Hum. Reprod. Advance Access originally published online on August 6, 2008
Human Reproduction 2008 23(11):2610-2611; doi:10.1093/humrep/den313
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Letters to the Editor |
Reply: Thrombophilic screening in clinical practice should be evidence-based
1 Instituto Valenciano de Infertilidad (IVI), Universidad de Valencia, Plaza de la Policía Local 3, 46015 Valencia, Spain 2 IVI Lisbon, Lisbon, Portugal
3 Correspondence address. Tel: +34-963050900; Fax: +34-963050999; E-mail: jbellver{at}ivi.es
We appreciate the comments by Drs Ricci and Simenone (2008)
and agree that thrombophilia screening should not be currently recommended in women with implantation failure (IF). Our published study (Bellver et al., 2008) suggested a possible relationship between thrombophilia and IF (as other previous papers have done—Coulam, 2006; Qublan et al., 2006) and, therefore, thrombophilia could constitute an etiologic factor for IF. The sample size considered in our work according to the strict inclusion criteria employed is not big enough to give a definitive answer.
Concerning the statistical queries, the analyses have been repeated and have confirmed the results published in the paper (Bellver et al., 2008). It is important to note the two statistical analyses performed in Table II. Given that categories were not ordered and defined different groups of patients [unexplained infertility, recurrent spontaneous abortion (RSA) and IF], their data could be analyzed as independent studies and considered as 2 x 2 tables against controls. Nevertheless, we performed the Bonferroni's correction to avoid multiple comparison biases, as stated in the manuscript. This second analysis was not significant, as described. These facts were discussed in the text. We must recognize that the very low frequencies obtained in some groups impose caution in the evaluation of the chi-square test results, but the very strict inclusion criteria of our work add strength to the data. There is only one typographical error in Table II regarding APCR. The P-value of 0.047 was obtained in the comparison between b and c, and not between a and c, as stated in the text.
Regarding the comments about the trend toward high prevalence of lupus anticoagulant (LA) in the IF group, the P-value is not significant in any case, as discussed by us, but an obvious increase exists (from 0% to 11.5%), and this could be statistically confirmed with an increased population size. Again, this aspect is highlighted in the text.
Concerning the revised classification criteria by Miyakis et al. (2006), these were established for a correct diagnosis and management of the antiphospholipid syndrome (APS). However, the definition of APS, based on Miyakis criteria (Miyakis et al., 2006) and previous international criteria (Wilson et al., 1999), includes not only a laboratory parameter (presence of LA/antiphospholipid antibodies) but also a clinical finding related to vascular thrombosis or pregnancy morbidity (recurrent miscarriage, fetal death or premature birth because of eclampsia/severe pre-eclampsia or placental insufficiency). Therefore, the Miyakis definition of APS is not applicable to our patients because, except for the group of RSA, the other three groups (IF, unexplained infertility and controls) did not present the clinical criteria. We only intended to determine the prevalence of antiphospholipid antibodies in our study groups, as other authors have done before (Stern et al., 1998; Qublan et al., 2006). On the other hand, as shown in the Materials and Methods section, our prospective study included women from 2004 to 2007. Hence, the inclusion criteria were established before 2004, when the new definition of APS by Miyakis et al. (2006) had not been published yet. At that time, anticardiolipin antibodies were considered positive in moderate or high titres, from 15 to 20 international ‘phospholipids’ units (Wilson et al., 1999; Levine et al., 2002), and that is the criterion we applied. Nowadays, these antibodies are considered positive at medium or high titres from 40 GPL or MPL or > the 99th centile (Miyakis et al., 2006). Finally, we do not consider the prevalence of antiphospholipid antibodies in our control group extremely high, since there were no positive cases of LA or IgG anticardiolipin antibodies, and only six (18.8%) of IgM anticardiolipin antibodies. In previous studies performed in healthy population of women without RSA or infertility, the presence of at least one of the antiphospholipid antibodies was estimated around 28% (Ober et al., 1993).
We really appreciate the observation by Drs Ricci and Simenone about the cases of combined thrombophilia in the IF group shown in Table III. In fact, as they have indicated and we described in Materials and Methods section, when APCR was positive and FVL too, we only considered the presence of FVL. When APCR was positive and FVL negative, we only took into account the presence of APCR. We have revised our database and previous drafts of the manuscript, and we have detected a mistake in the writing of the footnote of Table III. In fact, APCR was combined with hyperhomocystinemia and factor V Leiden with homozygous MTHFR mutation (lines 8 and 9 of the footnote of Table III). The prevalence of combined thrombophilia is therefore the same as published. Anyhow, the correction in the footnote does not change the meaning of the data, as no significant differences among groups were detected.
We agree with the last paragraph by Drs Ricci and Simenone. The results of our study do not indicate the inclusion of the thrombophilia screening in IF patients. In fact, in the discussion section (6th paragraph) we affirmed that ‘universal screening of thrombophilia should not be recommended in order to avoid over-diagnosis and over-treatment of healthy subjects’. Our paper only opens the way to further investigations about this, to date, unknown topic.
References
Bellver J, Soares SR, Álvarez C, Muñoz E, Ramírez A, Rubio C, Serra V, Remohí J, Pellicer A. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod (2008) 23:278–284.
Coulam CB. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online (2006) 12:322–327.[Web of Science][Medline]
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Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RHWM, de Groot PG, Koike T, Meroni PL, et al. International consensus statement on an update on the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost (2006) 4:295–306.[CrossRef][Web of Science][Medline]
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Stern C, Chamley L, Hale L, Kloss M, Speirs A, Baker HW. Antibodies to β2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil Steril (1998) 70:938–944.[CrossRef][Web of Science][Medline]
Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum (1999) 42:1309–1311.[CrossRef][Web of Science][Medline]
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