Publisher Summary
Multiple sclerosis (MS) is the most common debilitating disease of the central nervous system (CNS) of young adults, with a prevalence of approximately 1 per 1000 in the Western world. This chapter reviews how pregnancy affects the disease activity; pregnancy outcome among MS mothers; treatment of MS mothers during pregnancy and lactation; and immunologic basis of pregnancy-induced disease remission. Pregnancy typically is a stabilizing period in the clinical course of MS. During the third trimester, relapse rate can be 70% lower than the time before pregnancy, but aggravation of the disease commonly is observed after delivery. Based on studies it is has been found that mothers with MS needed operative delivery more often than healthy mothers, which might be due to MS-related symptoms such as neuromuscular perineal weakness and spasticity, in addition to fatigue and exhaustion. In a recent retrospective study in Spain, 38.6% of MS mothers on interferon-beta therapy did not discontinue the treatment until the first trimester of pregnancy. Hence, a significant proportion of MS mothers may be exposed to disease-modifying therapies (DMTs) during pregnancy. Taken together, the information on pregnancy outcomes for babies exposed to DMTs is increasing, but the study samples are still small. Thus, the safety of these medications has not been established fully and discontinuation of DMTs before pregnancy must still be recommended.
Introduction
Multiple sclerosis (MS) is the most common debilitating disease of the central nervous system (CNS) of young adults, with a prevalence of approximately 1 per 1000 in the Western world. About 80% of people with MS are diagnosed between the ages of 20 and 45 and, in adults, the female-to-male ratio is about 2.5 to 1. Hence, the majority of individuals obtaining the diagnosis of MS are women of childbearing age . These women are naturally concerned as to how a pregnancy will affect their disease, how the disease might modify the outcome of the pregnancy and influence the developing child, and how the medication they are using might affect the child. Several studies have been performed to answer these questions and a consensus has been reached about how pregnancy affects MS activity; the relapse rate is typically reduced during late pregnancy but increases in the postpartum period . The reasons for the increased postpartum activity are not entirely clear, but factors such as the abrupt decrease in estrogen levels immediately following delivery and the loss of immunosuppressive state of pregnancy are likely of importance . There is a general view that MS does not affect the course or outcome of pregnancy, but all original studies addressing these questions are either retrospective and register-based , or conclusions have been drawn from very small cohorts . In this chapter, we will review the following: (1) how pregnancy affects the disease activity; (2) pregnancy outcome among MS mothers; (3) treatment of MS mothers during pregnancy and lactation; and (4) immunologic basis of pregnancy-induced disease remission.
How Pregnancy Affects the Disease Activity
Relapses
Pregnancy typically is a stabilizing period in the clinical course of MS. During the third trimester, relapse rate can be 70% lower than the time before pregnancy, but aggravation of the disease commonly is observed after delivery.
Several early retrospective studies suggested that pregnancy has a beneficial effect on the clinical course of MS , but this view was not shared by all investigators . Uncertainty about how to advise young women with MS on family planning was resolved after the publication of the PRISMS study . In the largest prospective study so far to evaluate the effect of pregnancy on the clinical activity of MS, Confavreux et al. followed 254 women with MS through 269 pregnancies. The study was conducted as a multicenter study in 12 European countries. The enrollment was performed between 4 and 36 gestational weeks, and follow-up was continued for 1 year after delivery. Data were collected on relapse frequency and disability. During the year before pregnancy, 164 relapses occurred among the 227 women who were followed for the entire observation period, resulting in an annual relapse rate of 0.7. During pregnancy the relapse frequency steadily declined and reached the minimum annual relapse rate of 0.2 during the third trimester of pregnancy (meaning that during the third trimester only 12 of 225 women [=5%] experienced a relapse). In the 3 months following delivery, the number of relapses increased dramatically to 68 of 222 women (=31%; annual mean relapse rate: 1.2, P < 0.001 versus relapse rate during the year preceding pregnancy). A high frequency of relapses during pregnancy and a high level of physical disability before pregnancy were identified as predictors of postpartum attacks . A similar pattern of lack of active inflammation during pregnancy and an increase in signs of inflammation during the postpartum phase has been observed in studies using serial magnetic resonance imaging (MRI) . In addition, Saraste et al. described a patient with a record number of 200 gadolinium-enhancing lesions in a brain MRI scan performed only 4 weeks after delivery.
MRI Activity During and After Pregnancy
MRI is widely used during pregnancy, either for fetal or maternal diagnostics. In most cases, because of theoretical concerns, MRIs are not performed during the first trimester. Rise in body temperature especially locally in the uterus and acoustic noise exposure have been mentioned as potential risks. In animals, gadolinium has not been shown to be teratogenic but safety data in humans concerning gadolinium administration during pregnancy are lacking. Hence, use of gadolinium should be avoided during pregnancy.
Paavilainen et al. reported the first MRI study of a larger MS cohort (28 patients), which addressed disease activity during pregnancy and the postpartum period. There was a significant increase in the number of T2-lesions ( P =0.0009) and diffusion-weighted imaging (DWI)-positive lesions ( P =0.0098) as well as, in the total lesion load measured on FLAIR-images ( P =0.0126) in scans performed after delivery when compared to the scans performed during pregnancy; however, no changes were observed in the number of T1-lesions ( P =0.375). Fourteen of the patients (50%) showed T2-activity (i.e., the scans contained one or more new or enlarging lesions) in at least one of their postpartum scans (mean 3.7 active lesions, range 1–14). The majority of the active postpartum scans (9 of 14) were performed within 5 weeks of delivery. This indicates that MS activation commonly takes place at a very early stage after the delivery. Furthermore, active lesions also were observed in two scans performed at 35–37 gestational weeks, which suggests that alterations might already take place in patients’ immune systems during very late phases of pregnancy, indicating the preparation for the delivery of the fetus. In conclusion, during the 6-month postpartum period, 21 of 28 (75%) patients demonstrated MS disease activity either by a clinical MS relapse or T2-activity in the MRI scans .
Interestingly, blood estriol concentration begins to decline after 35 gestational weeks, reflecting the dysfunction of the aging placenta. Consequently, the loss of high estriol concentrations might lead to an increase in the disease activity in certain patients.
Pregnancy Outcome Among MS Mothers
Two large, retrospective register-based studies and a few prospective studies with smaller sample size have addressed the question of pregnancy outcome among MS patients . Presently, there is no concrete evidence that MS patients are more susceptible to pregnancy or delivery complications, such as ectopic pregnancy, preeclampsia, gestational diabetes mellitus, prolonged labor, or miscarriage than healthy women are, nor are their infants more likely to be delivered preterm, be of low birth weight, have malformations, or experience an early death. Fertility problems or congenital abnormalities also are uncommon in women with MS. However, in a register-based study on MS births between 1967 and 2002, the singleton children born to MS mothers had on average 123 g lower birth weight when compared to infants of healthy control mothers; a difference stated as statistically significant . Based on the same report, mothers with MS needed operative delivery more often than healthy mothers, which might be due to MS-related symptoms such as neuromuscular perineal weakness and spasticity, in addition to fatigue and exhaustion.
Delivery of MS Mothers
The possibility for a need of an operational delivery should be taken into account when planning a delivery of an MS mother but overall, the decision of an elective cesarean section should be made based on current obstetrical criteria. The mothers’ functional status should always be taken into account: a mother with significant functional disability will more likely encounter problems associated with fatigue and exhaustion during the second stage of delivery.
Anesthesia During Delivery
Epidural anesthesia during delivery was not associated with increased risk of postpartum flares or disability in women with MS in the PRISMS study . On the other hand, concerns have been raised about spinal anesthesia. It has been suggested that spinal anesthesia may be the explanation for postoperative relapses. The hypothetical ground for the concerns is that the local anesthetic might have a direct toxic effect on the demyelinated axons , but there are no real clinical data to support this view.
Treatment of MS Mothers During Pregnancy and Lactation
In a recent retrospective study in Spain, 38.6% of MS mothers on interferon-beta therapy did not discontinue the treatment until the first trimester of pregnancy . Hence, a significant proportion of MS mothers may be exposed to disease-modifying therapies (DMTs) during pregnancy. Interferon-beta has been associated with an increased risk of spontaneous abortion and lower birth weight of the newborn in one small prospective study , but other investigators have considered the drug safe in terms of pregnancy outcome . Taken together, the information on pregnancy outcomes for babies exposed to DMTs is increasing, but the study samples are still small. Thus, the safety of these medications has not been established fully and discontinuation of DMTs before pregnancy must still be recommended. Even though these drugs do not appear to cause any major fetal malformations, it is uncertain how they might affect the developing immune system of the fetus. In addition, the natural course of MS during pregnancy, that is, the pregnancy-associated low annual relapse rate, makes the necessity of DMTs questionable during pregnancy. Despite discontinuation of the DMTs before pregnancy, the mothers rarely experience disabling relapses during the course of pregnancy. It is still advisable for the patients to discontinue DMTs 1 month before the discontinuation of contraception, in order to allow mothers’ immune systems to recover from the effects of DMT before conception. If a mother would experience a disabling relapse during pregnancy, she could be treated safely with a course of Intravenous immunoglobulin (IVIG), or after the third trimester with high-dose methylprednisolone.
Breast-Feeding
The prevalence of breast-feeding was very high (90%) in a cohort of German MS mothers and in a cohort of Finnish MS mothers . This is in stark contrast to a South European MS population, where only 28.6% of mothers chose to nurse . Breast-feeding is considered beneficial for the mother–infant relationship, and it reduces the incidence of infections and allergies experienced by the infant . Moreover, both in the PRISMS study and a more recent small study performed in California , the MS patients who breast-fed their children had a lower relapse rate than women who did not breast-feed . This probably does not reflect a positive effect of breast-feeding on MS activity; it rather implies that the mothers with active disease chose DMTs instead of breast-feeding .
The postpartum period is a more challenging time regarding controlling the disease activity, especially in areas of high breast-feeding prevalence. Mothers with MS want to reduce the probability of experiencing postpartum relapses in order to best manage their child, but treatment with DMTs is not recommended during nursing. One therapeutic option is IVIG, which is safe to use during breast-feeding, and which has been suggested to reduce disease activity in MS , although in a later study no beneficial effects could be demonstrated . A retrospective study, however, suggested that IVIG may be efficient in preventing postpartum relapses . Recently, a large (173 patients) multicenter, randomized, double-blind clinical trial compared two different doses of IVIG treatment during the postpartum period, but no difference was observed between the two dosing regimens . A randomized, placebo-controlled study on the effect of IVIG in preventing postpartum relapses is, unfortunately, still lacking. The European Federation of Neurological Societies (EFNS) task force guidelines recommend that IVIG could be used in pregnancy in Relapsing Remitting MS (RRMS), but gives no opinion about using the drug during lactation . Taken together, prophylactic treatment with IVIG could be recommended in selected cases, such as for those mothers with a high pre-pregnancy disability and/or high relapse rate before and/or during pregnancy. In such cases, IVIG infusions could be recommended already in the maternity ward, for example, at a dose of 0.4 g/kg for 3 consecutive days to prevent relapses, and if the mother wishes to breast-feed, the IVIG infusions could be continued during the nursing period on monthly basis, for example, with 0.4 g/kg on a single day once a month.
Safety of MS Medication During Pregnancy and Lactation According to the FDA Risk Classification Scheme
The American Food and Drug Administration’s (FDA) pregnancy risk classification scheme gives information on the risk of whether a given medication could cause fetal loss, a major malformation, low birth weight, or infant death. This classification is based mostly on animal data or short-term human studies, and conclusions are drawn rather from lack of safety data in humans rather than from evidence of safety in human trials ( Table 1.1 ). The FDA safety scheme for drug treatment during pregnancy and lactation are shown in Tables 1.2 and 1.3 .
| Category | Interpretation |
|---|---|
| A | Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy |
| B | Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women |
| OR | |
| Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester | |
| C | Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women |
| OR | |
| No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women | |
| D | Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus |
| However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective | |
| X | Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risksThe use of the product is contraindicated in women who are or may become pregnant |
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