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During pregnancy, many women experience remission of autoimmune diseases like multiple sclerosis and uveitis and scientists have described a biological mechanism they say is responsible for changes in the immune system that helps explain that remission.

The expression of an enzyme known as pyruvate kinase is reduced in immune cells in pregnant women compared to non-pregnant women, says biophysicist Howard R. Petty from the University of Michigan Kellogg Eye Center, and Roberto Romero, M.D., of the National Institutes for Health.

Their study coming in the August issue of the American Journal of Reproductive Immunology also reports that expression of the enzyme is lower in pregnant women compared to those with pre-eclampsia, a condition with inflammatory components.

They say the study is significant because the newly discovered mechanism points to a pathway that could be targeted for treatment. "It may be possible to design drugs that mildly suppress pyruvate kinase activity as a means of replicating the immune status of normal pregnancy," says Petty. In addition to pre-eclampsia, he believes that rheumatoid arthritis, type 1 diabetes, and uveitis may eventually yield to similarly designed drugs.

In his search to explain the phenomenon, Petty says they knew to look for a metabolic pathway or mechanism with two characteristics; it had to reduce the intensity of the normal immune response, needed so that pregnant women do not reject their babies, which has proteins from the father that are "foreign" to the mother and it also must support cell growth needed by the developing fetus.

The activity of the enzyme pyruvate kinase and and its product, pyruvate, fills both roles -  promoting cell growth while modifying the immune response. Because pyruvate kinase activity is depressed during pregnancy, cell metabolism supports an increased production of lipids, carbohydrates, amino acids, and other substances that support cell growth.

Petty explains that our normal robust immune response depends upon pyruvate to promote calcium signaling, which, in turn, stimulates the production of messenger molecules called cytokines. When pyruvate is decreased during pregnancy, calcium signaling is also reduced, and the immune response is different than that in non-pregnant individuals.  "Modification of signaling along this pathway allows the pregnant woman to maintain an immune response, but at a level that will not harm the fetus."

The study included 21 women in their third trimester of a normal pregnancy, 25 women with pre-eclampsia, and a control group of non-pregnant women. Petty and colleagues used a variety of methods to confirm their findings, including fluorescence microscopy and flow cytometry, which are used to study cell signaling.

The higher levels of the enzyme seen in women with pre-eclampsia bolster the study's findings, says Petty.

"Pre-eclampsia has features of inflammatory disease. If you don't reduce these pyruvate levels, you heighten inflammatory disease," he adds. Petty says one day enzyme levels could be tested early in pregnancy to predict the likelihood of developing pre-eclampsia or other complications.

It is possible, says Petty, that the general mechanisms described in the current study may apply to more than one complication of pregnancy. This possibility—and that of designing drugs to suppress pyruvate kinase activity—is the focus of future research. "I have a long list of things I'd like to see developed for the clinic in the next five years," adds Petty.

Source: Scientific Blogging © 2010 ION Publications LLC (18/06/10)

A single dose of methylprednisolone given to new mothers with multiple sclerosis immediately after delivery reduced the risk of relapse for up to three months, researchers found.

During the first postpartum trimester, relapses occurred in 18% of new mothers who received 1 g of intravenous methylprednisolone compared with 46% of those not receiving treatment (P=0.0448), according to data presented here at the meeting of the Joint Consortium of Multiple Sclerosis Centers and America's Committee on Treatment and Research in Multiple Sclerosis.

In the following six months, there was no difference in the relapse rates between the two groups, Jose Avila, MD, of the Maxine Mesinger MS Comprehensive Clinic at Baylor College of Medicine in Houston, reported.

Preliminary work from other centers has suggested that IV methylprednisolone might be effective in reducing the relapse rate after birth. Avila's group had been using this treatment in many new mothers at their clinic and so performed a retrospective analysis of their outcomes to further understand its potential.

The researchers examined 50 patients with relapsing-remitting MS and two with primary progressive disease. Of those, 39 had received steroid treatment immediately after giving birth, and 13 had not. The mean ages of the women were the same in each group, as was the mean disability score. Both groups had similar relapse rates in the year before pregnancy, and each group contained one patient with the primary progressive form of the disease.

The results of the trial suggest that IV methylprednisolone immediately postpartum may be an important treatment option for women with MS, Avila said, although larger and prospective trials are needed first.

He also indicated that a second dose of methylprednisolone may be worth investigating, to determine if it can reduce relapse rate later into the postpartum period.

Prior research has demonstrated that relapse rates rise immediately following delivery. An alternative treatment, intravenous immunoglobulin, is significantly more expensive and more complex to administer than IV methylprednisolone.

"It was not actually expected that there would be such a difference between the two groups, but it is compelling to think that it could be somewhat preventative," said Kathleen Costello, MS, MSCN, of the Johns Hopkins Multiple Sclerosis Center. "Although data support that long-term outcomes are equal whether you have a relapse in the postpartum period or not, a relapse is the last thing a new mother is going to need in the first 12 weeks after delivery. So if this is a safe method of reducing that risk, I think it is a good idea. We'll need more data and replication, but I think it is very compelling."

Limitations of the study include its small sample size and retrospective nature, so caution should be exercised when considering the likely efficacy of this approach in other patients.

Source: International Journal of MS Care
Source reference:
Avila J, et al "The role of post-partum intravenous corticosteroids in the prevention of relapses in multiple sclerosis" International J MS Care 2010; 12(suppl1): 45.

Medpage Today © 2004-2010 MedPage Today, LLC (07/06/10)

Multiple Sclerosis (MS) is primarily a disease of women in their childbearing years.

Pregnancy and puerperium have opposite effects on the course of the disease.

Nevertheless, no studies have been carried out yet on the level of information among female MS-patients regarding the interaction between MS and pregnancy.

Findings: Demographic data, clinical features of MS, course of MS during pregnancy and puerperium as well as knowledge concerning MS and pregnancy were evaluated by means of a questionnaire in 154 female MS-patients. The level of information was significantly higher (p<0.001) in women who had been pregnant in the past with the diagnosis MS known at this point of time.

Furthermore patients reported about a lower frequency of relapses during pregnancy and a higher frequency of relapses in the first six months after giving birth.

Conclusions: The findings illustrate a lack of knowledge in female MS-patients concerning the interactions of MS and pregnancy. In order to make their own independent decision based on scientific facts known to date, female MS-patients need to be better informed on issues regarding MS and pregnancy.

Author: Peter AlbrechtDorothea Fischer Andreas Moser
Credits BMC Research Notes 2010, 3:91

Source: 7th Space Interactive (06/04/10)

Pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood.

We conducted a genome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls) followed during their pregnancy. Samples were obtained before, during (i.e. at the third, sixth, and ninth month of gestation) and after pregnancy. A validation of the expression profiles has been conducted by using the same samples and an independent group of 25 MS patients and 11 healthy controls. Finally, considering the total group of 32 MS patients, we compared expression profiles of patients relapsing during pregnancy (n = 6) with those of relapse-free patients (n = 26).

Results showed an altered expression of 347 transcripts in non-pregnant MS patients with respect to non-pregnant healthy controls. Complementary changes in expression, occurring during pregnancy, reverted the previous imbalance particularly for seven inflammation-related transcripts, i.e. SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Longitudinal analysis showed that the overall deregulation of gene expression reverted to “normal” already within the third month of gestation, while in the post-partum gene expressions rebounded to pre-pregnancy levels. Six (18.7%) of the 32 MS patients had a relapse during pregnancy, mostly in the first trimester. The latter showed delayed expression profiles when compared to relapse-free patients: in these patients expression imbalance was reverted later in the pregnancy, i.e. at sixth month.

Specific changes in expression during pregnancy were associated with a decrease in disease activity assessed by occurrence of relapses during pregnancy. Findings might help in understanding the pathogenesis of MS and may provide basis for the development of novel therapeutic strategies.

Francesca Gilli¹*, Raija L. P. Lindberg², Paola Valentino¹, Fabiana Marnetto¹, Simona Malucchi¹, Arianna Sala¹, Marco Capobianco¹, Alessia di Sapio¹, Francesca Sperli¹, Ludwig Kappos², Raffaele A. Calogero³, Antonio Bertolotto¹

¹ Regional Centre for Multiple Sclerosis (CReSM) and Clinical Neurobiology, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy, ² Departments of Biomedicine and Neurology, University Hospital Basel, Basel, Switzerland, ³ Genomics and Bioinformatics Unit, Department of Clinical and Biological Sciences, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy

Full Paper - http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008962

Source: PLoS ONE © 2010 Gilli et al. (02/02/10)

It is well known that in women with MS, the relapse rate decreases during pregnancy and can increase after delivery. The authors of this study propose that this increase of the relapse rate after pregnancy may be related to an immunological process (reflected by the decline in a specific type of immune cell) which starts during late pregnancy. They also suggest that this process can be interrupted by lactational amenorrhea (physiological suppression of menstruation while nursing) induced by exclusive breastfeeding.

OBJECTIVE: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period.

DESIGN: Case-control study.

SETTING: Kaiser Permanente Northern California and Stanford University.

PARTICIPANTS: Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum.

MAIN OUTCOME MEASURES: Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors.

RESULTS: Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses.

CONCLUSIONS: Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.

Langer-Gould A, Gupta R, Huang S, Hagan A, Atkuri K, Leimpeter AD, Albers KB, Greenwood E, Van Den Eeden SK, Steinman L, Nelson LM.

Department of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA 94305, USA.

Source: Pubmed PMID: 20065129 (20/01/10)

Giving birth seems to slow the progression of multiple sclerosis (MS), Belgian and Dutch researchers say.

The researchers tracked 330 women with MS for 18 years and found that among those who had children, severe disability took longer to develop.

Writing in the Journal of Neurology, Neurosurgery and Psychiatry, they say previous studies have suggested a worsening of MS just after birth.

But the MS Society said the study was flawed and further research was needed.

MS is a long-term inflammatory condition of the central nervous system.

It affects the transfer of messages from the nervous system to the rest of the body.

Women are twice as likely to develop MS as men and many of the new cases will be among women of childbearing age.

The researchers from Belgium and the Netherlands said all the women had been referred to one specialist centre and had had their first symptoms from the ages of 22 to almost 38.

Nearly a quarter of the women (24%) were childless; 170 had given birth before their symptoms developed (52%); 61 had their children after their symptoms developed (18%); and 19 had had children both before and afterwards (6%).

'Speed of progression'

The researchers used the Kurtzke Expanded Disability Status Scale (EDSS) which runs from one to 10, where 10 is death from MS and six is when an individual needs a cane, a crutch or a brace to walk 100m.

After an average of 18 years living with MS, over half the women (55%) were categorised as EDSS six.

They found that both the likelihood and speed of progression were affected by childbirth.

Women who had given birth to one or more children at any point before or after the start of MS symptoms were 34% less likely to progress to EDSS six than childless women.

Women whose children had been born after their MS began were 39% less likely to progress to EDSS six than women who had not had children.

They said this held true even after taking account of the age at which symptoms began.

Women who had no children after their MS symptoms started progressed to EDSS six within 13 to 15 years on average.

But women who did have children took an average of 22 to 23 years to reach this stage.

'Beneficial effect'

Dr Maria D'hooghe, from the National MS Centre in Melsbroek, Belgium, which co-ordinated the study, said it had shown for the first time the long-term effects of having a baby if you have MS.

She said: "It's possible that the hormones released in pregnancy are having a beneficial effect on the immune system.

"Certainly, animal studies show that pregnancy can lead to less damage in their brains.

"The other possibility is that it is lifestyle changes caused by having a baby that are delaying the effects of MS perhaps through increased activity or changes in the way we deal with stress."

But Dr Susan Kohlhaas, research communications officer for the MS Society, said it was a small study and they had not taken account of the fact that women with more severe MS may choose not to get pregnant because they are worried about a relapse or about taking care of a baby during a relapse.

She said: "It is difficult to form any meaningful conclusions from this research given the small size of the study and its flaws, but further studies will hopefully clarify the effects of pregnancy in women with MS."

Source: BBC News © British Broadcasting Corporation 2009 (24/11/09)

New research suggests that having multiple sclerosis puts pregnant women at slightly higher risk for giving birth via cesarean deliveries or having babies that grow at a slower rate in the womb.

But the researchers, whose findings were published online Nov. 18 in Neurology, also reported that pregnant women with MS were not more likely than other women to develop such conditions as preeclampsia or premature rupture of membranes.

The findings came from an examination of a national database that included details on about 18.8 million childbirths in 38 states, including deliveries by an estimated 10,000 women with MS.

The two groups of pregnant women differed somewhat. Those with MS were more likely than those without chronic medical conditions to have fetuses that suffered from restricted growth, as defined by weight measured through ultrasound. Among women with MS, 2.7 percent had fetuses in that category, compared with 1.9 percent of other women.

Women with MS were also more likely to have a cesarean delivery: 42 percent had a c-section, compared with 33 percent of other women.

However, the study found that women with MS had lower pregnancy complication rates than did women who had diabetes before becoming pregnant.

"These results are reassuring for women with MS," study author Dr. Eliza Chakravarty. of Stanford University School of Medicine. said in a news release from the American Academy of Neurology.

"Women and their doctors have been uncertain about the effect of MS on pregnancy, and some women have chosen to delay or even avoid pregnancy due to the uncertainty," Chakravarty said. "We found that women with MS did not have an increased risk of most pregnancy complications."

Source: My Optimum Health.com © 2009 OptumHealth, Inc. (19/11/09)

PURPOSE: Pregnancy management poses an extra challenge to physicians and their multiple sclerosis (MS) patients. There are few papers reporting databases on the subject.

METHOD: Brazilian database from nine MS clinical and research units, with complete data on 47 pregnant women (49 pregnancies).

RESULTS: Despite relatively high exposure to MS medications, no birth defects were reported. Low birth weight and prematurity were similar to those for developing countries. Three complications may have been associated with these medications, while three others were considered to be of purely obstetric nature.

CONCLUSION: Our results confirm previous findings on lower relapse rate during pregnancy and add to the present literature informing on data related to drug exposure.

Fragoso YD, Finkelsztejn A, Comini-Frota ER, da Gama PD, Grzesiuk AK, Khouri JM, Alves-Leon SV, Morales Rde R, Lana-Peixoto MA, Rocha CF.
Universidade Metropolitana de Santos, Santos, SP, Brazil.

Source: Pubmed PMID: 19722044 (09/09/09)

New mothers with multiple sclerosis who want to breast-feed but worry it might cause their disease to relapse may be reassured by a new study that discovered this is not the case for most women.

The study, in the June 8 issue of Archives of Neurology, found that almost two out of three women with multiple sclerosis (MS) who breast-fed exclusively for two months or more and who were not taking MS medications did not experience a relapse of their disease while they were breast-feeding.

"The most important thing for patients and physicians to know is that there's no evidence that breast-feeding is harmful for women with MS," said study author Dr. Annette Langer-Gould, who was at Stanford University at the time of the study but is now a neurologist and research scientist with Kaiser Permanente Southern California in Pasadena.

"If mothers decide to breast-feed and do what's best for baby, we couldn't see any evidence of risk, and it may even be better for mothers to breast-feed," she said.

How breast-feeding might help suppress a relapse, despite a lack of medications, isn't clear. In people with MS, the body's immune system mistakenly attacks myelin, a substance that covers nerve fibers.

Langer-Gould said that researchers have long known that women with MS often go into remission during pregnancy, which might indicate that hormones play some role in dampening the immune response that causes damage to the myelin. However, she said. the study's finding of continued MS remission during breast-feeding would suggest that pregnancy hormones, which decrease dramatically once the baby is delivered, cannot be the only reason for the suppression of MS.

"Previous research has ignored the postpartum factor, and what our study suggests -- if these findings can be repeated -- is that it's probably a factor that's common to pregnancy and lactation," Langer-Gould said.

Prolactin, a hormone that stimulates the production of breast milk and suppresses ovulation could be such a factor, suggested Patricia A. O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society.

"There's been some interest in prolactin, which has been shown to stimulate repair and myelination, but we don't know the complete story yet," O'Looney said.

Whatever the reason behind it, Langer-Gould and her colleagues found that women who breast-fed exclusively for at least two months were five times less likely to have a relapse than those who didn't breast-feed at all.

The study included 32 pregnant women with MS and 29 age-matched women who were pregnant and healthy. Overall, women who chose to breast-feed exclusively began menstruating again at a later time than did women who did not breast-feed. In women with MS, the researchers found that a lack of menstruation due to breast-feeding was associated with a reduced risk of postpartum relapse.

Of the women with MS, 52 percent chose not to breast-feed, and 87 percent of them experienced a disease relapse within two months. Just 36 percent of women who were breast-feeding had an MS relapse within two months, the study found.

Langer-Gould said that even after adjusting the data to account for the possibility that women who were sicker before pregnancy would be less likely to breast-feed, the incidence of reduced relapse remained.

"The findings were still robust," she said.

O'Looney, who described the findings as "an interesting study that needs further confirmation," recommended that women with MS who are thinking about breast-feeding consult their doctors.

"Every case is different, and one should make the decision based on many things," she said. "Some women may have weakness in their arms and be physically unable to breast-feed. Women have to weigh all of their options, such as how active their disease was before pregnancy. And, even though this study was encouraging, the possibility of relapse wasn't eliminated. We never want to send the message that a woman who chooses not to or cannot breast-feed should feel guilty in any way."

SOURCES: Annette Langer-Gould, M.D., Ph.D., neurologist and research scientist, Kaiser Permanente Southern California, Pasadena, Calif.; Patricia A. O'Looney, Ph.D., vice president, biomedical research, National Multiple Sclerosis Society, New York City; June 8, 2009, Archives of Neurology

Copyright©2009 ScoutNews,LLC.(09/06/09)

A study released today says that breastfeeding may reduce multiple sclerosis(MS) relapses.   Sorry guys, this only helps women MS sufferers and only after pregnancy.

For the study, researchers followed 32 pregnant women with MS and 29 pregnant women without MS during each trimester and up to a year after they gave birth. The women were interviewed about their breastfeeding and menstrual period history.

A total of 52 percent of the women with MS did not breastfeed or began supplemental formula feedings within two months of giving birth. Of those, 87 percent had a relapse after pregnancy compared to 36 percent of women with MS who breastfed exclusively for at least two months after pregnancy.

Sixty percent of the women reported their main reason for not breastfeeding exclusively was to start taking MS treatments again. Women who began taking MS treatments within the first two months after giving birth had significantly higher risk of suffering a relapse than women with MS who did not start taking medications early, regardless of whether they breastfed. Those who breastfed exclusively got their menstrual periods back later than the women who did not breastfeed or began early supplemental feedings.

"Our findings call into question the benefit of choosing not to breastfeed or stopping breastfeeding early in order to start taking MS therapies," said study author Annette Langer-Gould, MD, PhD, of Stanford University in California, and a member of the American Academy of Neurology. "Larger studies need to be done on whether women should delay taking MS medications in order to breastfeed."

The study was supported by the National Institutes of Health and the Wadsworth Foundation.

Results will also be presented at the American Academy of Neurology's 61st Annual Meeting in Seattle, April 25 to May 2, 2009.

Source: Scientificblogging © 2009 ION Publications LLC (20/02/09)

The objective was to determine if there is an increased risk to develop exacerbations in patients with multiple sclerosis (MS) after assisted reproduction technique (ART).

An increase in annual relapse rate (ARR) was described after ART in a small cohort of patients.

We investigated the associations between ART and relapse rate (RR) in 23 MS patients who underwent 78 hormonal stimulations in total. There was a statistically significant increase in the RR following ART independent of the hormonal approach or the time interval between the stimulations.

These results suggest that female MS patients who wish to have children should be informed that the RR may be increasing if ART is necessary.

Hellwig K, Schimrigk S, Beste C, Muller T, Gold R.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Source: Pubmed PMID: 19039223 (02/12/08)

At any one time, there are around 20 000 women of childbearing age with multiple sclerosis (MS) in the UK who may be considering having children. Neurologists can be asked for information from both patients and obstetric colleagues on a range of topics related to pregnancy and MS that extend beyond the well-known implications for relapse risk. This article aims to provide a brief overview for the general neurologist of the most commonly encountered issues and questions including those occasionally related to pregnancy management. The take-home message is that pregnancy does not hold adverse risks for the majority of patients with MS, or vice versa.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with onset typically in the second to third decade and is twice as prevalent in females as males. In the past, there has been speculation that pregnancy, together with other stressful life events, adversely affects the risk of relapse¹ or the course of the disease.² In fact, pregnancy appears to be associated with a temporary beneficial immune state for patients with MS partly mediated through an effect on T lymphocyte subsets. This effect may have relevance for autoimmune diseases in general.

The pathogenesis of MS remains incompletely understood but involves a maladaptive humoral and cell-mediated immune response to an as-yet undetermined antigen(s). The popular model begins with peripheral T cell sensitisation in response to macrophage presentation of a foreign "myelin mimicking" antigen in association with MHC class II.³ This results in peripherally activated T cells expressing, and recognising, vascular adhesion molecules facilitating their entry to the central nervous system (CNS). Inside the CNS, activated T cells release pro-inflammatory cytokines resulting in upregulation of local CNS microglia to antigen-presenting cells with the capacity to present self-myelin and other myelin-associated proteins. This leads to an "epitope spreading" phenomenon and further secondary activation of T cells triggering an autoimmune inflammatory cascade. A direct and bystander inflammatory response results in CNS conduction block, demyelination and axonal damage that variably contribute to reversible and persistent neuronal dysfunction with associated neurological disability. Other models of disease pathogenesis exist such as persistence of a foreign viral antigen as the perpetuating stimulus,⁴ but most models place T cells centre stage.

T cells can be subdivided into cytotoxic and helper T cells. The latter are associated with the MHC class II linked immune response underlying MS and subdivide into type-1 (Th-1) and type-2 (Th-2) helper cells. Th-1 cells release pro-inflammatory cytokines including IL2, INF- and TNF-, while Th-2 cells are broadly antagonistic, secreting IL-6 and IL-10 which suppress the Th-1 response and drive B cell maturation and antibody production.⁵ MS is believed primarily to be a Th-1 driven immune state with Th-1 associated pro-inflammatory cytokines promoting blood–brain barrier breakdown, further immune cell recruitment, myelin and axonal injury. The balance between Th-1 and Th-2 associated immune states therefore influences disease activity and itself appears hormonally sensitive with pregnancy favouring a Th-2 type response.

Pregnancy, by necessity, involves a relative state of immunosuppression as the fetus carries paternally derived antigens, and it is likely that high levels of oestrogen associated with pregnancy contribute to this. Oestrogen is known to be associated with a Th-2 type immune response and downregulation of microglial activity, and has been shown to suppress extrinsic allergic encephalomyeltis (EAE), an animal model of MS.⁶ There has been particular interest in the immunosuppressive role of oestriol, an oestrogen produced by the fetal–placental unit and detected only during pregnancy. Oestriol levels appear to mirror most closely the reduction in relapse frequency seen during the third trimester of pregnancy, and there has already been a pilot study of estriol as a therapeutic agent in non-pregnant patients with MS that reported an 80% reduction in MRI disease activity over 6 months.⁷ A follow-on phase II/III clinical trial is currently under way of oestriol as add-on therapy to Copaxone in female MS patients.

Unfortunately, the immunosuppressive oestrogen profile found in pregnancy does not appear to translate into a similar protective benefit in women with lower oestrogen levels seen outside pregnancy. Oestrogen levels in non-pregnant females appear associated with microglial upregulation and a less favourable Th-1 type immune response.⁸

There are a large number of other factors potentially linked with an immunosuppressive Th-2 associated immune response during pregnancy,^{9 10} an effect likely to be as beneficial to patients with other autoimmune diseases¹¹ as it is to patients with MS.¹² Of these factors, it is perhaps worth singling out the hormonal form of vitamin D, calcitriol. Calcitriol levels peak in the first trimester and fall rapidly postpartum, inversely reflecting MS disease activity. Outside pregnancy, low levels of vitamin D associated with reduced sun exposure with increasing latitude have been linked with MS susceptibility.¹³ The perceived immunosuppressive benefit of vitamin D has led to small pilot studies of vitamin D supplementation in patients with MS,¹⁴ though no firm conclusions regarding efficacy can yet be made.

In summary, hormonal and cytokine changes during pregnancy appear linked with a Th-2 type immune state likely to be beneficial for patients with autoimmune inflammatory conditions such as MS. Further knowledge of the nature of this effect may provide insight into additional treatment strategies for patients with MS.

PREGNANCY AND RELAPSES

During the first half of the twentieth century, it was generally held that pregnancy adversely affected the risk of relapse and course of the disease in patients with MS,² and therapeutic abortion was occasionally advocated. Several retrospective studies^{15 16} and more latterly results of the Pregnancy in Multiple Sclerosis (PRIMS) study¹⁰ have dispelled this myth, showing that pregnancy is probably neutral overall in terms of disease activity. The prospective PRIMS study of 227 European women with MS who had a full-term delivery reported a reduction in relapse rate during pregnancy, most marked in the third trimester, with a compensatory increase in the first postpartum trimester before returning to prepregnancy levels. An approximate 70% reduction in relapse rate was seen in the third trimester (double that of currently licensed standard disease modifying therapies (DMTs)). There was a similar increase above background prepregnancy rates for the first trimester postpartum. Overall, therefore, in the year which includes pregnancy and the 3 months after birth, the total number of relapses is similar to other years.

The clinical reduction in relapse activity during pregnancy is accompanied by evidence of a reduction in MRI activity. There was a marked reduction in new or enhancing disease activity on serial brain MRI scanning in two patients with MS who became pregnant while already enrolled on an MRI study. MRI lesion activity returned to prepregnancy levels postpartum.¹⁷

While the reduction in relapse rate during pregnancy is welcome, the risk of relapse postpartum raises questions about preventive therapy options. It is not possible to identify particular individuals at high risk for purposes of targeted therapy trials, but there have been a few small retrospective case series reports of both intravenous methylprednisolone¹⁸ and intravenous immunoglobulin¹⁹ given in the postpartum period to patients with MS. These studies suggest a reduction in relapse frequency (of 30–60%) but do not provide an evidence base on which to recommend treatment in the absence of any controlled trial data. Current practice is to consider treatment of postpartum relapse in the usual way with a short course of methylprednisolone. This is generally felt not to have significant implications for breast feeding. Intravenous immunoglobulin is generally avoided due to the potential for neonatal exposure to pooled blood product with intravenous immunoglobulin.

PREGNANCY AND MS ONSET

Disease progression was not affected by pregnancy in the PRIMS study, although the majority of patients had relapsing remitting disease, and follow-up was relatively short. Most other studies have not found any adverse effect of pregnancy on disease progression,²¹ and some reports suggest a favourable effect with increased time to progressive disease onset following pregnancy.²⁰ However, despite age and disability matching, it is difficult to remove conceptive behaviour bias from these studies. It does seem reasonable to conclude that there is at least no adverse effect of pregnancy on subsequent disease course.

MS AND PREGNANCY MANAGEMENT

Contraception
There is no evidence that oestrogen at doses contained in the combined contraceptive pill has an adverse effect on MS.²² A single study did suggest a slightly lower rate of MS onset in women taking the pill, although this difference was not statistically significant.²³ Oestrogen-containing oral contraceptives have been shown to suppress EAE in rats.²⁴ Caution is advised only in patients at increased risk of deep venous thrombosis due to immobility.

Conception
MS appears to have no physiological effect on fertility,²⁵ although sexual dysfunction may impact conception. Studies have highlighted the high prevalence of symptoms of sexual dysfunction in both male (around 65%) and female (around 40%) patients with MS compared with around 10% of case controls.²⁶ These symptoms are highly under-reported during routine care.²⁷

Inheritance
Susceptibility to multiple sclerosis is predicated upon a complex interaction between many individual genes and the external environment. The risk to offspring is small but can cause concern. Counselling for families with multiple sclerosis has been extensively reviewed elsewhere.^{28 29} Overall, parents can be reassured that the age-adjusted lifetime risk of an offspring developing multiple sclerosis is only around 4% if one parent has MS (the same rate as the frequency of birth defects in the population), although this is significantly greater than the background population risk of 0.2%. The rate can, however, be as high as 30% if both parents are affected.

Pregnancy outcome
Using the Norwegian Medical Birth Registry between 1967 and 2002, the outcomes of 649 births to women with MS were compared with births (2 million) in the remaining population. Higher rates of operative deliveries were seen in the MS group (OR 1.54); these included an increase in elective caesarean section together with an increase in unplanned instrumental deliveries. Slow progress in the second stage of labour was seen twice as frequently in MS patients, and there were increased rates of labour induction. The proportion of neonates small for gestational age was also increased (OR 1.45). However, there was no difference in Apgar scores, birth defects or perinatal mortality.³⁰

There is no evidence showing that patients with MS are at higher risk of developing stress-related urinary incontinence postpartum despite the potential for a longer second stage and slightly higher rate of instrumentation. Mode of delivery did not appear to influence the frequency of urinary disorders in a study of 273 MS patients having at least one pregnancy.³¹

MS THERAPIES AND PREGNANCY

Information on the risks of prednisolone and methylprednisolone in pregnancy is limited. The FDA places these drugs in group C (no adequate human or animal studies), though there have been concerns in the past that oral steroids in pregnancy might increase the risk of oral clefts.³² Greater experience now suggests, however, that this risk, if it exists, is small, and they are generally considered relatively safe. Theoretical concerns about fetal/neonatal adrenal suppression have not been borne out. Any fetal risks are likely to be small, primarily because this form of steroid is largely metabolised by the placenta so that very little reaches the fetus.

Current guidelines suggest stopping DMTs 3 months prior to conception for planned pregnancies. When conception on DMTs does occur, management is discussed with patients on a case-by-case basis, though the general recommendation is that they should consider stopping therapy due to a lack of evidence of safety. Animal data using 40 times the equivalent dose do not result in teratogenicity but do have an abortive effect.³³ Exposure data are few for disease modifying agents in patients with MS. A review of 41 pregnancies from 3361 MS patients across eight interferon-β (IFN) trials with in utero exposure suggested a non-significant increase in the rate of spontaneous abortion compared with population estimates but no overall increase in pregnancy loss or increased rate of anomaly.³⁴

A second report in the same journal of 23 IFN exposed pregnancies found a higher rate of pregnancy loss and lower birth weight (200 g, similar to that seen in smokers).³⁵ The degree to which the large molecule IFN crosses the placental barrier is not known, although it was not detectable in the fetal blood from two women taking IFN.³⁶ In the end, it might be argued that the advice to stop IFN use in pregnancy is strengthened by the knowledge that the risk of relapse on stopping DMTs may well be mitigated by the natural reduction in relapse rate associated with pregnancy itself.

Other drugs occasionally used in MS may also need to be considered. Azathioprine has not been associated with an increased risk of congenital malformations and is considered relatively safe in pregnancy. Methotrexate should be avoided because of its known abortifacient effects and risk of malformations. The need for other symptomatic medication such as antispasticity or neuropathic pain medication should be reviewed with the patient on an individual basis prior to pregnancy.

MANAGEMENT OF PREGNANCY IN MS PATIENTS

Questions regarding management during pregnancy can arise for the neurologist, particularly if the patient with MS has significant neurological disability. Overall, patients can be reassured that the majority will have no particular difficulties during their pregnancy, labour and delivery. Occasional difficulties similar to those seen in patients with spinal cord injury can occur in MS patients, particularly those with spinal variants of MS or in those undertaking pregnancy with very advanced MS.

Some MS patients with existing mobility difficulties report further reduction in mobility and increased spasticity as the pregnancy progresses due to increasing weight and changes in the centre of gravity. They should also be warned against falls and may need increased physical therapy.

Pregnancy is a prothrombotic state, and immobile pregnant women are at significant risk of thromboembolism. Thromboprophylaxis with compression stockings, low-dose aspirin or heparin may need to be considered.

Urinary tract infections (UTIs) with ureteric reflux and pyelonephritis are more common during pregnancy, particularly with a pre-existing neurogenic bladder and may require an increase in the frequency of intermittent catheterisation. Frequent or chronic urinary tract infections can also increase the risk of preterm labour (PTL) (ie, labour before 37 weeks of gestation), and some women with recurrent UTIs may need long-term low-dose prophylactic antibiotics for the duration of the pregnancy. Women with MS are not otherwise at a higher risk of preterm labour but may be less able to detect the symptoms of PTL if there is significant spinal involvement above T6. These patients should be aware of this possibility and in severe cases have instruction on uterine palpation techniques or consider home monitoring with a portable uterine activity sensor.

There are case reports of autonomic dysreflexia (ADR) in patients with advanced MS.³⁷ The risk is highest in patients with significant spinal cord pathology above T6, the level of splanchnic outflow, but can occur at lower levels. Loss of descending inhibitory spinal cord input and exacerbated afferent stimuli leads to sympathetic overactivity with vasoconstriction and hypertension below the level of spinal pathology and compensatory symptoms of parasympathetic overactivity (profuse diaphoresis, flushing and nasal congestion) above. Hypertension can be severe enough to precipitate seizures if untreated. Management is primarily through the awareness of precipitants (cold stirrups, vaginal examinations, catheter blockage) and early recognition (20–40 mm Hg systolic rise above baseline, headache and flushing). Rarely, pharmacological intervention with oral nifedipine may be required together with expedited delivery. Early use of epidural anaesthesia may be advocated in those at higher risk of ADR,³⁸ particularly if induction of labour is being considered.

There are usually no other particular issues during labour in patients with MS. The uterus is under neurohormonal control, so contractions are not adversely affected by spinal pathology in MS. The first stage of labour usually progresses as normal. Once the fetus descends into the pelvis, a minority of patients may require assistance with forceps or ventouse if pushing is impaired. While an increase in instrumental delivery rates was seen in the PRIMS study (3.4% to 7%), this was small. There is no evidence that epidural anaesthesia is contraindicated in patients with MS.

POSTPARTUM

Breastfeeding is usually unaffected in patients with multiple sclerosis. Occasionally, reduced milk production may occur after 6 weeks if there is reduced nipple stimulation secondary to sensory impairment. It is not known if β-interferon or copolymer-1 passes into breast milk, but it is advised that these are not used during breast-feeding. This consideration must be weighed against the desire to restart DMTs as early as possible in the postpartum period to minimise postpartum relapse risk.

Short courses of methylprednisolone are not contraindicated during breast-feeding. Only small concentrations are excreted in breast milk, and it has a short half-life. Breast-feeding does not impact on the risk of relapse within the postpartum period.³⁹

SUMMARY

Women with multiple sclerosis should be reassured that pregnancy does not appear to be harmful overall and may even be beneficial. The perceived adverse impact on disease activity of the recommendation to stop disease modifying therapy prior to pregnancy may potentially be offset by the immunosuppressive effect of pregnancy itself. Treatment beyond DMT to reduce the heightened risk of relapse postpartum is not currently recommended but may deserve further consideration. The outcome of pregnancy for the majority of patients with MS is not significantly different from that of the general population, though some precautions may be required in patients with advanced or spinal forms of MS. Further understanding of the mechanism behind reduced MS disease activity during pregnancy may have implications for treating autoimmune diseases in general.

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M Lee¹, P O’Brien²

¹ Department of Neurology, Norfolk & Norwich University Hospital, Norwich, UK
² Institute for Women’s Health, University College London Hospitals, London, UK

JNNP Online  © 2008 by the BMJ Publishing Group Ltd. (17/11/08)

Abstract (provisional)

Background
Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS.

Methods
We identified 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates of individuals born preterm were compared for index cases and controls.

Results
There were no significant differences between cases and controls with respect to preterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p=0.41.

Conclusions
Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect.

Source: BMC Neurology © 1999-2008 BioMed Central Ltd (12/08/08)

To investigate the influence of maternal MS on pregnancy, this study compared pregnancy, delivery, and birth outcome in births prior to onset of MS (pre MS), between MS onset and diagnosis (early MS), and after diagnosis of MS (manifest MS).

Mothers with MS were identified through linkage of the Norwegian MS Registry and the Medical Birth Registry of Norway (1967-2002).

All pre MS births (n = 1910), early MS births (n = 555), and manifest MS births (n = 308) were compared. There was a significantly lower mean birth weight in term births (adjusted for gestation in weeks, mother’s age, time period, and caesarean section) in the manifest MS compared to the pre MS group.

The rate of birth complications and interventions did not differ between the three groups. Manifest MS in birth-giving mothers seems to affect birth weight.

This study was performed by the Department of Clinical Medicine at the University of Bergen, Norway and the article is published in the Journal of Neurology.

Source: PubMed PMID: 18283397 (01/08/08) 

This study investigated factors (MS duration, MS relapse, symptoms, social support) that affect functional performance of 172 mothers with MS during the second 6-month postpartum period.

Data were analysed with descriptive statistics and path analysis.

Findings indicated a good fit of the path models to the data at 9 and 12 months. Significant effects at both 9 and 12 months included positive relationships between duration of MS and symptoms and between social support and functional performance. Significant negative relationships were observed between symptoms and both social support and functional performance. Social support mediated the relationship between symptoms and functional performance.

Findings suggest the importance of continuedsocial support throughout the first postpartum year.

Source: Western Journal of Nursing Research, Vol. 29, No. 5, 589-602 (2007) © 2007 SAGE Publications (30/07/07)