Description of the condition
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. Demyelination and axonal injury of the nerves within the central nervous system cause numerous neurologic symptoms. The etiology of the disease is unknown. However, autoimmunity, genetic and environmental factors may also play a role in the pathogenesis of the disease (Murray 2006).
MS affects more than 2. 5 million people all over the world. Mean age of onset is between 20 and 50 years, and MS is more commonly seen in women than in men (Orton 2006). The global median estimated prevalence of MS is about 30 per 100,000 population (range 5 to 80), with a female preponderance (female to male ratio of 3:1) (Trisolini 2010 ; WHO 2008). The median estimated incidence of MS globally is 2.5 per 100,000 (with a range of 1.1 to 4) (WHO 2008).
MS is believed to be associated with T helper cell type I (Th1) activities. This association is supported by findings that women are more likely to have Th1 responses than men, except during pregnancy when they shift to the Th2 system (Whitaker 1998). This may explain why women are more susceptible to MS and other autoimmune diseases linked to Th1-mediated immune responses (Drew 2000; Kim 1999).
The clinical course is variable, about 80% of patients initially have a relapsing-remitting course. After 5 to 15 years, approximately 50% of affected patients progresses to secondary progressive course with or without superimposed relapses. Between 10-15% of patients have progression from the beginning with continuous neurological deterioration with occasional plateaus and temporary minor improvements. A smaller percentage (5%) may have occasional relapses superimposed on the initial progression (Lublin 1996; Weinshenker 1987). The prognosis is highly variable and unpredictable,
The diagnosis of MS is based on the demonstration of white matter lesions disseminated in time and space in the absence of another identifiable explanation. MS remains a clinical diagnosis. Current diagnostic criteria are the McDonald's Criteria (McDonald 2001; Polman 2005; Polman 2011).
The pharmacological treatment of MS is divided into treatment of symptoms, treatment of relapses and disease modifying treatments.
Current approved disease modifying drugs are intramuscular and subcutaneous interferon beta 1-a (Biogen Idec 2012; FDA 2009; IFNB MS Study Group-UBC MS/MRI Analysis Group 1995; Jacobs 1996; PRISMS Study Group 1998), subcutaneous Interferon beta 1-b (FDA 2003), and glatiramer acetate (Johnson 1995; TEVA 2009). In recent years, natalizumab, a monoclonal antibody, has been approved the use (FDA 2006; Polman 2006). Fingolimod and recently teriflunomide are the first oral drugs approved for MS (FDA 2010; FDA 2012; Kappos 2010; O'Connor 2011). Mitoxantrone is the only immunosuppressive treatment approved for patients with aggressive relapsing-remitting form and for patients with secondary progressive form of the disease (Hartung 2002). These drugs are contraindicated during pregnancy and breastfeeding (NMSS 2008.
Two thirds of patients with MS are young women of childbearing age so there is concern about pregnancy, childbirth, breastfeeding and newborn health in this group of patients. It is well known that women with MS have fewer relapses during pregnancy and a high risk of relapse in the postpartum period. The immediate postpartum period is one of the established risk factors for increased disease activity, and between 20% and 40% of women experience relapse during this period (Confavreux 2008).
Factors that have been associated with an increased risk of postpartum relapse are:
number of relapses in the year before pregnancy;
number of relapses during pregnancy; and
the level of disability prior to pregnancy (Vukusic 2004).
Some studies have shown that administration of intravenous immunoglobulin (IVIG) after delivery significantly reduces relapses in this period (Achiron 1996; Achiron 2004; Haas 2007). Achiron 2004 conducted a retrospective study to evaluate IVIG treatment during pregnancy and the postpartum period. The study sample of 108 women was divided into three groups: those treated continuously during gestation and postpartum, those treated after childbirth, and a control group (an untreated group). The results showed that women who were treated during pregnancy with IVIG had a lower rate of relapses related to pregnancy and the postpartum period, with no unfavourable effects observed in the newborns.
A prospective, randomised study, evaluated the efficacy in reducing the relapse rate within three months postpartum of two-dose regimens of IVIG without placebo control (Haas 2007). One group received a dose of 150 mg/kg on day one followed by two placebo infusions. The second group received a total dose of 900 mg/kg daily during three days. This blinded treatment phase was followed by an open phase in which both groups received five subsequent doses of 150 mg/kg at intervals of four weeks between each. The percentage of patients free of relapse during the first three months' postpartum did not differ significantly between the two groups.
However, in spite of these studies the exact role of this intervention in this condition is still unknown.
Description of the intervention
IVIG is a fractionated blood product consisting of concentrated immunoglobulin, primarily immunoglobulin G(IgG), derived from human plasma in pools of 3000 to 10,000 or more donors (Feasby 2007).
IVIG mechanisms of action include the neutralisation of microorganisms and toxins, opsonisation, and phagocytosis of microorganisms, complement activation and antibody dependent cytotoxicity. Also have a role in homeostasis and regulation of immune response. IVIG modulates a number of immune effector pathways,including Fc receptor blockade, neutralisation, or enhanced clearance of autoantibodies; decreases production of cytokines; blocks adherence molecules; and inhibits the uptake of complement components on target tissues, modulation of apoptosis, and immune regulation of both B-cell and T-cell immune function (Ballow 2007).
Regarding safety the rate of systemic reactions to IVIG infusion is usually reported to be in the range of 3% to 15%. They include fever, chills, facial flush, tachycardia, palpitation, chest tightness or chest pain, anxiety, nausea, abdominal pain, dyspnoea, back pain, arthralgia, myalgia, hypotension, shock. Most of these infusion-related adverse events are typically self-limited, mild and reversible. These adverse reactions can occur at any time, especially during the advancement of the rate of the infusion. However, most occur near the end of the infusion at the higher infusion rates or within 24 hours of the completion of the infusion. Since these adverse reactions are usually related to the speed of the infusion, the first approach is to slow the rate or stop the infusion of IVIG, wait until vital signs and/or symptoms resolve, and then restart the infusion at a lower rate (Ballow 2007).
All IVIG preparations contain small amounts of immunoglobulin A (IgA), although some products have higher concentrations than others. These reactions may either be anaphylactic or anaphylactoid (Ballow 2007).
Acute renal failure secondary to infusion is due to a reversible alteration in most cases. Most patients recover renal function days or weeks after IVIG infusion. Risk factors for its occurrence correspond to high osmolarity formulas, high infusion rate, male gender, age older than 65 years, preexisting renal disease, diabetes, hypertension and obesity. Between 70% to 90% of the renal adverse effects are associated with IVIG preparations containing sucrose. It is recommended to evaluate renal function in all patients undergoing use of IVIG.
How the intervention might work
The mechanism by which IVIG prevented exacerbations is unknown. However, as the occurrence of exacerbations in MS is associated with the activation of T-cells, promoting their capacity to cross the blood-brain barrier and trigger an immune response, it can be postulated that IVIG has a modulatory effect on the immune system which might be associated with Tcell activation or cytokine production.
Why it is important to do this review
The increased relapse rate during the postpartum period prompt serious consideration for MS patients who need to be treated during this period and even during pregnancy. IVIG is a proposed intervention to avoid pregnancy and postpartum relapses in MS patients. Despite this, there is no confirmed efficacy of the intervention in this condition and much uncertainty exists in this issue considering the evidence. The importance of systematic search as well as the analysis of the evidence will clarify some aspects in managing pregnant MS patients (Achiron 2004; Vukusic 2004).