Prenatal and Postnatal Nutritional Mismatch, Reflected by Birth Weight and Adult BMI, and Cardiometabolic Disease Risk.

Aims: This study aimed to investigate how nutritional exposures in early life, represented by birth weight (BW), and in later life, indicated by adult body mass index (BMI), interact to influence cardiometabolic disease (CMD) risk and to examine the underlying causal relationships.

Methods: Included were 254,224 participants of White European ancestry from the UK Biobank. To evaluate the joint associations of BW and adult BMI with CMD risk, BW was categorized as low (LBW, <2.5 kg) or high (HBW, ≥2.5 kg), and BMI as low (LBMI, <30 kg/m²) or high (HBMI, ≥30 kg/m²). Multivariable Cox proportional hazards models and 2x2 factorial Mendelian randomization (MR) analyses were employed to assess these associations and the underlying causality.

Results: Compared to the participants with HBW-LBMI, the hazard ratio (HR) for atherosclerotic cardiovascular disease (ASCVD) was 1.19 (95% CI: 1.12 to 1.26) in the LBW-LBMI group, 1.33 (1.28 to 1.38) in the HBW-HBMI group, and 1.62 (1.50 to 1.75) in the LBW-HBMI group. The LBW-HBMI group also exhibited higher risks for hypertension (HR: 2.42 [2.26-2.59]), diabetes (HR: 5.16 [4.73-5.63]), and hyperlipidemia (HR: 1.95 [1.81-2.10]). Additive interactions between LBW and HBMI were identified for metabolic diseases but not for ASCVD. The causality of these associations was confirmed by MR analysis.

Conclusions: Combined exposure to LBW and HBMI was most strongly associated with an elevated risk of CMD, underscoring the critical role of the mismatch between early-life and adult nutritional status in shaping long-term cardiometabolic health.