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Inherited thrombophilia and in vitro fertilization implantation failure

2001; Elsevier BV; Volume: 76; Issue: 1 Linguagem: Inglês

10.1016/s0015-0282(01)01832-5

1556-5653

Elvira Grandone, Donatella Colaizzo, Arianna Lo Bue, Maria Gabriella Checola, E Cittadini, Maurizio Margaglione,

Hemophilia Treatment and Research

Genetic causes of thrombophilia are associated with the occurrence of repeated or recurrent pregnancy losses (1Grandone E Margaglione M Colaizzo D D'Addedda M Cappucci G Vecchione G et al.Factor V Leiden is associated with repeated and recurrent fetal losses.Thromb Haemost. 1997; 77: 822-824PubMed Google Scholar). In this respect, the role of factor V (FV) Leiden has been clearly demonstrated, whereas factor II (FII) A20210 mutation is more controversial (2Brenner B Sarig G Weiner Z Younis J Blumenfeld Z Lanir N Thrombophilic polymorphism are common in women with fetal loss without apparent cause.Thromb Haemost. 1999; 82: 6-9PubMed Google Scholar, 3Martinelli I Taioli E Cetin I Marinoni A Gerosa S Villa M.V et al.Mutation in coagulation factors in women with unexplained late fetal loss.N Engl J Med. 2000; 343: 1015-1018Crossref PubMed Scopus (301) Google Scholar). To date, information about the prevalence of genetic causes of thrombophilia in in vitro fertilization (IVF) implantation failure has been lacking. These mutations may also have a role in IVF implantation failure or in pregnancy loss after IVF. From February 1999 to July 2000, 435 women underwent 844 treatment cycles at the Centro di Biologia della Riproduzione in Palermo. From this group we enrolled 18 women in our study (Group A) who had had at least 3 IVF cycles with subsequent fetal loss (n = 8) or implantation failure (n = 10). A second group of IVF patients (Group B, n = 24) was randomly selected from among the women who were concomitantly attending the same center; Group B was composed of women at their first or second IVF attempt and those with almost one successful pregnancy after an IVF cycle. A third group of parous women (Group C, n = 216) who had conceived spontaneously and had uneventful pregnancies were also included in our study for comparison. All the Group C women were white and lived in Southern Italy. The three groups were comparable for social status. All participants signed an informed consent; the approval of the institutional review board was obtained and the study was carried out according to the Principles of the Declaration of Helsinki. All of the women included in Groups A and B underwent a complete screening for congenital (FV Leiden and FII A20210 mutations, and antithrombin, protein C, and protein S deficiencies) and acquired (lupus anticoagulant and/or anticardiolipin antibodies) causes of thrombophilia. The women and their partners both had karyotype screenings. We performed a large panel of autoantibodies, as well as FT3, FT4, and TSH evaluations. The statistical significance of differences in mean was evaluated by nonparametric test; the statistical significance of any difference in proportions was evaluated by χ2 test. The statistical significance of the difference of alleles and genotypes observed between the groups was tested using the Fisher exact test. The participants' mean age, cause(s) of infertility, and genetic and biochemical findings are illustrated in Table 1. In Group A, all the patients except one had had no previous deliveries. Among women included in Group A (see Table 1), two showed the FV Leiden and three the FII A20210 mutation. One of these patients showed the contemporary presence of the FV Leiden mutation and a positive test result for aCL IgG; another woman tested positive for antitireoperoxidase antibodies. One woman also exhibited antibodies against smooth muscle cells in absence of acquired or inherited thrombophilia. In Group B, none of the women carried the FV Leiden or the FII A20210 mutation (P=NS, Fisher exact test).Table 1Features of the different settings. legenda P=.01 vs. Group B (Fisher's exact test)., legendb P=.007 vs. Group A (Fisher's exact test)., legendGrandone. Inherited thrombophilia and IVF implantation failure. Fertil Steril 2001.Group A (n = 18) ≥3 IVF attempts with fetal loss or implantation failureGroup B (n = 24) First or second IVF attemptGroup C (n = 216) Women conceiving spontaneouslyMean (±SD) age in y32.9 ± 4.535.6 ± 4.133.8 ± 7.1Causes and type of infertilityMale1218—Tuba33—Unexplained23—Endometriosis1——Factor V Leiden n (%)2 (11.1)04 (1.9)Factor II A20210 n (%)3 (16.6)09 (4.1)Both5 (27.7)a013 (6.0)blegend a P=.01 vs. Group B (Fisher's exact test).legend b P=.007 vs. Group A (Fisher's exact test).legend Grandone. Inherited thrombophilia and IVF implantation failure. Fertil Steril 2001. Open table in a new tab Overall, there were five (27.7%) carriers of one of the prothrombotic mutations in Group A (P=.010, Fisher exact test), and none in Group B. Moreover, two women in Group B had antiphospholipid antibodies (LA and/or aCL), and one had antitireoperoxidase antibodies. In both Groups A and B, protein C, protein S, and antithrombin levels were normal. Five women in Group A had a history of spontaneous fetal losses: two of them showed the FV Leiden and the FII A20210 mutation, respectively; another woman tested positive for anticardiolipin antibodies. Among the women included in Group B, two had had previous spontaneous fetal losses in apparent absence of any acquired or inherited thrombophilia. The FV Leiden mutation was found in four (1.9%) women in Group C, the obstetric population (women who had conceived spontaneously). There were also nine (4.2%) carriers of the FII A20210 allele in this group. The frequencies of the FV Leiden and FII A20210 mutations in this group were not significantly different from those found in a sample of 431 healthy women from the same ethnic background (4Margaglione M D'Andrea G D'Addedda M Giuliani N Cappucci G Iannaccone L et al.The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutations.Thromb Haemost. 1998; 79: 907-911PubMed Google Scholar). One woman in Group A showed a history of superficial venous thrombosis in one leg; no instances of deep vein thrombosis were registered in Groups B and C. A family history of thrombophilia was present in one woman in Group A who carried the A20210 FII variant; her father had suffered from a myocardial infarction at 62 years of age. Overall, the prevalence of the FV Leiden and FII A20210 mutations in Group C was 6.1%, which was significantly different from that observed in Group A (P=.007, Fisher exact test). The difference in the frequency of each mutation was not statistically significant between Group A and Group B, although the difference in the prevalence of the FII A20210 allele did show a trend toward significance (P=.071, Fisher's exact test). This lack of statistical significance seems to be due to the small sample size. Indeed, grouping the FV Leiden and the FII A20210 carriers, the prevalence of these mutations in Group A was significantly higher than was found among the women in Group B (P=.010, Fisher's exact test). Our data suggest that prothrombotic gene mutations in the form of the FV Leiden and possibly the FII A20210 allele, alone or combined with acquired factors, can have a role in implantation failure or in fetal loss after IVF. If other, larger series confirm these data, it could be hypothesized that anticoagulation therapy or prophylaxis could be useful in increasing the implantation rate. The authors thank Giuseppe Cappucci and Gennaro Vecchione for their helpful technical assistance.