Unexplained Infertility and Inherited Thrombophilia

5 02 2009

To the Editor:

Approximately 15% to 30% of couples (1) will be diagnosed with unexplained infertility (UI) 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 and intrauterine insemination (IUI), controlled ovarian hyperstimulation (COH) with IUI, and in vitro fertilization (IVF). Moreover 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 (RPL) referred to our Centre for genetic counselling. The infertile couples had been trying to achieve successful pregnancy for greater 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 RPL 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 0.001) and for MTHFR C677T homozygosity (p 0.02). No significant associations were found for factor V-Leiden, MTHFR-A1298C homozygosity, compound heterozigosity for C677T and A1298C and heterozigosity for C677T or A1298C respectively.

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 while 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 UI couples repeated menstrual cycles retardation during the months were often reported. On the basis of this clinical observation and genetic thrombophilia mechanisms study, we think 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. 

Sebastiano Bianca, MDa
Barbara Barranoa
N. Cutulib
Lara Indacoa
Antonella Cataliottia
C. Baronea
Giuseppe Ettorec

aCentro di Consulenza Genetica e di Teratologia della Riproduzione Laboratorio di Citogenetica
Dipartimento Materno Infantile
ARNAS Garibaldi Nesima
Catania, Italy

bLaboratorio di Genetica Molecolare
AOU Policlinico
Catania, Italy

cUOC Ginecologia e Ostetricia
Dipartimento Materno Infantile
ARNAS Garibaldi Nesima
Catania, Italy


1. The Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril. 2006; 86: S111-S114.

2. The Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006; 86: S264-S267.

3. Coulam CB, Jeyendran RS. Thrombophilic gene polymorphisms are risk factors for unexplained infertility. Fertil Steril. 2008 Oct 16. [Epub ahead of print]

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.02.007

The Authors Respond:

We agree with Dr. Bianca and  associates in their contribution supporting the role of inherited thrombophilias in human reproductive disorders including unexplained infertility.  They compared the frequency of 5 thrombophilic gene mutations between couples with a history of unexplained infertility and those with a history of recurrent pregnancy loss and found an association between them with Factor V H1299r heterozygosity and MTHFR C677T homozygosity.  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.  Taken together, these observations suggest that the association of reproductive disorders (as well as cardiovascular disease) and inherited thrombophilia is manifest by total number of thrombophilic mutations rather than specific genes involved.  As such, inherited thrombophilia represents multiple gene defects rather than single gene defects.


The mechanism by which thrombophilic gene mutations impact the frequency of recurrent miscarriage is thought to be related to clotting of placental vessels (6), of recurrent implantation failure to be involved with the effects of hypofibrinolysis on trophoblast migration (2),  and of  unexplained infertility  to entail folic acid metabolism (1).  While individuals with unexplained infertility may experience very early implantation failures, the mechanisms involved would be expected to be different than those with recognized recurrent implantation failure involving hypofibrinolysis.  The embryotoxic effects associated with MTHFR homozygosity have been postulated to be related to the influence of folic acid on the proliferation of rapidly dividing embryonic cells. Folic acid supplementation has been associated with an increase in dizygotic twinning (7).

Carolyn B. Coulam, MD
Pregnancy Success Center and Rinehart Center for Reproductive Medicine
Millenova Immunology Laboratories
Chicago, Illinois

1. Coulam CB, Jeyendran RS.  Thrombophilic gene polymorphisms are risk factors for unexplained infertility.  Fertil Steril 2008;Oct 16[Epub aheah of print].

2. Coulam CB, Jeyendran RS, Fishel LA, Roussev RG. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online     2006; 12: 322-327.

3. Coulam CB, Jeyendran RS, Fishel LA, Roussev RG.  Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol 2006;55:360-368.

4. Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R 2006  Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol 2006;56:230-236.

5. Coulam CB, Wallis D, Weinstein J, DasGupta DS, Jeyendran RS. Thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis.  Am J Reprod Immunol 2008;59:463-517.

6. Many A, Schrieber L Rosner S, Lessing JB, Eldor A. Kupferminc MJ:  Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.  Obstet Gynecol 2001;98:1041-1044.

7. Hasbargen U, Lohse P, Thaler CJ.  The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C>T mutation.  Hum Reprod 2000; 15:2659-2662.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.02.008




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