OBJECTIVE: Spontaneous miscarriage is a frequent occurrence in human reproduction, including 2-5% of couples who experience recurrent pregnancy loss. Patient management is contentious with up to 50% of cases having no identifiable reason. Recent diagnostic approaches have included the investigation of placental function and maternal-fetal immunology. In this study we examined the molecular signature of spontaneous pregnancy loss in a fertile mouse model. DESIGN: Experimental study. MATERIALS AND METHODS: Morphologically similar hatching blastocysts (F1 C57BL/6 x DBA) were transferred to recipient females (one per uterine horn). On day 16 of fetal development, uterine horns were surgically removed to confirm either the presence of a healthy fetus or a non-viable implantation (absorption). Total RNA was isolated from individual biopsies of healthy placenta (n=10) and absorptions (n=10) for microarray transcriptome analysis and quantitative real-time PCR. RESULTS: Comprehensive transcriptome analysis of biopsied healthy placenta and absorptions allowed for the molecular characterization of spontaneous pregnancy loss, including 5918 differentially expressed transcripts (P<0.05). The most predominant altered pathways were the complement and coagulation cascades in which 26 transcripts were disrupted (P<0.05). Validation was confirmed for 10 transcripts with quantitative real-time PCR. Three transcripts showed decreased gene expression in absorptions including the coagulation inhibitor Tfp1 (P<0.05), while seven transcripts displayed increased expression in absorptions including the key complement factors: C3, C1q and C2 (P<0.05). CONCLUSION: In this study, inappropriate complement and coagulation cascade activation, resulting in differential expression of activators and inhibitors, was significantly associated with spontaneous miscarriage in a fertile mouse model. Ongoing strategies to unravel the molecular basis of non-viable implantation may allow development of novel clinical interventions to prevent pregnancy loss.