Oct 16, 2008 - inition, empiric because it does not address a specific defect or functional impairment (1). The principal treatments for un- explained infertility ...
LETTER TO THE EDITOR Unexplained infertility and inherited thrombophilia To the Editor: Approximately 15%–30% of couples (1) will be diagnosed with unexplained infertility after their diagnostic workup, as suggested in guidelines (2), 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 (1). 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 (3), 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 (G1691ALeiden 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 (P¼.001) and for MTHFR C677T homozygosity (P¼.02). 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
e4
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. S. Bianca, M.D., Ph.D.a B. Barrano, M.D., Ph.D.a N. Cutuli, M.D.b L. Indaco, M.D.a A. Cataliotti, M.D.a G. Milana, M.D.b C. Barone, M.D.a G. Ettore, M.D.c a Centro di Consulenza Genetica e di Teratologia della Riproduzione, Laboratorio di Citogenetica, Dipartimento Materno Infantile, ARNAS Garibaldi Nesima, Catania, Italy b Laboratorio di Genetica Molecolare, AOU Policlinico c UOC Ginecologia e Ostetricia, Dipartimento Materno Infantile, ARNAS Garibaldi Nesima, Catania, Italy February 1, 2009
REFERENCES 1. The Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril 2006;86:S111–4. 2. The Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril 2006;86: S264–7. 3. Coulam CB, Jeyendran RS. Thrombophilic gene polymorphisms are risk factors for unexplained infertility. Fertil Steril. Published online October 16, 2008 [Epub ahead of print].
doi:10.1016/j.fertnstert.2009.02.007
Fertility and Sterility Vol. 92, No. 1, July 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00
