Online newspaper of professor Yasser Metwally

I am professor Yasser Metwally

www.yassermetwally.com 

MULTIPLE SCLEROSIS AND PREGNANCY 

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system, causing fluctuating neurologic symptoms over time. A chronic, progressive disorder resulting in the inexorable accumulation of disability over time, MS is unique in its primary feature of unpredictability. As the average age of onset is in the late 20s, pregnancy and childbearing issues are prominent concerns.

• Demographics and epidemiology

The incidence of MS in the general population is approximately 0.1% and an estimated 250,000 people are living with MS in the United States. The demographics of MS are well characterized. The most common form of MS is relapsing remitting and females are affected primarily. In contrast, the incidence of primary progressive MS is equal in men and women. The average age of onset is 28 in women, whereas men typically present slightly older, with onset in their early 30s.

Although historically considered a disorder predominantly of the Caucasian population, the incidence in other ethnic groups seems to be rising. The prognosis of MS seems to be gender and racially dependent. Historically, men, despite their older age of onset, have a worse prognosis. Recently, retrospective data have begun to accumulate suggesting that African Americans may have a worse prognosis than their Caucasian counterparts 1.

One unique feature of MS is the difference in prevalence dependent on geographic location. A worldwide phenomenon is that the incidence of MS rises with increasing distance from the equator. Rates of MS in Africa are extremely low, whereas the highest prevalence is in the Scandinavian countries.

Evidence for the role of environmental factors contributing to the development of MS is supported by the fact that an individual’s risk for developing MS is related to where he or she lived before the age of 15. For example, a woman born in the south who then moves north after the age of 15 maintains her lower risk for developing MS. Yet, for unexplained reasons, if she moves north before the age of 15, she assumes the increased risk of her new northern location 2.

Several infectious agents are implicated as possible triggering factors contributing to the onset of MS. Despite reports of virus-like particles isolated from MS brains, evidence of active infection is not documented. A causative relationship between infectious etiologies and MS is not established [3–5].

• Diagnosis

The diagnosis of MS has remained a clinical diagnosis based on varied neurologic events separated in time and space. Historically, the diagnosis of MS has required a second clinical event to confirm the diagnosis of clinically definite MS [6,7]. The importance of the clinically isolated syndrome (ie, a single neurologic event) is recognized. Certain clinically isolated events, such as optic neuritis in the face of an abnormal MRI, have a high predictive value for the patient meeting the diagnostic criteria for clinical definite MS within 10 years 8.

The importance of MRI in reflecting subclinical activity increasingly is recognized. Serial MRI studies show that the MRI may reflect 5 to 10 new lesions that may not have been evident clinically through relapses 9. Recently proposed diagnostic schema, the McDonald criteria, attempt to incorporate MRI identified lesions into making the diagnosis earlier and increasing the accuracy of diagnosis 10. Ancillary testing, such as MRI, spinal fluid testing, and evoked potentials, are used in lieu of a second clinical event.

• Course

MS is characterized clinically by unpredictable episodes of neurologic dysfunction, ranging from weakness to sensory phenomena, such as visual loss. The early course of relapsing remitting MS is characterized by the acute onset of neurologic symptoms lasting at least 24 hours. The acute episodes, or relapses, may resolve completely or partially. Over time, usually 15 to 20 years, the stepwise nature of the course, or relapsing remitting phase, transitions, in the majority of patients, to a more insidious, steady decline in neurologic function, with the subsequent accumulation of progressive disability. This phase of the disease is known as secondary progressive and may or may not have superimposed relapses.

Primary progressive MS, which occurs in approximately 10% of patients who have MS, has a distinct clinical course, in that there are no acute events and the history is that of progressive decline of function. There is increasing evidence to support that primary progressive and relapsing remitting MS indeed may be two distinct disorders and not different presentations of the same disease.

• Treatment

The treatment of MS consists of four arms of therapy: immunomodulatory treatment, symptom management, rehabilitation, and alternative treatments. The goal of immunomodulatory treatment is to decrease the number and severity of relapses and slow the progression of disability over time 11. Since 1993, five Food and Drug Administration (FDA) approved medications have become available for the treatment of MS. Four treatments, interferon (INF) ß-1a (Avonex, Rebif), INFß-1b (Betaseron), and glatiramer acetate (Copaxone) are indicated to decrease the frequency of neurologic events and the subsequent accumulation of disability [12–15]. The fifth medication, mitoxantrone (Novantrone), is FDA approved for worsening MS 16.

Unfortunately, the current immunomodulating agents are only partially effective, with an average reduction of approximately 40% in clinical relapses. Advances in treatment of MS include the recognition of the importance of early treatment and the sustained benefit of long-term therapy 11. Recent research has focused on combination therapy as a way of boosting the effectiveness of current treatment options.

Aggressive symptom management is paramount, especially as it relates to quality of life issues. Symptom management encompasses problems ranging from urinary incontinence to the treatment of spasticity or fatigue. Rehabilitation, not only in the face of acute neurologic events but also as an intervention for functional decline, has become an important arm of therapy.

A discussion of the treatment of MS is not complete without mention of the use of alternative treatments. It is estimated that 80% of patients living with MS either currently use, or have used, alternative treatments. Alternative treatments range from high-dose vitamin therapy to special diets to bee sting therapy. Maintaining open lines of communication between the patient and the physician is imperative so that educated decisions can be made about efficacy and safety, especially because alternative therapies also may confer risk to the developing fetus in the event of a planned or unplanned pregnancy.

• Prognosis in multiple sclerosis

In conversations regarding family planning, the issue of an individual patient’s prognosis frequently arises. Although there are many natural history studies, it is not possible to extrapolate accurately an individual’s prognosis from data derived from large populations. Recent attempts to help predict prognosis include information gained from MRI and genetic factors, such as apolipoprotein E (ApoE) and cerebrospinal fluid (CSF) biologic markers [17,18]. Gender and race also may have important roles in predicting prognosis 1.

• Pathophysiology of multiple sclerosis

The trigger leading to the cascade of events that characterizes MS is unknown. The current theoretic model is as follows: an unknown antigen is recognized by the immune system as foreign. The immune system mounts a response that is led predominately by the cytotoxic lymphocytes.

Although ordinarily the blood-brain barrier protects the central nervous system from attack of these activated cytotoxic lymphocytes, in MS this barrier is compromised and breached. Once entering into the CNS, the activated, cytotoxic lymphocytes trigger a cascade of events ultimately leading to the demyelination of the axons. The demylinated axon develops conduction slowing, or block, which, depending on the area of the CNS involved, is expressed either clinically or subclincally.

Although historically, attention has centered on the prominent areas of demyelination in the brain and spinal cord, the importance of axonal involvement is becoming more apparent. The axonal involvement may underlie the fixed deficits seen in MS 19.

The current concept of the pathophysiology of MS is that the disease reflects the biphasic nature of the clinical course. The relapsing remitting phase of MS correlates to an initial inflammatory phase. The secondary progressive phase, with its more insidious development of disability, may reflect a neurodegenerative phase of the disease process.

The proposed pathophysiologic explanations for the mechanisms of MS are complicated and diverse. Recent pathologic studies suggest that MS may be not one disorder but a body of disorders. Pathologic changes in biopsy and autopsy specimens reveal that in a single patient, the changes are consistent, but among patients, different patterns can be identified. These patterns vary from a more neurodegenerative pattern, with what seems to be a primary oligodendrogliopathy, to prominent inflammatory patterns 20.

• Pathophysiology of pregnancy

Symptoms of autoimmune diseases may increase or decrease during pregnancy. Cell-mediated disorders, such as rheumatoid arthritis and MS, tend to improve during pregnancy, whereas antibody-mediated autoimmune disorders, such as systemic lupus erythematosus, tend to have a worsening of symptoms. This effect of pregnancy is believed to be mediated by immune system changes precipitated by the pregnancy itself.

The immune system during pregnancy changes from predominately cell mediated to predominately antibody mediated 21. This shift benefits the pregnancy, as it allows the presence of the fetus to continue despite its being essentially an allograft with half of its antigens inherited from the father and thus foreign to the mother. This shift is essential to preventing fetal rejection 22. After delivery, there is a reverting of the immune system to its customary balance between the cell-mediated and antibody-mediated systems.

Many pregnancy factors also are implicated as candidates contributing to the improvement in disease activity. Estrogen, progesterone, testosterone, cortisol, and alpha-fetoprotein are present in maternal serum and all are shown to modulate the immune system 23.

• Hormones and multiple sclerosis

Communication between the immune system and the endocrine system occurs through receptors on the immune cells for the various sex hormones. With the recognition of the communication between the immune and endocrine systems, there has been increased scrutiny of the effects of the sex hormones on MS. Testosterone was one of the first hormones implicated as a possibly beneficial treatment of MS. The rationale for examining testosterone has two parts. First, men are relatively protected from developing relapsing remitting MS. Second, the age of onset is older in men, which coincides with a physiologic decrease in endogenous testosterone levels. Experimental autoimmune encephalomyelitis (EAE) is an animal model used to study various features of MS. In mice, gender differences in susceptibility to the development of EAE have been found. EAE is easier to induce in female mice than in male mice. Female mice treated with testosterone derivatives are found to have less severe disease courses 24.

Animals pretreated with estrogen and then exposed to known triggers of EAE are less likely to develop the disease 25. In animal models of EAE, a decreased severity of active disease was seen in animals treated before induction and those treated after the induction of disease 26. In contrast to the beneficial effects of estrogens seen in animal models of EAE, progesterone has not demonstrated a protective effect.

• Pregnancy and prognosis for multiple sclerosis

The prognosis for MS related to pregnancy can be divided into two issues: the effect pregnancy has on future disability and the effect of pregnancy on the risk for developing MS. Before 1950, women who had MS were discouraged strongly from having children. Gowers, in his 1893 edition of Diseases of the Nervous System, observed, “I have known it [Multiple Sclerosis] to begin during pregnancy, remain stationary until the next pregnancy and then become progressive” 27. Women were counseled regularly against having children and, in fact, therapeutic abortions frequently were recommended out of fear that pregnancy would worsen their clinical course. Tillman, in 1950, was the first to report that pregnancy did not affect the course of MS negatively 28. Many studies since then have supported his initial finding.

The effect of self-selection bias (ie, women who have higher frequencies of relapses and higher levels of disability are less likely to pursue pregnancy) has to be kept in mind when reviewing the literature on prognosis and pregnancy. Nonetheless, an extensive body of literature supports the view that pregnancy has an overall positive effect on the prognosis in MS.

• Effect of pregnancy on risk for developing multiple sclerosis

There is evidence to support that pregnancy actually may have a positive effect on the risk for developing MS. Runmarker and Anderson reviewed a cohort of 153 women who had MS 29. The risk for developing MS was compared between “non” pregnant times to the risk for onset during pregnancy. The risk for onset during pregnancy was reduced, whereas the risk for onset during the postpartum period was the same as the risk during other nonpregnant periods of time. This suggests a protective effect of pregnancy on the development of MS. It is estimated that 10% to 20% of women have their onset of MS during pregnancy. This finding helps to alleviate the concern that pregnancy either brings on MS or that pregnancy can trigger the onset of MS.

The risk of MS was compared between women who had been pregnant and women who never had been pregnant 29. Nulliparity was associated with a higher risk for developing MS. This association strengthened over time, with the risk for developing MS increasing over time in women who never had been pregnant.

• Effect of pregnancy on multiple sclerosis prognosis

Pregnancy seems to have a positive benefit on the development of disability in women who have been pregnant. A 5-year, prospective study compared the rate of progression in disability between childless women, women who had onset of MS after childbirth, and women who had onset before or during their pregnancy 30. Depite the study’s small cohorts and the expected increase in disability over the 5 years in all groups, distinct differences were found between the groups. The rates of disability increased over the 5 years most rapidly in the group who were childless. The average expanded disability status scale (EDSS) did not have a statistically significant change over 5 years in women who had their onset of MS at least 6 months after delivery, suggesting a possible positive effect of pregnancy on the rate of progression of disability. Women who had their onset of MS before or during pregnancy had rates of disability progression lower than the childless group but higher than in women who had onset after pregnancy.

The rate of relapses during pregnancy has been examined definitively in a prospective cohort of 254 women who had MS 31. The average rate of relapse in the year before pregnancy, the cohort’s baseline relapse rate, was 0.7 per woman, per year. The relapse rate declined precipitately over the 9 months of pregnancy, reaching a nadir of 0.2 per year in the third trimester. The positive effect of pregnancy on the relapse rate was tempered by the finding that the relapse rate rebounded to a peak of 1.2 in the first 3 months post partum before returning to the prepregnancy rate.

An imaging correlation to the decrease in clinical relapse rates was provided by a serial MRI study of two women who become pregnant during the study and who chose to continue to have frequent MRI scans performed 32. A dramatic decrease in new lesions was seen over the three trimesters with a rebound in the postpartum period. These MRI findings correlated closely with the changes in relapse rates observed clinically.

The effects of epidural analgesia and breastfeeding on postpartum relapse rates also have been examined. The risk for relapse after delivery was not affected by the use of an epidural during delivery and no difference was found in relapse rates between women who had epidurals and women who did not [31,33]. The effect of breastfeeding on relapse rates was positive. Women who breastfed their infants had significantly lower rates of relapse than women who did not.

Although relapse rates are important, evaluation of disability may be more pertinent in terms of prognosis related to pregnancy. In the Pregnancy Related Relapse in Multiple Sclerosis (PRIMS) study, there is an increase in the EDSS score by a mean of 0.7, which is consistent with natural history data for a comparable time period 31. This increase in disability did not seem to accelerate during the postpartum time. The use or nonuse of epidural analgesia or breastfeeding was not found to have an affect on progression of disability over the 33 months.

• Estrogen and multiple sclerosis

Estrogen and progesterone levels rise steadily during pregnancy, peaking in the third trimester. The precipitous drop in estrogens at delivery correlates with the timing of a rebound in relapse rates in the postpartum period. This correlation serves as supporting evidence for a possible vital role of estrogens in the changes in relapse rates throughout pregnancy.

The findings of disease modulation in EAE models, in concert with the observations of decreased disease activity in MS during pregnancy, has led to an interest in hormone manipulation as a treatment of MS. A pilot study using pregnancy doses of estriol in women who had MS attempted to recapitulate the benefit of pregnancy on relapse rates 34. Patients were followed clinically and radiologically for 6 months to establish a baseline level of disease activity. They then were treated with oral estriol for 6 months, with observation continuing for 6 months after the estriol was discontinued. Treatment was tolerated well, with the main side effect menstrual irregularities. A decrease in Th1 response and a decrease in the levels of the Thelper (Th1) cytokine IFN-? were found. Radiologically, there was a decrease in number and volume of gadolinium-enhancing lesions in relapsing remitting patients. An important observation was that although there was a gradual increase in new lesions observed, there was not a rebound in the number of gadolinium-enhancing lesions in the post-treatment phase. Patients later were rechallenged with estriol in combination with progesterone to protect from the development of endometrial hyperplasia. Once again, a reduction in new lesions was seen.

• Genetic counseling

The lifetime risk for developing MS is 0.1% in the general population. The risk for developing MS approaches 4% if one parent has MS. In the relatively unlikely event that both parents have MS, the risk is substantially higher, approaching 20%. Approximately 15% of patients who have MS have at least one other family member affected by MS 35. Genetics clearly has some role in the development of MS, but the role is seen less dramatically than in other disorders, such as diabetes or hypertension.

Effect of multiple sclerosis on the course of pregnancy

MS does not have a detrimental effect on pregnancy 36. The incidence of miscarriage, prematurity, or complications of pregnancy, such as eclampsia, is not increased in women who have MS. If teratogenic medications are avoided, the rates of infant morbidity and mortality and congenital malformations also are not increased. In addition, newborn infants of women who have MS have normal birth weights and head circumferences 37.

• Drug therapy during pregnancy

Types of medications related to MS used during pregnancy can be divided into disease-modifying therapies and symptomatic medications. The disease-modifying agents that are FDA approved for MS are IFN-ß1a, IFN-ß1b, glatiramer acetate, and mitoxantrone. Of these, IFN-ß1a and IFN-ß1b (Avonex, Betaseron, and Rebif) are classified as FDA category C [12,13,15]. In animal studies, an increased risk for miscarriage was seen. No consistent human teratogenic effects are reported. Glatiramer acetate (Copaxone) has a FDA rating of B: no known fetal risk found in animal studies, but there is inadequate human data 14. Mitoxantrone (Novantrone) carries a FDA classification of D: evidence of fetal risk, but benefits may outweigh risks 16. Table 1 summarizes the pregnancy risk categories of immunomodulators commonly used in the treatment of MS.

Table 1. Pregnancy risk categories of commonly used immunomodulators

In 2001, a case series of 11 women who remained either on IFN-ß or glatiramer acetate during pregnancy was reported. In the 11 women who were followed, no developmental abnormalities were seen in their infants 38. Coyle reviewed the pregnancies that occurred during the clinical trials and postmarketing surveys exposed to glatiramer acetate 39. The results of pregnancies with known outcomes were documented as healthy/normal in 96.3% of cases. Congenital anomalies were reported in 6 of 161 live births and consisted of single case reports of failure to thrive, finger abnormality, cardiomyopathy, urethrostenosis, adrenal cyst, and anencephaly. Spontaneous abortions were the most common adverse fetal outcome, but rates were consistent with historical rates in the general populations.

As the majority of pregnancies are unplanned, the two reports discussed previously may help with postconception counseling for expectations of the outcome of the pregnancy for women who conceive on these drugs. Despite the lack of data suggesting detrimental effects of exposure to the immunomodulating agents, it should be emphasized that the evidence is not strong enough to recommend their use during conception or pregnancy. Preconception counseling is paramount in the face of treatment with immunomodulating agents. It is recommended that women discontinue their disease-modifying therapy 1 to 3 months before attempting to conceive, during pregnancy, and while breastfeeding.

Symptomatic therapy encompasses acute treatment of relapses and chronic therapies. Although relapses during pregnancy tend to be mild, in the event of major relapses that are functionally impairing, corticosteroids can be used. Although they are not teratogenic, with prolonged use, neonatal adrenal suppression can occur.

The potential risks versus benefits of symptomatic management during pregnancy have to be evaluated carefully. Trials of nonpharmacologic therapy, if appropriate, should be considered. The concept of the least toxic drug at the lowest effect dose is a paradigm in evaluating treatment options. Table 2 has the FDA classification of commonly used symptomatic medications used to treat MS.

Table 2. Commonly used symptomatic medications 

Another important issue arises in the postpartum period. Although the decrease in relapse rate during pregnancy is comforting, the rebound in the relapse rate in the postpartum period is problematic, especially as the increased risk for relapse is occurring during a time that is particularly physically demanding. Three studies have looked at using intravenous immunoglobulin (IVIG) in the postpartum period as a response to the increased risk for relapses. The first is a pilot study that administered IVIG in the postpartum period to women who had had relapses after prior pregnancies 40. Nine patients with a history of childbirth related relapses were treated with IVIG in the postpartum period. None of the patients treated had relapses in the first 6 months after delivery. Nine patients with a history of child birth related relapses were treated with IVIG in the post partum period. None of the patients treated had relapses in the first 6 months after delivery. A second study treated 14 women with IVIG and had no reported relapses in the postpartum period 41. In 2000, Haas reported his experience using IVIG in the postpartum period in patients believed at high risk for exacerbations 42. The relapses rate in the patients treated with IVIG were 33% lower than the 1.2 relapse rate found previously in the postpartum period. Treatment with the IVIG was well tolerated.

• Preconception counseling

Keeping in mind that the majority of pregnancies are unplanned, preconception counseling should be initiated at diagnosis. The neurologist should play a central role in ensuring that the patient has the data to make informed decisions concerning family planning. In interviews of women who had MS and were pregnant, two main concerns arose: the unpredictability of MS and the effect that pregnancy might have on MS 43. Information now is available for counseling patients appropriately as they consider family planning.

Despite the notoriously unpredictable nature of MS, the 90% reduction in relapse rates by the third trimester is significant. Discussion of the rebound in relapse rates in the postpartum period should be tempered by the fact that only approximately one third of women who have MS and become pregnant have a relapse in the postpartum period. The risk for relapse in the postpartum period can be handled by developing plans for increased assistance during that vulnerable time and, possibly, with consideration of IVIG as a preventive measure.

SUMMARY

Overall, evidence suggests the effect of pregnancy is at least neutral and possibly positive on the course of MS. The lack of effect MS has on pregnancy outcomes also is significant. In the end, pregnancy is an individual decision. Physicians, and in particular neurologists, play a key role in providing tools to assist women who are living with MS make the most appropriate decision concerning family planning for themselves and their families.

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