Key Points• Prophylactic transfusion in pregnant women with SCD may reduce maternal mortality, vaso-occlusive pain events, and pulmonary complications.• Prophylactic transfusion in pregnant women with SCD may similarly reduce perinatal mortality, neonatal death, and preterm birth.Pregnancy in women with sickle cell disease is associated with adverse maternal and neonatal outcomes. Studies assessing the effects of prophylactic red blood cell transfusions on these outcomes have drawn inconsistent conclusions. The objective of this systematic review was to assess the effect of prophylactic compared with on-demand red blood cell transfusions on maternal and neonatal outcomes in women with sickle cell disease. A systematic search of several medical literature databases was conducted. Twelve studies involving 1291 participants met inclusion criteria. , and preterm birth (9 studies, 1123 participants; OR, 0.59; 95% CI, 0.37-0.96). Event rates for most of the results were low. Prophylactic transfusions may positively impact several adverse maternal and neonatal outcomes in women with sickle cell disease; however, the evidence stems from a relatively small number of studies with methodologic limitations. A prospective, multicenter, randomized trial is needed to determine whether the potential benefits balance the risks of prophylactic transfusions. (Blood. 2015;126(21):2424-2435