Unexplained infertility and inherited thrombophilia

Abstract

To the Editor: Approximately 15%–30% of couples (1The Practice Committee of the American Society for Reproductive MedicineEffectiveness and treatment for unexplained infertility.Fertil Steril. 2006; 86: S111-S114PubMed Scopus (156) Google Scholar) will be diagnosed with unexplained infertility after their diagnostic workup, as suggested in guidelines (2The Practice Committee of the American Society for Reproductive MedicineOptimal evaluation of the infertile female.Fertil Steril. 2006; 86: S264-S267Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), fails to reveal any abnormality. The treatment for unexplained infertility is therefore, by definition, empiric because it does not address a specific defect or functional impairment (1The Practice Committee of the American Society for Reproductive MedicineEffectiveness and treatment for unexplained infertility.Fertil Steril. 2006; 86: S111-S114PubMed Scopus (156) Google Scholar). The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, clomiphene citrate (CC) and IUI, controlled ovarian hyperstimulation (COH) with IUI, and IVF. In addition, the likelihood of pregnancy without treatment among couples with unexplained infertility is less than that of fertile couples but greater than zero. It is possible that unexplained infertility represents the lower extreme of the normal distribution of fertility with no defect present. Recently a possible association between unexplained infertility and genetic thrombophilia gene mutations have been reported (3Coulam CB, Jeyendran RS. Thrombophilic gene polymorphisms are risk factors for unexplained infertility. Fertil Steril. Published online October 16, 2008 [Epub ahead of print].Google Scholar), with a significant statistically association with MTHFR C677T polymorphisms. We have examined 32 couples with unexplained infertility compared with a control group of 130 couples with recurrent pregnancy loss referred to our Centre for genetic counseling. The infertile couples had been trying to achieve a successful pregnancy for more than 1 year without success and known causes of infertility were excluded (semen anomalies, karyotype abnormalities, uterine malformations, tubal occlusion, hormonal dysfunctions, and celiac disease). In the recurrent pregnancy loss group all pregnancy losses were registered in the first trimester of pregnancy, anatomical anomalies of the uterus, chromosomal, immunologic risk factors (including antiphospholipid antibodies, antinuclear antibodies, antithyroid antibodies, and lupus anticoagulant), and celiac disease were excluded. Genetic evaluation included factor V (G1691A-Leiden and H1299R); factor II prothrombin (G20210A), and methylenetetrahydrofolate reductase (MTHFR) with C677T and A1298C mutations that represent the most common, clinically significant, inherited thrombophilias. The other gene mutations included in the thrombophilic diagnostic tests were performed but were excluded for this analysis. Our results showed a statistically significant association between the two groups for factor V- H1299R mutation heterozygosity (P=.001) and for MTHFR C677T homozygosity (P=.02). No significant associations were found for factor V-Leiden, MTHFR-A1298C homozygosity, compound heterozigosity for C677T and A1298C, and heterozigosity for C677T or A1298C. Inherited thrombophilia is believed to be a multiple gene disease with more than one defect, which explains why some women with thrombophilia never have a thrombotic event, whereas others have complications. Testing may be performed in individuals with a personal or family history of venous thromboembolism and in women with a history of pregnancy loss and other pregnancy complications. The presence of genetic thrombophilia was also associated with an increased risk of recurrent implantation failure. There are no clear hypotheses to correlate the statistical association between unexplained infertility and genetic thrombophilia. In the reproductive anamnesis of our couples with unexplained infertility, repeated menstrual cycles retardation during the months were often reported. On the basis of this clinical observation and genetic thrombophilia mechanism study, we believe that a possible explanation for the observed association may be an early implantation failure with repeated unrecognized pregnancies that overlap with infertility. In conclusion, unexplained infertility may represent another indication to perform genetic thrombophilia screening. Reply of the authors: Unexplained infertility and inherited thrombophiliaFertility and SterilityVol. 92Issue 1PreviewWe agree with Dr. Bianca and associates supporting the role of inherited thrombophilias in human reproductive disorders including unexplained infertility. They compared the frequency of five thrombophilic gene mutations in couples with a history of unexplained infertility and in those with a history of recurrent pregnancy loss and found an association between them with factor V H1299r heterozygosity and MTHFR C677T homozygosity (1). These findings are in agreement with those previously published among individuals with a history of not only unexplained infertility (1), recurrent implantation failure (2), and recurrent pregnancy loss (3, 4), but also deep vein thrombosis (5) as shown in Figure 1. Full-Text PDF