Results

Figure 1 shows the flow diagram of mother-child pairs’ selection procedure(power calculation provided in supplementary file S1). The baseline characteristics of participants are shown inTable 1 . The majority(91.20%) of maternal blood samples were collected after overnight fasting. Maternal mid-pregnancy weight, fasting glucose, and lipids profile were measured at a mean of 20.0(SD=4.0), 24.6(SD=1.4), and 20.5(SD=3.5) gestation weeks, respectively. Cord blood samples were stored for a median of 488(IQR 394 to 707) days before analysis.

Association of maternal metabolic parameters with birthweight and CBI

Table 2 presents the associations between the association of maternal pre-pregnancy BMI, GWG, and maternal mid-pregnancy fasting glucose/HDL-C/TG levels with neonatal outcomes. Pre-pregnancy BMI(adjustedβ=29.25, 95%CI: 22.77 to 35.73g per Kg/m2), GWG(adjustedβ =18.75, 95%CI: 13.06 to 24.43g per Kg), fasting glucose(adjustedβ=84.32, 95%CI: 42.65 to 125.98g per mmol/L), and triglycerides(adjustedβ=67.97, 95%CI: 42.38 to 93.55g per mmol/L) were positively associated with birthweight, while HDL-C was negatively associated with birthweight(adjustedβ=45.78, 95%CI: 5.59 to 85.97g per mmol/L). There was no evidence of an association between maternal TC and LDL-C levels and birthweight(Supplementary file S6).
Elevated maternal pre-pregnancy BMI, early GWG, fasting blood glucose and triglycerides level were significantly associated with an increased risk of LGA. The risk was particularly high for fasting glucose(OR=2.06, 95%CI 1.31 to 3.24). Higher pre-pregnancy BMI and triglycerides were significantly associated with lower odds of SGA. There was no evidence of an association between maternal HDL-C level and risk of LGA/SGA.
Maternal fasting glucose(adjustedβ=2.23, 95%CI: 0.89 to 3.57 μU/ml per mmol/L) and triglycerides levels(adjustedβ=0.88, 95%CI: 0.05 to 1.71 μU/ml per mmol/L) were significantly associated with higher CBI. Pre-pregnancy BMI, GWG, TC, and LDL-C levels did not show an association with CBI(Table 2 and Supplementary file S6).

Association of maternal metabolic parameter Z-scores with birthweight and CBMI Z-scores

Table 3 shows the estimates of the association of maternal metabolic parameter Z-Scores with birthweight Z-Score and CBI Z-Score, and subgroup estimates for boys and girls. Maternal pre-pregnancy BMI(adjustedβ=0.20, 95%CI 0.15 to 0.24), early GWG(adjustedβ=0.17, 95%CI 0.12 to 0.22), triglycerides(adjustedβ=0.12, 95%CI 0.08 to 0.16), and glucose(adjustedβ=0.08, 95%CI 0.04 to 0.12) Z-scores had positive associations with birthweight Z-Score. Maternal HDL-C Z-Score showed a negative association with birthweight Z-Score in boys(adjusted β=-0.06, 95%CI -0.12 to -0.01) only. The association of pre-pregnancy BMI, GWG, glucose, and triglycerides Z-Scores with birthweight Z-Score remained statistically significant after adjusting for other four maternal metabolic risk factors.
Maternal glucose Z-Score(adjustedβ=0.13, 95%CI 0.08 to 0.18) appears to be the most important contributor to CBI Z-Score in both boys and girls. Both maternal pre-pregnancy BMI(adjustedβ=0.10, 95%CI 0.05 to 0.15) and triglycerides(adjustedβ=0.06, 95%CI 0.01 to 0.11) Z-Scores showed positive associations with CBI Z-Score. No statistically significant association was observed between maternal early GWG and HDL-C Z-Scores with CBI Z-Score.

ABN analysis results for interdependent maternal metabolic parameters

Figure 2 shows the optimal summary DAGs inferred by ABN analysis(Supplementary file S5). The adjusted regression coefficients(β) in the graph represent how much the dependent variable changes per unit increase in the independent variable. Maternal pre-pregnancy BMI appeared to be the most influential upstream factor for both maternal metabolic parameters in pregnancy(glycaemia: β=0.14, 95%CI 0.09 to 0.19; early GWG: β=-0.12, 95%CI -0.17 to -0.06; triglycerides: β=0.23, 95%CI 0.18 to 0.28; HDL-C: β=-0.12, 95%CI -0.17 to -0.07) and birthweight(β=0.27, 95%CI 0.22 to 0.32). An indirect effect on neonatal insulin secretion was also observed. Our DAGs results showed that maternal glycaemia was associated with CBI(β=0.12, 95%CI 0.07 to 0.17). Birthweight was also associated with CBI(β=0.24, 95%CI 0.19 to 0.29). Neither triglycerides nor HDL-C were linked to birthweight or CBI.