Worsening fetal gas exchange is the hallmark of frequently observed placental dysfunction after fetal bypass. Several factors influence this pathophysiology, but the optimal prime constituents for fetal bypass have yet to be defined. Calcium and sodium bicarbonate are frequently added to prime solutions for adjustments toward physiologic values. We examined whether similar manipulations are warranted with fetal bypass. Ovine fetuses (n = 10) at 104-110 days' gestation were placed on bypass for 30 minutes. Calcium chloride and sodium bicarbonate were added to adjust prime ionized calcium and pH. Fetal hemodynamics and arterial blood gases were collected immediately before, and 15 and 30 minutes on bypass. Statistical significance was determined by Student's t test and best fit correlations. Calcium addition negatively correlated with fetal pH (R ≥ 0.63) and po2 (R ≥ 0.41), and displayed a robust positive correlation with pco2 (R = 0.88) during bypass. Similarly, bicarbonate addition revealed correlations for pco2 (R ≥ 0.70) and po2 (R ≥ 0.57), with a strong negative correlation to umbilical blood flow (R ≥ 0.75). Calcium addition to the prime adversely affects fetal gas exchange worsening acidosis during fetal bypass. Bicarbonate addition to the prime is also detrimental to the fetus resulting in greater CO2 production and impaired hemodynamics.