- To investigate immediate perinatal outcome of RhD-negative patients carrying RhD-positive fetuses who received antenatal Rh immunoglobulin for the prevention of RhD-mediated hemolytic disease of the fetus and newborn. A retrospective population-based analysis was conducted comparing pregnancies of all RhD-negative women who received antenatal Rh immunoglobulin prophylaxis (anti-D), to RhD-positive parturients, during the years 1988-2003. All women were RhD-negative without evidence of RhD sensitization. Patients received anti-D during the 28-30th week of pregnancy, and an additional dosage within 72 hours following delivery after confirmation of the newborn's RhD status. Of 145,437 deliveries during the study period, 6.8% were of RhD-negative women (n = 9961). Perinatal mortality rate was significantly higher among the RhD-negative women who received antenatal prophylaxis rhesus immunoglobulin as compared with the controls (17/1000 vs. 12/1000, OR = 1.3, 95%CI 1.2-1.6; p < 0.001). This higher mortality rate was related to a higher rate of intrauterine fetal demise (IUFD) (10/1000 vs. 6/1000, OR = 1.5, 95%CI 1.2-1.9; p < 0.001). The association remained significant after controlling for RhD isoimmunization leading to hydrops fetalis, using the Mantel-Haenszel technique (weighted OR = 1.3; 95% CI 1.1-1.5; p = 0.001). The rate of RhD isoimmunization was 0.6% (n = 58). Using a multivariable analysis with IUFD as the outcome variable, controlling for known confounders for fetal demise, RhD-negative status was an independent risk factor for IUFD. RhD-negative women carrying RhD-positive newborns are at an increased risk for IUFD despite Rh immunoprophylaxis.