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Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

ABSTRACT: BACKGROUND:Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism. OBJECTIVE:We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771). DESIGN:We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet. RESULTS:We identified 6 differentially methylated CpGs in Gambians [2.5-5.0% reduction in intervention group, all false discovery rate (FDR) <5%], the majority mapping to ESM1, which also represented a strong signal in regional analysis. One CpG passed FDR <5% in the Indian cohort, but overall effect sizes were small (<1%) and did not have the characteristics of a robust signature. We also found strong evidence for enrichment of metastable epialleles among subthreshold signals in the Gambian analysis. This supports the notion that multiple methylation loci are influenced by micronutrient supplementation in the early embryo. CONCLUSIONS:Maternal preconceptional and pregnancy micronutrient supplementation may alter DNAm in children measured at 7-9 y. Multiple factors, including differences between the nature of the intervention, participants, and settings, are likely to have contributed to the lack of replication in the Indian cohort. Potential links to phenotypic outcomes will be explored in the next stage of the EMPHASIS study.

SUBMITTER: Saffari A

PROVIDER: S-EPMC7528567 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

Saffari Ayden A Shrestha Smeeta S Issarapu Prachand P Sajjadi Sara S Betts Modupeh M Sahariah Sirazul Ameen SA Tomar Ashutosh Singh AS James Philip P Dedaniya Akshay A Yadav Dilip K DK Kumaran Kalyanaraman K Prentice Andrew M AM Lillycrop Karen A KA Fall Caroline H D CHD Chandak Giriraj R GR Silver Matt J MJ

The American journal of clinical nutrition 20201001 4

<h4>Background</h4>Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism.<h4>Objective</h4>We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India ...[more]

PMID: 32889533

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Project description:BackgroundMicronutrient malnutrition has been associated with maternal depressive symptoms (MDS), but little is known about the effects of preconceptional micronutrient supplementation. This paper examined the effects of preconceptional micronutrient supplementation on MDS during pregnancy and postpartum.MethodsWe used data from a double-blind controlled trial (PRECONCEPT) in which 5011 Vietnamese women were randomized to receive weekly supplements containing either a) multiple micronutrients (MM) b) iron and folic acid (IFA) or c) folic acid (FA) until conception (n = 1813). Maternal mental health was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline (preconception), and the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and 3 months postpartum. Elevated MDS was defined as EPDS score ≥ 4. All group comparisons were done using ANOVA or chi-square tests of proportions intention to treat and per protocol analyses (women consumed supplements ≥26 weeks before conception). We also conducted stratified analyses by preconception CES-D scores, underweight, or anemia status using generalized linear models.ResultsBaseline CES-D scores were similar across treatment groups. The proportion of women experiencing elevated MDS was 11.3, 8.1 and 4.9% at first, second and third trimesters of pregnancy, respectively, and 3.6% at 3 mo postpartum. Mean EPDS scores at first (1.5 ± 2.7), second (1.1 ± 2.4), and third trimester of pregnancy (0.7 ± 2.0) and early postpartum (0.6 ± 1.8) were low and did not differ by treatment group. However, among women in the highest tertile of CES-D scores at preconception, mean EPDS scores in the first and second trimesters of pregnancy were lower in the MM and IFA groups compared to FA only (P < 0.05).ConclusionsWeekly preconceptional micronutrient supplements containing iron did not improve depression measures relative to folic acid alone among all women, but may have benefitted women who were at risk for depression.Trial registrationThe trial was registered retrospectively at ClinicalTrials.Gov as NCT01665378 on August 13, 2012.

Project description:OBJECTIVES/BACKGROUND: Given the widespread prevalence of micronutrient deficiencies in developing countries, supplementation with multiple micronutrients rather than iron-folate alone, could be of potential benefit to the mother and the fetus. These benefits could relate to prevention of maternal complications and reduction in other adverse pregnancy outcomes such as small-for-gestational age (SGA) births, low birth weight, stillbirths, perinatal and neonatal mortality. This review evaluates the evidence of the impact of multiple micronutrient supplements during pregnancy, in comparison with standard iron-folate supplements, on specific maternal and pregnancy outcomes of relevance to the Lives Saved Tool (LiST). DATA SOURCES/REVIEW METHODS: A systematic review of randomized controlled trials was conducted. Search engines used were PubMed, the Cochrane Library, the WHO regional databases and hand search of bibliographies. A standardized data abstraction and Child Health Epidemiology Reference (CHERG) adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) technique were used for data abstraction and overall quality of evidence. Meta-analyses were performed to calculate summary estimates of utility to the LiST model for the specified outcome of incidence of SGA births. We also evaluated the potential impact of multiple micronutrients on neonatal mortality according to the proportion of deliveries occurring in facilities (using a threshold of 60% to indicate functionality of health systems for skilled births). RESULTS: We included 17 studies for detailed data abstraction. There was no significant benefit of multiple micronutrients as compared to iron folate on maternal anemia in third trimester [Relative risk (RR) = 1.03; 95% confidence interval (CI): 0.87 - 1.22 (random model)]. Our analysis, however, showed a significant reduction in SGA by 9% [RR = 0.91; 95% CI: 0.86 - 0.96 (fixed model)]. In the fixed model, the SGA outcome remained significant only in women with mean body mass index (BMI) ? 22 kg/m2. There was an increased risk of neonatal mortality in studies with majority of births at home [RR = 1.47, 95% CI: 1.13-1.92]; such an effect was not evident where ? 60% of births occurred in facility settings [RR = 0.94, 95% CI: 0.81-1.09]. Overall there was no increase in the risk of neonatal mortality [RR = 1.05, 95% CI: 0.92 - 1.19 (fixed model)]. CONCLUSION: This review provides evidence of a significant benefit of MMN supplementation during pregnancy on reducing SGA births as compared to iron-folate, with no significant increase in the risk of neonatal mortality in populations where skilled birth care is available and majority of births take place in facilities. Given comparability of impacts on maternal anemia, the decision to replace iron-folate with multiple micronutrients during pregnancy may be taken in the context of available services in health systems and birth outcomes monitored.

Project description:Maternal caregiving capacity, which is affected in part by cognition and mood, is crucial for the health of mothers and infants. Few interventions aim to improve maternal and infant health through improving such capacity. Multiple micronutrient (MMN) supplementation may improve maternal cognition and mood, since micronutrients are essential for brain function. We assessed mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind cluster-randomized trial in Indonesia comparing MMN supplementation to iron and folic acid (IFA) during pregnancy and until three months postpartum. We adapted a set of well-studied tests of cognition, motor dexterity, and mood to the local context and administered them to a random sample of 640 SUMMIT participants after an average of 25 weeks (SD = 9) of supplementation. Analysis was by intention to treat. Controlling for maternal age, education, and socio-economic status, MMN resulted in a benefit of 0.12 SD on overall cognition, compared to IFA (95%CI 0.03-0.22, p = .010), and a benefit of 0.18 SD on reading efficiency (95%CI 0.02-0.35, p = .031). Both effects were found particularly in anemic (hemoglobin<110 g/L; overall cognition: B = 0.20, 0.00-0.41, p = .055; reading: B = 0.40, 0.02-0.77, p = .039) and undernourished (mid-upper arm circumference<23.5 cm; overall cognition: B = 0.33, 0.07-0.59, p = .020; reading: B = 0.65, 0.19-1.12, p = .007) mothers. The benefit of MMN on overall cognition was equivalent to the benefit of one year of education for all mothers, to two years of education for anemic mothers, and to three years of education for undernourished mothers. No effects were found on maternal motor dexterity or mood. This is the first study demonstrating an improvement in maternal cognition with MMN supplementation. This improvement may increase the quality of care mothers provide for their infants, potentially partly mediating effects of maternal MMN supplementation on infant health and survival. The study is registered as an International Standard Randomized Controlled Trial, number ISRCTN34151616. http://www.controlled-trials.com/ISRCTN34151616.

Dataset Information

Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

Publications

Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

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