Antiphospholipid antibodies and reproductive failure

Talia Eldar-Geva1,3 and Alan O. Trounson2

1 IVF Unit, Shaare-Zedek Medical Center, P.O.Box 3235, Jerusalem, 91031, Israel 2 Centre for Early Human Development, Monash Medical Centre, Monash University, 246 Clayton Road, Clayton, Vic 3168, Australia

Dear Sir,

We appreciate Dr Stern's interest in our study on antiphospholipid antibodies in IVF patients (Eldar-Geva et al., 1999Go). As we wrote in our introduction, `the relevance of the presence of antiphospholipid antibodies to IVF outcome is still a matter of debate'. However, the citation of Birdsall et al. (1992, 1996) as a dissenter to our conclusions is misleading since these authors found an association between antiphospholipid antibodies (APAs) and pregnancy complications, but not IVF failure.

The concern of Dr Stern and her colleagues regarding a small negative study is unfounded. They failed to comprehend the data presented. They did not take into account that the group of pregnant women (77 patients, 86 pregnancies) was much smaller than the entire study group (173 patients, 464 embryo-transfer procedures). Furthermore, their interest in confidence limits (that were calculated but were not presented) missed the point of the study. The null hypothesis was that APA seropositive patients would have a lower pregnancy rate. We think that it is very clear from the data presented that the cumulative pregnancy rates were not lower in seropositive patients compared to borderline or seronegative ones. For example, the cumulative pregnancy rate for seronegative, borderline and seropositive patients, were 17.3, 18.5 and 18.8% for one cycle, 30.6, 32.9 and 32.6% for two cycles and 50, 53.8 and 52.2% for six cycles.

We agree that since APAs levels are not normally distributed, it would be better for Matzner et al. (1994) to use non-parametric statistics for the definition of `normal controls'. Unfortunately, Dr Stern did not cite our methods properly. We defined seropositivity only if the levels were greater than 3 standard deviations above the mean and borderline results if the level was greater than 2 standard deviations above the mean. This published method (Matzner et al., 1994Go) was used by other investigators (Sher et al., 1994) to show that in a selected group of patients APAs were associated with IVF failure. Furthermore, it was claimed that anti-thrombotic or steroid treatment of seropositive patients improved IVF outcome (Birkenfeld et al., 1994Go; Sher et al., 1994, 1998Go). Our results, using not only the same method but actually the same laboratory, showed no relationship between APAs and ART outcome. Two other large studies in non-selected ART patients support this conclusion (Kowalik et al., 1997; Denis et al., 1998). Using the above method, the well-known association between recurrent miscarriage and APA was re-established (Sher et al., 1994; Egbase et al., 1999Go; Eldar-Geva et al., 1999Go).

Although some investigators support the hypothesis that ß2 glycoprotein I autoantibodies or ß2 glycoprotein-dependent anticardiolipin antibodies are associated with recurrent abortion (Katano et al., 1996Go; Stern et al., 1998Go) or IVF failure (Stern et al., 1998Go), others showed contrary results (Maejima et al., 1997; Chong et al., 1998Go). Furthermore, Aoki et al. (1995) found a significant correlation between positivity in two of anticardiolipin, antiphosphatidylserine and antiphosphatidylinositol and the ß2 glycoprotein-dependent anticardiolipin antibodies. According to American College of Obstetrics and Gynecology (ACOG) recommendations (1998), the clinical application of any single APA, other than anticardiolipin and lupus anticoagulant, is uncertain and should not be a basis for diagnosis or treatment.

Finally, regarding the low prevalence of lupus anticoagulants (LAC) in both our studies. Contrary to Dr Stern's study, we did not investigate patients with recurrent miscarriage. In Dr Stern's study, the prevalence of both anticardiolipin antibobies (4.1%) and lupus anticoagulants (0%) in patients with recurrent miscarriage were much lower than those reported previously in larger series (Lockwood et al., 1989Go; Harris and Spinnato, 1991Go), average incidence 7 and 17% respectively, although the prevalence in normal fertile controls was comparable (1.9% in Stern's study compared to 1–3% in the literature).

Notes

3 To whom correspondence should be addressed. E-mail: gevat{at}szmc.org.il Back

References

American College of Obstetrics and Gynecology (ACOG) Educational Bulletin Number 244, February 1998.

Aoki, K., Dudkiewicz, A.B., Matsuura, E., et al. (1995) Clinical significance of ß2-glycoprotein I-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: Correlation with conventional antiphospholipid antibody detection systems. Am. J. Obstet. Gynecol., 172, 926–931.[ISI][Medline]

Birdsall, M., Pattison, N., and Chamley, L. (1992) Antiphospholipid antibodies in pregnancy. Aust. N. Z. J. Obstet. Gynaecol., 32, 328–330.[ISI][Medline]

Birdsall, M.A., Lockwood G.M., Ledger, W.L. et al. (1996) Antiphospholipid antibodies in women having in-vitro fertilization. Hum. Reprod., 11, 1185–1189.[Abstract]

Birkenfeld, A., Mukaida, T., Minichiello, L. et al. (1994) Incidence of autoimmune antibodies in failed embryo transfer cycles. Am. J. Reprod. Immunol., 31, 65–68.[ISI][Medline]

Chong, P., Matzner, W., and Ching, W. (1998) Correlation between beta 2-glycoprotein antibodies and antiphospholipid antibodies in patients with reproductive failure. Am. J. Reprod. Immunol., 40, 414–417.[ISI][Medline]

Egbase, P.E., Al-Sharhan, M., Diejomaoh, M., and Grudzinskas, J.P. (1999) Antiphospholipid antibodies in infertile couples with two consecutive miscarriages after in-vitro fertilization and embryo transfer. Hum. Reprod., 14, 1483–1486.[Abstract/Free Full Text]

Eldar-Geva, T., Wood, C., Lolatgis, N. et al. (1999) Cumulative pregnancy and live birth rates in women with antiphospholipid antibodies undergoing assisted reproduction. Hum. Reprod., 14, 1461–1466.[Abstract/Free Full Text]

Harris, E.N. and Spinnato, J.A. (1991) Should anticardiolipin tests be performed in otherwise healthy pregnant women? Am. J. Obstet. Gynecol., 165, 1272[ISI][Medline]

Katano, K., Aoki, K., Sasa, H., et al. (1996) ß2-glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women. Hum. Reprod., 11, 509–512.[Abstract]

Lockwood, C.J., Romero, R., Feinberg, R.F. et al. (1989) The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am. J. Obstet. Gynecol., 161, 369[ISI][Medline]

Maejime, M., Fujii, T., Okai, T. et al. (1997) ß2-glycoprotein I-dependent anticardiolipin antibody in early recurrent spontaneous abortion. Hum. Reprod., 10, 2140–2142.

Matzner, W., Chong, P., Xu, G. and Ching, W. (1994) Characterisation of antiphospholipid antibodies in women with recurrent spontaneous abortions. J. Reprod. Med., 39, 27–30.[ISI][Medline]

Sher, G., Zouves, C., Feinman, M. et al. (1998) A rational basis for the use of combined heparin/aspirin and IVIG immunotherapy in the treatment of recurrent IVF failure associated with antiphospholipid antibodies. Am. J. Reprod. Immunol., 39, 391–394.[ISI][Medline]

Stern, C., Chamley, L.W., Hale, L. et al. (1998) Antibodies to ß2-glycoprotein I are significantly associated with in-vitro-fertilisation implantation failure as well as recurrent miscarriage: results of a prospective prevalence study. Fertil. Steril., 70, 938–944.[ISI][Medline]





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