Fetal cardiac surgery may allow us to correct primary cardiac defects before secondary effects are fixed. Though technically feasible, feto-placental unit (FPU) failure occurs. Various interventions reduce the damage: most particularly Hemopump bypass is more succesful though the reason is unknown. We have shown that fetal Hemopump bypass activates complement and neutrophils and explored whether roller pump bypass was more damaging due to a greater inflammatory response. Sixteen 120 day old sheep fetuses underwent fetal bypass using a roller pump or Hemopump for 30 minutes. Arterial pressure, heart rate, and combined ventricular output monitored hemodynamics and blood gas analysis FPU function. Blood samples were drawn prior to bypass(1), at the end of bypas (2), 1 hour after bypass (3), and in survivors after another hour (4) for C3a and lactoferrin assay. Animal survival, hemodynamic measurements, and FPU function were significantly better with the Hemopump. With the Hemopump C3a levels rose from 152 +/- 44 (1) to 204 +/- 37 (2), then fell to 155 +/- 15 (3) with a late secondary rise to 192 +/- 48 (4). Lactoferin levels rose initially; 132 +/- 17 (1), 328 +/- 46 (2), 2163 +/- 758(3), then fell to 1201 +/- 521 (4). C3a levels for roller pump bypass were 158+/- 9 (1), 208 +/- 14 (2), 162 +/- 14 (3), and 190 +/- 4 (4) and lactoferrin levels 116 +/- 16 (1), 271 +/- 103 (2), 3767 +/- 435 (3), and 5888 +/- 592(4). There was no significant difference in C3a levels between the two groups at any time. By ANOVA repeated measures analysis, though there was no significant difference in lactoferrin level between the groups through time point (3), there was a highly significant difference when taken to time point(4)[p<0.001]. Thre was the same direct relationship between lactoferrin level and FPU deterioration for both bypass techniques. We conclude that there is much greater neutrophil activation with roller pump bypass than Hemopump though complement activities are similar. The direct relationship between lactoferin level and FPU deterioration suggests neutrophil activation may be the mechanism of FPU failure following fetal cardiac bypass.