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Meta-Analysis
. 2015 Oct 30;10(10):e0141588.
doi: 10.1371/journal.pone.0141588. eCollection 2015.

The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data

Pia Egerup  1 , Jane Lindschou  2 , Christian Gluud  2 , Ole Bjarne Christiansen  3 ; ImmuReM IPD Study Group
Collaborators, Affiliations
Meta-Analysis

The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data

Pia Egerup et al. PLoS One. .

Abstract

Background: Immunological disturbances are hypothesised to play a role in recurrent miscarriage (RM) and therefore intravenous immunoglubulins (IVIg) have been tested in RM patients.

Objectives: The objectives were to investigate the benefits and harms of IVIg versus placebo, no intervention, or treatment as usual in women with RM.

Search strategy: We searched the published literature in all relevant databases.

Selection criteria: Randomised trials investigating IVIg versus placebo, no intervention, or treatment as usual in women with RM.

Data collection and analysis: We undertook meta-analyses of aggregated data and individual patient data using a two-step approach, and we conducted bias domain assessments and trial sequential analyses to assess the risks of systematic and random errors.

Main results: We identified 11 randomised clinical trials. No significant difference in the frequency of no live birth was found when IVIg was compared with placebo or treatment as usual (RR 0.92, 95% CI 0.75-1.12, p = 0.42). Trial sequential analysis showed that the required information size of 1,008 participants was not obtained. IVIg compared with placebo seems to increase the risk of adverse events. Subgroup analysis suggests that women with RM after a birth (secondary RM) seemed most likely to obtain a potential beneficial effect of IVIg (RR for no live birth 0.77, 95%CI 0.58-1.02, p = 0.06), however, trial sequential analysis showed that insufficient information is presently accrued.

Conclusion: We cannot recommend or refute IVIg in women with RM. IVIg should therefore be assessed in further randomised clinical trials with positive outcomes before any clinical use is considered.

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Conflict of interest statement

Competing Interests: One of the review team members, Ole B. Christiansen (OBC), was investigator in three of the randomised clinical trials on the topic and another, Pia Egerup (PE), was investigator in one of the randomised clinical trials on the topic. To avoid potential bias, OBC did not participate in the selecting of relevant trials or in the data analyses and PE did not participate when the data of the trial that she co-authored were analysed. The remaining review team members controlled PE’s work. The remaining review team members (JL and CG) declare that they have no competing interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. PRISMA flow diagram illustrating the selection procedure.
Fig 2
Fig 2. Meta-analysis for the outcome no live birth for all trials (A) and Trial sequential analysis for the outcome no live birth for all trials (B).
A) Forest Plot of the meta-analysis for the outcome no live birth, B) The diversity-adjusted required information size (DARIS) of 1,008 patients was calculated on the basis of type I error of 5%, type II error of 20%, the control group event proportion (PC) of 43%, a relative risk reduction (RRR) of 20%, and the diversity (D2) 0% of the meta-analysis. The cumulative Z-curve does not cross the trial sequential monitoring boundaries for benefits, harms, or futility, and the required information size was not reached.
Fig 3
Fig 3. Meta-analysis for the subgroup analysis for women with primary RM compared to secondary RM (A) and Trial sequential analysis for women with secondary RM (B).
A) Forest Plot for the outcome no live birth, B) The diversity-adjusted required information size (DARIS) of 698 patients was calculated on the basis of type I error of 5%, type II error of 20%, the control group event proportion (PC) of 53%, a relative risk reduction (RRR) of 20%, and the diversity (D2) 0% of the meta-analysis. The cumulative Z-curve does not cross trial sequential monitoring boundaries for benefits, harms, or futility, and the required information size was not reached.
See this image and copyright information in PMC

References

    1. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006. August 12;368(9535):601–11. - PubMed
    1. Christiansen OB. Reproductive immunology. Mol Immunol. 2013;55(1):8–15. 10.1016/j.molimm.2012.08.025 - DOI - PubMed
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    1. Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. 2002;17(3):809–16. - PubMed

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