Folate (Pregnancy)

Congenital abnormalities (CAs) are a major contributor to perinatal mortality and morbidity in India, particularly among abortuses and stillbirths. Despite the Ministry of Health and Family Welfare, India, introducing stillbirth surveillance guidelines, national data on the burden of CAs remain limited. This systematic review and meta-analysis aimed to estimate the pooled prevalence of CAs in fetal losses and assess variations by organ system, region, and diagnostic approach. A comprehensive search following PRISMA 2020 guidelines was conducted in PubMed and Google Scholar. Twenty-two hospital-based studies published between 1967 and 2024 were included. Data were critically appraised using the Joanna Briggs Institute's Critical Appraisal checklist. Meta-analysis was performed in Review Manager software using a random-effects model. Subgroup analyses explored differences by fetal outcome, publication year, diagnostic method, and geographic region, while publication bias was assessed using funnel plots and Egger's test. The pooled prevalence of CAs in fetal losses was 0.21 (95% CI: 0.17-0.25), higher among abortuses (0.38) than stillbirths (0.12) and in autopsy-based studies (0.26) than non-autopsy studies (0.09). Central nervous system anomalies were most frequent (0.42), followed by multiple anomalies (0.37). The Central region reported the highest prevalence (0.66) and the North-East the lowest (0.03). The findings highlight the need for consistent surveillance, improved diagnostic methods, and preventive strategies-particularly periconceptional folic acid supplementation and integration of CA reporting into national programmes-to reduce fetal losses and enhance maternal and child health outcomes in India and similar low- and middle-income settings. © 2026 Japanese Teratology Society.

BACKGROUND: Small vulnerable newborn (SVN) types, defined by combinations of being born too soon or too small, have distinct determinants, health consequences, and prevention strategies. The effects of prenatal balanced energy and protein (BEP) supplementation on SVN types remain unknown. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual participant data from eight randomized controlled trials of prenatal BEP supplements (N = 10,252, with 5,164 in the BEP arm and 5,088 in the control arm) in low- and middle-income countries were used. The control arms varied across studies and included context-specific standards of care, iron and folic acid supplements, or multiple micronutrient supplements. Newborns were classified into 10 groups through the combinations of preterm birth, small for gestational age (SGA) birth, and low birthweight (LBW), such as term-appropriate-for-gestational-age (AGA)-nonLBW, preterm-SGA-LBW, preterm-large-for-gestational-age-LBW, term-SGA-LBW, preterm-AGA-nonLBW, and other permutations. Newborns were also analyzed using a four-group categorization that included term-nonSGA, preterm-nonSGA, term-SGA, and preterm-SGA. Log-binomial models were used to estimate study-specific risk ratios (RRs), which were pooled using meta-analyses. Subgroup analyses were conducted by maternal age, parity, gestational age at enrollment, early pregnancy body mass index, and maternal anemia status. In the 10-group categorization of SVNs, on average, prenatal BEP supplementation led to a 30% lower risk of preterm-SGA-LBW (RR: 0.70; 95% CI [0.53, 0.91]; P = 0.009), a 25% lower risk of preterm-AGA-LBW (RR: 0.75; 95% CI [0.60, 0.93]; P = 0.009), and a 20% lower risk of term-SGA-LBW (RR: 0.80; 95% CI [0.72, 0.90]; P < 0.001). In the four-group categorization, prenatal BEP supplementation led to a 31% lower risk of preterm-SGA (RR: 0.69; 95% CI [0.52, 0.91]; P = 0.008) and a 12% lower risk of term-SGA (RR: 0.88; 95% CI [0.81, 0.96]; P = 0.005). The protective effect of prenatal BEP supplementation on preterm-SGA was stronger among multiparous women and women without anemia. The protective effects on all three SVN types under the four

BACKGROUND: Neural tube malformation is a common congenital malformation and its influencing factors were still unclear. This paper aims to explore the main influencing factors of neural tube malformation, and provide reference for the primary prevention of neural tube malformation. METHODOLOGY: Case-control literatures on the influencing factors of neural tube malformation from 1990 to 2021 were searched from Chinese and English websites. The quality of the included literatures was evaluated according to Newcastle-Ottawa Scale (NOS) scale and data were extracted. Meta-analysis was performed on the data using funnel plot and Egger's est evaluated publication bias, and sensitivity analysis was performed by eliminating individual studies one by one. RESULTS: A total of 49 case-control studies were included. Meta-analysis showed that the main influencing factors of neural tube malformation were folic acid (odds ratio (OR)OR=0.31, 95%CI: 0.20-0.47), fever (OR=3.02, 95%CI: 2.38-3.83), obesity (OR=1.76, 95%CI: 1.39-2.21), passive smoking (OR=1.91, 95%CI: 1.52-2.40). Antiepileptic drugs (OR=6.10, 95%CI: 2.58-14.43); Heavy metals (Zinc: OR=2.37, 95%CI: 1.06-5.30, mercury: OR= 4.61, 95%CI: 2.85-7.47). CONCLUSION: Prenatal supplementation with folic acid and zinc has been shown to reduce the risks of neural tube defects. It is recommended that women of childbearing age take folic acid and zinc supplements before and during pregnancy. Other factors such as fever, obesity, passive smoking, antiepileptic drugs, and mercury exposure have been associated with an increased incidence of neural tube abnormalities. Neurological tube abnormalities can be reduced by folic acid and zinc, which act as protective factors. The incidence of neural tube abnormalities is increased by fever, obesity, passive smoking, antiepileptic drugs, and mercury. © 2025 Wu X et al.

BACKGROUND: Low folate levels in women of childbearing age can cause various health issues. Additionally, low perinatal folate concentrations are a significant cause of neural tube defects. Currently, folic acid supplements mainly consist of folic acid and the active form of folate. Therefore, this systematic review and meta-analysis aimed to evaluate the effectiveness and safety of the active form of folate in women of childbearing age. METHODS: We searched the published literature in PubMed, Medline, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, and Wanfang. Randomized controlled trials (RCTs) were obtained to assess the effects of the active form of folate versus folic acid in women of childbearing age. The random or fixed effects model was used to analyze the data in meta-analysis. The results were expressed as standardized mean differences or risk ratios along with their corresponding 95% confidence intervals. RESULTS: Eleven RCTs were identified in our systematic review. The results indicated that the active form of folate supplementation might significantly increase plasma folate (P = .04), increase erythrocyte folate (P = .01), and decrease unmetabolized folic acid (P < .0001). Supplementation with the active form of folate might increase the subsequent pregnancy rates (P = .0005) and might decrease the incidence of adverse pregnancy outcomes (P = .0003) in women with a history of adverse pregnancy outcomes. However, there were no significant differences in homocysteine, vitamin B12, and betaine. In addition, subgroup analyses showed a significant increase in plasma folate and erythrocyte folate in the active form of folate supplementation group, specifically in subgroups with dosage ≥0.4 mg, intervention of the active form of folate supplementation versus the equimolar mass of folic acid, and intervention duration ≥12 weeks. CONCLUSION: Active form of folate supplementation might contribute to higher plasma folate, erythrocyte folate, and subsequent pregnancy rates, lower unmetabolized folic acid, and lower incidence of adverse pregnancy outcomes in women of childbearing age. Due to the limitation in the quality of involved stud

BACKGROUND: Melatonin (MT) is involved in the regulation of various important biological processes related to reproduction. Many studies have investigated the effects of MT supplementation on outcomes following assisted reproductive technology (ART), yielding conflicting results. The aim of this systematic review was to synthesize evidence from clinical studies regarding the impact of MT on the key outcomes of ART. METHODS: PubMed, Embase, Web of Science, and Google scholar were searched. Clinical trials that studied the effect of MT supplementation on outcomes following ART and published in English from inception to April 2020, were included. One author assessed the risk of bias in the studies using the Cochrane Collaboration checklist. Dichotomous outcomes were analyzed as risk ratios (RR) using the Mantel-Haenszel statistical method and a random/fixed effect model. Continuous outcomes were analyzed as Mean Difference (MD) using the Inverse Variance statistical method. The funnel plot was used to assess the publication bias. RESULTS: Eleven studies conducted between 2008 and 2019 were included in this meta-analysis. Clinical pregnancy rate (CPR), live birth rate (LBR), Miscarriage rate (MR), fertilization rate (FR), Number of oocytes retrieved, MII oocytes, top-quality embryos was reported in 10, 3, 6, 7, 9, 8, and 6 studies, respectively. MT supplementation significantly increased the CPR (RR, 1.24; 95% confidence interval [CI], 1.04, 1.47), the number of MII oocytes (MD, 1.39; 95% CI, 0.74, 2.04), the number of top-quality embryos (MD, 0.56; 95% CI, 0.24, 0.88), and the FR (4 studies with RR, 1.10; 95% CI, 1.03, 1.17; 3 studies with MD, 0.13; 95% CI, 0.01, 0.24). However, there was no significant difference in LBR (RR, 1.23; 95% CI, 0.85, 1.80), the number of oocytes retrieved (MD, 0.58; 95% CI, -0.12, 1.27), and the MR (RR, 0.96; 95% CI, 0.50, 1.82). When studies were sub-grouped by the control interventions, either myoinositol(MI) plus folic acid (FA) or placebo/no treatment, MT supplementation increased number of MII oocytes (MT + MI + FA vs. MI + FA, MD, 0.91; 95% CI, 0.40, 1.41; MT vs. Placebo/no treatment, MD, 2.06; 95% CI, 0.73, 3.39) and number of to

INTRODUCTION: Although newborn anemia has severe lifelong consequences on the health and well-being of newborns, it receives little attention from healthcare providers in Ethiopia. Therefore, this review aimed to estimate the pooled prevalence and associated factors of newborn anemia in Ethiopia. METHODS: A systematic review and meta-analysis were performed based on the PRISMA guideline. We searched electronic databases including PubMed/Medline, EMBASE, Web of Science, Google Scholar, as well as local institutional libraries to retrieve relevant articles. The Joanna Briggs Institute (JBI) critical appraisal tool was utilized for studies critical appraisal. A fixed-effect model was used to estimate the pooled prevalence of anemia among newborns with a 95 % confidence interval. RESULT: The pooled prevalence of anemia among newborns in Ethiopia was 26.53 % (95 % CI: 24.43, 28.62). Variables such as maternal anemia (AOR = 1.71, 95 % CI: 1.22, 2.40), antenatal care visit <4 times (AOR = 2.20, 95 % CI: 1.52, 3.19), poor iron-folic acid supplementation adherence (OR = 1.88; 95 % CI: 1.36, 2.59), low birth weight (AOR = 1.80, 95 % CI: 1.20, 2.70), and no vegetable consumption (AOR = 0.68, 95 % CI: 0.46, 0.51) were significant predictors of anemia in newborns. CONCLUSION: The prevalence of anemia among newborns in Ethiopia was significant. Therefore, collaborative measures such as early treatment initiation for complications and increased ANC visits are important. IMPLICATIONS TO PRACTICE: Strengthening antenatal care visits, routine anemia screening, iron-folic acid supplementation and promotion of nutritional education, is essential for reducing newborn anemia.

OBJECTIVE: The present study aims to evaluate the prevalence and risk factors of asthma in children through a meta-analysis. DATA SOURCES: The PubMed, Embase, Cochrane, and Web of Science databases were comprehensively retrieved for studies on the prevalence and risk factors of childhood asthma (CA) published between January 1, 2015, and July 8, 2024. Studies were screened and selected based on predefined eligibility criteria, and pertinent data were extracted. The quality of eligible studies was evaluated through the Newcastle-Ottawa Scale (NOS). Statistical analyses were undertaken via Stata 16 and R 4.4.1. STUDY SELECTION: 45 studies comprising 647,414 participants were included. RESULTS: The pooled prevalence of CA was 11.9% (95% CI: 8.8-15.8%). The meta-analysis identified several risk factors for CA, including prenatal exposure to per- and polyfluoroalkyl substances (PFAS) (OR = 0.89, 95% CI: 0.80-0.98, P = 0.021), prenatal exposure to acid-suppressive medications (OR = 1.11, 95% CI: 1.04-1.19, P = 0.002), maternal folic acid supplementation during pregnancy (OR = 1.18, 95% CI: 1.10-1.27, p < 0.001), as well as Helicobacter pylori infection in childhood (OR = 2.07, 95% CI: 1.35-3.15, p = 0.001). CONCLUSIONS: The prevalence rate of asthma among children was approximately 11.9%. Prenatal exposure to PFAS and acid-suppressive medications, Helicobacter pylori infection in childhood were proved to be risk factors for asthma. Folic acid supplementation during pregnancy is positively associated with a reduced risk of asthma in children. Further large-scale prospective research is warranted to unveil the roles and significance of these factors.

OBJECTIVE: To evaluate zinc supplementation's efficacy in pregnancy, addressing gaps in previous reviews regarding high-risk subgroups and combination therapies. METHODS: Systematic review of six databases through March 27, 2025 for randomized controlled trials (RCTs) on prenatal zinc supplementation. Risk of bias was assessed using the Cochrane Risk of Bias 2. Stratified analyses was conducted by participant or intervention characteristics, with meta-analysis or qualitative synthesis when appropriate. Sensitivity analyses was conducted by excluding studies with high risk of bias. The systematic review was registered in PROSPERO (CRD42023440314). RESULTS: 77 RCTs were included. Compared with no zinc, zinc monotherapy among healthy pregnant women resulted in higher serum zinc level (standard mean difference (SMD) the second trimester = 0.32, 95% confidence interval (CI) 0.20 to 0.44; SMDthe third trimester = 0.51, 95% CI 0.27 to 0.76), lower fetal intrauterine retardation rate (risk ratio = 0.23, 95% CI 0.16 to 0.35), longer neonatal birth length (SMD = 0.66, 95% CI 0.21 to 1.12), bigger birth head circumference (SMD = 0.58, 95% CI 0.08 to 1.09), higher 1-min Apgar score (SMD = 0.28, 95% CI 0.06 to 0.49) and cord blood zinc level (SMD = 0.36, 95% CI 0.17 to 0.56). No additional benefits observed with zinc-iron-folate combinations versus iron-folate alone. Qualitative synthesis of limited evidence suggested potential benefits for high-risk groups (anemia, gestational diabetes, zinc deficiency or impaired intravenous glucose tolerance test). CONCLUSIONS: Zinc monotherapy may benefit healthy pregnancies and high-risk groups, but combination regimens show no additional advantages. Further research should confirm these findings. © 2025 The Author(s). Journal of Evidence‐Based Medicine published by Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.

Background/Objectives: Folic acid (FA) supplementation can effectively reduce the occurrence of neural tube defects (NTDs). Vitamin B12 is involved in folate metabolism; however, studies have not reached a definitive conclusion on the association between vitamin B12 and NTDs independent of folate levels. A systematic review and meta-analysis were performed to summarize existing research and investigate the effect of vitamin B12 on NTDs. Methods: Studies were systematically searched in PubMed, Web of Science, Embase, and Cochrane, published before 1 March 2024. Standardized mean difference (SMD) with 95% confidence interval (CI) was employed to assess the association between maternal vitamin B12 in blood and NTDs. Results: A total of 38 studies were included, with a total of 2316 NTDs and 4298 controls, covering 14 countries worldwide. Compared with the non-NTD group, the NTD group exhibited a lower vitamin B12 level [SMD = -0.23, 95% CI (-0.32, -0.14), p < 0.001, I2 = 58.3%] with a statistically significant difference. Additionally, there was a significant association between maternal vitamin B12 concentration and NTDs when there was no significant difference in folate between the NTD and control groups [SMD: -0.19, 95% CI (-0.28, -0.10)]. Conclusions: Vitamin B12 supplement is also essential for the prevention of NTDs besides folic acid. Monitoring vitamin B12 concentration among pregnant women and considering appropriate supplementation with a combination of vitamin B12 and folic acid could be explored.

BACKGROUND: Maternal intake of folic acid prevents most cases of neural tube defects (NTDs), and arsenic exposure may increase NTD risk. In Bangladesh, where arsenic exposures are high, understanding the potential impacts of arsenic reduction and folic acid-based interventions can guide decision-making. METHODS: We conducted a systematic review and meta-analysis to estimate the prevalence of NTDs in Bangladesh. We searched PubMed, Embase, Web of Science, Global Health, and Bangladesh Journals Online and extracted data using standardized forms. We used forest plots and random effects models to estimate the prevalence of all NTDs and spina bifida. Decision analysis used assumptions from the literature to compare expected NTD prevalence under strategies incorporating combinations of folic acid supplementation, fortification, and arsenic filters. Sensitivity analyses aimed to quantify the influence of adherence to supplements on estimates. RESULTS: Eleven studies were included. Prevalences of NTD and spina bifida were 27.4 and 11.2 per 10,000 births, respectively; however, when estimated from population red blood cell folate concentrations, NTD prevalence was higher in both high arsenic exposure (drinking water ≥ 50 μg/L) and lower arsenic exposure groups (34.3 and 25.3 per 10,000 births, respectively). Folic acid fortification reduced the prevalence of NTDs to 11.1 and 9.1 per 10,000 births among high exposure and low exposure groups, respectively. Arsenic filters provided little marginal benefit. Benefits of supplements equaled those of fortification when adherence to supplements exceeded 90%. CONCLUSIONS: Bangladesh has high rates of NTDs and high arsenic exposures. Folic acid fortification is projected to be the most effective strategy for NTD prevention. © 2025 The Author(s). Birth Defects Research published by Wiley Periodicals LLC.

Objective: To investigate the efficacy and safety of mFOLFOXIRI combined with bevacizumab plus cytoreductive surgery (CRS) in patients with resectable peritoneal metastasis of colorectal cancer (CRC). Methods: A single-center, prospective randomized controlled design was conducted. Inclusion criteria: confirmed synchronous or metachronous peritoneal metastasis of CRC, aged >18 years, adequate organ function and tolerance to chemotherapy, resectable peritoneal lesions with peritoneal cancer index (PCI) <20, Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1, and tolerance to CRS. Exclusion criteria: intolerance or inefficacy to oxaliplatin, distant unresectable metastasis, emergency surgery, active malignancy, history of thromboembolism, pregnancy or lactation, and other severe comorbidities. Between August 2022 and December 2024, eligible patients with resectable peritoneal metastasis of CRC treated at the Sixth Affiliated Hospital, Sun Yat-sen University were enrolled and randomly assigned at a 1:1 ratio to the neoadjuvant therapy group (mFOLFOXIRI plus bevacizumab followed by CRS) or the direct CRS group. The primary endpoint was the 1-year progression-free survival rate. Secondary endpoints included the response to neoadjuvant therapy, completeness of cytoreduction (CC) score, length of postoperative hospital stay, and postoperative complications. Results: A total of 53 patients who underwent surgery were included, with 19 in the neoadjuvant therapy group and 34 in the direct CRS group. There were no statistically significant differences between the two groups in age, sex, BMI, primary tumor location, pathological type, pattern of peritoneal metastasis (synchronous/metachronous), extraperitoneal metastasis, history of prior systemic therapy, baseline radiological PCI score, or tumor markers (CEA, CA19-9, CA125) (all P>0.05). In the neoadjuvant therapy group, post-treatment radiological PCI score was significantly lower than baseline [M(Q1,Q3): 6.0 (4.0, 12.0) vs. 8.0 (5.0, 12.0), Z=-3.086, P=0.002], and CEA was significantly reduced [3.9 (2.8, 7.3) μg/L vs. 7.7 (4.1, 16.1) μg/L, Z=-2.809, P=0.005]. Hemoglobin and albumin levels were als

BACKGROUND: Prenatal multiple micronutrient supplementation (MMS) including iron, folic acid, and other essential micronutrients, has shown potential to improve birth outcomes in controlled studies. We did an effectiveness study in Ethiopia to determine the effect on mean birthweight of MMS provided as part of routine antenatal care, relative to iron-folic acid supplementation (IFA). METHODS: A pragmatic, two-arm, facility-based, cluster-randomised controlled trial was conducted across 42 districts in five regions of Ethiopia to determine the effect on birthweight of MMS relative to IFA. Districts were randomly assigned to either retain IFA as part of routine antenatal care or switch to MMS. Randomisation was stratified by region and done using a random number generator within statistical software. All live singleton births at participating health facilities were eligible for inclusion and birthweights were recorded. Additionally, data were collected on maternal receipt and utilisation of MMS or IFA. The primary outcome was birthweight, analysed in the intention-to-treat population. This completed trial is registered at ClinicalTrials.gov, NCT05708183. FINDINGS: Between Jan 1, 2023, and Dec 31, 2024, birthweights were recorded for 47 325 babies in the 21 IFA districts and 36 473 babies in the 21 MMS districts. Mean age of mothers was 26·2 years (SD 5·3) and median gestational age of babies at birth was 38 weeks (IQR 38-39). The effect of MMS on birthweight was a mean increase of 38 g (95% CI 20-55) in the MMS arm relative to the IFA arm after adjustment for time, geographical region stratification factor, gestational age, sex of baby, and parity. Among women who reported taking at least 90 tablets of their assigned supplement, the increase in mean birthweight in the MMS arm relative to the IFA arm was 58 g (38-79). Stillbirth risk was 7·5 per 1000 births in the IFA arm and 6·9 per 1000 births in the MMS arm. INTERPRETATION: The findings of this trial are consistent with those from efficacy trials in other settings, indicating that the transition from IFA to MMS as part of routine antenatal care in Ethiopia could lead to a small but clear improvement in birthweig

BACKGROUND: Vitamin B12 deficiency is common in populations with limited animal-source foods and has been linked to delayed infant neurodevelopment and adverse pregnancy outcomes. Evidence on the benefits of maternal B12 supplementation for improving infant neurodevelopment remains mixed, particularly in low-income and middle-income countries where deficiency is prevalent. METHODS: This double-blind, randomised controlled trial was conducted in two tertiary maternity care centres in India and Nepal. Pregnant women in their first trimester, following a vegetarian diet, were enrolled and randomised to receive either a daily oral supplement of 250 µg (group A) or 50 µg (group B) of methyl-cobalamin from enrolment to 6 months post partum. The primary outcomes were infant neurodevelopment assessed at 9-12 months using the Development Assessment Scale of Indian Infants and biochemical B12 status in mothers and infants measured through blood tests. RESULTS: 531 mothers completed the study (group A n=255; group B n=276). There were no significant differences in baseline characteristics between mothers at both centres or in groups A and B. Mental developmental quotients (DQs) were higher in the infants of group A: 103.7 (7.7) than group B: 101.7 (8.8); p=0.008). This corresponds to a mean difference of 7.8 centiles (p=0.007). Mean motor DQs were not significantly different between the groups. Maternal vitamin B12 levels rose from the first to third trimester in both groups, with a larger increase in group A (104.9 pg/mL (SD 159.1)) than group B (47.5 pg/mL (SD 118.0)), p<0.001. Holotranscobalamin levels improved similarly (p<0.001). All infant levels of vitamin B12 were within the normal range. Newborn anthropometry, APGAR scores and morbidity profiles were similar in both groups (p>0.05). Serum ferritin, vitamin D and folate were similar (p>0.05). CONCLUSIONS: Daily supplementation with 250 µg of vitamin B12 during pregnancy in vegetarian mothers significantly improved infant mental DQ and maternal B12 status compared with a 50 µg dose. © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY. Published by BMJ Group.

BACKGROUND: Maternal periconceptional nutrition is important for birth outcomes, but few studies examine long-term effects on offspring growth and development. OBJECTIVES: We assessed the impact of weekly preconception multiple micronutrients (MM) or iron and folic acid (IFA) supplements compared to folic acid (FA) alone, on cognitive function and nutritional status at 10-11 y. We also examined associations with early-life biological and socioenvironmental factors. METHODS: We conducted a follow-up study of 1599 children from a preconception randomized trial in Vietnam, in which females received weekly FA, IFA, or MM before conception and daily IFA during pregnancy. We assessed cognitive function, academic achievement, and nutritional status at ages 10-11 y. Early biological factors included maternal nutritional status, birth characteristics, and postnatal linear growth; socioenvironmental variables were maternal schooling, ethnicity, depression, infant feeding, socioeconomic status (SES), and home environment. Analyses used intention-to-treat and per protocol comparisons with inverse-probability-of-censoring weights to account for loss to follow-up. RESULTS: Offspring in the MM and IFA groups had higher perceptual reasoning scores than the FA group {mean difference [95% confidence interval (CI): MM: 1.68 (0.01, 3.35); IFA: 2.04 (0.33, 3.74)]}. The IFA groups also had higher reading scores [0.78 (0.11, 1.44)] and lower anemia prevalence [-4.26 (-7.60, -0.91)]. No differences were observed in full-scale intelligence quotient (FSIQ) or anthropometric measures. Maternal underweight was negatively associated with FSIQ [β (95% CI): -1.62 (-3.06, -0.18)] and reading scores [-0.59 (-1.12, -0.06)] whereas postnatal linear growth was positively associated with FSIQ [1.67 (0.91, 2.43)], mathematics [0.36 (0.12, 0.61)], and reading scores [0.47 (0.21, 0.74)]. Maternal schooling, home environment, SES, were also linked to improved cognitive and academic outcomes [β range: 0.64 (0.01, 1.27) to 8.89 (5.20, 12.58)], and exclusive breastfeeding was linked with higher mathematics scores [0.73 (0.27, 1.19)]. CONCLUSIONS: Preconception MM and IFA supplementation improved certain a

BACKGROUND: Poor ovarian response (POR) is a serious problem that decreases the effectiveness of conventional ovarian stimulation. Its concern is elevated production of reactive oxygen species, causing DNA destruction and mitochondrial malfunction, which contributes to the decline in oocyte quality. OBJECTIVE OF THE STUDY: This trial aimed to identify the impact of Coenzyme Q10 as an antioxidant on ovarian reserve markers and Intra-cytoplasmic sperm injection results in poor ovarian responders. METHODS: A prospective controlled study included 100 patients classified as poor ovarian responders according to the Bologna criteria. The patients were randomly allocated to two groups. Fifty participants in group A were administrated Coenzyme Q10 plus folic acid for one month prior to the ICSI cycle and through the ICSI cycle. Fifty patients in group B were administrated folic acid only for a similar duration. The primary outcome measured was the count of oocytes obtained. The chemical pregnancy rate was considered a secondary outcome. RESULTS: The baseline features were equivalent among the groups. CoQ10 markedly improved the oocyte count and peak E2 (p <0.001). Higher levels of antral follicle count at the start of the induction were observed in the treated group (p= 0.001). Endometrial thickness was greater in the CoQ10 group than in the control group (p=0.004). Significant differences were found in the count of embryos transferred and the percentage of women who underwent no embryo transfer (p=0.011). No substantial variations were detected in the gonadotropin doses, induction days, or progesterone levels among the two groups. The chemical and clinical pregnancy rates and completed cycles were equivalent between the two groups, with insignificant differences. CONCLUSION: CoQ10 promotes ovarian response to conventional induction and has a beneficial effect on ovarian reserve and embryological measures in poor responders. Despite this, additional investigations are essential to determine its influence on pregnancy rates. CLINICAL TRIAL ID: NCT06405204. © 2026 Abdelrahman et al.

BACKGROUND: Folic acid (FA) fortification of cereal grains reduces the prevalence of folate insufficiency among adult females and related neural tube defects (NTDs) in their offspring. However, fortifiable cereal grains have limited reach in many lower-income countries, so additional fortification options need to be developed and evaluated. OBJECTIVES: This study assessed the effects of FA fortification of iodized salt on women's discretionary salt intakes, biomarkers of folate and iodine status, and the occurrence of adverse events. METHODS: We conducted a community-based, 3-arm, household-randomized dose-response trial among 360 nonpregnant Ethiopian females 18 to 49 y of age. We delivered iodized salts containing 32 parts per million (ppm) iodine and 99, 36, or 0 ppm FA to households bi-weekly for 26 wk. We measured participants' fasting red blood cell (RBC) folate, serum folate, homocysteine, thyroglobulin, vitamin B-12 biomarkers, glucose, and insulin, and urinary iodine/creatinine ratios before and during the intervention. We quantified participants' salt intakes using weighed food records, and we systematically recorded adverse events. RESULTS: The overall median (IQR) RBC folate concentration at baseline was 476 (371, 580) nmol/L. Participants' mean usual intakes of study salts (7.8 ± 1.8 g/d) did not differ by study arm (P = 0.58). The final median (IQR) RBC folate concentrations were 1275 (1120, 1521) nmol/L, 1004 (819, 1212) nmol/L, and 468 (366, 596) nmol/L in the respective study arms (all significantly different, P < 0.001). There were no group-wise differences in urinary iodine/creatinine ratios, serum thyroglobulin, insulin resistance, or reported adverse events. CONCLUSIONS: FA fortification of salt is an effective and safe method to improve women's folate status and thereby reduce the risk of NTD-affected pregnancies. This trial was registered on the ClinicalTrials.gov website (registration number NCT06223854): https://clinicaltrials.gov/study/NCT06223854?term=Transcobalamin%20Deficiency&viewType=Table&rank=4.

To assess the feasibility of a randomized controlled trial (RCT) comparing 5-methyltetrahydrofolate (5-MTHF) and folic acid (FA) in couples with recurrent pregnancy loss. Pregnancy loss affects up to 15% of pregnancies, with over half of cases remaining unexplained. Emerging evidence suggests that folate metabolism, particularly in individuals carrying methylenetetrahydrofolate reductase polymorphisms such as C677T and A1298C variants, may influence reproductive outcomes. A double-blind, RCT feasibility trial was conducted in Australia with 22 reproductive dyads randomized to receive either 5-MTHF or FA prenatal multivitamins. Participants adhered to dietary restrictions, abstained from conception for two cycles, and completed regular assessments. Primary outcomes included feasibility, adherence, acceptability, and preliminary efficacy based on biochemical markers and pregnancy outcomes. The trial demonstrated high acceptability (86% in arm A [MTHF-A] and 94% in arm B [FA-B]) and adherence rates for supplement use over 78% in each arm. Unmetabolized FA concentration decreased in the 5-MTHF group but rose significantly in the FA group. A critical finding was the degradation of 5-MTHF in retained samples, highlighting formulation instability as a confounder. A fully online RCT comparing 5-MTHF and FA is feasible. Future trials should address formulation stability and expand sample size to evaluate clinical efficacy and personalized folate strategies.

OBJECTIVES: Asprosin is a newly discovered adipokine associated with insulin resistance and diabetes mellitus. Currently, its role during gestation is under investigation, as asprosin seems to increase during pregnancy, contributing to the onset of complications, like gestational diabetes. Considering the beneficial effects of myo-inositol to support the physiological pregnancy, recovering and preventing adverse maternal and fetal outcomes, we aimed to evaluate the effects of its supplementation on serum asprosin levels in pregnant women. DESIGN: We enrolled 40 patients at the early stages of pregnancy and randomly distributed them to a study group, which received 2-g myo-inositol and 200-μg folic acid twice a day, or to a control group, which received the sole folic acid. RESULTS: After 20-22 weeks of treatment, we recorded a decrease of serum asprosin values as well as of HOMA-IR index in the group supplemented with myo-inositol, while the group that took only folic acid showed an increase in asprosin levels and no worsening of insulin resistance indices (HOMA-IR index). LIMITATIONS: The small number of patients could be a limitation of the study. CONCLUSIONS: Asprosin may be modulated by myo-inositol. This opens the possibility of considering this adipokine as a useful marker of insulin resistance to assess in pregnant women and to efficaciously target in clinical practice. Trial Registration: ClinicalTrials.gov identifier: NCT05943158.

BACKGROUND: In a recent double-blind randomized controlled trial (RCT) in Nepal, we found a negative effect of maternal vitamin B-12 supplementation during pregnancy on motor performance in their young infants. OBJECTIVES: The objective of this study is to examine whether the negative effect of the vitamin B-12 supplementation on motor performance in these infants aged 8 to 12 wk differed by baseline maternal characteristics. METHODS: These are secondary analyses of an RCT where 800 pregnant women were randomly assigned to receive vitamin B-12 or placebo from early pregnancy to 6 mo postpartum. The outcome was motor development measured by the test of infant motor performance (TIMP) in 712 infants at age 8 to 12 wk. We examined whether plasma markers of baseline maternal vitamin B-12 status [cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), and cB12], folate and hemoglobin concentration, and socioeconomic status (SES) modified the effect of vitamin B-12 on the TIMP scores. The subgrouping variables were categorized according to predefined cutoffs and included as interaction terms in generalized linear models, with treatment group as the exposure and TIMP scores (continuous and categorical) as the outcomes. RESULTS: Overall, the negative effect of the vitamin B-12 supplementation was observed in most subgroups. Except for plasma folate concentration (P-interaction = 0.015), the maternal baseline characteristics did not significantly modify the effect of vitamin B-12 supplementation on the TIMP scores. There was a tendency for a stronger negative effect of vitamin B-12 among infants of women with adequate baseline vitamin B-12 status (i.e. concentrations of cobalamin >220, tHcy <10, MMA <0.26, and cB12 values >-0.5) and with folate concentration in the lower tertile. CONCLUSIONS: The negative effect of vitamin B-12 supplementation on infant motor performance cannot be explained by any subgroup specific effects. However, the effect appears to be more pronounced in mothers with adequate B-12 status. This trial was registered at clinicaltrials.gov as NCT03071666 (https://www. CLINICALTRIALS: gov/study/NCT03071666).

BACKGROUND: This study directly examined the effects of antenatal micronutrient supplementation on adolescent blood pressure (BP). METHODS: This study involved adolescents from two rural counties in western China. Their mothers had previously participated in a cluster-randomized trial of antenatal micronutrient supplementation. All pregnant women were randomized to take a daily capsule of folic acid (FA) as control, folic acid plus iron (IFA), or multiple micronutrients (MMNs) until delivery. Adolescent BP was assessed using a validated electronic sphygmomanometer and converted into percentiles by population reference. We examined the effects of antenatal micronutrient supplementation on adolescent BP and BP percentiles using generalized estimation equations. Multinomial logistic regression was employed to examine the associations between antenatal micronutrient supplementation and categorical BP outcomes, with relative risk reduction estimated. RESULTS: Among 4488 singleton births eligible for long-term follow-up, 1994 (44.4%) adolescents were followed, and among them, 59.2% were male, with a mean age of 11.73 (SD, 0.86) years old. After adjusting for a range of covariates, antenatal MMNs supplementation relative to FA alone was associated with a 1.13 (95% CI -2.09, -0.17) mmHg lower systolic blood pressure (SBP) and a 2.59 (95% CI -5.01, -0.17) points lower SBP percentile. The similar benefits of MMNs were observed for categorized adolescent high BP (SBP and/or diastolic blood pressure (DBP) ≥ the 95th percentile for age, sex, and height). CONCLUSIONS: Compared with folic acid alone, antenatal MMNs supplementation was associated with lower adolescent SBP. This finding suggests that comprehensive antenatal nutritional interventions may offer a potential strategy for the primordial prevention of hypertension in offspring. TRIAL REGISTRATION: ISRCTN08850194, retrospectively registered December 14, 2006. https://www.isrctn.com/ISRCTN08850194?q=ISRCTN08850194&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10 . © 2025. The Author(s).

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of 'catch up' growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin's transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

Genomic imprinting is important for mammalian development and its dysregulation can cause various developmental defects and diseases. The study evaluated the effects of different dietary combinations of folic acid and B12 on epigenetic regulation of IGF2R and KCNQ1OT1 ncRNA in C57BL/6 mice model. Female mice were fed diets with nine combinations of folic acid and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks postweaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. Dietary deficiency of folate (BNFD and BOFD) and B12 (BDFN) with either state of other vitamin or combined deficiency of both vitamins (BDFD) in comparison to BNFN, were overall responsible for reduced expression of IGF2R in the placenta (F1) and the fetal liver (F2) whereas a combination of folate deficiency with different levels of B12 revealed sex-specific differences in kidney and brain. The alterations in the expression of IGF2R caused by folate-deficient conditions (BNFD and BOFD) and both deficient condition (BDFD) was found to be associated with an increase in suppressive histone modifications. Over-supplementation of either folate or B12 or both vitamins in comparison to BNFN, led to increase in expression of IGF2R and KCNQ1OT1 in the placenta and fetal tissues. The increase in the expression of IGF2R caused by folate over-supplementation (BNFO) was associated with decreased DNA methylation in fetal tissues. KCNQ1OT1 noncoding RNA (ncRNA), however, showed upregulation under deficient conditions of folate and B12 only in female fetal tissues which correlated well with hypomethylation observed under these conditions. An epigenetic reprograming of IGF2R and KCNQ1OT1 ncRNA in the offspring was evident upon different dietary combinations of folic acid and B12 in the mice. © 2021 Wiley Periodicals LLC.

OBJECTIVE: Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. DESIGN: We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. METHODS: We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir-disoproxil-fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). RESULTS: Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (-1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (-5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by -3.3 ± 8.1 with TDF/FTC/EFV arm. CONCLUSION: Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.

BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- and middle-income countries. They are exacerbated in pregnancy due to the increased demands of the developing fetus, leading to potentially adverse effects on the mother and baby. A consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane Review in 2017, evidence from several trials has become available. The findings of this review will be critical to inform policy on micronutrient supplementation in pregnancy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: For this 2018 update, on 23 February 2018 we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation with iron and folic acid during pregnancy and its effects on pregnancy outcomes were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but excluded quasi-randomised trials. Trial reports that were published as abstracts were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified 21 trials (involving 142,496 women) as eligible for inclusion in this review, but only 20 trials (involving 141,849 women) contributed data. Of these 20 trials, 19 were conducted in low- and middle-income countries and compared MMN supplements with iron and folic acid to iron, with or without folic acid. One trial conducted in the UK compared MMN supplementation with placebo. In total, eight trials were cluster-randomised.MMN with iron and folic acid versus iron, w

BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- to middle-income countries. They are exacerbated in pregnancy due to the increased demands, leading to potentially adverse effects on the mother and developing fetus. Though supplementation with MMNs has been recommended earlier because of the evidence of impact on pregnancy outcomes, a consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane review, evidence from a few large trials has recently been made available, the inclusion of which is critical to inform policy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 March 2015) and reference lists of retrieved articles and key reviews. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation with iron and folic acid during pregnancy and its effects on the pregnancy outcome were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Nineteen trials (involving 138,538 women) were identified as eligible for inclusion in this review but only 17 trials (involving 137,791 women) contributed data to the review. Fifteen of these 17 trials were carried out in low and middle-income countries and compared MMN supplements with iron and folic acid versus iron with or without folic acid. Two trials carried out in the UK compared MMN with a placebo. MMN with iron and folic acid versus iron, with or without folic acid (15 trials): MMN resulted in a significant decrease in the number of newborn infant

For decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine-pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria-endemic countries. We conclude that formal cost-benefit analyses are required. © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

BACKGROUND: A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. METHODS: A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB.nl, a pharmacy prescription database. RESULTS: Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies. CONCLUSIONS: Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.

29. Seishin Shinkeigaku Zasshi. 2015;117(11):918-27. [Monitoring and Care of Expectant Mothers with Epilepsy]. [Article in Japanese] Watanabe M, Honda M. Women with epilepsy are exposed to social stigma, and they have anxiety and lose self-confidence in their social role as a woman. Psychiatrists, especially female psychiatrists, are able to support them. Important considerations are: 1) Pre-pregnant counseling; Physicians give appropriate advice and guidance. We need to provide the latest information on the teratogenicity of AEDs, and replace them with a safer combination of AEDs BEFORE pregnancy. Folate supplementation is also recommended. 2) Management during pregnancy: Patients are advised to adhere to taking AEDs as instructed, which prevents not only seizures during pregnancy but also reduces the risk of miscarriage and premature delivery. Doses of AED are to be increased after the second trimester. 3) Collaborating with obstetricians at delivery: Obstetricians are also nervous when faced with women with epilepsy. Basically, patients can deliver spontaneously, and the correct way to deal with unexpected seizures during labor should be fully understood. 4) Parental care: women with epilepsy can breastfeed. Physicians advise other family members on how to bottle feed at night to help mothers avoid a lack of sleep due to breastfeeding. Childcare is one of the most precious experiences in life. Patients with epilepsy, especially women, have a lower self-esteem; however, once they experience delivery, they act positively and become even-tempered. Physicians should be aware that childcare fosters a profound insight into their lives, allowing them to mature as a person.

BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- to middle-income countries. They are exacerbated in pregnancy due to the increased demands, leading to potentially adverse effects on the mother and developing fetus. Though supplementation with MMNs has been recommended earlier because of the evidence of impact on pregnancy outcomes, a consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane review, evidence from a few large trials has recently been made available, the inclusion of which is critical to inform policy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 March 2015) and reference lists of retrieved articles and key reviews. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation during pregnancy and its effects on the pregnancy outcome were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Nineteen trials (involving 138,538 women) were identified as eligible for inclusion in this review but only 17 trials (involving 137,791 women) contributed data to the review. Fifteen of these 17 trials were carried out in low and middle-income countries and compared MMN supplements with iron and folic acid versus iron with or without folic acid. Two trials carried out in the UK compared MMN with a placebo. MMN with iron and folic acid versus iron, with or without folic acid (15 trials): MMN resulted in a significant decrease in the number of newborn infants identified as low birth

BACKGROUND: Cadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited. METHODS: We examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤ 12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight. RESULTS: Elevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p < 0.05). CONCLUSIONS: Our data suggest the association between pre-natal Cd and offspring DNA methylation at regulatory sequences of imprinted genes may be sex- and gene-specific. Essential metals such as Zn may mitigate DNA methylation response to Cd exposure. Larger studies are required.