The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis

This study did not show a role for immunotherapy in women undergoing in vitro fertilization treatment or for prevention of recurrent pregnancy loss; therefore it should currently not be used in routine clinical practice.

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Volume 110, Issue 6, Pages 1089–1100


Chiara Achilli, M.D., Montserrat Duran-Retamal, M.D., Wael Saab, M.R.C.O.G, Paul Serhal, M.R.C.O.G, Srividya Seshadri, M.D.



To study the current evidence on the role of immunotherapy in IVF and in the management of recurrent pregnancy loss (RPL).


Systematic review and meta-analysis.


A literature search was performed using MEDLINE, PUBMED, CINAHL, and EMBASE until May 2017. Only randomized controlled trials were included, and a meta-analysis was carried out where appropriate.


Women undergoing IVF treatment with or without a history of recurrent implantation failure and women with idiopathic RPL.


Assessment of the efficacy of commonly used immunomodulators such as IV use of [1] immunoglobulin, [2] lymphocyte immunotherapy and [3] intralipid; intrauterine infusion of [4] granulocyte colony-stimulating factor and [5] peripheral blood mononuclear cells; subcutaneous administration of [6] TNF-alpha inhibitors, [7] leukaemia inhibitory factor; and oral administration of [8] glucocorticoids.

Main Outcome Measure(s)

The primary outcomes were live birth rate and miscarriage rate; secondary outcome was clinical pregnancy rate.


Of the 7,226 publications identified, 53 were selected during the initial screening; 30 satisfied the selection criteria and were included in this review.


The available medical literature shows controversial results about the role of immunotherapy when used for improving reproductive outcomes. This study did not show a role for immunotherapy in improving the live birth rate in women undergoing IVF treatment or in the prevention of idiopathic RPL. Currently, immunotherapy should be used in the context of research and should not be used in routine clinical practice to improve reproductive outcomes.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.


Go to the profile of Ole Bjarne Christiansen
Ole Bjarne Christiansen over 1 year ago

Dear authors

I read the recent systematic review and meta-analysis about immunotherapy in in vitro-fertilization (IVF) and recurrent pregnancy loss (RPL) by Achilli et al. (1) with great interest but was severely disappointed in discovering that the study was flawed especially due to substantial lack of rigor in data collection. Many studies of lymphocyte therapy in RPL e.g. Mowbray et al. (2) were not included and the authors have by error switched the text “favors controls” and “favors experimental” in all or most of the figures depicting forest plots.

However, I will focus my criticism on the misquoting of data from my own randomized controlled trials (RCTs) of intravenous immunoglobulin (IvIg) in RPL.

In figure 4 of the article by Achilli et al. (1) a forest plot shows the odds ratio for live birth in RPL patients with secondary RPL receiving IvIg or placebo. The authors have included data from 3 RCTs (3-5). I will point out two errors regarding this figure which, if corrected, will result in a completely other combined odds ratio and conclusion.

In Figure 4 is claimed that in the Christiansen et al. 1995 study (3), 9/17 IvIg treated patients gave birth compared with 5/17 in placebo group. However, as indicated in the title of the article (3), the patients in this study was a mixture of patients with secondary RPL and patients with at least one second trimester miscarriage and not necessarily secondary RPL. In the text of my article (3) on page 2692 is clearly written that in the subset with secondary RPL, 9/14 (64%) who had IvIg gave birth compared with 2/10 (20%) in the placebo group.

Furthermore, in the results of the article by Achilli et al. (1) is written that data from the Christiansen et al., 2002 RCT (6) could not be included in the meta-analysis because: quote ”Due to impossibility to discriminate between data from patients with primary and secondary RPL …” However, if the authors spent a little time reading the article (6) they would find that in Table III is clearly indicated that among patients in the study with secondary RPL, 6/12 (50%) in the IvIg group gave birth compared with 3/13 (23%) in the placebo group.

If the real data regarding secondary RPL patients from my two studies (3,6), which can easily be extracted from the original articles, were included in the forest plot of Figure 4 in the Achilli et al. article (1), I am convinced that the authors will find that IvIg significantly increases the live birth rate in secondary RPL and this is indeed a completely other conclusion that is promoted in their article. In the meta-analysis by Wang et al., 2016 (7), which is quoted by the authors and the meta-analysis by Egerup et al., 2015 (8), which was strangely not quoted, much more comprehensive and valid meta-analyses were performed.  


Ole B. Christiansen, Professor, D.M.Sc

Centre for Recurrent Pregnancy Loss of Western Denmark

Department of Obstetrics and Gynecology

Aalborg University Hospital, Aalborg, Denmark


  1. Achilli C, Duran-Retamal M, Saab W, Serhal P, Seshadi S. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril 2018; 110: 1089-1100


  2. Mowbray JF, Gibbings C, Liddell H, Reginal PW, Underwood JL, Beard RM. Controlled trial of treatment of recurrent spontaneous abortions by immunization with paternal cells. Lancet 1985; i: 841-43.


  3. Christiansen OB, Mathiesen O, Husth M, Rasmussen KL, Ingerslev HJ, Lauritsen JG, Grunnet N. Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin. Hum Reprod 1995; 10: 2690-5.


  4. Christiansen OB, Larsen EC, Egerup P, Lunoee L, Egestad L, Nielsen HS. Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial. BJOG 2015; 122, 500-8.


  5. Jablonowska B, Selbing A, Palfi M, Enerudh J, Kjelberg S, Lindton B.  Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod 1999; 14: 838-41.


6. 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, 809-16.

7. Wang SW, Zhong SY, Lou LJ, Hu ZF, Sun HY, Zhu HY. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a metanalysis. Reprod Biomed Online. 2016; 33: 720-36.

8. Egerup P, Lindschou J, Gluud C, Christiansen OB. ImmunoREM IPD study group. The effects of intravenous immunoglobulins in women with recurrent miscarriages: A systematic review of randomized trials with meta-analyses, trial sequential analyses and trial sequential analyses including individual patient data. PLoS ONE 2015; 10: e141588.