We have read with great interest the study by Dossenbach-Glaninger et al demonstrating a significant association between the protein-Z (PZ) intron 79G allele and recurrent pregnancy loss (1). In a recent study of 51 women with recurrent early pregnancy loss vs. 47 control women with at least one successful pregnancy and no spontaneous abortions, this finding was not confirmed (2); however, a significant association between low PZ levels and recurrent pregnancy loss was observed, in agreement with a previous larger-scale study (3).
We also pooled the above (2) data with 10 parous women who had a history of endometrial death with or without recurrent early abortions and 13 nulliparous women with no history of spontaneous abortions. Interestingly, in GLM-AN(C)OVA and logistic regression analysis, low protein-Z levels were independently associated not only with recurrent early pregnancy loss (F=15.575, P<0.001), but also with achievement of a successful pregnancy [F=4.022, P=0.047; OR(95%CI)=1.99(1.1-3.599), P=0.02 independent of a history of recurrent early abortions or late endometrial death] (Figure 1). Again, no particular association between the G79A polymorphism and recurrent pregnancy loss or parity was observed.
Given the above evidence, we postulate that low PZ levels, rather than the presence of the F 79G allele, might be a novel risk factor for infertility due to otherwise unexplained recurrent early pregnancy loss.Smaragda Effraimidou, MSc
Dimitrios Farmakiotis, MD
Maria Topalidou, MD
Haemostatis Unit, Department of Haematology “Papageorgiou” General Hospital,
1. Dossenbach-Glaninger A, van Trotsenburg M, Helmer H, Oberkanins C, Hopmeier P. Association of the protein Z intron F G79A gene polymorphism with recurrent pregnancy loss. Fertil Steril 2008;90:1155-60.
2. Topalidou M, Effraimidou S, Farmakiotis D, Papadakis E, Papaioannou G, Korantzis I, Garipidou V. Protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss. Thromb Res; in press. Reference #: TR 3537
3. Gris JC, Quere I, Dechaud H, Mercier E, Pincon C, Hoffet M, Vasse M, Mares P. High frequency of protein Z deficiency in patients with unexplained early fetal loss. Blood 2002;99:2606-8.
Published online in Fertility and Sterility DOI: 10.1016/j.fertnstert.2008.12.100
The Authors Respond:
Effraimidou et al. question the association of recurrent early pregnancy loss with the protein Z intron F G79A polymorphism. Their criticism is mainly based on combined data of women with recurrent pregnancy loss, of nulliparous women with no history of abortions and of women with a history of endometrial death (1). However, pooling data with different pathologies is not suitable to provide additional information on a possible causative relation of protein Z levels or genotypes with recurrent pregnancy loss.
Moreover, certain auto-antibodies against coagulation proteins are known to be strong risk factors for vascular pregnancy complications. In this context, Gris et al. report a good inverse correlation between protein Z-IgM antibody level and protein Z concentration in women with recurrent embryo losses and protein Z deficiency (2,3). Therefore, protein Z levels should not be correlated with protein Z genotypes without determination of protein Z antibodies.Astrid Dossenbach-Glaninger, MD
Pierre Hopmeier, MD
Department of Laboratory Medicine
1. Topalidou M, Effraimidou S, Farmakiotis D, Papadakis E, Papaioannou G, Korantzis I, Garipidou V. Protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss. Thromb Res; in press. Reference #: TR 3537
2. Gris JC, Quéré I, Dechaud H, Mercier E, Pincon C, Hoffet M, Vasse M, Marès P. High frequency of protein Z deficiency in patients with unexplained early fetal loss. Blood 2002;99:2606-8.
3. Gris JC, Amadio C, Mercier E, Lavigne-Lissalde, Dechaud H, Hoffet M, Quéré I, Amiral J, Dauzat M, Marès P. Anti-protein Z antibodies in women with pathologic pregnancies. Blood 2003;101:4850-4852.
Published online in Fertility and Sterility DOI: 10.1016/j.fertnstert.2008.12.101