is practically no sharp progression of multiple sclerosis. This is due to the fact that a woman’s immune system does not work at full capacity. If multiple sclerosis worsens precisely during pregnancy, then the treatment regimen is significantly different. Corticosteroids are not prescribed; plasmaphoresis is preferentially used.

At the same time, multiple sclerosis can appear immediately after the baby is born and in the first six months of his life. Exacerbations of the disease are influenced by difficult, protracted labor, stress and difficulties in caring for the child.

MULTIPLE SCLEROSIS IN CHILDREN

The diagnosis of multiple sclerosis is now often made in adolescents aged 10 to 15 years, and the disease often affects very young children. Conducted studies have shown that sclerosis in children develops gradually and in most cases its onset is provoked by hypothermia, severe respiratory infections, and stressful situations.

At the onset of the disease, the child complains of the following symptoms:

• Flashing of flies before the eyes, a foggy veil. Usually, with these signs, parents take the child to an ophthalmologist, and the doctor most often diagnoses neuritis.
• Weakness in the limbs, difficulty walking.
• Urinary incontinence is more common in younger children.
• Tremor of the fingers, tingling and numbness in the limbs.

After the first manifestations of the disease, children may experience a remission of many months, but during this time the damage to the nerve fibers continues. The next attack manifests itself with more developed symptoms and a number of examinations are required to establish an accurate diagnosis. It was found that children born with hypoxic encephalopathy are most predisposed to multiple sclerosis. Research results suggest that earlier onset of sclerosis in children under 10 years of age has a more favorable course. Whereas the onset of the disease at the age of 12-15 years almost always occurs with severe symptoms and a malignant course of the disease. Forms and course of the disease. The relapsing form is considered a typical manifestation of the disease - periods of exacerbation are followed by remission.

The relapsing-progressive form is characterized by incomplete restoration of neurological functions after each exacerbation. In the intervals between remissions, an increase in the symptoms of the disease is observed.

Primary progressive form of sclerosis - the onset of the disease is delayed without severe symptoms, no obvious exacerbations are observed. However, multiple neurological changes develop over several years.

The secondary progressive form is a variant of the relapsing and relapsing-progressive course of the disease several years after the first exacerbation. With this form, there is a gradual and irreversible development of neurological disorders.

clinically isolated form of multiple sclerosis is diagnosed at the first onset of the disease and in the future it can develop in different variants of its course.

MULTIPLE SCLEROSIS IS CHARACTERIZED BY THE PARALLEL DEVELOPMENT OF TWO PATHOLOGICAL PROCESSES:

1. THE APPEARANCE OF AREAS OF INFLAMMATION - sclerotic plaques in the spinal cord and brain. Such foci of inflammation precede an exacerbation of the disease or develop directly during it.

2. DEGENERATIVE CHANGES, leading to atrophy of different parts of the brain and spinal cord.

In recurrent forms of sclerosis, the presence of symptoms is explained by the formation of plaques, and in a progressive variant of the course of the disease, degenerative phenomena come to the fore.

With a long course of the disease, atrophic changes begin to predominate, and inflammatory changes fade into the background. Determining the form of the disease is necessary to select the correct treatment regimen.

An exacerbation of multiple sclerosis is an outbreak of the disease during which a person experiences worsening neurological impairment over several days or weeks. Signs of exacerbation may persist for several weeks, after which remission occurs.

After several exacerbations, the symptoms do not disappear completely, persistent defects appear in the nervous system, and the patient with multiple sclerosis gradually becomes disabled.

There is a direct connection in the course of the disease due to the duration of exacerbations and remissions. The less often exacerbations occur, the greater the chance that the myelin sheath of the nerves will recover completely, which means that the symptoms of the disease will not be as pronounced, and the patient’s quality of life will remain virtually unchanged. That is why it is important to start treatment immediately after an exacerbation, and during remission to carry out preventive therapy.

DIAGNOSIS OF THE DISEASE

The diagnosis of multiple sclerosis is established on the basis of anamnesis and neurological symptoms. The diagnosis must be confirmed by instrumental studies, among which MRI of the brain plays a leading role.

When performing a tomography, plaques are detected, although their absence is not an indication for making a diagnosis. MRI also allows us to detect conduction disorders in the auditory, motor, visual, and somatosensory pathways.

PREDICTIONS AND CONSEQUENCES

The prognosis for multiple sclerosis depends on the form of the disease, the time of its detection, and the frequency of exacerbations. Early diagnosis and prescription of appropriate treatment ensure that the sick person practically does not change his lifestyle - he works at his previous job, actively communicates, and the signs are not noticeable outwardly.

Prolonged and frequent exacerbations can lead to many neurological disorders, resulting in a person becoming disabled. We should not forget that patients with multiple sclerosis often forget to take medications, and their quality of life depends on this. Therefore, the help of relatives in this case is irreplaceable.

In rare cases, an exacerbation of the disease occurs with a deterioration in cardiac and respiratory activity, and the lack of medical care at this time can lead to death.

TREATMENT OF MULTIPLE SCLEROSIS

The earlier treatment for multiple sclerosis is started, the greater the patient’s chances of living a long life with the majority of vital functions preserved. A good prognostic sign is considered to be earlier than the onset of MS and the presence of only a few symptoms of the disease.

Unfortunately, at present it is not possible to completely cure multiple sclerosis, but it is possible to reduce the frequency of exacerbations and their course by taking appropriate medications.

Medicines

Patients with newly diagnosed sclerosis are subject to hospitalization in specialized centers, where the most effective treatment regimen is selected for them. Treatment is mainly based on taking the following groups of medications:

• Hormones . Corticosteroids are prescribed in the first days of illness in a short course. Hormones suppress the immune system, reduce inflammatory reactions and accelerate the process of restoration of nerve fibers.
• Antiviral drugs : Betaferon, Reaferon, Avonex, Cytostatics - Mitoxantrone.
• Symptomatic therapy - includes the use of nootropics, B vitamins, muscle relaxants, antioxidants. Antimetabolites, such as cladribine, are also sometimes used for multiple sclerosis. The immunomodulator Copaxone prevents further destruction of myelin. Plasmophoresis.

Massage

Massage for MS is used to relieve pain, relieve muscle spasms, and restore movement in the affected limbs. The main purpose of massage is to combat spastic paralysis. The technique of massage movements for MS has its own subtleties, so only a qualified specialist should perform the procedures.

Nutrition and diet

Many diets have been developed for patients with multiple sclerosis; some doctors claim that proper nutrition affects both the course of the disease and life expectancy.

It is recommended to consume vegetable fiber, vegetables, and fresh fruits, this speeds up metabolic processes. Linoleic acid is considered beneficial for MS; it is found in vegetable oil, nuts, vegetable margarine, and whole grain cereals.

Caution should be exercised when consuming foods rich in cholesterol - eggs, fatty cheeses and meats, peanut butter, chocolate, and offal.

Patients with multiple sclerosis who are limited in physical activity should pay attention to calorie intake. Gaining extra pounds leads to obesity and a worsening of all symptoms of the disease.

Modern methods

Treatment of sclerosis with stem cells has been carried out since 2003; a similar technique is certified in Russia. Steroid cells restore the myelin sheath, resolve scar tissue and thus improve the passage of nerve impulses. After the introduction of stem cells, impaired functions are quickly restored.

Stem cells are taken from the patient's own biomaterial, then they are grown under sterile conditions for several weeks. After cultivation, some of the stem cells are introduced immediately, the second after a few months. The introduction of cells is usually carried out on an outpatient basis, and the patient tolerates the procedure well. The first positive changes can be noticed after about three months. Drugs based on monoclonal antibodies reduce the frequency of exacerbation periods and lead to less progression of the disease, which also affects the patient’s better quality of life. Monoclonal antibodies inhibit the activity of lymphocytes, which cause damage to the nerve endings of the brain. When using them, the number of sclerosis foci decreases, and new ones do not appear. Drugs based on monoclonal antibodies are prescribed when other methods of therapy are ineffective, but their use must be approached after assessing all the risks. In immunocompromised patients, there is a risk of developing infectious complications.

Multiple sclerosis is a serious disease, but it is always necessary to remember that its manifestations depend on the desire of the patient himself to be cured. If therapy for the disease is started on time, the patient takes all medications, both during exacerbations and for prevention, then the probability of his normal life approaches almost 90%. The use of new drugs and techniques also opens up prospects for treatment.

Symptomatic therapy during pregnancy with MS

According to a therapeutic opinion from MS experts published in 2014, a conservative approach involves stopping all symptomatic therapy before pregnancy; if it continues, it is necessary to use the minimum effective doses of symptomatic drugs for the shortest possible period of time. Drugs for which there is no data on use during pregnancy should be avoided. Pregnant patients with MS should receive folic acid and vitamin D.

Management of childbirth in MS

Numerous studies on the management of childbirth in women with MS, conducted in different countries over the past 50 years, have not revealed any differences from the management of childbirth in healthy women. Both epidural anesthesia and general anesthesia are safe for MS. Neither caesarean section nor epidural anesthesia has a negative effect on the postpartum course of MS. The frequency of application of obstetric forceps or a vacuum extractor does not differ from that in healthy women [28, 29, 36, 46]. When choosing a method of delivery, it is necessary to take into account a complex of factors, including the obstetric situation, as well as the severity of the patient’s neurological deficit.

Feeling worse

Pregnant women with multiple sclerosis sometimes experience cases of severe gestosis with increased blood pressure and eclampsia during childbirth. However, in women who do not suffer from this disease, the frequency of such complications is almost the same. In many cases, pregnant patients experience unexpected effects. Instead of the predicted deterioration by the beginning of the third trimester, the condition, on the contrary, improves, exacerbations of the disease stop, and it proceeds more mildly. Everything is explained simply. The fetus is foreign to the mother. To avoid rejection reactions with spontaneous abortion, the activity of the maternal immune system decreases, and autoimmune reactions, the main mechanism of multiple sclerosis, partially or completely stop.

Breastfeeding in MS, taking DMTs

Some publications suggest an effect of breastfeeding on the incidence of postpartum relapses. Thus, according to B. Beaber et al. [11] and K. Hellwig et al. [39], mixed or artificial feeding leads to a significant increase in the risk of postpartum relapses compared to natural breastfeeding. In women who continued breastfeeding for at least 4 months and had lactational amenorrhea, exacerbations during the 1st year after childbirth were observed in 36% of cases, while among those who did not breastfeed - in 87%. This effect can be explained by changes in hormonal and cytokine status, since mixed or artificial feeding, which leads to early restoration of the menstrual cycle, is pro-inflammatory in nature, while exclusive breastfeeding has an anti-inflammatory effect.

There is another opinion with recommendations for a short course of breastfeeding with its complete cessation by the end of the 1st month after birth and the rapid start of taking DMTs to reduce the risk of exacerbations by the 3rd month [4].

Summarizing the available data, it is likely that at this stage an individual approach to this issue is necessary, taking into account the characteristics of the course of MS before and during pregnancy, and possible concomitant pathology. Of course, further research is needed to conclusively confirm or refute the cause-and-effect relationship between natural feeding and a reduced risk of postpartum relapses in women with MS.

According to a therapeutic opinion from MS experts published in 2014, there is no reliable evidence of either the benefits or harms of breastfeeding for patients with MS. Data on the penetration of DMTs and symptomatic drugs into breast milk and, accordingly, on the effect on newborns are limited. In general, it is recommended not to use DMTs during lactation or to discontinue breastfeeding if continued therapy is necessary. The decision to restart DMT immediately after delivery must be weighed against the potential benefits of breastfeeding.

Neurology Center in Moscow

Can I face problems during pregnancy?

MS does not increase the risk of problems that may occur during pregnancy. The risk of developing pregnancy-induced hypertension, also called toxemia or preeclampsia, or preterm labor (preterm birth) does not increase with multiple sclerosis.

What should I expect during pregnancy?

If multiple sclerosis affects your ability to walk, you may notice that walking becomes even more difficult during pregnancy. This is because the weight you gain during pregnancy can change your balance. You may have to take extra care to avoid falling. You may need crutches or other devices to help you walk, or you may need a wheelchair. You may also notice that you get tired more quickly, especially later in pregnancy. Plan ahead to allow enough time for rest in your schedule.

Talk to your partner, family and friends if you need help caring for other children, doing housework or running errands. Get the support you need. Urinary tract infections (UTIs) are more common in pregnant women with multiple sclerosis. Drink plenty of water and tell your doctor if you have any symptoms. Your doctor may ask you to have a urine test every month to make sure there is no risk of a urinary tract infection.

Will I be able to continue taking the medicine?

If you are planning to become pregnant, consult your doctor in advance. Some medications used to treat symptoms of multiple sclerosis are not safe for your baby during pregnancy. These include a group of drugs called “disease-modifying drugs” and another group called “chemotherapeutic drugs,” such as azathioprine or methotrexate. Your doctor may tell you to stop taking these medications before trying to get pregnant. Some other medications that are considered safe during pregnancy may be helpful in treating symptoms of multiple sclerosis. Your doctor may recommend that you change your medications when you are trying to get pregnant and during pregnancy.

Will MS cause problems during childbirth?

Some women with multiple sclerosis have damage to their spinal cord, making it difficult for them to tell when labor is about to begin. This is rare, but can be a concern for some women. If you have decreased sensation in your pelvic or abdominal area, talk to your doctor. He or she can talk to you about other clues that can help you determine that you are going into labor. Sometimes women with multiple sclerosis experience damage to the nerves that help the muscles push during childbirth. In this case, you may need additional assistance with a vaginal birth or you may need a caesarean section. You may also have a caesarean section if you are very tired during labour.

Will anesthesia be dangerous due to multiple sclerosis?

Research shows that anesthesia during childbirth is no more dangerous for women with MS than for other women.

Will my child be healthy?

Children born to women with MS are no more likely to have birth defects or physical or mental disabilities than children of other women. Sometimes children of women with MS have slightly lower birth weight, but this does not lead to health problems.

Will my child have MS?

Your child's risk of developing multiple sclerosis will be slightly higher than that of a child who does not have a family member with multiple sclerosis. But the risk is still very low.

Will I be able to breastfeed?

Some medications may not be safe if you want to breastfeed. And you may need some of these medications if your MS symptoms get worse after giving birth. Talk to your doctor if you plan to breastfeed your baby. Your doctor can tell you what options are available to help you breastfeed safely.

What should I expect after giving birth?

It's a good idea to plan ahead for how you'll live after giving birth. Women with multiple sclerosis often notice an increase in symptoms (called “flares”) after childbirth. You may also feel chronic fatigue. Fatigue combined with disability or movement problems can contribute to depression. Even women without multiple sclerosis are at risk of depression after childbirth (postpartum depression).

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REQUEST TO THE CLINIC

Monitoring the course of MS during pregnancy

Currently, MRI is generally accepted as the main non-clinical method for monitoring the course of MS. In addition, MRI currently plays a significant role in clarifying the pathogenesis of MS [1]. However, when performing MRI during pregnancy, there are potential risks to the fetus, including the heating effect of radiofrequency pulses, acoustic effects, and teratogenicity. In this regard, in cases where MRI is truly a necessary study, it is recommended to postpone it until the end of the first trimester of pregnancy. However, MRI may be performed if the potential clinical benefit clearly outweighs the risk [50]. The use of intravenous gadolinium-containing contrast agents can be carried out during pregnancy only for extreme indications.

Lumbar puncture or electrophysiological tests are not associated with specific risks to the mother or fetus, but their use should be minimized due to the potential for discomfort in the pregnant woman [50].

In conclusion, once again emphasizing the multifaceted nature of the problem of managing pregnancy in MS, I would like to draw attention to the need for further research in this area, as well as the advisability of creating appropriate registries. Detailing the specific pathways of natural modulation of MS activity during pregnancy may contribute to the development of effective prognostic criteria for the course of MS in the postpartum period. Of course, large ongoing studies regarding the safety of the use of DMTs during pregnancy and lactation are extremely relevant. Finally, certain prospects may be associated with clarifying the role of sex hormones in MS, including their therapeutic potential.

Management of pregnancy in multiple sclerosis

Features of medical management of pregnancy in multiple sclerosis:

• If it is necessary to contain the activity of multiple sclerosis, it is possible with the help of intravenous administration of immunoglobulins. Intravenous immunoglobulins (IVIG) are safe for the unborn child, block autoimmune aggression and help fight infections. We administer IVIG on an outpatient basis (no hospitalization is required), in the clinic, under the supervision of medical staff.
• Approximately once every 2-3 months, we will ask you to perform control tests of blood, saliva, and urine. In case of movement towards activation of autoimmunity or any infection, we will take the necessary measures.
• We will ask you to get enough sleep (this is a necessary condition).
• During an epidemiologically dangerous period of the year, we will insist on protective measures (wearing a mask in public places, nasal administration of interferon ointment, etc.).

In addition to the above, we will carry out standard procedures for pregnancy management by a gynecologist in accordance with the standards accepted in Russia.