BACKGROUND: Patients with amniotic fluid embolism (AFE) (major cardiac and pulmonary symptoms plus consumptive coagulopathy) have high circulating tissue factor concentrations. Recombinant factor VIIa (rVIIa) has been used to treat hemorrhage in AFE patients even though rVIIa can combine with circulating tissue factor and form intravascular clots. A systematic review was done of case reports from 2003 to 2009 of AFE patients with massive hemorrhage who were and were not treated with rVIIa to assess the thrombotic complication risk. METHODS: MEDLINE was searched for case reports of AFE patients receiving rVIIa (rVIIa cases) and of AFE patients who received surgery to control bleeding but no rVIIa (cohorts who did not receive rVIIa). Additional AFE case reports were obtained from the Food and Drug Administration, the Australian and New Zealand Haemostasis Registry, and scientific meeting abstracts. The risk of a negative outcome (permanent disability or death) in rVIIa cases versus cohorts who did not receive rVIIa was calculated using risk ratio and 95% confidence interval. RESULTS: Sixteen rVIIa cases and 28 cohorts were identified who did not receive rVIIa. All patients had surgery to control bleeding. Death, permanent disability, and full recovery occurred in 8, 6, and 2 rVIIa cases and 7, 4, and 17 cohorts who did not receive rVIIa (risk ratio 2.2, 95% CI 1.4-3.7 for death or permanent disability vs. full recovery). CONCLUSION: Recombinant factor VIIa cases had significantly worse outcomes than cohorts who did not receive rVIIa. It is recommended that rVIIa be used in AFE patients only when the hemorrhage cannot be stopped by massive blood component replacement.