Reproductive Biology Unit, Royal Womens Hospital, Carlton, 3053, Australia University Department of Obstetrics and Gynaecology, National Womens Hospital, Epsom Rd, Auckland, New Zealand
Dear Sir,
We were very interested to read the recent paper which investigated the usefulness of testing for antibodies to ß2 glycoprotein-I in patients with recurrent abortion or IVF implantation failure (Balasch et al., 1999). The authors concluded that screening for this antibody is not worthwhile in patients who are not seropositive for other, more commonly tested antiphospholipid antibodies such as lupus anticoagulant or anticardiolipin antibody.
Our study (Stern et al., 1998) showed that immunoglobulin M (IgM) antibodies to ß2 glycoprotein-I (ß2GPI) were significantly associated with recurrent spontaneous abortion (RSA) and IVF/implantation failure. It must be noted that our patient groups were very strictly defined: in our study, patients with recurrent miscarriage were women who had previously suffered at least three sequential first trimester miscarriages and patients with IVF/implantation failure had previously had at least 10 embryos transferred without achieving a clinical pregnancy. In that paper, in the interests of brevity, we did not specifically report the prevalence of antibodies to ß2 glycoprotein-I in women who were negative for all other antiphospholipid antibodies. We have now tested 327 women with RSA and 523 women with IVF/implantation failure and can report on the relevant results pertaining to IgM antibodies for ß2GPI. None of the 105 fertile controls (women with proven fertility) tested positive for ß2GPI IgM, compared with 3/53 (5.7%) infertile controls who had not yet commenced treatment, 37/327 (11.3%) of women with RSA (P < 0.0005), and 49/523 (9.4%) of patients with IVF/implantation failure (P < 0.0005). Of patients who were positive for ß2GPI IgM, only 7/37 (18.9%) with RSA were also positive for other antiphospholipid antibodies, while only 8/49 (16.3%) patients with IVF/implantation failure were also positive for other antibodies. We did not find that testing for IgG antibodies to ß2GPI was useful.
Thus, in this large series with clearly defined patient groups, IgM antibodies to the co-factor ß2GPI are a significant finding independent of results of testing for other antibodies. We do believe it is important to test for ß2GPI IgM in patients with RSA and IVF/implantation failure.
Notes
1 To whom correspondence should be addressed
References
Balasch, J., Reverter, J.C., Creus, M. et al. (1999) Human reproductive failure is not a clinical feature associated with ß2 glycoprotein-I antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid/cofactor syndrome). Hum Reprod., 14, 19561959.
Stern, C., Chamley, L., Hale, L. et al. (1998) Antibodies to ß2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil. Steril., 70, 938944.[ISI][Medline]
Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic, Hemotherapy and Hemostasis Unit; Hospital Clínic, C/Casanova 143, 08036-Barcelona, Spain
We thank Dr Stern and colleagues for their interest on our article (Balasch et al., 1999) and their additional comments trying to clarify their previous work (Stern et al., 1998
). They claim that `it is important to test for ß2 glycoprotein-I (ß2GPI) immunoglobulin M (IgM) antibodies in patients with recurrent miscarriage and IVF implantation failure'. In our opinion, this contention is not supported by current literature which may be summarized as follows:
Recent work by us (Balasch et al., 1999) and others (Chong et al., 1998
; Hollier et al., 1999
; Lee et al., 1999
) does not support routine testing for anti-ß2GPI in addition to testing for antiphospholipid antibodies (aPL) in women with reproductive failure, including both recurrent miscarriage (Balasch et al., 1999
; Lee et al., 1999
) and repeated implantation failure after IVF (Chong et al., 1998
; Balasch et al., 1999
).
Available data (including seven recently published articles; reviewed in Lee et al., 1999) suggest that anti-ß2GPI antibodies are strongly correlated with medical (thrombosis and thrombocytopaenia), as opposed to obstetric, complications of antiphospholipid syndrome (APS).
The very recent `International Consensus Statement on Preliminary Classification Criteria for Definite Antiphospholipid Syndrome' (Wilson et al., 1999) concluded that `laboratory features of APS such as anti-ß2GPI antibodies, require further standarization and/or study and should not be included as criteria at the present time'. The lack of universally accepted standards is currently analysed through an international collaborative study.
Whilst anti-ß2GPI antibodies may be less sensitive than aPL for APS (Hollier et al., 1999), the use of additional assays increases the chances of obtaining false-positive results and increases medical costs (Hatasaka et al., 1997
).
Although women undergoing IVF may have a higher prevalence of aPL, the antibodies do not appear to affect outcome. In fact, no autoantibody markers have been identified which can reliably predict the outcome of individuals undergoing IVF (Hatasaka et al., 1997).
Very recent prospective data indicate no increased risk for adverse pregnancy outcome in women with elevated titers of anti-ß2GPI antibodies (Lynch et al., 1999).
Taken together, available data clearly indicate that much more work is necessary before routine testing for ß2GPI antibodies in patients with recurrent miscarriage and IVF implantation failure may be proposed. At present, there are not potential benefits to using testing for such antibodies in addition to traditional testing for aPL in patients with reproductive failure associated with APS.
References
Balasch, J., Reverter, J.C., Creus, M. et al. (1999) Human reproductive failure is not a clinical feature associated with ß2 glycoprotein-I antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid/cofactor syndrome). Hum. Reprod., 14, 19561959.
Chong, P., Matzner, W. and Ching, W. (1998) Correlation between ß2-glycoprotein antibodies and antiphospholipid antibodies in patients with reproductive failure. Am. J. Reprod. Immunol., 40, 414417.[ISI][Medline]
Hatasaka, H.H., Branch, D.W., Kutteh, W.H. et al. (1997) Autoantibody screening for infertility: explaining the unexplained? J. Reprod. Immunol., 34, 137153.[ISI][Medline]
Hollier, N., Franklin, R.D., Kutteh, W.H. et al. (1999) Lack of correlation between antiphospholipid antibodies and beta 2-glycoprotein 1 antibodies in patients with recurrent pregnancy loss. [Abstract P-451.] In Conjoint Annual Meeting of the American Society for Reproductive Medicine and The Canadian Fertility and Andrology Society, Toronto, Ontario, Canada, September 1999. S-236.
Lee, R.M., Emlen, W., Scott, J.R. et al. (1999) Anti-ß2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome. Am. J. Obstet. Gynecol., 181, 642648.[ISI][Medline]
Lynch, A., Byers, T., Emlen, W. et al. (1999) The association of antibodies to ß2-glycoprotein I with pregnancy loss and pregnancy induced hypertension: a prospective study in low risk pregnancy. Obstet. Gynecol., 93, 193198.
Stern, C., Chamley, L., Hale, L. et al. (1998) Antibodies to ß2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil. Steril., 70, 938944.[ISI][Medline]
Wilson, W.A., Gharavi, A.E., Koike, T. et al. (1999) International Consensus Statement on Preliminary Classification Criteria for Definite Antiphospholipid Syndrome. Report of an International Workshop. Arthritis Rheum., 42, 13091311.[ISI][Medline]