The global pediatric obesity epidemic necessitates preventative strategies. Early life, particularly the prenatal period, presents a critical window for intervention. Maternal diet significantly influences offspring health, and the Mediterranean Diet (MD), rich in fiber, antioxidants, and polyphenols, offers potential benefits. While observational studies suggest a link between MD during pregnancy and reduced childhood obesity risk, evidence from randomized controlled trials (RCTs) is lacking. The PREMEDI trial aimed to address this gap by assessing the impact of MD nutritional counseling during pregnancy on the incidence of overweight or obesity in offspring at 24 months of age.

Existing research on the relationship between maternal diet during pregnancy and childhood obesity yields mixed results. Some observational studies show an inverse association between maternal adherence to the Mediterranean Diet and offspring obesity risk, indicated by lower BMI or waist circumference. However, other studies have found no significant association. This inconsistency highlights the need for a well-designed RCT to definitively assess the impact of MD during pregnancy on childhood obesity.

The PREMEDI study employed a parallel-arm, randomized controlled trial design. 104 pregnant women in their first trimester were randomly assigned (1:1 ratio) to either a control group (standard obstetrical care) or an intervention group (standard care plus MD nutritional counseling). The intervention consisted of three personalized counseling sessions (one per trimester). The primary outcome was the proportion of children with overweight or obesity at 24 months, assessed using IOTF growth charts. Maternal MD adherence (MedDiet Score), weight gain, and epigenetic modulation of metabolic pathways in cord blood were also evaluated. Intention-to-treat (ITT) and per-protocol (PPA) analyses were conducted. Sample size calculation was based on an expected 25% incidence of obesity and aimed to detect a 20% absolute difference with 80% power and a 5% dropout rate. Randomization utilized a central procedure with allocation concealment to ensure blinding of the treatment assignment to the participants, although blinding of the outcome assessors was possible. Cord blood samples were analyzed for genome-wide DNA methylation using the Infinium EPIC array and high-resolution amplicon-bisulfite sequencing for leptin gene methylation. Statistical analyses included Pearson's Chi-square test for the primary outcome, binomial regression for risk difference, random-effects linear regression for maternal outcomes, and Student's t-test for methylation comparisons.

After accounting for loss to follow-up, 97 mother-child pairs completed the study. In the per-protocol analysis, children of mothers in the MD group showed a significantly lower prevalence of overweight or obesity at 24 months (6% vs. 30% in the control group, absolute risk difference = -24%, 95% CI -38% to -9%, p = 0.003; number needed to treat = 4, 95% CI 2 to 12). The intervention group demonstrated significantly increased MD adherence compared to the control group, particularly from the second trimester onwards. Maternal weight gain did not differ significantly between the two arms. Importantly, the mean methylation rate of the leptin gene in cord blood was considerably higher in the MD group (30.4% vs. 16.9% in the control group, p < 0.0001), suggesting epigenetic modification of leptin expression may contribute to the observed reduction in obesity risk. While the intention-to-treat analysis showed a similar trend, it was less significant under the worst-case scenario of imputation for missing data. This signifies the importance of per-protocol analysis in this trial.

The PREMEDI trial provides strong evidence supporting the effectiveness of MD nutritional counseling during pregnancy in reducing the risk of childhood obesity. The significant reduction in obesity prevalence in the offspring of mothers adhering to the MD, coupled with the observed higher leptin gene methylation in the intervention group, suggests a plausible biological mechanism. The higher methylation rate of the leptin gene promoter could lead to lower leptin expression and potentially contribute to weight regulation. The results align with prior research indicating the potential benefits of MD on maternal and offspring health. However, it is important to note that the study's findings are specific to the Mediterranean diet and a structured nutritional intervention, rather than generalized healthy eating. The findings contribute significantly to the field by demonstrating the efficacy of a targeted nutritional intervention during pregnancy in preventing childhood obesity through a plausible epigenetic mechanism.

This RCT demonstrates that nutritional counseling promoting MD adherence during pregnancy significantly reduces the risk of overweight or obesity in offspring at 24 months. This protective effect appears partly mediated by epigenetic modification of leptin gene expression. The findings support the adoption of MD as a cost-effective strategy for preventing pediatric obesity. Future studies should explore other epigenetic modifications and long-term effects, as well as assess the feasibility and sustainability of the intervention in diverse populations.

The PREMEDI study had some limitations. Due to the nature of the intervention, blinding of participants was not possible. The relatively small sample size and limited number of samples for genome-wide methylation analysis might affect the generalizability of the findings. The absence of an assessment of other biomarkers of MD adherence beyond the MedDiet Score could limit a fuller understanding of the complex interplay of dietary components and the observed effects. Further research with a larger sample size and a more comprehensive evaluation of MD adherence is needed to validate these findings.