Impact of preconception and antenatal supplementation with myo-inositol, probiotics, and micronutrients on offspring BMI and weight gain over the first 2 years.

BACKGROUND: Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. METHODS: Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. RESULTS: At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] - 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the "normal" weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). CONCLUSIONS: Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171-8056). Registered on 16 July 2015.

The effect of a preconception and antenatal nutritional supplement on children's BMI and weight gain over the first 2 years of life: findings from the NiPPeR randomised controlled trial.

BACKGROUND: Nutritional intervention before and throughout pregnancy might promote healthy infant weight gain; however, clinical evidence is scarce. Therefore, we examined whether preconception and antenatal supplementation would affect the body size and growth of children in the first 2 years of life. METHODS: Women were recruited from the community before conception in the UK, Singapore, and New Zealand, and randomly allocated to either the intervention (myo-inositol, probiotics, and additional micronutrients) or control group (standard micronutrient supplement) with stratification by site and ethnicity. Measurements of weight and length were obtained from 576 children at multiple timepoints in the first 2 years of life. Differences in age and sex standardised BMI at age 2 years (WHO standards) and the change in weight from birth were examined. Written informed consent was obtained from the mothers, and ethics approval was granted by local committees. The NiPPeR trial was registered with ClinicalTrials.gov (NCT02509988) on July 16, 2015 (Universal Trial Number U1111-1171-8056). FINDINGS: 1729 women were recruited between Aug 3, 2015, and May 31, 2017. Of the women randomised, 586 had births at 24 weeks or more of gestation between April, 2016, and January, 2019. At age 2 years, adjusting for study site, infant sex, parity, maternal smoking, maternal prepregnancy BMI, and gestational age, fewer children of mothers who received the intervention had a BMI of more than the 95th percentile (22 [9%] of 239 vs 44 [18%] of 245, adjusted risk ratio 0·51, 95% CI 0·31-0·82, p=0·006). Longitudinal data revealed that the children of mothers who received the intervention had a 24% reduced risk of experiencing rapid weight gain of more than 0·67 SD in the first year of life (58 [21·9%] of 265 vs 80 [31·1%] of 257, adjusted risk ratio 0·76, 95% CI 0·58-1·00, p=0·047). Risk was likewise decreased for sustained weight gain of more than 1·34 SD in the first 2 years (19 [7·7%] of 246 vs 43 [17·1%] of 251, adjusted risk ratio 0·55, 95% CI 0·34-0·88, p=0·014). INTERPRETATION: Rapid weight gain in infancy is associated with future adverse metabolic health. The intervention supplement taken before and throughout pregnancy was associated with lower risk of rapid weight gain and high BMI at age 2 years among children. Long-term follow-up is required to assess the longevity of these benefits. FUNDING: National Institute for Health Research; New Zealand Ministry of Business, Innovation and Employment; Société Des Produits Nestlé; UK Medical Research Council; Singapore National Research Foundation; National University of Singapore and the Agency of Science, Technology and Research; and Gravida.

Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).

BACKGROUND: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. METHODS: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. RESULTS: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. CONCLUSIONS: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

DNA methylation at birth within the promoter of ANRIL predicts markers of cardiovascular risk at 9 years.

AIMS: Antisense non-coding RNA in the INK4 locus (ANRIL) fixed genetic variants have consistently been linked with coronary heart disease (CHD) risk. We investigated relationships between perinatal ANRIL promoter DNA methylation and CHD risk markers in children aged 9 years. Genetic variants in the non-coding RNA ANRIL identify it as an important CHD risk locus. Increasing evidence suggests that the early life environment may act through epigenetic processes to influence later CHD risk markers such as increased arterial pulse wave velocity (PWV, a measure of arterial stiffness) blood pressure or heart rate. METHODS AND RESULTS: Using pyrosequencing, ANRIL DNA methylation at nine CpG sites was measured in the umbilical cord from 144 children in a UK mother-offspring cohort and related to the descending aorta PWV measured by velocity-encoded phase contrast MRI at age 9 years. Perinatal methylation was not associated with child's later blood pressure, but higher methylation at CpG5 was associated with increased childhood PWV (ß = 0.066 m/s/10 % methylation increase [95 % CI, 0.004 to 0.128], p = 0.037); 10 % decreases in methylation at CpG1 and CpG2 were associated with increased heart rate (CpG1 ß = 1.93 [0.07 to 3.8] beats/min, p = 0.041; CpG2 ß = 2.30 [0.18 to 4.41] beats/min, p = 0.033, accounting for potential confounding variables). The associations with perinatal ANRIL promoter methylation were independent of neighbouring fixed genetic variants. CONCLUSIONS: Our findings suggest developmental epigenetic regulation of ANRIL promoter methylation as a factor in later CHD risk in children.