Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion

Candidate gene studies show moderate associations with idiopathic recurrent spontaneous abortion. Because of large differences between studies regarding definition of the condition and selection criteria for participants, consensus is needed.

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Volume 107, Issue 1, Pages 150-159


Nina Pereza, M.D., Ph.D., Saša Ostojić, M.D., Ph.D., Miljenko Kapović, M.D., Ph.D., Borut Peterlin, M.D., Ph.D.



1) To perform the first comprehensive systematic review of genetic association studies (GASs) in idiopathic recurrent spontaneous abortion (IRSA); 2) to analyze studies according to recurrent spontaneous abortion (RSA) definition and selection criteria for patients and control subjects; and 3) to perform meta-analyses for the association of candidate genes with IRSA.


Systematic review and meta-analysis.


Not applicable.


Couples with IRSA and their spontaneously aborted embryos.


Summary odds ratios (ORs) were calculated by means of fixed- or random-effects models.

Main Outcome Measure(s)

Association of genetic variants with IRSA.


The systematic review included 428 case-control studies (1990–2015), which differed substantially regarding RSA definition, clinical evaluation of patients, and selection of control subjects. In women, 472 variants in 187 genes were investigated. Meta-analyses were performed for 36 variants in 16 genes. Association with IRSA defined as three or more spontaneous abortions (SAs) was detected for 21 variants in genes involved in immune response (IFNG, IL10, KIR2DS2, KIR2DS3, KIR2DS4, MBL, TNF), coagulation (F2, F5, PAI-1, PROZ), metabolism (GSTT1, MTHFR), and angiogenesis (NOS3, VEGFA). However, ORs were modest (0.51–2.37), with moderate or weak epidemiologic credibility. Minor differences in summary ORs were detected between IRSA defined as two or more and as three or more SAs. Male partners were included in 12.1% of studies, and one study included spontaneously aborted embryos.


Candidate gene studies show moderate associations with IRSA. Owing to large differences in RSA definition and selection criteria for participants, consensus is needed. Future GASs should include both partners and spontaneously aborted embryos. Genome-wide association studies and large-scale replications of identified associations are recommended.

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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.