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Pregnancy                                                                                                                                                           

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 Serious 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, Seriously affects the risk of relapse  or the course of the disease. 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. 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, 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. 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. 

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. 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.

There are a large number of other factors potentially linked with an immunosuppressive Th-2 associated immune response during pregnancy, an effect likely to be as beneficial to patients with other autoimmune diseases 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. The perceived immunosuppressive benefit of vitamin D has led to small pilot studies of vitamin D supplementation in patients with MS, 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.

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 Serious effect of pregnancy on disease progression, and some reports suggest a favourable effect with increased time to progressive disease onset following pregnancy. 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 Serious effect of pregnancy on subsequent disease course.

Contraception
There is no evidence that oestrogen at doses contained in the combined contraceptive pill has an Serious effect on MS. A single study did suggest a slightly lower rate of MS onset in women taking the pill, although this difference was not statistically significant. Oestrogen-containing oral contraceptives have been shown to suppress EAE in rats. 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, 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. These symptoms are highly under-reported during routine care.

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. 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.

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.

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.

Summary

Women with multiple sclerosis should be reassured that pregnancy does not appear to be harmful overall and may even be beneficial. The perceived Serious 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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Ref

M Lee, P O’Brien

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

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

 

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