Anumba et al. Reproductive Biology and Endocrinology 2010, 8:62 http://www.rbej.com/content/8/1/62 Open Access RESEARCH © 2010 Anumba et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Research Circulating levels of matrix proteases and their inhibitors in pregnant women with and without a history of recurrent pregnancy loss Dilly OC Anumba*, Saad El Gelany, Sarah L Elliott and Tin C Li Abstract Background: We have recently shown that serum relaxin-2 levels are attenuated in women with a history of recurrent pregnancy loss (RPL). We sought to determine whether a history of RPL is also associated with changes in serum matrix metalloproteases (MMPs) and tissue inhibitors of matrix metalloproteases (TIMP) -1 and -2. Methods: We obtained serum from 20 pregnant women with a history of RPL and 20 age-matched pregnant women with no history of RPL (NRPL) at 6-8, 10-12, 20, and 34 weeks gestation, and from cord blood. We quantified total serum concentrations of MMP-1, MMP-3, MMP-9 and TIMP-1 and TIMP-2 by ELISA. We determined whether these serum marker levels were associated with a history of RPL and delivery before 37 weeks gestation. Results: There was no difference in the rates of miscarriage, preterm birth or prelabour rupture of fetal membranes between RPL and NRPL. However babies born to RPL were lighter than those born to NRPL. Serum MMP-1, 9, and TIMP- 1 did not differ between RPL and NRPL but MMP-3 was higher in RPL vs. NRPL at 6-8 weeks (P < 0.05). Serum TIMP-2 levels were higher in RPL women at all gestations (P < 0.01). The ratio of RLX-2 (reported previously) to TIMP-2 at 10-12 weeks gestation was more strongly associated with a history of RPL than either peptide separately - area under the ROC curves for RLX-2 0.79 (95% CI 0.57 to 0.92), TIMP-2 0.83 (95% CI 0.63 to 0.95), and for RLX-2:TIMP-2 ratio 0.92 (95% CI 0.74 to 0.99). Conclusions: Women with a history of RPL demonstrate increased serum TIMP-2 and reduced RLX-2 during a subsequent viable pregnancy. Determination of both markers in early pregnancy enhances the discrimination of women with a history of RPL. These observations suggest roles for these two peptides in early implantation and placental development. Whether these may prove to be reliable early predictive markers for subsequent pregnancy loss in the index pregnancy is unknown and will require further studies. Background Recurrent pregnancy loss (RPL) is a distressing clinical problem and affects 1% of all women. Although some of the associated conditions are known [1-4], the aetiology remains poorly understood and the course of any future pregnancy remains uncertain. Several serum factors are altered in some women with RPL but none of them reli- ably predicts repeat miscarriage [5-8]. Insulin resistance characterises RPL associated with the polycystic ovary (PCOS) syndrome but is not a reliable marker for repeat pregnancy loss [3]. We have recently demonstrated that serum Relaxin-2 (RLX-2) levels are attenuated in women with a history of RPL [9] and correlate with uterine artery Doppler resis- tance parameters in first trimester, consistent with a cru- cial role for this peptide in implantation and placental development [10,11]. Higher rates of adverse pregnancy outcomes associated with uteroplacental insufficiency have been reported in women with a history of RPL [12]. Matrix metalloproteinases (MMPs) are a family of pro- teolytic enzymes that play a central role in the breakdown and reorganization of extracellular matrix. The group consists of > 20 members and includes collagenases * Correspondence: d.o.c.anumba@sheffield.ac.uk 1 Section of Endocrinology and Reproduction, Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, 4th Floor, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK Full list of author information is available at the end of the article