This review discusses epigenetic mechanisms and the relationship of infertility in men and women in relation to parameters pertaining to nutrition. The prevalence of infertility worldwide is 8–12 %, and one out of every eight couples receives medical treatment. Epigenetic mechanisms, aging, environmental factors, dietary energy and nutrients and non-nutrient compounds; more or less energy intake, and methionine come into play in the occurrence of infertility. It also interacts with vitamins B12, D and B6, biotin, choline, selenium, zinc, folic acid, resveratrol, quercetin and similar factors. To understand the molecular mechanisms regulating the expression of genes that affect infertility, the environment, the role of genotype, age, health, nutrition and changes in the individual's epigenotype must first be considered. This will pave the way for the identification of the unknown causes of infertility. Insufficient or excessive intake of energy and certain macro and micronutrients may contribute to the occurrence of infertility as well. In addition, it is reported that 5–10 % of body weight loss, moderate physical activity and nutritional interventions for improvement in insulin sensitivity contribute to the development of fertility. Processes that pertain to epigenetics carry alterations which are inherited yet not encoded via the DNA sequence. Nutrition is believed to have an impact over the epigenetic mechanisms which are effective in the pathogenesis of several diseases like infertility. Epigenetic mechanisms of individuals with infertility are different from healthy individuals. Infertility is associated with epigenetic mechanisms, nutrients, bioactive components and numerous other factors.

Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6S)-5-methyltetrahydrofolic acid ((6S)-5-MTHF) is available in some commercial prenatal vitamins as an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomised sixty pregnant individuals at 8–21 weeks’ gestation to 0·6 mg/d folic acid or (6S)-5-MTHF × 16 weeks. Fasting blood specimens were collected at baseline and after 16 weeks (endline). Erythrocyte and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolised folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake and gestational weeks. At endline (n 54), the mean values and standard deviations (or median, inter-quartile range) of erythrocyte folate, serum folate and plasma UMFA (nmol/l) in those supplemented with (6S)-5-MTHF v. folic acid, respectively, were 1826 (sd 471) and 1998 (sd 421); 70 (sd 13) and 78 (sd 17); 0·5 (0·4, 0·8) and 1·3 (0·9, 2·1). In regression analyses, erythrocyte and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0·6 nmol/l higher (95 % CI 0·2, 1·1) in those supplementing with folic acid as compared with (6S)-5-MTHF. In conclusion, supplementation with (6S)-5-MTHF may reduce plasma UMFA by ∼50 % as compared with supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.

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 χ2 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.

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 χ2 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.

Despite the high burden of neural tube defects (NTD) in eastern Ethiopia, there is no evidence that it is related to maternal dietary practice. The aim of the present study was to compare dietary practice between women who gave birth to newborns with and without NTDs. A comparative cross-sectional study was performed on a total of 276 (138 in each group) mothers who delivered neonates with or without NTD. Study participants were selected from three hospitals found in the eastern part of Ethiopia. The dietary practice was determined using the indicators including meal frequency, dietary diversity score (DDS), food variety score (FVS) and consumption of animal source food (ASF) generated from the dietary data collected using validated and pre-tested Food Frequency Questionnaire (FFQ). A multivariable logistic regression model was fitted to isolate independent predictors of dietary practices. The prevalence of good dietary practice was 29 % (95 % CI 23·6 %, 34·3 %). There was a significant difference in dietary practices (P = 0·034), in FVS (P = 0·01), in DDS (P = 0·045) between the two groups. In multivariable logistic regression, independent predictors of having good dietary practice were: not being the mother of a newborn with NTDs [adjusted odds ratio (AOR) 2·1, 95 % CI 1·07, 4·1], being from a rural residence area (AOR 0·29, 95 % CI 0·1, 0·7) and being illiterate (AOR 0·16, 95 % CI 0·03, 0·8). The present study found that dietary practice is associated with the development of NTDs. Nutrition education, food fortification and supplementation are needed to address this issue, and further research is needed to explore the mechanism.

The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999–2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear–face–neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999–2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear–face–neck, heart or oral clefts were not observed.

Folic acid (FA) supplementation is recommended in the periconceptional period, for the prevention of neural tube defects. Limited data are available on the folate status of New Zealand (NZ) pregnant women and its association with FA supplementation intake. Objectives were to examine the relationship between plasma folate (PF) and reported FA supplement use at 15 weeks’ gestation and to explore socio-demographic and lifestyle factors associated with PF. We used data and blood samples from NZ participants of the Screening for Pregnancy Endpoints cohort study. Healthy nulliparous women with singleton pregnancy (n 1921) were interviewed and blood samples collected. PF was analysed via microbiological assay. Of the participants, 73 % reported taking an FA supplement at 15 weeks’ gestation – of these, 79 % were taking FA as part of/alongside a multivitamin supplement. Of FA supplement users, 56 % reported consuming a daily dose of ≥800 μg; 39 % reported taking less than 400 µg/d. Mean PF was significantly higher in women reporting FA supplementation (54·6 (se 1·5) nmol/l) v. no FA supplementation (35·1 (se 1·6) nmol/l) (P<0·0001). Reported daily FA supplement dose and PF were significantly positively correlated (r 0·41; P<0·05). Younger maternal age, Pacific and Maori ethnicity and obesity were negatively associated with PF levels; vegetarianism was positively associated with PF. Reported FA supplement dose was significantly associated with PF after adjustment for socio-demographic, lifestyle confounders and multivitamin intake. The relationship observed between FA supplementation and PF demonstrates that self-reported intake is a reliable proxy for FA supplement use in this study population.

Twin pregnancies discordant for neural tube defects (NTD) is a management dilemma. Risks of preterm delivery from polyhydramnios must be balanced with the risks of selective termination (ST) of the anomalous fetus. We investigated the prevalence of twin pregnancies discordant for NTD and the rate of pregnancy complications in our institution over a 10-year period. Cases were obtained by searching the hospital ultrasound database and findings were confirmed by expert review of ultrasound images. Outcomes of ST and expectant management were assessed. Each unaffected co-twin was assigned to three consecutive twin pregnancy controls matched by chorionicity and maternal age. Primary outcome was birth before 34 weeks’ gestation. Secondary outcomes were small for gestational age, mode of delivery, neonatal unit admission, and neonatal death. In total, 13 pregnancies were identified as potential cases. Of these, 11 were included in the analysis: 9 dichorionic diamniotic and 2 monochorionic diamniotic twins. Seven cases had ST and four were managed expectantly. We found 100% (4/4) of expectantly managed pregnancies delivered <34 weeks compared with 14% (1/7) of the ST group (p = .015). Polyhydramnios complicated three expectantly managed pregnancies and one pregnancy in the ST group. The birthweight SD score of all unaffected co-twins was ≥-2. The case–control analysis showed a higher rate of polyhydramnios in twin pregnancies discordant for NTD compared with controls, but little evidence for differences between groups in delivery rates <34 weeks, birthweight, neonatal unit admission, or neonatal death. ST warrants serious consideration to avoid potential complications to the unaffected co-twin.

Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C→T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene–nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation.

Spina bifida meningomyelocele (SBM) is a neurodevelopmental disorder associated with intact word decoding and deficient text and discourse comprehension. This study investigated the ability to adjust reading in accordance with specified reading goals in 79 children and adolescents with SBM (9–19 years of age) and 39 controls (8–17 years of age). Both groups demonstrated slower reading times and enhanced comprehension when reading to study or to come up with a title than when reading for specific information or for entertainment. For both groups, verbal working memory contributed to comprehension performance in those reading conditions hypothesized to require more cognitive effort. Despite their sensitivity to the goals of reading, the group with SBM answered fewer comprehension questions correctly across all reading goal conditions. The results are discussed in relation to the hypothesized cognitive underpinnings of comprehension deficits in SBM and to current models of text comprehension. (JINS, 2010, 16, 517–525.)

Spina bifida meningomyelocele with hydrocephalus (SBM) is commonly associated with anomalies of the corpus callosum (CC). We describe MRI patterns of regional CC agenesis and relate CC anomalies to functional laterality based on a dichotic listening test in 90 children with SBM and 27 typically developing controls. Many children with SBM (n = 40) showed regional CC anomalies in the form of agenesis of the rostrum and/or splenium, and a smaller number (n = 20) showed hypoplasia (thinning) of all CC regions (rostrum, genu, body, and splenium). The expected right ear advantage (REA) was exhibited by normal controls and children with SBM having a normal or hypoplastic splenium. It was not shown by children with SBM who were left handed, missing a splenium, or had a higher level spinal cord lesion. Perhaps the right hemisphere of these children is more involved in processing some aspects of linguistic stimuli. (JINS, 2008, 14, 771–781.)

The risk for specific defects among twins compared to singletons was studied using data collected by the Spanish Collaborative Study of Congenital Malformations (ECEMC). A total of 136 twins had a major and/or minor congenital defect. The overall rate of congenital defects in twins (2.37%) did not deviate significantly from the rate in singletons (2.21%). Like-sex (LS) and male-male (MM) twin pairs had a slightly higher rate of birth defects than unlike-sex (US) and female-female (FF) pairs, respectively. Defects of the central nervous system, cardiovascular system and genitourinary system were significantly more frequent in LS twins than in singletons, with relative risks of 2.8, 2.5 and 1.6, respectively. No significantly increased risk was found among US twins. Among defects of the central nervous system, the rates of anencephaly, encephalocele and hydrocephaly were significantly higher in total and LS twins; however, no significantly increased risk for spina bifida was observed when compared to singletons. MM twins were also 1.9 times more likely to have hypospadias, but the risk among males of male-female (FM) pairs was decreased.