Genetic mid-trimester amniocentesis is a common invasive procedure. The origin of the commonly quoted 0.5% rate of procedure-related pregnancy loss after amniocentesis is obscure and is in conflict with the only randomized prospective study that reported a procedure-related rate of loss of 1.0%. This review was performed to establish an estimate of procedure-related pregnancy loss after mid-trimester amniocentesis. The impact of placental puncture on the rate of loss and the risk of direct needle injury to the fetus were also examined. The National Library of Medicine database was used to identify English language reports of >1000 amniocenteses with sufficient detail and follow up data to allow the calculation of the rate of spontaneous pregnancy loss after amniocentesis but before 28 completed weeks. These reports were divided into 2 groups to assess the impact of the ultrasound technique. Group I described only preamniocentesis ultrasound evaluation; group II described primarily concurrent ultrasound needle guidance. Pregnancy loss between the 2 groups was compared. The impact of placental puncture and reported direct fetal trauma were examined. The significance of differences was tested using chi-square analysis, with significance at a probability value of < or =.05. Twenty-nine reports that totaled 68,119 amniocenteses were examined. In a comparison of all studies in group I with all studies in group II, there was a lower rate of loss after amniocenteses with the use of concurrent guidance (1.4%) compared with the use of preamniocentesis ultrasound evaluation (2.1%) that was significant ( P <.001). Among only the 5 controlled studies that used preamniocentesis ultrasound evaluation, the difference in rate of loss between amniocentesis patients and control subjects was 0.6% ( P =.0042; 95% CI, 0.19, 1.03), which was identical to the difference in the rate of loss of 0.6% between amniocentesis patients and control subjects from the 5 controlled studies that used concurrent ultrasound needle guidance ( P <.0001; 95% CI, 0.31, 0.90). Multiple case reports and small series of presumed fetal needle trauma were reviewed, but most of these attributed causation to the amniocentesis needle based only on circumstantial association. Two cases with direct evidence of fetal needle trauma are discussed. Finally, the rate of loss after placental puncture from among 9 reports that provided this detail was 1.4% and not different from the overall rate of loss that was noted in group II. This examination of experience with 68,119 amniocenteses from both controlled and uncontrolled studies provides a substantive basis for several conclusions: (1) Contemporary amniocentesis with concurrent ultrasound guidance in controlled studies appears to be associated with a procedure-related rate of excess pregnancy loss of 0.6% (95% CI, 0.31, 0.90). To determine the total rate of loss, this must be added to the reported natural rate of loss without amniocentesis among control patients of 1.08%. (2) The use of concurrent ultrasound guidance appears to reduce the number of punctures and the incidence of bloody fluid. Concurrent ultrasound guidance was associated with a reduced rate of loss when all studies were compared, but not among controlled studies. (3) Direct fetal needle trauma is rare, and rarely proved, but may occur more frequently than is reported because of a failure to diagnose and a failure of the consistent production of sequelae. (4) This experience does not substantiate an increased rate of pregnancy loss if placental puncture is required.