Intravenous immunoglobulin to prevent relapses during pregnancy and postpartum in multiple sclerosis

  • Protocol
  • Intervention


  • Nora Fernández Liguori,

    Corresponding author
    1. Hospital Enrique Tornú, Multiple Sclerosis Clinic, Neurology Section, Buenos Aires, Argentina
    • Nora Fernández Liguori, Multiple Sclerosis Clinic, Neurology Section, Hospital Enrique Tornú, Combatiente de Malvinas 3002, Buenos Aires, 1427, Argentina.

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  • Juan Ignacio Rojas,

    1. Hospital Italiano Buenos Aires, Neurology Department, Buenos Aires, Buenos Aires, Argentina
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  • Diana S Klajn,

    1. Hospital Tornu, Academic and Research Department, Buenos Aires, Argentina
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  • Agustín Ciapponi

    1. Southern American Branch of the Iberoamerican Cochrane Centre, Argentine Cochrane Centre IECS, Institute for Clinical Effectiveness and Health Policy, Buenos Aires, Capital Federal, Argentina
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This is the protocol for a review and there is no abstract. The objectives are as follows:

The objective of this review is to evaluate if IVIG prevent relapses during pregnancy and postpartum period in patients with relapsing-remitting MS.


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).

Autoimmune diseases are more common in women who account for about 70% of patients with these conditions (Ansar 1985; Beson 1994; Rose 1993; Wegmann 1993).

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: 

  1. number of relapses in the year before pregnancy;

  2. number of relapses during pregnancy; and

  3. 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.

The risk of infectious complications from IVIG is extremely low (Feasby 2007). IVIG is considered to be safe during breastfeeding (Ferrero 2004) .

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).  


The objective of this review is to evaluate if IVIG prevent relapses during pregnancy and postpartum period in patients with relapsing-remitting MS.


Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and quasi randomised controlled trials. Uncontrolled or non-randomised trials will be excluded.

Types of participants

  • Inclusion criteria

  • Exclusion criteria

    • Immunomodulatory MS treatment later than 4 weeks after their last menstrual period

    • History of other autoimmnune disease other than MS

    • Sensitivity to blood or plasma derived products

    • Other serious diseases involving: renal or cardiovascular system

A relapse is defined as a newly developed or recently worsened symptoms of neurological dysfunction, with or without objective confirmation, lasting more than 24 hours and typically progressing over a period of few days and of variable duration (days or months), preceded by a period of disease stability or improvement for at least 30 days and followed by complete or partial recovery (Poser 1983).

Types of interventions

  • Experimental intervention

    • IVIG during gestation and the postpartum period (0.4 g/kg of body weight/day for five consecutive days within the six to eight weeks of gestation with additional booster doses of 0.4 g/kg body weight/day once every six weeks until 12 weeks postpartum)

  • Control group

    • No treatment

Types of outcome measures

Primary outcomes
  1. Number of patients who experienced relapses during pregnancy and postpartum period (at 12 and 24 weeks postpartum)

  2. Mean number of relapses during the whole pregnancy and postpartum period (at 12 and 24 weeks postpartum)

  3. Number of relapse-free patients for pregnancy and postpartum period (at 12 and 24 weeks postpartum)

Secondary outcomes
  1. Number of patients with severe adverse effects (defined as severe when leading to one of the following: death, hospitalisations, pregnancy interruption)

  2. Mean change of quality of life assessment using validated multidimensional questionnaires (e.g. Multiple Sclerosis Quality of Life-54 Instrument (MSQoL-54)) (Vickerrey 1995)

Search methods for identification of studies

Electronic searches

The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Trials Search Co-ordinator will search the Group's Trials Register which, among other sources, contains CENTRAL (The Cochrane Library, latest issue), MEDLINE (PubMed) (1966 to date), EMBASE (1974 to date), CINAHL (1981 to date), LILACS (1982 to date) and PEDro. We will also look for ongoing trials in clinical trial registries.

Information on the Group's Trials Register and details of search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module.

The keywords we will use in the search strategy are listed in (Appendix 1).

Searching other resources

Reference lists of all located studies for other potentially relevant publications.

Personal communication with authors of identified clinical trials to collect unpublished, insufficient or missing data.

We will handsearch symposia reports from the most important neurological associations and MS societies (The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and American Academy of Neurology) (from 1999 to date).

Data collection and analysis

Selection of studies

Titles and abstracts of the citations retrieved by the literature search will be screened independently by two authors (NFL, JIR). If it is clear that the study does not meet the eligibility criteria, it will be excluded. If unclear, the full text of study will be obtained and evaluated independently by the authors for possible inclusion.

Data extraction and management

Two authors (NFL, JIR) will independently extract the data and collect them on a predefined collection form for each trial. Disagreement about extracted data will be resolved by consensus among all review authors. In case this is not possible, and further information is necessary to resolve the dilemma, data will not be entered and the trial will be added to those awaiting assessment in order to solve by the intervention of a third author (AC).

Assessment of risk of bias in included studies

Two authors (NFL, JIR) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). We will assess the following domains as 'Low risk of bias', 'Unclear risk of bias' or 'High risk of bias':

  1. selection bias through evaluation of the randomisation procedure and allocation concealment;

  2. performance bias through an evaluation of the blinding of the patients and the people administering the treatment;

  3. attrition bias through an evaluation of the number of patients withdrawn from the studies, reported for each group and through analysis by intention-to-treat;

  4. detection bias through an evaluation of the blinding of outcome assessment;

  5. reporting bias through an evaluation of the differences between the reported and unreported findings; and

  6. any other sources of bias present in the studies if relevant.

Disagreements among the review authors on the methodological quality of the identified studies will be discussed and resolved by consensus.

Measures of treatment effect

For continuous outcomes, the mean difference or the standardised mean difference (SMD) will be calculated with 95% confidence intervals (CIs). Standard deviation will be calculated from confidence intervals or t-tests when it is not reported. For dichotomous outcomes, individual and pooled statistics will be calculated as risk ratios (RRs) for relative measures and risk difference (RD) for absolute measures.

Unit of analysis issues

Outcomes data will be grouped according to the clinically important time points specified in the 'Types of outcome measures' section of the review and we will follow the recommendations on their analysis and reporting provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). 

Dealing with missing data

If sufficient data are not available from published reports, the authors will be contacted for further details

Assessment of heterogeneity

Heterogeneity among trials will be examined using the I2 statistic (Higgins 2003). The I2 estimate greater than the 50% is interpreted as indicating moderate or high levels of heterogeneity and its causes will be investigated.

If there is no statistically significant heterogeneity, the fixed-effect model will be used; if there is a moderate level of heterogeneity, a random-effects model will be applied.

If heterogeneity persists, we plan to present results separately and to report its reasons.

Assessment of reporting biases

We will examine the funnel plots (a graphical display) of the size of the treatment effect for the primary outcome against trial precision (1/standard error) for asymmetry, to evaluate if there is evidence of publication bias.

Data synthesis

We will use the Cochrane Collaboration's statistical software, Review Manager 2013, for data management and analysis. Data will be entered so that the area to the left of the line of no effect indicates a favourable outcome for IVIG.

We will analyse the strength of evidence by considering internal and external factors, mainly methodological issues of included studies as well as the number of the studies in the review.

Subgroup analysis and investigation of heterogeneity

We will undertake subgroup analyses to explore potentially sources of heterogeneity:

  • disability score at inclusion (Expanded Disability Status Scale (EDSS) > 3 vs. ≥3) (Kurtzke 1983);

  • age (18 to 35 years vs. > 35 years);

  • time since the beginning of the disease (1-3 years vs. > 3 years);

  • dosages and period of treatment during pregnancy and postpartum.

Sensitivity analysis

If a sufficient number of studies (≥ 3) are included we plan to conduct sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of studies with moderate and high risk of bias.

Overall quality of the body of evidence: 'Summary of findings' table

We will generate a 'Summary of findings' table using the software GRADEprofiler 2011. This table will evaluate the overall quality of the body of evidence for the main review outcomes, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). We will justify, document and incorporate into our reporting of results for each outcome our judgements about evidence quality (high, moderate or low).


Appendix 1. Search strategy for the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Specialised Register

{immunoglobulin\*} OR {intravenous immunoglobulins} OR {intravenous} OR {Intravenous IG} OR {IV Immunoglobulins} OR {Intravenous Antibodies} OR {IVIG} And Pregnancy And Postpartum

Contributions of authors

All authors contributed in developing the protocol.

Selection of studies and data extraction and management: Nora Fernandez Liguori and Juan Ignacio Rojas.

Assessment of risk of bias of selected studies: Diana Klajn and Agustin Ciappon

Declarations of interest

Nora Fernández Liguori has received honoraria as scientific advisor from Biogen Idec and Novartis Argentina. She has received honoraria as a speaker from Merck Serono Argentina, Biogen Idec and Ivax. She has received travel expenses for attending national and international meetings from Biogen Idec, Merck Serono Argentina and Novartis Argentina. She has received honoraria for expert testimony from Genzyme.