Читать книгу Clinical Obesity in Adults and Children - Группа авторов - Страница 52

Several of the most well‐described early life predictors of subsequent obesity can be grouped together under the umbrella of “overnutrition.” Higher maternal weight or obesity entering pregnancy are strong predictors of excess offspring weight not only at birth but also throughout childhood [34–37] (Fig. 3.2). Evidence exists that this association results at least in part from mechanisms other than shared genetic risks. For example, maternal obesity is a stronger predictor of offspring obesity compared with paternal obesity [38]. Children born to mothers after bariatric surgery, when mothers had lost a substantial amount of weight, have lower obesity risk compared with siblings born before the surgery when they were conceived at a time when their mothers had a much higher BMI [39].

Other factors related to a mother’s weight entering pregnancy may also be important for programming offspring obesity. Greater gestational weight gain predicts offspring attained weight and obesity risk, and this association appears to be independent of maternal pre‐pregnancy weight [34,35,40]. Unfortunately, randomized trials to provide gestational weight gain advice and improve diet and/or physical activity have generally had no or minimal effect on gestational weight gain [24,41]. There is emerging evidence that this type of intervention reduces excessive fetal growth and infant adiposity [42,43]. Interestingly, in observational studies, higher weight gain in early pregnancy is most strongly predictive of offspring adiposity, whereas maternal weight gain during the third trimester, when both maternal weight gain and fetal growth are greatest, is not predictive of later obesity [44,45]. Thus, it is possible that the intervention trials conducted to date (which generally began after the end of the first trimester) have begun too late to influence offspring outcomes.

Additionally, intrauterine exposure to pre‐gestational or gestational diabetes mellitus also predicts offspring obesity risk, with supportive results from both observational studies [46] and sibling comparisons [16]. Potential mechanisms might include reduced beta‐cell function as a consequence of exposure to hyperglycemia during gestation [47]. However, children whose mothers had participated in a randomized clinical trial (RCT) of treatment of mild gestational diabetes did not have different BMI at school age [23]. Overall, the extent to which the association of intrauterine exposure to diabetes with later BMI is independent of the fact that mothers who develop diabetes are themselves generally heavier is uncertain.

Figure 3.2 Associations of maternal pre‐pregnancy BMI and gestational weight gain with the risk of overweight/obesity and childhood BMI. The circles, squares, and triangles represent odds ratios (ORs) (a and c) or regression coefficients (b and d) (95% confidence intervals) obtained from multilevel binary logistic or linear regression models that reflect the risk of overweight/obesity or differences in early, mid, and late childhood BMI standard deviation score (SDS) in the different maternal pre‐pregnancy BMI or gestational weight gain groups, as compared to the reference group (20.0–22.5 kg/m² for maternal BMI, −1.0 to 0.0 SD for gestational weight gain (largest groups), primary y‐axis). The lines are trendlines through the estimates. The models are adjusted for maternal age, education level, ethnicity, parity, and smoking during pregnancy. The bars represent the percentage of overweight/children with obesity (a and c) or the median childhood BMI SDS (b and d) in early (2.0–5.0 years, violet bars), mid (5.0–10.0 years, brown bars), and late childhood (10.0–18.0 years, light blue bars) in the study population (secondary y‐axis).

Source: From Voerman et al. [35] © 2019 Voerman et al. Open Access.

These human observations are well supported in the experimental animal literature. Rodent models of both maternal obesity and maternal diabetes during pregnancy have been shown to lead to increased adiposity in the offspring, even though in these cases, fetal growth might not be greater in the exposed pups. One of many examples is that a high‐fat maternal diet consumed by mother rats during pregnancy and lactation can result in excess adiposity in the offspring, even if the offspring’s post‐weaning diet comprises standard lab chow [48]. Experimental administration of streptozosin induces diabetes in female rats; their offspring have greater adiposity and associated metabolic changes, including impaired glucose tolerance, abnormal insulin secretion [49,50]. Furthermore, offspring exposed to intrauterine hyperglycemia have differences in DNA methylation that are intergenerational and inherited [50].

Each of these three factors – maternal obesity entering pregnancy, excess gestational weight gain, and diabetes mellitus – is associated with excess macronutrient status of the mother, which could result in the delivery of excess nutrients, including carbohydrates and fatty acids, to the fetus. On average, babies born to mothers with obesity are heavier at birth and have a higher risk for large for gestational age (LGA) birth. However, in both humans and in animal models, obesity during pregnancy has also been associated with a higher risk of small for gestational age (SGA). Placental dysfunction as a consequence of maternal obesity may contribute to the increased risk of SGA [51].

Other DoHAD research has focused on the paradigm of early‐life undernutrition, whether globally or of specific nutrients, in programming chronic disease risk. For example, offspring of maternal rats subject to global undernutrition are at higher risk for developing obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high‐fat diet after weaning [20]. An extensive body of research, originally championed by David Barker, has shown that infants who weigh less at birth or in the first year of life have higher risks for later obesity‐related conditions such as hypertension, coronary heart disease, and type 2 diabetes [52]. In support of this theory, young men who survived early prenatal exposure to the Dutch Hunger Winter during World War II, a period of severe famine, have been found to be at higher risk for obesity [53]. However, the preponderance of evidence suggests that this relationship between early life undernutrition and later life cardiometabolic disease is not primarily mediated by higher attained obesity. Abundant data confirm that there is a direct association between larger size at birth and higher BMI in later life; high birth weight predicts higher average BMI and obesity risk in later life, whereas low birth weight does not [54,55]. Thus, it is likely that higher risks for obesity observed with early undernutrition in some analyses may be largely driven by differences between animal models and humans, survivor bias in retrospective cohort studies, or analytic approaches that inappropriately account for causal mediators [56]. Additionally, associations could be related to the fact that babies born SGA are more likely to gain weight rapidly after birth, which, as discussed in more detail, is itself a predictor for later adiposity [57].