OBJECTIVE: To assess whether levels of first-trimester pregnancy-associated plasma protein A (PAPP-A) differ between women with and without sickle cell disease (SCD). METHODS: Retrospective study of 101 singleton pregnancies in women with SCD (including 55 with genotype HbSS, 37 with genotype HbSC, and nine with other genotypes). Measured levels of PAPP-A were converted to multiple of the median (MoM) values corrected for gestational age and maternal characteristics. Median PAPP-A MoM in the SCD group was compared with that of 1010 controls. RESULTS: In the SCD group median, PAPP-A MoM was lower than in the non-SCD group (0.72, interquartile range [IQR] = 0.54-1.14 versus 1.09, IQR = 0.74-1.49; P < .001). Within the SCD group median PAPP-A MoM was lower for those with genotype HbSS than HbSC (0.62, IQR = 0.44-1.14 versus 0.94, IQR = 0.72-1.25; .006). In 7.3% (4/55) of the HbSS group, there was stillbirth, and in these cases, PAPP-A was less than or equal to 0.5 MoM; in the control group, the incidence of stillbirth was lower (1%; P < .001). In HbSS disease, the incidence of small for gestational age (SGA) neonates was increased. CONCLUSION: Pregnancies with HbSS have lower PAPP-A MoM values and higher incidence of stillbirth and birth of SGA neonates than in non-SCD controls.