Multiple sclerosis in women: features of the course at different stages of fertile function

Full Text

Introduction

Multiple sclerosis (MS) is a chronic demyelinating disease, which is based on a complex of autoimmune inflammatory and neurodegenerative processes leading to multiple focal and diffuse lesions of the central nervous system, which results in patient disability and a significant reduction in quality of life [1; 2].

Multiple sclerosis, like many other autoimmune diseases, is more often diagnosed in women than in men. This tendency is explained by the influence of sex hormones, as well as the possible influence of sex-linked genes that increase the tendency of women to develop autoimmune disorders. This is confirmed by the fact that in men the disease usually manifests itself later in life, which coincides with the natural decline in testosterone levels. For example, among patients under 20 years of age, the ratio of women to men is 3.2: 1, while in the general population of patients with MS this ratio decreases to 2: 1 [3].

Despite the increased risk of multiple sclerosis, women often have a less aggressive course of the disease. Thus, women are more likely to have a remitting onset of the disease, they are less likely to have a malignant course of multiple sclerosis, women are characterized by a lower rate of progression and brain atrophy [4]. Despite these overall gender differences, the course and prognosis of individual women can vary greatly [5; 6].

In most cases, multiple sclerosis has its onset between the ages of 18 and 45. This period coincides with the active reproductive phase of human life. Women planning a pregnancy face many issues, including the impact of multiple sclerosis on fertility; concerns about the risk of passing multiple sclerosis on to offspring; the impact of medications used for multiple sclerosis on the fetus; the impact of pregnancy on the progression of the disease; the impact of multiple sclerosis on the mother's ability to care for her child and the socioeconomic burden on the family [7].

The aim of the study is to analyze the literature data on the characteristics of the course of multiple sclerosis in women in the context of age-related physiological changes.

An analysis of the literature presented in the aggregator databases was conducted: PubMed, Google Scholar, CyberLeninka, eLIBRARY. The review included the results of studies, meta-analyses, systematic reviews. For the search, queries were formed with the following keywords: "multiple sclerosis", "multiple sclerosis in women", "reproductive health", "fertility in multiple sclerosis", "pregnancy in multiple sclerosis", "childbirth in multiple sclerosis", "menopause in multiple sclerosis".

Multiple Sclerosis and Fertility

Multiple sclerosis is an autoimmune disease that predominantly affects women of reproductive age. The higher prevalence in women is typical for most autoimmune diseases, which may reflect the potential impact of sex hormones on the nervous, endocrine and immune systems. The higher incidence of the disease in women is associated with the influence of hormonal changes that women experience throughout their lives. Studies have shown that in multiple sclerosis, central regulation disorder causes a deficiency of estrogens, progesterone and testosterone, with sex hormones playing an important role in modulating disease activity and the extent of brain damage [5; 8]. As E.V. Predtechenskaya notes, in many patients the onset of multiple sclerosis coincides with menstrual cycle disorders, such as hypomenstrual syndrome or bleeding during puberty. In addition, women with multiple sclerosis often experience hormonal changes, including increased levels of follicle-stimulating hormone, luteinizing hormone and prolactin, which can negatively affect fertility [9; 10]. In such patients, in early reproductive age, a hypergonadotropic state and hypoandrogenism of mixed genesis associated with dysfunction of the ovaries and adrenal glands are detected. This indicates a decrease in the steroid-synthetic activity of the ovaries, which may be one of the causes of problems with conception [11; 12].

At the same time, the presence of multiple sclerosis in itself does not make a woman infertile: the probability of infertility in patients with multiple sclerosis is comparable to that in women without this disease. However, in some cases, the question arises about the need to use assisted reproductive technologies, such as in vitro fertilization (IVF). It is important to consider that the IVF procedure involves the use of high doses of hormonal drugs, which can lead to hormonal imbalance. This, in turn, can provoke an increase in disease activity in patients with multiple sclerosis [13–15].

Risks of Transmission of Multiple Sclerosis to the Offsping

Familial aggregation is an epidemiological feature of multiple sclerosis. It has been shown that children with one parent with multiple sclerosis have a 2 % chance of developing the disease at some point in their lives. This probability increases to 6–2 % if both parents have multiple sclerosis, suggesting that the risk of developing the disease is determined by genetic factors inherited from both parents [16]. A link between the risk of developing multiple sclerosis and the month of birth was found in some studies. Thus, the risk is slightly higher for people born in the spring and lower for those born in the fall, especially in cases of familial multiple sclerosis. This feature indicates the role of a combination of genetic and external factors associated with climate in the development of the disease. However, subsequent studies have shown that these results were distorted by geographic and seasonal differences in fertility rates. At the same time, a number of studies suggest an inverse correlation between vitamin D levels and the risk of multiple sclerosis. It is noted that the risk of developing multiple sclerosis in women whose mothers consumed large amounts of vitamin D during pregnancy was lower [17; 18].

Pregnancy with Multiple Sclerosis

Just a few decades ago, opinions on the impact of pregnancy on the course of multiple sclerosis were quite controversial. The prevailing belief was that pregnancy could aggravate the course of the disease, provoking exacerbations, and many patients with multiple sclerosis were advised not to plan childbearing. However, since the end of the 20th century, this issue has been studied more detailly. It has been established that pregnancy has a more favorable effect on patients with remitting type of multiple sclerosis compared to those with secondary-progressive course. This is associated with the age of patients and their reproductive potential at the time of pregnancy [19].

The data analysis showed that during pregnancy, women with multiple sclerosis experience clinical improvement and a decrease in the frequency of exacerbations. However, in the postpartum period, especially by the third month after delivery, there is a significant increase in the frequency of exacerbations, after which the disease activity returns to the level observed before pregnancy. These data allowed us to suggest that pregnancy contributes to a temporary decrease in autoimmune activity [3].

Pregnancy is accompanied by significant changes in hormonal levels, including increased levels of estriol, 17-β-estradiol, progesterone, prolactin and testosterone. These hormones have a neuroprotective effect, slowing down degenerative processes in the central nervous system. In addition, natural immunosuppression occurs during pregnancy, which leads to a decrease in the activity of chronic inflammation and demyelination, which can also help slow down the progression of the disease [20–23].

The decrease in the frequency of exacerbations in the third trimester of pregnancy and their increase after delivery, as well as the autoimmune nature of multiple sclerosis and the successful use of disease-modifying drugs (DMDs), prompted researchers to study in more detail the immunosuppressive effect of pregnancy. It has been established that the fetus, which is an allogeneic transplant for the mother's body, produces cytokines that reduce the production of proinflammatory factors and promote the prevalence of anti-inflammatory reactions. This leads to temporary suppression of cytotoxic immune reactions and activation of mechanisms necessary for the transfer of antibodies from mother to fetus. Such immunosuppression is an important adaptive response that prevents fetal rejection [24]. After delivery, the balance of immune responses is restored, which explains the increase in the frequency of exacerbations. In addition, the postpartum period is often accompanied by an increased risk of infections, which themselves can provoke exacerbations of multiple sclerosis. Therefore, for women with multiple sclerosis, it is important to carefully monitor and prevent infectious complications after delivery [7; 25; 26].

Thus, current data indicate that pregnancy with multiple sclerosis can proceed favorably, especially with the remitting type of the disease. However, each case requires an individual approach, since a pronounced neurological deficit at the time of pregnancy may be a predictor of a more rapid transition to a secondary progressive course of the disease.

Drugs Administration by Pregnant Women with Multiple Sclerosis

Treatment of multiple sclerosis during pregnancy should be tailored to the needs of each patient, taking into account variables such as age, disease progression, clinical and radiographic remission, previous relapses, disability, risks of treatment discontinuation, risks of treatment continuation, and patient preferences. Due to the lack of safety data with respect to DMDs for pregnant women, effective contraception is recommended during treatment. In the vast majority of cases, therapy should be discontinued prior to conception because of the potential for exposure to the developing fetus. The generally accepted time period for drug withdrawal prior to conception, based on exponential tapering, is five maximum half-lives. For drugs used in multiple sclerosis, this period is usually two to six weeks (the exception is teriflunomide, for which conception should be tied to a blood serum level of less than 0.02 µl/ml, according to the manufacturer) [26]. A pregnancy test should be considered before initiating any therapy for multiple sclerosis, including infusions. In women with highly active multiple sclerosis, the known benefits of DMDs (especially when switching to glatiramer acetate) may override the unknown risks to the fetus. In women at particularly high risk of relapse after stopping DMDs, this risk can be reduced prior to conception by monthly administration of intravenous corticosteroids at the beginning of each menstrual period (if pregnancy test is negative). Corticosteroids should be avoided during pregnancy, especially during the first trimester, because of the risk of fetal malformations such as cleft palate. High doses of methylprednisolone are relatively safe for relieving exacerbations of multiple sclerosis in the second and third trimesters, but their use should be limited to severe, disabling relapses. Although methylprednisolone is metabolized in the placenta and does not reach the fetus, it can cause moderate leukocytosis and immunosuppression in newborn infants [26].

In experimental animals given higher doses of interferon (IFN) than humans, the abortive effects of the drug were shown to increase in a dose-dependent manner during the first trimester. A small amount of IFN is excreted in breast milk. Contraception should be used during treatment with the drug. Women with multiple sclerosis and planning pregnancy should stop treatment with interferons. The literature describes about 1000 cases of patients taking IFN during pregnancy [7]. However, in most cases the drug was administered only during the first weeks of the first trimester, as treatment was stopped immediately after pregnancy was confirmed. These studies report a low incidence of fetal malformations (rates similar to those in the general population). At the same time, there is insufficient data to exclude a link between interferon treatment and rare fetal abnormalities. In some cases, a small increase in preterm births and low birth weight was observed in pregnant women receiving IFN [1]. These data have not been confirmed by the results of other series.

Glatiramer acetate has a more favorable safety profile, as no drug-related changes have been observed in animal models. This molecule cannot cross the placenta or be excreted in breast milk due to its high molecular weight. A study of 400 pregnant women given glatiramer acetate confirmed the safety of the drug based on normal fetal development [4; 7]. However, given the small number of pregnant women receiving the drug, the risk of fetal malformations cannot be completely excluded, so glatiramer acetate should be used with caution.

There is little information on the use of other drugs, including natalizumab, fingolimod, dimethyl fumarate, and alemtuzumab, during pregnancy. Natalizumab has been associated with increased rates of miscarriage in animals. Patients are advised to discontinue administration of natalizumab and wait 3 months before conceiving. The drug crosses the placenta in the second trimester of pregnancy and is excreted in small amounts in breast milk. Administration of natalizumab in the third trimester to patients with highly active multiple sclerosis resulted in thrombocytopenia and hemolytic anemia in eight of nine live births [27]. Experiments on animals have shown that fingolimod crosses the placenta, has a teratogenic effect, and is excreted in breast milk. In case of planned pregnancy, its use should be discontinued and a 2-month withdrawal period should be performed [28]. Dimethyl fumarate is toxic to the fetus and causes testicular problems, low birth weight, and behavioral changes in experimental animals [26]. Teriflunomide has been shown to be teratogenic in animal models and is therefore contraindicated during pregnancy. It has a long plasma half-life, but cholestyramine can be administered concomitantly to accelerate elimination in women planning to conceive [29]. Mitoxantrone should be discontinued during pregnancy due to its potential teratogenicity. The drug may also cause infertility, premature ovarian failure, and amenorrhea, especially in women over 35 years of age [26].

Disease remission and stable progression should be achieved before conception is planned, however, in women with highly active relapsing-remitting multiple sclerosis, discontinuation of DMDs may be associated with an increased risk of relapse [26].

Current research shows that some DMDs do not have a teratogenic effect on the fetus when used early in pregnancy. With an average duration of therapy of 30 days during pregnancy, the risk of birth defects in the fetus does not increase. In particular, foreign studies confirm that the use of interferon and glatiramer acetate in the first trimester of pregnancy is not associated with the occurrence of congenital abnormality [30]. However, it is recommended to discontinue DMDs upon the onset of pregnancy in order to minimize any potential risks [26].

Despite the fact that pregnancy is accompanied by natural immunosuppression, which reduces the likelihood of exacerbations of multiple sclerosis, their development is still possible. In such cases, glucocorticoids may be required. Methylprednisolone is the preferred choice for reversing exacerbations during pregnancy because it is metabolized before crossing the placental barrier, unlike dexamethasone. Methylprednisolone is administered as intravenous pulse therapy at a dose of 1 g per day for 3–5 days. When administered in the first trimester, teratogenic effects are unlikely, although rare exacerbations such as cleft palate or cataracts have been reported. In the second and third trimesters, the risk of teratogenic effects is even lower, making methylprednisolone a safe option for treating exacerbations during these periods [9]. Intravenous immunoglobulins can also be used to relieve exacerbations during pregnancy [26].

If an exacerbation occurs after childbirth and glucocorticoids are required, breastfeeding should be temporarily discontinued, as these drugs penetrate into breast milk. Resumption of breastfeeding is possible no earlier than 12 hours after completion of hormonal pulse therapy [31].

As for diagnostic methods, magnetic resonance imaging (MRI) during pregnancy is possible to confirm the diagnosis or in the event of an exacerbation of multiple sclerosis. To date, no significant risk to the fetus has been identified when performing routine MRI in the first trimester. However, given the active process of organogenesis during this period, MRI should be performed only in cases where the potential benefit to the mother overrides the possible theoretical risks to the fetus [32].

Childbirth in Women with Multiple Sclerosis

Modern research demonstrates that the method of delivery does not affect the likelihood of exacerbation of multiple sclerosis in the postpartum period. The diagnosis of multiple sclerosis in itself is not an indication for cesarean section, however, when choosing a method of delivery, it is necessary to take into account the individual characteristics of the patient's neurological status. For example, the presence of lower paraparesis, sensory disturbances in the lower body, pelvic disorders or increased fatigue may be grounds for performing a cesarean section. This is due to the risk of developing weak labor, prolonged labor and fetal hypoxia, which in the worst case can lead to its death. At the same time, the risk of complications such as eclampsia or premature birth in women with MS does not exceed the average rates in the general population [33].

When choosing anesthesia for patients with MS, epidural anesthesia is preferred because it provides a lower concentration of anesthetic drug in the cerebrospinal fluid. The use of spinal anesthesia may be associated with a risk of neurotoxicity in areas of spinal cord demyelination due to high drug concentrations in the cerebrospinal fluid, which can potentially provoke postpartum exacerbations. However, this risk has been significantly reduced due to the use of modern anesthetic drugs [3].

Postpartum Period in Women with Multiple Sclerosis

Given the connection between MS activity and the patient's psychoemotional state, as well as the significant physiological impact of childbirth on the body of the woman and the child, it is important to adhere to the generally accepted practice of early attachment of the newborn to the mother's breast. However, it should be remembered that long-term breastfeeding does not protect a woman with MS from an increase in the frequency of exacerbations, which often occur as early as the third month after childbirth. In this regard, patients with MS should be informed about the possible risk of exacerbations during prolonged lactation [34].

It is also important to actively discuss with the patient the possibility of early transfer of the child to artificial feeding with complete cessation of lactation by the end of the first month after birth. This will allow for rapid resumption of DMDs and reduce the risk of exacerbations by the third month. The drug of choice for resumption of therapy after birth should be the one that was successfully used before pregnancy. However, if there have been exacerbations of the disease during pregnancy, it is recommended to consider the use of β-interferons as first-line drugs. They begin to act on average after three months, in contrast to glatiramer acetate, the effect of which develops only after six months [35; 36].

Thus, an individual approach to the management of patients with MS in the postpartum period, including discussion of breastfeeding issues and timely resumption of therapy, plays a key role in minimizing the risk of exacerbations and improving the quality of life of women with this disease.

Menopause in Women with Multiple Sclerosis

In most women, MS activity persists until menopause. Available data suggest that multiple sclerosis does not affect the age at which menopause occurs – on average, in patients with multiple sclerosis and healthy individuals, it is 51.5 years. Several factors may become clinically apparent during this period. First, the symptoms of multiple sclerosis and menopause may overlap, creating problems in patient management. These overlapping symptoms include sleep disturbances, mood changes, cognitive complaints. Careful questionnaires can distinguish subacute relapses of MS from the gradual development of menopausal symptoms. Secondly, vasomotor symptoms (especially hot flashes) can worsen MS symptoms due to the Uhthoff phenomenon, causing pseudo-exacerbations. Thirdly, a slight worsening of MS in postmenopause is possible due to a decrease in estrogen levels in the body [37].

There are very limited data on the effects of menopausal hormone therapy on the course of MS. A clinical trial of oral administration of estriol in 10 women with relapsing multiple sclerosis showed improvement in MRI imaging. These effects may be due to a hormone-induced decrease in Th1 responses and an increase in Th2 responses. A crossover study of transdermal testosterone administered to 10 men with relapsing MS found no change in the incidence of gadolinium-enhanced MRI lesions but a reduction in cerebral atrophy. This may be due to increased production of neurotrophic factors by peripheral blood mononuclear cells. The results of these studies indicate a neuroprotective and immunomodulatory effect of estrogens in women and testosterone in men [7].

The effect of oral contraceptives on exacerbations was also assessed using MRI. There was a reduction in the number of new lesions over a 2-year follow-up period in the group with high-dose estrogen administration. These results indicate that high-dose estrogen-containing oral contraceptives may enhance the effects of interferon. Another study analyzed the efficacy of 10 mg nomegestrol acetate versus placebo in the postpartum period for 12 weeks; no difference in recurrence was found between groups [4].

Conclusions

Pregnancy is an important stage in a woman’s life, and in the presence of a chronic disabling disease such as MS, it should be carefully planned. If a patient with MS decides to become pregnant, it is recommended to refer her to a specialized center (department, office or clinical diagnostic center) for consultation on the specifics of the pregnancy and the postpartum period. Although MS is not an indication for termination of pregnancy [1], it is important to discuss with the patient the possible impact of pregnancy on the frequency of exacerbations both during pregnancy and after delivery. To date, there is no reliable data indicating an increased risk of intrauterine pathology in newborns whose parents suffer from MS.

Given the active use of DMDs, special attention should be paid to the correction of therapy or its cancellation due to the potential impact on the fetus. It is also important to promptly resume taking DMDs after childbirth to reduce the risk of postpartum exacerbations. The diagnosis of MS does not affect the choice of labor management tactics and anesthesia, but the presence of certain symptoms, such as lower paraparesis or pelvic dysfunction, may indicate the risk of obstetric complications, which requires an individual approach to delivery.

Pregnancy has a beneficial effect on the course of MS, reducing the frequency of relapses. This is due to the anti-inflammatory effect of sex hormones such as estradiol and estriol, the level of which increases significantly during pregnancy due to active production by the placenta and then the liver of the fetus [19]. Estradiol, estriol, progesterone and testosterone have an immunosuppressive effect, which helps not only reduce inflammation, but also restore the myelin sheath and axons. However, in the first months after childbirth, there is an increase in the frequency of relapses compared to the period before pregnancy. The frequency of exacerbations returns to the original level during the first year after childbirth [24; 36; 37].

Thus, MS does not have a negative impact on the course of pregnancy and childbirth: the incidence of infertility, miscarriage, gestosis and complications during childbirth in patients with MS does not differ from the rates in the general population [38–40]. In most cases, children born to mothers with MS are healthy, and the rate of infant mortality and congenital pathologies does not exceed those in children born to healthy women.

About the authors

Oksana A. Kicherova

Tyumen State Medical University

Author for correspondence.
Email: pan1912@mail.ru
ORCID iD: 0000-0002-7598-7757
SPIN-code: 3162-0770

DSc (Medicine), Associate Professor, Head of the Department of Neurology with the Course in Neurosurgery of the Institute of Clinical Medicine

Russian Federation, Tyumen

Ilfira N. Akhmedova

Tyumen State Medical University

Email: abubyackirova.ilfira@yandex.ru
ORCID iD: 0009-0006-2976-2940

Resident of the Department of Neurology with the Course in Neurosurgery of the Institute of Clinical Medicine

Russian Federation, Tyumen

Lyudmila I. Reikhert

Tyumen State Medical University

Email: lir0806@gmail.com
ORCID iD: 0000-0003-4313-0836
SPIN-code: 1703-2302

DSc (Medicine), Professor, Professor of the Department of Neurology with a Course in Neurosurgery of the Institute of Clinical Medicine

Russian Federation, Tyumen

Tatyana P. Shevlyukova

Tyumen State Medical University

Email: tata21.01@mail.ru
ORCID iD: 0000-0002-7019-6630

DSc (Medicine), Professor of the Department of Obstetrics and Gynecology of the Institute of Maternity and Childhood

Russian Federation, Tyumen

Irina A. Bulatova

Ye.A. Vagner Perm State Medical University

Email: bula.1977@mail.ru
ORCID iD: 0000-0002-7802-4796

MD, Professor of the Department of Faculty Therapy No. 2, Occupational Pathology and Clinical Laboratory Diagnostics 

Russian Federation, Perm

References

Supplementary files