Human fetal bilirubin levels and fetal hemolytic disease

The development of secondary fetal anemia in association with maternal red blood cell alloimmunization requires hemolysis. In specimens obtained at the time of a clinically indicated cordocentesis, total and direct umbilical venous bilirubin was measured and the indirect umbilical venous bilirubin calculated in 43 antigen-positive and 30 control fetuses. Twenty-two (51%) of the antigen-positive fetuses had or subsequently developed severe anemia (hematocrit less than 30%). Umbilical venous total bilirubin (r = 0.47, p = 0.0008) and direct bilirubin (r = 0.520, p = 0.04) levels each rose with gestation. Indirect bilirubin did not vary significantly with gestation. Bilirubin was unrelated to hemoglobin. In contrast to the control fetuses, umbilical venous total bilirubin for antigen-positive fetuses was inversely related to hemoglobin (r = -0.57, p less than 0.0001) independent of gestational age (r = 0.53, p less than 0.0001) (multiple R of hemoglobin and gestational age for umbilical venous total bilirubin = 0.76, p less than 0.0001). Eighteen of 22 (82%) fetuses in whom anemia developed had an umbilical venous total bilirubin greater than or equal to 97.5 percentile compared with only eight of 21 (38%) fetuses in whom anemia did not develop (p = 0.009). In longitudinal study the umbilical venous total bilirubin frequently rose above normal weeks before the development of anemia. An umbilical venous total bilirubin greater than 3 mg/dl represented the warning line. Fifteen of 16 (94%) fetuses in whom either severe antenatal anemia or significant postnatal hyperbilirubinemia developed had an umbilical venous total bilirubin greater than 3 mg/dl. We conclude that the normal placental capacity for the transport of fetal bilirubin is exceeded in the face of enhanced fetal hemolysis. An elevated fetal bilirubin often precedes the development of antenatal anemia. The antigen-positive fetus with an elevated bilirubin is at high risk to develop anemia antenatally.