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To evaluate the ability of maternal serum-free β-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha fetoprotein (AFP) levels in the screening of fetuses with hemoglobin (Hb) Bart's disease among pregnancies at risk.Pregnancies at risk for fetal Hb Bart's disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Maternal serum-free β-hCG, PAPP-A, and AFP concentrations were measured before cordocentesis, and the final fetal diagnosis of Hb Bart disease was based on fetal Hb typing using high-performance liquid chromatography.Of 57 recruited pregnancies, 11 had fetal Hb Bart's disease and 46 were unaffected. Maternal serum alpha-fetoprotein (MSAFP) concentrations were significantly higher in women with fetal Hb Bart's disease than those with unaffected fetuses (median 99.53 vs 50.83, P < 0.001), whereas the concentrations of free β-hCG and PAPP-A were not significantly different between the two groups (P = 0.543 and 0.777, respectively).Second-trimester MSAFP may be clinically a useful screening test for fetal Hb Bart's disease among pregnancies at risk. Copyright © 2011 John Wiley & Sons, Ltd.