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].
Maternal diet quality
Beyond total energy intake, there has been interest in characterizing the extent to which the quality of a mother’s diet in pregnancy might program offspring growth and body composition. At this point in time, we do not believe that the evidence is sufficient to allow for comprehensive identification of diet components or patterns associated with higher or lower offspring obesity risk. Nonetheless, some evidence suggests that certain aspects of a mother’s diet quality may influence these outcomes in the next generation.
Dietary components examined to date generally follow those already found to be associated with obesity or related metabolic risks among children and nonpregnant adults. For example, a Project Viva analysis examined associations of maternal sugary beverage intake and child adiposity. Each additional serving per day of sugary drinks (SDs) consumed by mothers during pregnancy was associated with higher child BMI z scores (0.07 units; 95% confidence interval (CI): −0.01 to 0.15), fat mass index (0.15 kg/m2; 95% CI: −0.01 to 0.30), and waist circumference (0.65 cm; 95% CI: 0.01 to 1.28) [58]. Further analyses suggested that the associations were due primarily to maternal, not child, SD intake, and to sugary soda rather than fruit drinks or juice. Interestingly, in the same cohort, maternal intake of non‐nutritive sweeteners during pregnancy also was associated with increased childhood BMI z‐score and body fat from birth to teenage years. This finding aligns with research in other populations suggesting that consumption of artificial sweeteners may promote weight gain rather than preventing it [59].
The traditional Mediterranean diet is characterized by a high intake of olive oil, fruits, vegetables, legumes, nuts, and whole‐grain products; a moderate intake of fish; and only small amounts of red and processed meat. This dietary pattern is low in saturated fat intake and high in monounsaturated fat intake from olive oil; it is rich in fiber, provides a balanced ratio of n‐6/n‐3 essential fatty acids, and contains high amounts of antioxidants. Several epidemiological studies and clinical trials support the role of the Mediterranean diet in preventing obesity, type 2 diabetes mellitus, and metabolic syndrome in adults [60], but the effects of maternal prenatal intake have not been well studied. One analysis examined maternal Mediterranean dietary patterns during pregnancy in two cohorts with different dietary habits and socio‐demographics – the Boston, MA area Project Viva cohort and the Rhea Cohort based in Crete, Greece – in relation to offspring outcomes [28]. In Project Viva, the mean (standard deviation) Mediterranean Diet Score (MDS) was 2.7 (1.6) out of 9 possible points; in Rhea, it was 3.8 (1.7). In each cohort, higher MDS was associated with lower BMI (Fig. 3.3).