Pregnancy is a complicated and long procedure during one or more offspring development inside a woman. A short period of oxygen shortage after birth is quite normal for most babies and does not threaten their health. However, if babies have to suffer from a long period of oxygen shortage, then this condition is an indication of pathological fetal intolerance, which probably causes their death. The identification of the pathological fetal intolerance from the physical oxygen shortage is one of the important clinical problems in obstetrics for a long time. The clinical syndromes typically manifest five symptoms that indicate that the baby may suffer from fetal intolerance. At present, liquid biopsy combined with high-throughput sequencing or mass spectrum techniques provides a quick approach to detect real-time alteration in the peripheral blood at multiple levels with the rapid development of molecule sequencing technologies. Gene methylation is functionally correlated with gene expression; thus, the combination of gene methylation and expression information would help in screening out the key regulators for the pathogenesis of fetal intolerance. We combined gene methylation and expression features together and screened out the optimal features, including gene expression or methylation signatures, for fetal intolerance prediction for the first time. In addition, we applied various computational methods to construct a comprehensive computational pipeline to identify the potential biomarkers for fetal intolerance dependent on the liquid biopsy samples. We set up qualitative and quantitative computational models for the prediction for fetal intolerance during pregnancy. Moreover, we provided a new prospective for the detailed pathological mechanism of fetal intolerance. This work can provide a solid foundation for further experimental research and contribute to the application of liquid biopsy in antenatal care.