Equipping People To Make Sense Of What They Are Told
Onset during Pregnancy
Disease progression was not affected by pregnancy in the PRIMS study, although the
majority of people 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 people 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 men (around 65%) and woman (around 40%) people 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 people, 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 people 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 people
having at least one pregnancy.
Postpartum
Breastfeeding is usually unaffected in people 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 women with MS is not significantly different
from that of the general population, though some precautions may be required in people
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.
Pregnancy and MS -At any one time, there are about 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 people 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 people with MS.
Relapse Risk
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.
Pregnancy appears to be associated with a temporary beneficial immune state for women
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.
Immune Suppression
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 down-regulation 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 people 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
woman MS people.
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 women 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 people with other autoimmune diseases as it is to people 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 people with MS, though no firm conclusions regarding
efficacy can yet be made.
Summary
Hormonal and cytokine changes during pregnancy appear linked with a Th-2 type immune
state likely to be beneficial for people with autoimmune inflammatory conditions
such as MS. Further knowledge of the nature of this effect may provide insight into
additional treatment strategies for people with MS.
