BACKGROUND: Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms. OBJECTIVES: The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity. METHODS: We included 450 African-American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study pregnancy cohort. LC-MS was used to conduct metabolomic profiling on maternal plasma samples of the second trimester. The childhood growth outcomes of interest included BMI trajectories from birth to age 4 y (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4 y. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian randomization (MR) method. RESULTS: Among the 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4 y, respectively, and 5 mediated both outcomes. The MR analysis suggested 6 of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2,N2-dimethylguanosine). CONCLUSIONS: Our study provides further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways, including identified metabolite mediators, might provide novel intervention targets for preventing the intrauterine development of obesity in the offspring of mothers with obesity.

Background

We investigated the individual and additive effects of three modifiable maternal metabolic factors, including pre-pregnancy overweight/obesity, gestational weight gain (GWG), and gestational diabetes mellitus (GDM), on early childhood growth trajectories and obesity risk.

Methods

A total of 1425 mother-offspring dyads (953 black and 472 white) from a longitudinal birth cohort were included in this study. Latent class growth modeling was performed to identify the trajectories of body mass index (BMI) from birth to 4 years in children. Poisson regression models were used to examine the associations between the maternal metabolic risk factors and child BMI trajectories and obesity risk at 4 years.

Results

We identified three discrete BMI trajectory groups, characterized as rising-high-BMI (12.6%), moderate-BMI (61.0%), or low-BMI (26.4%) growth. Both maternal pre-pregnancy obesity (adjusted relative risk [adjRR] = 1.96; 95% confidence interval [CI]: 1.36-2.83) and excessive GWG (adjRR = 1.71, 95% CI: 1.13-2.58) were significantly associated with the rising-high-BMI trajectory, as manifested by rapid weight gain during infancy and a stable but high BMI until 4 years. All three maternal metabolic indices were significantly associated with childhood obesity at age 4 years (adjRR for pre-pregnancy obesity = 2.24, 95% CI: 1.62-3.10; adjRR for excessive GWG = 1.46, 95% CI: 1.01-2.09; and adjRR for GDM = 2.14, 95% = 1.47-3.12). In addition, risk of rising-high BMI trajectory or obesity at age 4 years was stronger among mothers with more than one metabolic risk factor. We did not observe any difference in these associations by race.

Conclusion

Maternal pre-pregnancy obesity, excessive GWG, and GDM individually and jointly predict rapid growth and obesity at age 4 years in offspring, regardless of race. Interventions targeting maternal obesity and metabolism may prevent or slow the rate of development of childhood obesity.

Objective

Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring.

Methods

This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes.

Results

The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively.

Conclusions

Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

We investigated the associations between maternal dietary patterns during pregnancy and early childhood growth trajectories and overweight/obesity risk in offspring. Maternal diet was assessed using a food frequency questionnaire during the second trimester, and dietary patterns were derived by reduced rank regression. The associations between maternal dietary pattern scores and body mass index (BMI) trajectories from birth to age four (rising-high, moderate, and low BMI trajectories) as well as overweight/obesity risk at age four were analyzed (n = 1257). Two maternal dietary patterns were identified. The fast food pattern included a higher intake of fried chicken and fish, fruit juices, mayonnaise, and sugar-sweetened beverages, while the processed food pattern included a higher intake of dairy, salad dressing, processed meat, and cold breakfast cereal. Women with greater adherence to the fast food pattern were more likely to have children in the rising-high BMI trajectory group [OR (95% CI) = 1.32 (1.07-1.62); p = 0.008] or having overweight/obesity at age four [OR (95% CI) = 1.31 (1.11-1.54); p = 0.001]. The processed food pattern was not associated with these outcomes. The maternal dietary pattern during pregnancy represented by fried foods and sugar-sweetened beverages may contribute to rapid early childhood growth and increased risk for obesity in offspring.