UNLABELLED: While previous research has established correlations between pre-pregnancy body mass index (BMI), late-pregnancy blood glucose, and late-pregnancy blood lipid levels during pregnancy and offspring's physical development, the underlying mechanism of their interaction remains elusive. A birth cohort study was conducted on pregnant women, who are biologically female, delivering at a tertiary hospital in Wuhan City between May 2023 and April 2024, encompassing 1620 participants. We collected maternal socio-demographic data through questionnaires and obtained information on fasting blood glucose (FPG), lipid levels during the third trimester, and neonatal physical development from medical records. This study aims to explore the correlation between pre-pregnancy BMI and offspring physical development by conducting statistical analyses and the mediating pathway of FPG levels and lipid levels during the third trimester. The final analysis included 1378 participants with complete records. After adjusting for potential confounders, the odds of giving birth to fetal macrosomia were significantly elevated in the overweight or obese pre-pregnancy BMI group (OR = 2.997, 95% CI 1.238-7.258). Receiver operating characteristic (ROC) curve analysis showed that BMI, FPG, triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) had the best-combined prediction effect on macrosomia, and the area under the curve (AUC) was 0.833 (P <
0.05). Chain mediation analysis revealed that FPG and TG jointly mediated the associations between pre-pregnancy BMI and birth weight (BW), BMI, and head circumference, with mediated proportions of 1.96%, 1.84%, and 1.43%, respectively. Additionally, FPG and HDL-C jointly mediated the influence of maternal pre-pregnancy BMI on BW and BMI, with mediated proportions of 1.48% and 3.8%, respectively. CONCLUSION: The findings of the study indicate that pre-pregnancy BMI is associated with offspring's physical development at birth, with the overweight or obese pre-pregnancy BMI group having an increased risk of macrosomia. The most effective prediction for macrosomia comes from a combination of BMI, FPG, TG, and HDL-C levels. Moreover, the influence of pre-pregnancy BMI on offspring's physical development is partially mediated by FPG, TG, and HDL-C. WHAT IS KNOWN: • Previous research has established correlations between pre-pregnancy BMI and offspring's physical development. • Previous studies have demonstrated that late pregnancy blood lipid and glucose levels significantly predict fetal physical development. WHAT IS NEW: • The combination of pre-pregnancy BMI, FPG, TG, and HDL-C is the most effective predictor of macrosomia. • FPG, TG, and HDL-C jointly mediate the effect of pre-pregnancy BMI on physical growth.