Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.

Associations of unintended pregnancy with autism spectrum disorders and the modification of folic acid supplements.

There is limited evidence on the associations of unintended pregnancy with autism spectrum disorders (ASD). This study aimed to examine this relationship and the modification of pre-conceptional and prenatal folic acid supplements. Six thousand and five toddlers aged 16 to 30 months from seven cities of six provinces in China were eligible for participation. Information on unintended pregnancy and folic acid supplements was obtained via questionnaires from caregivers of toddlers. The diagnosis of ASD was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the Chinese version of the Childhood Autism Rating Scale (CARS). Of the 6005 toddlers in the study (3337 boys and 2668 girls), 71 (1.18%) received the diagnosis of ASD. Generalized linear models with a logit link function showed unintended pregnancy was positively associated with ASD (odds ratios [OR] = 1.69, 95% confidence interval [CI], 1.05-2.79). Stratified estimates indicated that the association remained stable among toddlers of mothers without pre-conceptional and prenatal folic acid supplements (OR = 2.75, 95% CI, 1.04-7.27; n = 1243, 20.70%). Unintended pregnancy was associated with higher odds of ASD in 16-30 months of toddlers, and the association was consistent among toddlers of mothers without prenatal folic acid supplements. Our findings emphasize the need to raise awareness of the risk of unintended pregnancy and the benefits of folic acid supplements among Chinese women.

Enhanced recovery in patients with gestational diabetes mellitus and MTHFR 677 TT genotype after taking high-dose folic acid supplements during mid-late pregnancy: an open-label interventional study.

Objective: To explore the relationship between folic acid supplementation and the recovery rate of gestational diabetes mellitus (GDM) in women with methylenetetrahydrofolate (MTHFR) 677 TT genotypes in mid-late pregnancy. Methods: 9, 096 pregnant women were recruited with their MTHFR gene genotyped. 5,111 women underwent a 75-g oral glucose tolerance test (OGTT) and 2,097 were confirmed with GDM. The association between MTHFR genotypes and GDM risk was estimated using logistic and log-binomial regression, with age and parity set as the covariates to control their confounding effects. Further assessment of GDM risk on glucose levels was done using the ANCOVA model. As an open-label intervention study, 53 GDM patients with TT genotype were prescribed 800µg/day of folic acid as the high-dose group, while 201 GDM patients were given 400µg/day as the standard-dose group at their 24-28 weeks of pregnancy. A rate ratio (RR) of GDM recovery was estimated at each available time point for both groups. The time-to-GDM persistence events were analyzed with the Kaplan-Meier method and Cox-regression model. The trend of glucose levels over time was estimated using the linear model. Results: MTHFR 677 TT genotype has no significant association with the glucose levels and GDM risk, with an adjusted OR of 1.105 (95% CI 0.853, 1.431; p=0.452) and an adjusted PR of 1.050 (95% CI 0.906, 1.216; p=0.518) compared to the wildtype CC group. Patients in the high-dose group (n=38; 15 drop-outs; 40.69 days (95% CI 33.22, 48.15)) recovered from GDM approximately 27 days faster than those in the standard-dose group (n=133; 68 drop-outs; 68.09 days (95% CI 63.08, 73.11)). Concomitantly, the RR of GDM recovery rose and reached 1.247 (95% CI 1.026, 1.515) at 100 days of treatment with the standard-dose group as reference. Conclusion: High-dose folic acid supplement intake in mid-late pregnancy is associated with faster GDM relief in patients with MTHFR 677 TT genotype compared to the standard dose, which would be served as a novel and low-cost alternative therapy for the treatment of GDM.

Opportunities and barriers for maternal nutrition behavior change: an in-depth qualitative analysis of pregnant women and their families in Uttar Pradesh, India.

Background: Maternal undernutrition during pregnancy remains a critical public health issue in India. While evidence-based interventions exist, poor program implementation and limited uptake of behavior change interventions make addressing undernutrition complex. To address this challenge, Alive & Thrive implemented interventions to strengthen interpersonal counseling, micronutrient supplement provision, and community mobilization through the government antenatal care (ANC) platform in Uttar Pradesh, India. Objective: This qualitative study aimed to: (1) examine pregnant women's experiences of key nutrition-related behaviors (ANC attendance, consuming a diverse diet, supplement intake, weight gain monitoring, and breastfeeding intentions); (2) examine the influence of family members on these behaviors; and (3) identify key facilitators and barriers that affect behavioral adoption. Methods: We conducted a qualitative study with in-depth interviews with 24 pregnant women, 13 husbands, and 15 mothers-in-law (MIL). We analyzed data through a thematic approach using the Capability-Opportunity-Motivation-Behavior (COM-B) framework. Results: For ANC checkups and maternal weight gain monitoring, key facilitators were frontline worker home visits, convenient transportation, and family support, while the primary barrier was low motivation and lack understanding of the importance of ANC checkups. For dietary diversity, there was high reported capability (knowledge related to the key behavior) and most family members were aware of key recommendations; however, structural opportunity barriers (financial strain, lack of food availability and accessibility) prevented behavioral change. Opportunity ranked high for iron and folic acid supplement (IFA) intake, but was not consistently consumed due to side effects. Conversely, lack of supply was the largest barrier for calcium supplement intake. For breastfeeding, there was low overall capability and several participants described receiving inaccurate counseling messages. Conclusion: Key drivers of maternal nutrition behavior adoption were indicator specific and varied across the capability-opportunity-motivation behavior change spectrum. Findings from this study can help to strengthen future program effectiveness by identifying specific areas of program improvement.

The role of social support and interpersonal trust to improve compliance of iron supplementation amongst adolescent girls: A qualitative approach.

Context: Adolescence is a crucial phase in preventing and controlling anaemia. One of the efforts made by the Indonesian government to overcome adolescent girl's anaemia is the iron and folic acid (IFA) supplementation programme. This programme is one of the most effective interventions that various countries have used to overcome anaemia. The key to the success of the supplementation of IFA is the compliance of adolescent girls. Aims: This study investigates the compliance and its contributing factors of IFA supplementation and the role of social support and interpersonal trust as a source of information and reminder amongst adolescent girls in Sidoarjo, Indonesia. Methods: This research was a qualitative study using the in-depth interview to collect data. Thirteen adolescent girls from three high schools in Sidoarjo, Indonesia, were recruited using a snowball sampling technique. Results: Most of the girls did not comply with IFA supplementation. Contributing factors were the influence of peers, influence of teachers, parental influence, risk and benefit of taking IFA tablet and also failure to remember to take IFA tablet. The social environment that provided information and reminder came from teacher, parent, peer and also health worker. Interpersonal trust was needed to have positive perceived social support. Conclusions: Compliance with the consumption of IFA supplements requires the cooperation of various parties (teachers, parents, peers and health workers) and also interpersonal trust between adolescent girls to their social environment so the programme could be run optimally.

Effect of Picture-based health education and counselling on knowledge and adherence to preconception Iron-folic acid supplementation among women planning to be pregnant in Eastern Ethiopia: a randomized controlled trial.

The present study examined the effect of picture-based nutrition education on knowledge and adherence to pre-conception iron-folic acid supplement (IFAS) in Ethiopia, a country where there is a high burden of neural tube defects (NTDs) and anaemia. In eastern Ethiopia, a parallel randomised controlled trial design was employed among women planning to get pregnant. The interventional arm (n 122) received a preconception picture-based nutrition education and counselling along with an IFAS and the control arm (n 122) received only a preconception IFAS. The effects of the intervention between-group differences were assessed using a χ 2 and independent sample t-test. Bivariate and multivariable linear regression model was fitted to detect independent variables affecting the outcome. The outcome measures regarding the knowledge and adherence to the IFAS intake during the three months of the intervention period were deteremined. It was observed that large proportion of women in the intervention group (42⋅6 %) had an adherence to IFAS compared to the control group (3⋅3 %); (P < 0⋅0001). Based on bivariate and multivariable linear regression analyses, among NTDs affecting pregnancy, the history of spontaneous abortion and knowledge were independently associated with adherence to the IFAS (P < 0⋅05). Preconception nutrition education with regular follow-ups could be effective in improving knowledge and adherence to the IFAS intake. This intervention is very short, simple, cost-effective and has the potential for adaptation development to a large-scale implementation in the existing healthcare system in Ethiopia to prevent NTDs and adverse birth outcomes among women who plan to get pregnant. This clinical trial was registered on 6 April 2021 under the ClinicalTrials.gov with an identifier number PACTR202104543567379.

Preconception of folic acid supplementation knowledge among Ethiopian women reproductive age group in areas with high burden of neural tube defects: a community based cross-sectional study.

Periconceptional folic acid supplementation is effective in the prevention of neural tube defects (NTDs). The aim of the present study was to determine the level of knowledge about the benefits of preconceptional folic acid supplementation in a sample of women of childbearing age and its associated factors. A cross-sectional community-based study design was carried out on a total of 441 women of childbearing age. Questionnaires included knowledge of preconception of folic acid supplements and socio-demographic characteristics. The χ 2 was used to compare categorical data. Multivariate logistic regression was used to isolate the predictive variables and examined individually by calculating the adjusted odds ratio. Statistical significance is declared as P < 0·05. We found that 35·1 % (n 155) knew preconceptional folic acid supplementation could prevent NTDs, and 3·8 % (n 17) knew the right time to take preconceptional folic acid supplementation and only 1·7 % (n 7) who had a history of NTDs. Attended secondary education (OR 2·7; 95 % CI 1·1, 6·0, P = 0·017), governmental employee (OR 3·5; 95 % CI 2·3, 17·8, P < 0·001), current pregnancy status (OR 3·0; 95 % CI 2·1, 4·2, P = 0·043), history of visiting the antenatal care service during pregnancy (OR 2·9; 95 % CI 1·07, 7·8, P = 0·03), history of taking folic acid supplement (OR 4·5; 95 % CI 2·9, 7·1, P < 0·001) were associated. More than half of the participant women did not know about preconception of folic acid supplements that reduce the risk of NTDs. Identification of the level of knowledge on preconception of folic acid may allow for targeted educational or other interventions to further encourage folic acid use.

Individualized Supplement of Folic Acid Based on the Gene Polymorphisms of MTHER/MTRR Reduced the Incidence of Adverse Pregnancy Outcomes and Newborn Defects.

BACKGROUND: The association between conventional folic acid supplement (FAS) in pregnancy and the occurrence of adverse pregnancy outcomes, newborn defects has been proven. However, recent researches have reported a weakened association. Based on the different maternal metabolism capability of folic acid, it's beneficial for clinicians to provide pregnant women with different doses of FAS, that's individualized FAS. SUBJECTS AND METHODS: A total of 2,677 pregnant women in Dazu, Chongqing, China were recruited in this cohort study. 1,539 women volunteered to receive individualized FAS, in which FAS dose increased with the risk level of maternal genotype? specify MTHFR and MTRR (write in full then abbreviate bracket open and close) while 1,138 women received conventional FAS with unified FAS dose. Additionally, 1,964 pregnant women without FAS were retrospectively analyzed as the control. Finally, the incidence of adverse pregnancy outcomes and newborn defects were recorded. RESULTS: Based on the genotype of MTHFR and MTRR, women were identified as five risk levels of folic acid metabolism. The distributions of genotype and risk levels were not significantly different between FAS-individualized supplement group and FAS-unified supplement group. However, compared with control or FAS-unified supplement group, the incidence of spontaneous abortion, prolonged pregnancy, premature labor, fetal macrosomia and congenital heart disease were significantly decreased in FAS-individualized supplement group. In subgroup analysis, individualized FAS significantly improved pregnancy outcomes for women between 20-40 years old and inhibited the occurrence of newborn defects in both women of the first gestation and women of ≥2 gestations. CONCLUSIONS: The application of individualized FAS based on gene polymorphisms was more effective in preventing adverse outcomes in the mother and child.

Adherence to Iron and Folic Acid Supplements and Associated Factors Among Pregnant Mothers Attending ANC at Gulele Sub-City Government Health Centers in Addis Ababa, Ethiopia.

BACKGROUND: Even though antenatal care (ANC) visits seems to be the key strategy to increase adherence to iron and folic acid supplements during pregnancy, the problem still remains unresolved. Therefore, this study planned to assess adherence to iron and folic acid supplements and associated factors among pregnant mothers attending ANC at Gulele sub-city Government Health Centers in Addis Ababa, Ethiopia, 2019. METHODS: An institution-based cross-sectional study design was conducted on 403 pregnant women attending ANC at governmental health centers in Gulele sub city of Addis Ababa from May to June, 2019. The study participants were selected by systematic random sampling techniques, and an interviewer administered questionnaire was used to collect data. Descriptive statistics and logistic regression models were used to analyze the data. The results were considered statistically significant at p-value <0.05. RESULTS: The proportion of mother's adherent to iron and folic acid supplements was 62.3% with a 95% CI of 57.5-67.0. Women who had no formal education (AOR=2.37; 95% CI=1.25-4.51), poor knowledge about anemia (AOR=1.97; 95% CI=1.24-3.13), developing any other health problem during current pregnancy (AOR=2.59; 95% CI=1.55-4.32), attending health information about iron/folic acid supplement (AOR=2.06; 95% CI=1.08-3.921 and forgetful (AOR=2.23; 95% CI=1.40-3.56) mothers were more likely to be non-adherent to the supplement compared with their counterparts. CONCLUSION AND RECOMMENDATION: The status of maternal adherence was medium compared with other studies, and maternal educational status, knowledge about anemia, exposure to information, experiencing of health problems, and forgetfulness were associated with adherence behavior. This indicates that improving dissemination of information about the supplements and designing a reminder mechanism was needed to improve the adherence status of mothers to the supplement.

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

Maternal periconceptional folate status and infant atopic dermatitis: A prospective cohort study.

BACKGROUND: Maternal folate status is linked with the risk of allergic disorders including atopic dermatitis (AD) in children, but findings remain inconclusive. We aim to assess the relationship between maternal folate status in early gestation and early-onset infant AD, based on a prospective mother-child cohort study. METHODS: Pregnant women were recruited at 12-14 weeks of gestation. Red blood cell folate (RBC folate) and serum folate concentrations were examined at enrollment. Periconceptional folic acid supplementation was investigated through a self-administered questionnaire. The primary outcome was AD incidence before 6 months of age, diagnosed according to Williams' criteria. Multivariate logistic regression was used to evaluate associations of maternal folate status with infant AD by adjusting parental and child covariates. RESULTS: In total, 107 (23.4%) of 458 infants developed AD before 6 months, with more male infants affected (P = .002). Higher maternal RBC folate levels (per 100 ng/mL) were associated with an increased risk of AD (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.04-1.31). An RBC folate level ≥620 ng/mL was associated with increased infant AD by 91% (aOR 1.91, 95% CI 1.09-3.36). However, associations were not observed for maternal serum folate at early gestation or periconceptional folic acid supplement intakes. CONCLUSIONS: We provide the first evidence that higher maternal RBC folate concentrations during early gestation are associated with increased early-onset infant AD. Our findings support the importance of maintaining appropriate folate levels during the periconceptional period to reduce the risk of AD in infants.

Maternal risk associated with the VACTERL association: A case-control study.

BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.

Prevalence and determinants of inadequate use of folic acid supplementation in Japanese pregnant women: the Japan Environment and Children's Study (JECS).

OBJECTIVE: The aim of the study was to clarify the prevalence and determinants of inadequate use of folic acid supplementation in pregnant Japanese women. METHODS: This study was part of the Japan Environment and Children's Study, a nationwide and government-funded birth cohort study. We collected information on the use of folic acid supplementation before and during pregnancy and characteristics of participants using self-administered questionnaire. RESULTS: Among 9849 women who completed the data collection for this study, the prevalence of inadequate users was 92.6% of the total population and varied from 84.5% to 96.2% among regions. On the basis of multivariate logistic regression analysis, younger age, not married, lower family income, multipara, natural conception and no history of spontaneous abortion were found to be determinants for inadequate users of folic acid supplementation. CONCLUSION: Most Japanese pregnant women show inadequate folic acid supplementation use. Japanese women of child-bearing age need to be specifically informed about the need for periconceptional intake of folic acid to prevent neural tube defects.