ObjectiveThis study aims to evaluate the correlation and diagnostic value of maternal serum placental markers: pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (free β-hCG), and alpha fetoprotein (AFP) in relation to placenta previa. MethodsA retrospective case-control study was conducted to gather data on 137 pregnant women who were hospitalized for delivery at Hangzhou Obstetrics and Gynecology Hospital. These women participated in the late stage of early and mid-term maternal serum prenatal screening between January 2018 and December 2020. Of the 137 women, 45 were diagnosed with placenta previa, while 92 were selected at random as the control group, in a ratio of 1:2. Independent samples t-test or Mann-Whitney U test were utilized to compare the quantitative data of the two groups, and the Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of maternal serum placental marker levels for placenta previa. ResultsThe levels of first trimester and second trimester free beta subunit of human chorionic gonadotropin (FT-Free β-hCG; ST-Free β-hCG) in the placenta previa group were higher than those in the normal group [1.38 (0.55-6.03) MoM vs.1.08 (0.32-4.00) MoM, 1.38 (0.39-4.10) MoM vs.1.01 (0.29-4.12) MoM], and the differences between the groups were statistically significant (Z = 2.830, Z = 2.846, both P < 0.05). The AFP level was higher than the normal group [1.13 (0.65-2.15) MoM vs. 0.94 (0.51-2.02) MoM], and the difference was statistically significant (Z = 2.551, P < 0.05). There was no significant difference in PAPP-A between the placenta previa group and the normal group (Z = 1.396, P > 0.05). The ROC curve analysis results showed that the AUCs of FT-Free β-hCG and ST-Free β-hCG for placenta previa were 0.649 (95% CI: 0.551-0.747, P=0.005), 0.634 (95% CI: 0.539-0.730, P=0.011), and 0.650 (95% CI: 0.554-0.746, P=0.004). Using PPV, NPV, FPR, FNR, +LR, and -LR as evaluation indicators for the 5 models, the results showed that FT-Free β-hCG was the best performer in terms of PPV, FPR, and +LR, with values of 0.725, 0.600, and 2.632, respectively. The three-indicator combined detection model (AFP + ST-Free β-hCG + FT-Free β-hCG) had the best performance in terms of NPV and -LR, with values of 0.770 and 0.298, respectively. ConclusionThe elevated maternal serum levels of Free β-hCG and AFP may be associated with placenta previa. The combined detection of maternal serum markers in the early and mid-trimesters has better diagnostic value for predicting placenta previa than individual detection.