Objective To explore the clinical value of combined detection of maternal IgG antibody titer in the first trimester in predicting severe Hemolytic Disease of the Newborn (HDN). Methods: 75 pregnant women who established medical records and gave birth in the outpatient department of our hospital from January 2022 to December 2024 were selected as the research subjects. The research subjects were divided into the severe HDN group and the non-severe HDN group based on whether the newborns developed severe hemolytic disease. All the research subjects had their venous blood collected from 6 to 12 weeks of early pregnancy. Irregular antibodies and prenatal maternal titers were detected using IgG anti-human globulin test cards. Meanwhile, the concentration of specific IgG antibodies in serum was quantitatively detected by enzyme-linked immunosorbent assay. The titers of IgG antibodies in the early stage of pregnancy, the concentrations of serum specific IgG antibodies and the hematological indicators of newborns in the two groups were analyzed and compared. The efficacy of IgG antibody titers in predicting severe HDN was analyzed using the ROC curve. Result Among the 75 pregnant women, 18 cases had severe HDN and 57 cases had non-severe HDN. There were no significant differences in baseline data such as age, number of pregnancies, number of deliveries, gestational weeks at delivery, and neonatal birth weight between the two groups (P > 0.05). The titer of IgG antibodies in the early stage of pregnancy in the severe HDN group was significantly higher than that in the non-severe HDN group (P<0.001). The proportions of pregnant women with antibody titers ≥1:256 and ≥1:512 in the severe HDN group were significantly higher than those in the non-severe group (P<0.001). The concentrations of serum-specific anti-A IgG, anti-B IgG and anti-D IgG in the severe HDN group were significantly higher than those in the non-severe HDN group (P<0.001). The hemoglobin level of newborns in the severe HDN group was significantly lower than that in the non-severe HDN group (P<0.001), and the serum bilirubin level was significantly higher than that in the non-severe HDN group (P<0.001). The proportions of phototherapy and blood exchange therapy in the severe HDN group were significantly higher than those in the non-severe HDN group (P<0.001), and the hospital stay in the severe group was significantly longer than that in the non-severe group (P<0.001). The area under the ROC curve of IgG antibody titer for predicting severe HDN was 0.892, the sensitivity was 83.33%, the specificity was 87.72%, and the optimal cut-off value was 1:256. Conclusion: The combined detection of maternal IgG antibody titers in the early stage of pregnancy has a high clinical value in predicting severe hemolytic disease of the newborn.