To explore the diagnostic efficacy of echocardiography combined with maternal serum thrombospondin-1 (TSP-1) and lipoprotein-associated phospholipase A2 (Lp PLA2) levels of pregnant women for their fetal congenital heart disease (CHD). Methods: 157 pregnant women with the suspected fetal heart abnormalities by the antenatal examination from May 2022 to May 2023 were selected as the study subjects. According to the pregnancy outcomes, these women were divided into control group (85 women without fetal CHD) and study group (72 women with fetal CHD) based on whether the fetal CHD occurred or not. The fetal heart of the pregnant women was examined by color Doppler ultrasound system during the first trimester of pregnancy, and the fetal aortic and pulmonary artery blood flow parameters were recorded. The serum TSP-1 and Lp-PLA2 levels of the women were detected. Pearson correlation analysis was used to analyze the correlation between the TSP-1, Lp-PLA2 levels of the women and their fetal aortic and pulmonary artery blood flow parameters values. Multivariate logistic regression was used to analyze the influencing factors of the fetal CHD occurrence. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of the echocardiography results combined with the TSP-1 and Lp-PLA2 levels of the women for their fetal CHD. Results: There were 48 women with fetal CHD in the study group and 3 women with fetal CHD in the control group. The values of ESRV, VRI and PVmax/AVmax, and the serum TSP-1 and Lp-PLA2 levels of the women in the study group were significantly higher than those of the women in the control group, while the values of PSV, PSV/ESRV, ET and ACT of the women in the study group were significantly lower. The serum TSP-1 and Lp-PLA2 levels of the women with fetal CHD were positively correlated with their ESRV, VRI and PVmax/AVmax values, while were negatively correlated with their PSV, PSV/ESRV, ET, DT and ACT values. The increased levels of TSP-1 and Lp-PLA2 of the pregnant women with were the independent risk factors of their fetal CHD occurrence (all P<0.05). The area under the curve (AUC) of the echocardiography results, the serum TSP-1 level and the Lp-PLA2 level of the women for diagnosing their fetal CHD were 0.816, 0.811, and 0.806, respectively. The AUC of the combined the echocardiography results and the levels of the serum TSP-1 and the Lp-PLA2 of the women for diagnosing their fetal CHD was 0.950, and which was significantly higher than that of the echocardiography results, the serum TSP-1 level or the Lp-PLA2 level alone (all P=0.000). The sensitivity and the specificity of the combined the echocardiography results and the levels of the serum TSP-1 and the Lp-PLA2 of the women for diagnosing their fetal CHD were 84.7% and 94.3%. Conclusion: The levels of TSP-1 and Lp-PLA2 of the pregnant women with fetal CHD increase abnormally, which are correlated with the fetal aortic and pulmonary blood flow parameters. The elevated levels of TSP-1 and Lp-PLA2 of the pregnant women are the independent risk factors of their fetal CHD occurrence. The combined the echocardiography results and the levels of the serum TSP-1 and the Lp-PLA2 of the women for diagnosing their fetal CHD has higher clinical value.