Improving prenatal thalassemia carrier detection with a combined MCV and MCH strategy: a 24-year retrospective cohort study

Carrier screening for thalassemia conventionally uses a mean corpuscular volume (MCV) cutoff ≤ 80 fL. However, silent carriers harboring mild mutations often present with borderline indices, which, if missed, may result in offspring with hemoglobin H disease or other significant hemoglobinopathies. Thus, we aimed to evaluate whether alternative hematological cutoffs could reduce this detection gap. Of 15,212 prenatal samples collected in Taiwan between 2000 and 2024, this retrospective cohort study analyzed 9,949 genetically confirmed thalassemia carriers (α-thalassemia, n = 7,473; β-thalassemia, n = 2,476) and 3,025 genotype-negative individuals, who served as the noncarrier reference group. The sensitivity and specificity of the conventional MCV threshold and alternative strategies incorporating higher MCV cutoffs and mean corpuscular hemoglobin (MCH) ≤ 27 pg were calculated and compared, stratified by sex. -- SEA deletion (78.71% of α-thalassemia carriers) and IVS-II-654 mutation (34.65% of β-thalassemia carriers) were the predominant genotypes. Under the conventional MCV threshold, approximately 5.3% of carriers were missed, including 6.3% and 2.3% of α- and β-thalassemia carriers, respectively. Among the predefined candidate thresholds evaluated, the MCV ≤ 82 fL or MCH ≤ 27 pg criterion achieved sensitivity exceeding 99% in both sexes in this cohort and reduced the missed-carrier rate to < 1%, with lower specificity and more false-positive classifications. Because the preferred MCV threshold was selected after examination of the observed candidate performance, these findings are exploratory, apply to initial screening rather than diagnosis, and require prospective validation in an unselected prenatal population.