Immunotherapy for recurrent miscarriage: Cochrane systematic review

Abstract

Assessed as up to date: 2014/02/11

Background

Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss.

Objectives

The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immunoglobulin on the live birth rate in women with previous unexplained recurrent miscarriages.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 February 2014) and reference lists of retrieved studies.

Selection criteria

Randomized trials of immunotherapies used to treat women with three or more prior miscarriages and no more than one live birth after, in whom all recognized non-immunologic causes of recurrent miscarriage had been ruled out and no simultaneous treatment was given.

Data collection and analysis

The review author and the two co-authors independently extracted data and assessed study quality for all studies considered for this review.

Main results

Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third-party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; or intravenous immunoglobulin, (eight trials, 303 women), Peto OR 0.98, 95% CI 0.61 to 1.58.

Authors' conclusions

Paternal cell immunization, third-party donor leukocytes, trophoblast membranes, and intravenous immunoglobulin provide no significant beneficial effect over placebo in improving the live birth rate.

Author(s)

Wong Luchin F, Porter T Flint, Scott James R

Summary

Immunotherapy for recurrent miscarriage

Immunotherapy does not lower the risk of future miscarriage in women who repeatedly miscarry.

Background
Recurrent miscarriage is three or more consecutive early miscarriages. One theory is that for some women, this might be caused by an immune system response to the embryo or fetus. Therapies that try to immunize the woman against the 'foreign' cells of a future pregnancy have been tried. Immunotherapies have included white blood cells (leukocytes) from the woman's partner or a donor, products derived from early embryos (trophoblast membranes), or antibodies derived from blood (immunoglobulin).

Review question
We sought to determine whether immunological treatments would improve the chance of live births in women with a history of recurrent miscarriage.

Study characteristics
We included 20 randomized controlled trials involving 1137 women, which took place from 1985 and 2004 in 11 countries. The trials examined four different forms of immunotherapy: immunization using white blood cells from the woman's partner (12 trials, 641 women), white blood cells from a third-party donor (three trials, 156 women), products derived from early embryos (one trial, 37 women), or antibodies derived from blood (intravenous immunoglobulin) (eight trials 303 women).

Quality of the evidence and conclusions
Overall, we considered the risk of bias for the majority of included studies to be low.

The review of trials found that none of these treatments provided a significant beneficial effect over placebo in improving the live birth rate or lowered the risk of future miscarriage in women who have recurrent miscarriages.

Reviewer's Conclusions

Implications for practice

Neither immunization with paternal leukocytes nor treatment with intravenous immunoglobulin (IVIG) improve the live birth rate in women with unexplained recurrent miscarriage. Both are expensive and have potential serious side effects. Moreover, women should be spared the pain and grief associated with false expectations that an ineffective treatment might work. These therapies should no longer be offered as treatment for unexplained recurrent pregnancy loss. Furthermore, immunological laboratory tests, which have been previously been advocated as justification for immunotherapies, have no predictive value for pregnancy success and should be abandoned.

Implications for research

Effective treatment of an alleged alloimmune cause of recurrent miscarriage awaits more complete knowledge of the underlying pathophysiology. A specific assay to diagnose immune-mediated early pregnancy loss and a reliable method to determine which women might benefit from manipulation of the maternal immune system are urgently needed. It is not presently known exactly how many recurrent early pregnancy losses are the result of anembryonic or chromosomally abnormal conceptuses, anatomic or structural abnormalities and how many are embryonic or fetal deaths. It is likely that some unexplained early losses are due to as yet undefined subchromosomal genetic abnormalities impairing early development of the conceptus (Copp 1995; Pegoraro 1997; Quenby 2002; Rossant 2001; Spandidos 1998; Tempfer 2001; Tsai 1998). New molecular techniques should be directed at understanding the factors responsible for successful pregnancy as well as pregnancy loss.

To establish definitively or to rule out the efficacy of any proposed treatment for recurrent pregnancy loss, randomized controlled trials with adequate numbers of participants are needed. These should be studies approved by institutional review boards in centers with research expertise and interest in this problem. New therapeutic modalities should be tested only under protocol with rigorous study designs. Finally, further studies on complications of treatment and long-term follow-up of offspring are necessary. The National Institutes of Health (NIH) in the United States and other funding agencies should be encouraged to support proposals that offer new and innovative approaches to this problem. The Agency of Health Care Policy and Research in the United States and similar funding agencies in other countries need to support proposals to evaluate outcome of treatments especially for large trials.

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