Macrosomia is a significant perinatal complication with potential risks for both mother and child. Although diabetes is a known major risk factor, specific clinical and metabolic factors contributing to macrosomia in non-diabetic pregnancies are not fully understood. Therefore, this study aimed to explore the clinical characteristics and potential metabolic risk factors associated with non-diabetes-related neonatal macrosomia. Additionally, this study aimed to examine the relationship between metabolic dysregulation and the presence of exosomes in umbilical cord blood.

A retrospective analysis of 356 non-diabetic pregnant women (170 non-diabetic pregnant women with macrosomic infants and 186 normal pregnant women) was conducted. Additionally, umbilical cord blood plasma samples were collected from 16 participants (8 macrosomia and 8 normal deliveries). After separating exosomes from plasma, RNA was extracted and sequenced. Weighted gene co-expression network analysis (WGCNA) was used to explore the correlation between clinical characteristics and gene expression.

Among the baseline characteristics, the pre-pregnancy body mass index (BMI) and overall weight gain in non-diabetic mothers with macrosomic infants were significantly higher than those in the normal group (p < 0.05). The lipid profiles revealed that triglyceride (TG) and low-density lipoprotein (LDL) levels were significantly elevated, whereas the high-density lipoprotein (HDL) levels were significantly decreased (p < 0.05). Logistic regression analysis showed that pre-pregnancy BMI, gestational weight gain, LDL levels, and alkaline phosphatase (ALP) levels in the third trimester were risk factors for macrosomia, while primiparas and HDL levels were protective factors. WGCNA analysis revealed that the expression of the mRNA royalblue module and the lncRNA darkgrey module presented a significant positive correlation with gestational weight gain (p < 0.05). Compared to the normal group, the expressions of transmembrane protein 175 (TMEM175) and HIF1A antisense RNA 2 (HIF1A-AS2) were downregulated, whereas the expressions of phosphoglycerate kinase 1 (PGK1) and methionine adenosyltransferase 2B (MAT2B) were upregulated in the exosomes derived from the umbilical cord blood plasma in the macrosomic group.

Messenger RNAs (mRNA) (TMEM175, PGK1, MAT2B) and long non-coding RNAs (lncRNA) (HIF1A-AS2) may potentially contribute to the development of fetal macrosomia in non-diabetic pregnancies.