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Review

Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development

1
Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, No 38 College Rd, Haidian District, Beijing 100191, China
2
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, No 38 College Rd, Haidian District, Beijing 100191, China
3
School of Public Health, Peking University, No 38 College Rd, Haidian District, Beijing 100191, China
4
Department of Health Education, Cangzhou City Center for Disease Prevention and Control, Cangzhou 061000, China
*
Author to whom correspondence should be addressed.
Nutrients 2025, 17(12), 2040; https://doi.org/10.3390/nu17122040
Submission received: 30 March 2025 / Revised: 14 June 2025 / Accepted: 17 June 2025 / Published: 19 June 2025
(This article belongs to the Special Issue The Importance of Nutrition in Fertility and Pregnancy)

Abstract

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.

1. Introduction

Neural tube defects (NTDs), common types of birth defects, have received considerable attention in the past few decades and have been greatly prevented [1]. However, in 2021, the global incidence of NTDs was still up to 93.47 per 100,000 live births [2], and low sociodemographic index regions (e.g., Eastern Sub-Saharan Africa) were the most affected [3]. Therefore, NTDs remain a serious public health concern worldwide given their substantial role in perinatal mortality.
It is well established that folic acid (FA) supplementation during the periconceptional period can prevent NTDs [1], as countries implementing FA supplementation or mandated FA fortification have reported a marked decrease in NTD prevalence [4,5,6]. Vitamin B12 is involved in folate metabolism, and its deficiency can impair the conversion and utilization of methylated folate [7,8]. The biochemical speciation of vitamin B12 in the human body is complex, the assessment of which employs multiple biomarkers. Total B12, holo-transcobalamin (holo-TC), methylmalonic acid (MMA), and homocysteine, as sensitive metabolic indicators, could be used to screen for vitamin B12 status [9].
Biologically, vitamin B12 can encompass DNA synthesis and regulation, neurological maintenance, and erythropoiesis [10], all of which are particularly critical during pregnancy, necessitating elevated dietary intake of vitamin B12 to counteract the physiological decline in serum B12 concentrations [11]. Emerging evidence has suggested that high intakes of one-carbon cofactors, such as vitamin B12, were associated with reducing NTD risk in the offspring among mothers meeting folic acid recommendations [12,13]. A study also found that vegetarian dietary habits were associated with suboptimal B12 intake and resulted in a 1.6-fold increased NTD risk [14]. Furthermore, among pregnant women, concentrations of MMA were higher in women who gave birth to children with NTDs than in the control group (130 vs. 105 nM), with a strong dose-dependent association with NTD risk [15]. Holo-TC II levels were related to the risks of having a child with an NTD [16], and pregnant women who gave birth to children with NTDs had significantly lower serum or plasma vitamin B12 levels [17,18,19,20,21]. However, certain studies reported an association between maternal vitamin B12 and NTD risk without adequately controlling for folate’s influence, making it impossible to determine vitamin B12’s specific role [18,22,23]. In addition to contemporary shifts in dietary patterns (e.g., increased prevalence of vegetarianism) and lifestyle behaviors (e.g., weight management practices), further investigation into the role of vitamin B12 in NTD etiology remains essential.
To address these research gaps, we performed this systematic review to explore the association between maternal vitamin B12 status and NTDs.

2. Materials and Methods

2.1. Search Strategy

This systematic review and meta-analysis strictly adhered to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines recommendations. We comprehensively searched PubMed, Web of Science, Embase, and Cochrane to identify all relevant studies published before 1 March 2024. Databases were searched by following terms: vitamin B12; b 12 vitamin; cyanocobalamin; cobalamins; cobalamin; methylcobalamin; eritron; neural tube defects; NTDs; developmental neural tube defects; anencephaly; brain congenital absence; anencephalus; incomplete anencephaly; spina bifida; spinal dysraphism; encephalocele; meningocele; myelomeningocele; lipomyelomeningocele; hydranencephaly. The total search strategy is listed in Table S1.

2.2. Study Selection and Data Extraction

A study was included when it was (1) a cohort study or case–control study, or (2) a study that showed a comparison of serum vitamin B12 or plasma vitamin B12 concentrations in women with NTD-affected pregnancy and women without NTD-affected pregnancy.
Studies were excluded when (1) their title, abstract, or full text was not relevant to the topic under study; or (2) they were reviews, conference abstracts, letters, patents, meta-analyses, or academic thesis; or (3) their full text was not available; or (4) they were cross-sectional study, intervention experiments or animal experiments; or (5) they were not in English; or (6) they had no relevant values for concentrations of vitamin B12, folate, or other study variables.
Two reviewers (LN and XL [Xinru Liu]) independently assessed publications for eligibility. Eventually, this study involved 43 studies that met the inclusion criteria (Figure 1). From all eligible articles, two reviewers independently extracted data from each study based on a pre-designed Excel table. Data included the name of the first author, year of publication, nationality of participants, study design, number of participants (NTD/non-NTD), time of specimen collection, folate between the NTD and control groups (significant/non-significant), and the method for the determination of B12 levels. Quality was assessed by using the Newcastle–Ottawa Scale. If any discrepancies were found, a third reviewer would join the review.
Given the established critical role of folate in NTDs, we accounted for its effect by performing stratified analyses. One subgroup was defined by non-significant differences in maternal folate between the NTD and control groups, and another subgroup was defined by significant differences in maternal folate between the NTD and control groups. The analysis of the subgroup without significant differences in folate revealed the effect of vitamin B12 on NTD risk.

2.3. Statistical Analysis

This study was conducted using R software (version 4.3.3). All the results are demonstrated as standardized mean differences (SMDs) with 95% confidence intervals (CIs) for continuous variables (concentrations of vitamin B12) between the NTD group and the control group. Sensitivity analysis was conducted to assess the robustness of the synthesized results. The p value < 0.05 was considered statistically significant in all tests. The 11 studies provided only the median and interquartile range, so the approximate mean and standard deviation were calculated [24]. Given the assessment of vitamin B12 samples over different periods, it was expected that there would be considerable heterogeneity in all results. The I2 statistic was used to evaluate the heterogeneity among studies. I2 values >50% indicated substantial heterogeneity, and therefore subgroup analyses were further conducted to explore the cause. Publication bias was identified by the symmetry of the visualized funnel plot and assessed by Egger’s linear regression method.

3. Results

Following systematic screening, a total of 2385 studies were initially identified. Ultimately, 38 studies met the inclusion criteria, comprising 2316 cases of NTD-affected pregnancies and 4298 controls across 14 countries. The characteristics of the included studies are illustrated in Table 1. All the included studies were case–control studies. Among the 38 studies, 26 found no significant differences in maternal folate [19,20,21,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47], whereas 12 revealed significant differences in maternal folate [18,22,23,48,49,50,51,52,53,54,55,56]. Overall, the specimen collection time was inconsistent, including during the second or third trimester, throughout the entire pregnancy, and during the postpartum period. Additionally, some studies did not specify the timing of collection at all. Additionally, of the 38 studies, 3 were from Africa (including Egypt and Ethiopia), 7 were from America (including Mexico, US–Mexico border, US, and southern Brazil), 9 were from Asia (including China, northern Iran, and India), and 19 were from Europe (including Turkey, Ireland, France, The Netherlands, UK, Finland, and Scotland) (Figure S1).
The SMDs of maternal vitamin B12 concentration (pmol/L) between the NTD and control groups are demonstrated in Figure 2. Compared with the non-NTD group, a significantly lower concentration of vitamin B12 was found in the NTD group [SMD = −0.23, 95% CI (−0.32, −0.14), p < 0.001, I2 = 58.3%]. Due to the presence of moderate heterogeneity, a random-effect model was applied. There was publication bias in the analysis (Figure S2), and the result of Egger’s test was significant (p = 0.013).
In the sensitivity analysis, we excluded studies that provided only the median and interquartile range (Figure 3). The results remained consistent, with lower B12 concentrations in the NTD group [SMD = −0.27, 95% CI (−0.39, −0.16), p < 0.001, I2 = 56.6%]. There was no publication bias in the sensitivity analysis (Figure S3), and Egger’s test was non-significant (p = 0.107), indicating that the asymmetry of the original funnel plot was more likely to be caused by data conversion errors than by selective publication. This supports the reliability of our findings despite variability in data reporting formats.
In the subgroup analysis (Figure 2), there was a significant association between the 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)]. A similar trend was found when there was a significant difference in folate between the NTD and control groups [SMD = −0.30, 95% CI (−0.48, −0.12)]. We further analyzed ethnicity (Figure 4). When there was no significant difference in folate, the concentration of vitamin B12 was lower in the NTD group among Europeans [SMD = −0.21, 95% CI (−0.34, −0.08)] and Americans [SMD = −0.19, 95% CI (−0.36, −0.03)] (Figure 4A). Meanwhile, the group with significant differences in folate showed lower vitamin B12 concentration in the NTD group among Africans [SMD = −0.61, 95% CI (−0.83, −0.40)], European [SMD = −0.24, 95% CI (−0.41, −0.07)], and Asians [SMD = −0.59, 95% CI (−0.85, −0.32)] (Figure 4B). Furthermore, different methods for the determination of B12 levels also had a certain effect (Figure S4).

4. Discussion

In this systematic review and meta-analysis, we revealed a statistically significant reduction in vitamin B12 concentration among mothers with NTD-affected pregnancy compared to controls, which was consistent with previous meta-analytic findings [57]. We further controlled for maternal folate, and when there was no significant difference in folate between the NTD and control groups, vitamin B12 was lower in the NTD group, suggesting an independent role of vitamin B12.
Vitamin B12 and folate are closely interrelated micronutrients that play essential roles in one-carbon metabolism [58]. The predominant circulating form of folate, 5-methyltetrahydrofolate (5-MTHF), serves as a cofactor in the remethylation of homocysteine to methionine, a reaction catalyzed by methionine synthase using vitamin B12 as a cofactor [59]. The resulting methionine is essential for the synthesis of key biomolecules, including creatine, phospholipids, proteins, neurotransmitters, and methylated nucleic acids [59]. Insufficient B12 levels may impair folate metabolism. The methyl trap hypothesis could best explain the interrelationship between these two vitamins, which holds that vitamin B12 deficiency impairs methionine synthase activity, thereby blocking the conversion of 5-methyltetrahydrofolate to biologically active tetrahydrofolate required for DNA biosynthesis and cell division [60,61]. Thus, cells suffer from a kind of folate pseudo-deficiency, which means adequate folate stores are rendered functionally unavailable for critical methylation processes and nucleotide biosynthesis, predisposing to NTD pathogenesis [60]. Additionally, high folic acid intake can resolve the anemia associated with vitamin B12 deficiency, potentially delaying the detection or treatment of the underlying B12 deficiency and even resulting in negative health outcomes [62]. Due to the close connection between folate and vitamin B12, special attention should be paid to supplementation. Furthermore, genetic factors also play a crucial role in the relationship between NTDs, folate, and vitamin B12. Deshmukh’s study identified a strong association between the MTHFR C677T polymorphism and NTDs [63]. Additionally, polymorphisms in the genes involved in vitamin B12 absorption and metabolism are associated with NTDs, such as mutations in exons 1 and 3 of the gastric intrinsic factor gene, variants in the lipoprotein-related protein 2 gene, alterations in the transcobalamin receptor gene, and the well-documented C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, which is in part related to vitamin B12 deficiency [28,64,65,66,67]. However, given the inconsistent data on the effect of vitamin B12 on NTDs, future clinical trials using folic acid and vitamin B12 supplements are necessary.
It is worth noting that vitamin B12 showed a downward trend in the NTD group independent of folate levels in our study. Vitamin B12, acting as a cofactor for methionine synthase and homocysteine remethylation, regulates two biochemically consequential pathways (Figure 5). Firstly, insufficient vitamin B12 could compromise the synthesis of S-adenosylmethionine (SAM), a universal methyl donor required for methylation reactions involving DNA, RNA, histones, proteins, neurotransmitter metabolism, and membrane phospholipid synthesis [68]. Aberrant methylation patterns from SAM depletion could disrupt neural tube closure mechanisms [69]. Secondly, low vitamin B12 could cause elevated homocysteine levels, which could exert direct embryotoxic effects and damage endothelial and smooth muscle cells independently of folate status [70,71]. Lower vitamin B12, alongside elevated homocysteine in pregnancies, has been identified as a potential biomarker of NTD risk [22]. High homocysteine in mothers with NTDs can impact DNA methylation and synthesis in the developing fetus. This disruption affects the genes that regulate the closure of the neural tube [72]. It is worth noting that further increases in homocysteine concentration are toxic, generating free radicals through auto-oxidation which pose additional risks to fetal development [73].
Overall, despite widespread prenatal supplementation, low vitamin B12 still exists. In low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia, 26% to 51% of pregnant women had vitamin B12 deficiency [74]. Meanwhile, vitamin B12 deficiency is not confined to low-income countries [75,76]. Vitamin B12 is naturally found only in animal-derived foods. It might be because of poverty and limited access to foods containing vitamin B12, as well as cultural or religious customs, health pursuits, environmental problems, and personal restrictions (e.g., vegetarianism), that such foods are deliberately avoided [77,78,79]. Studies have shown significantly lower cobalamin levels in vegans compared to non-vegans, and a European study reported a high prevalence of inadequate dietary vitamin B12 intake among vegan populations [80,81]. Genetic factors have an influence on vitamin B12 status. Higher concentrations of total vitamin B12 were found in black compared with white populations [82]. Furthermore, in China, a population-based cross-sectional study involving 1170 women further illustrated that the total prevalence of vitamin B12 deficiency was 45.5%, which indicated that vitamin B12 deficiency remained prevalent [83]. Similarly, among pregnant women in eastern Turkey, 12.5% exhibited low folate concentrations, 33.7% exhibited vitamin B12 deficiency alone, and 29.8% had both deficiencies concurrently [17]. Consequently, attention to monitoring vitamin B12, especially in women of reproductive age, is of great importance.
To the best of our knowledge, this study is a comprehensive meta-analysis that covers a larger number of studies and a wider area across 14 countries, including developed countries and developing countries, delving into the association of vitamin B12 with NTDs. Secondly, studies were stratified based on whether there was a statistically significant difference in folate between the NTD group and the control group to assess the independent association between vitamin B12 levels and NTDs. Finally, we conducted a sensitivity analysis to further enrich and support our findings. The results revealed a similar direction and effect with the main analysis.
This study has limitations. Firstly, as the included studies were designed as case–control studies, further evidence based on a cohort study was needed. Secondly, the current study mainly focused on serum or plasma vitamin B12 status as the main biomarker. Although this is a commonly used and important indicator, other active forms of vitamin B12 in the human body were not taken into account. Future research should integrate other complementary indicators (e.g., methylmalonic acid, holo-transcobalamin) to comprehensively evaluate B12 status.

5. Conclusions

In conclusion, this systematic review and meta-analysis revealed that the NTD group exhibited a lower vitamin B12 level, especially when there was no significant difference in folate between the NTD and control groups, suggesting an independent role of vitamin B12. It may be beneficial to monitor vitamin B12 concentrations among pregnant women, and the consideration of appropriate supplementation with a combination of vitamin B12 and folic acid could be explored based on individual needs and clinical recommendations.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu17122040/s1, Figure S1: Country/regional distribution of included studies; Figure S2: Funnel plots for effect of vitamin B12 concentration (pmol/L) on NTDs; Figure S3: Sensitivity analysis: Funnel plots for effect of vitamin B12 concentration (pmol/L) on NTDs after excluding studies that provided only the median and interquartile range; Figure S4: SMDs of vitamin B12 concentration (pmol/l) on NTDs by different methods for determination of B12; Table S1: Search strategy in the study.

Author Contributions

Conceptualization, J.L.; methodology, J.L., L.N. and X.L. (Xinru Liu); validation, L.N. and X.L. (Xinru Liu); formal analysis, L.N.; investigation, L.N. and X.L. (Xinru Liu); resources, L.N. and X.L. (Xinru Liu); writing—original draft preparation, L.N.; writing—review and editing, L.N., X.L. (Xinru Liu), X.L. (Xiaoxue Li), Z.R., X.C. and Y.W.; visualization, L.N. and X.L. (Xinru Liu); supervision, Z.L. and J.L.; project administration, Z.L. and J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Key Project of the Regional Innovation and Development Joint Fund of the National Natural Science Foundation of China (U23A20420).

Data Availability Statement

Data is contained within the article or Supplementary Materials.

Acknowledgments

We would like to gratefully acknowledge the reviewers for their valuable comments and suggestions, which have significantly contributed to the enhancement of this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Berry, R.J.; Li, Z.; Erickson, J.D.; Li, S.; Moore, C.A.; Wang, H.; Mulinare, J.; Zhao, P.; Wong, L.Y.; Gindler, J.; et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect. Prevention. N. Engl. J. Med. 1999, 341, 1485–1490. [Google Scholar] [CrossRef] [PubMed]
  2. Liu, H.; Chen, K.; Wang, T.; Ruan, X.; Wei, J.; Tang, J.; Li, L.; Qin, J. Emerging trends and cross-country health inequalities in congenital birth defects: Insights from the GBD 2021 study. Int. J. Equity Health 2025, 24, 50. [Google Scholar] [CrossRef]
  3. Bai, Z.; Han, J.; An, J.; Wang, H.; Du, X.; Yang, Z.; Mo, X. The global, regional, and national patterns of change in the burden of congenital birth defects, 1990–2021: An analysis of the global burden of disease study 2021 and forecast to 2040. EClinicalMedicine 2024, 77, 102873. [Google Scholar] [CrossRef]
  4. Martinez, H.; Benavides-Lara, A.; Arynchyna-Smith, A.; Ghotme, K.A.; Arabi, M.; Arynchyn, A. Global strategies for the prevention of neural tube defects through the improvement of folate status in women of reproductive age. Childs Nerv. Syst. 2023, 39, 1719–1736. [Google Scholar] [CrossRef] [PubMed]
  5. Honein, M.A.; Paulozzi, L.J.; Mathews, T.J.; Erickson, J.D.; Wong, L.Y. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001, 285, 2981–2986. [Google Scholar] [CrossRef]
  6. Hertrampf, E.; Cortés, F.; Erickson, J.D.; Cayazzo, M.; Freire, W.; Bailey, L.B.; Howson, C.; Kauwell, G.P.; Pfeiffer, C. Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J. Nutr. 2003, 133, 3166–3169. [Google Scholar] [CrossRef]
  7. Bermejo, F.; Algaba, A.; Guerra, I.; Chaparro, M.; De-La-Poza, G.; Valer, P.; Piqueras, B.; Bermejo, A.; García-Alonso, J.; Pérez, M.J.; et al. Should we monitor vitamin B12 and folate levels in Crohn’s disease patients? Scand. J. Gastroenterol. 2013, 48, 1272–1277. [Google Scholar] [CrossRef]
  8. Reynolds, E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006, 5, 949–960. [Google Scholar] [CrossRef] [PubMed]
  9. Nexo, E.; Parkner, T. Vitamin B12-Related Biomarkers. Food Nutr. Bull. 2024, 45, S28–S33. [Google Scholar] [CrossRef]
  10. Giedyk, M.; Goliszewska, K.; Gryko, D. Vitamin B12 catalysed reactions. Chem. Soc. Rev. 2015, 44, 3391–3404. [Google Scholar] [CrossRef]
  11. Bondevik, G.T.; Schneede, J.; Refsum, H.; Lie, R.T.; Ulstein, M.; Kvåle, G. Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered? Eur. J. Clin. Nutr. 2001, 55, 856–864. [Google Scholar] [CrossRef] [PubMed]
  12. Petersen, J.M.; Parker, S.E.; Crider, K.S.; Tinker, S.C.; Mitchell, A.A.; Werler, M.M. One-carbon cofactor intake and risk of neural tube defects among women who meet folic acid recommendations: A multicenter case-control study. Am. J. Epidemiol. 2019, 188, 1136–1143. [Google Scholar] [CrossRef] [PubMed]
  13. Petersen, J.M.; Smith-Webb, R.S.; Shaw, G.M.; Carmichael, S.L.; Desrosiers, T.A.; Nestoridi, E.; Darling, A.M.; Parker, S.E.; Politis, M.D.; Yazdy, M.M.; et al. Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: A United States population-based case-control study of women meeting the folic acid recommendations. Am. J. Clin. Nutr. 2023, 118, 720–728. [Google Scholar] [CrossRef]
  14. Deb, R.; Arora, J.; Samtani, R.; Garg, G.; Saksena, D.; Sharma, N.; Kumar Kalla, A.; Nava Saraswathy, K. Folic acid, dietary habits, and homocysteine levels in relation to neural tube defects: A case-control study in North India. Birth Defects Res. 2018, 110, 1148–1152. [Google Scholar] [CrossRef]
  15. Adams, M.J., Jr.; Khoury, M.J.; Scanlon, K.S.; Stevenson, R.E.; Knight, G.J.; Haddow, J.E.; Sylvester, G.C.; Cheek, J.E.; Henry, J.P.; Stabler, S.P.; et al. Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects. Teratology 1995, 51, 311–317. [Google Scholar] [CrossRef]
  16. Afman, L.A.; Van Der Put, N.M.; Thomas, C.M.; Trijbels, J.M.; Blom, H.J. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects. QJM-Int. J. Med. 2001, 94, 159–166. [Google Scholar] [CrossRef] [PubMed]
  17. Ayaz, R.; Asoglu, M.R. Neural tube defects in eastern Turkey; Is low folate status or vitamin B12 deficiency or both associated with a high rate of NTDs? J. Matern. Fetal Neonatal Med. 2020, 33, 3835–3840. [Google Scholar] [CrossRef]
  18. Hassan, M.H.; Raslan, M.A.; Tharwat, M.; Sakhr, H.M.; El-Khateeb, E.E.-S.; Sakr, S.F.; Ameen, H.H.; Hamdan, A.R. Metabolic analysis of methylenetetrahydrofolate reductase single nucleotide polymorphisms (MTHFR 677C<T and MTHFR 1298A<C), serum folate and vitamin B12 in neural tube defects. Indian J. Clin. Biochem. 2023, 38, 305–315. [Google Scholar] [CrossRef]
  19. Lacasaña, M.; Blanco-Muñoz, J.; Borja-Aburto, V.H.; Aguilar-Garduño, C.; Rodríguez-Barranco, M.; Sierra-Ramirez, J.A.; Galaviz-Hernandez, C.; Gonzalez-Alzaga, B.; Garcia-Cavazos, R. Effect on risk of anencephaly of gene-nutrient interactions between methylenetetrahydrofolate reductase C677T polymorphism and maternal folate, vitamin B12 and homocysteine profile. Public Health Nutr. 2012, 15, 1419–1428. [Google Scholar] [CrossRef]
  20. Mobasheri, E.; Keshtkar, A.; Golalipour, M.J. Maternal folate and vitamin b(12) status and neural tube defects in northern iran: A case control study. Iran. J. Pediatr. 2010, 20, 167–173. [Google Scholar]
  21. Sirinoglu, H.A.; Pakay, K.; Aksoy, M.; Bakirci, I.T.; Ozkaya, E.; Sanverdi, I. Comparison of serum folate, 25-OH vitamin D, and calcium levels between pregnants with and without fetal anomaly of neural tube origin. J. Matern. Fetal Neonatal Med. 2018, 31, 1490–1493. [Google Scholar] [CrossRef]
  22. Kucha, W.; Seifu, D.; Tirsit, A.; Yigeremu, M.; Abebe, M.; Hailu, D.; Tsehay, D.; Genet, S. Folate, vitamin B12, and homocysteine levels in women with neural tube defect-affected pregnancy in Addis Ababa, Ethiopia. Front. Nutr. 2022, 9, 873900. [Google Scholar] [CrossRef] [PubMed]
  23. Peker, E.; Demir, N.; Tuncer, O.; Üstyol, L.; Balahoroğlu, R.; Kaba, S.; Karaman, K. The levels of vitamın B12, folate and homocysteine in mothers and their babies with neural tube defects. J. Matern. Fetal Neonatal Med. 2016, 29, 2944–2948. [Google Scholar] [CrossRef] [PubMed]
  24. Wan, X.; Wang, W.; Liu, J.; Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014, 14, 135. [Google Scholar] [CrossRef] [PubMed]
  25. Chhabra, A.; Mahajan, J.K.; Kaur, J.; Rao, K.L.N. Correlation of folic acid, homocysteine and vitamin B12 levels in neonates with neural tube defects and their mothers with the disease occurrence. Int. J. Pharm. Clin. Res. 2023, 15, 133–141. [Google Scholar]
  26. Turkyilmaz, G.; Kucukbas, G.N.; Erturk, E.; Turkyilmaz, E.; Karaaslan, O.; Sahin, H.G. Comparison of maternal B12 and folate status in prenatally diagnosed neural tube defects: A case-control study. J. Istanb. Fac. Med. 2020, 83, 325–329. [Google Scholar] [CrossRef]
  27. Yildiz, S.H.; Ozdemir Erdogan, M.; Solak, M.; Eser, O.; Arıkan Terzi, E.S.; Eser, B.; Kocabaş, V.; Aslan, A. Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group. Genet. Mol. Res. 2016, 15, 1–8. [Google Scholar] [CrossRef]
  28. Aydin, H.; Arisoy, R.; Karaman, A.; Erdoğdu, E.; Çetinkaya, A.; Geçkinli, B.B.; Şimşek, H.; Demirci, O. Evaluation of maternal serum folate, vitamin B12, and homocysteine levels andfactor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatallydiagnosed neural tube defects. Turk. J. Med. Sci. 2016, 46, 489–494. [Google Scholar] [CrossRef]
  29. Godbole, K.; Gayathri, P.; Ghule, S.; Sasirekha, B.V.; Kanitkar-Damle, A.; Memane, N.; Suresh, S.; Sheth, J.; Chandak, G.R.; Yajnik, C.S. Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India. Birth Defects Res. A Clin. Mol. Teratol. 2011, 91, 848–856. [Google Scholar] [CrossRef]
  30. Wang, L.; Wang, F.; Guan, J.; Le, J.; Wu, L.; Zou, J.; Zhao, H.; Pei, L.; Zheng, X.; Zhang, T. Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. Am. J. Clin. Nutr. 2010, 91, 1359–1367. [Google Scholar] [CrossRef]
  31. Ceyhan, S.T.; Beyan, C.; Atay, V.; Yaman, H.; Alanbay, I.; Kaptan, K.; Başer, I. Serum vitamin B12 and homocysteine levels in pregnant women with neural tube defect. Gynecol. Endocrinol. 2010, 26, 578–581. [Google Scholar] [CrossRef] [PubMed]
  32. Zeyrek, D.; Soran, M.; Cakmak, A.; Kocyigit, A.; Iscan, A. Serum copper and zinc levels in mothers and cord blood of their newborn infants with neural tube defects: A case-control study. Indian Pediatr. 2009, 46, 675–680. [Google Scholar]
  33. Shaw, G.M.; Finnell, R.H.; Blom, H.J.; Carmichael, S.L.; Vollset, S.E.; Yang, W.; Ueland, P.M. Choline and risk of neural tube defects in a folate-fortified population. Epidemiology 2009, 20, 714–719. [Google Scholar] [CrossRef] [PubMed]
  34. Felkner, M.; Suarez, L.; Canfield, M.A.; Brender, J.D.; Sun, Q. Maternal serum homocysteine and risk for neural tube defects in a Texas-Mexico border population. Birth Defects Res. A Clin. Mol. Teratol. 2009, 85, 574–581. [Google Scholar] [CrossRef]
  35. Gaber, K.R.; Farag, M.K.; Soliman, S.E.T.; El-Bassyouni, H.T.; El-Kamah, G. Maternal vitamin B12 and the risk of fetal neural tube defects in Egyptian patients. Clin. Lab. 2007, 53, 69–75. [Google Scholar] [PubMed]
  36. Zhao, W.; Mosley, B.S.; Cleves, M.A.; Melnyk, S.; James, S.J.; Hobbs, C.A. Neural tube defects and maternal biomarkers of folate, homocysteine, and glutathione metabolism. Birth Defects Res. A Clin. Mol. Teratol. 2006, 76, 230–236. [Google Scholar] [CrossRef]
  37. Luo, X.; Zhang, L.; Wei, H.; Liu, W.; Wang, M.; Ning, Q. Methylmalonic acid in amniotic fluid and maternal urine as a marker for neural tube defects. J. Huazhong Univ. Sci. Technol. Med. Sci. 2004, 24, 166–169. [Google Scholar] [CrossRef]
  38. Groenen, P.M.W.; Van Rooij, I.A.L.M.; Peer, P.G.M.; Gooskens, R.H.; Zielhuis, G.A.; Steegers-Theunissen, R.P.M. Marginal maternal vitamin B12 status increases the risk of offspring with spina bifida. Am. J. Obstet. Gynecol. 2004, 191, 11–17. [Google Scholar] [CrossRef]
  39. Suarez, L.; Hendricks, K.; Felkner, M.; Gunter, E. Maternal serum B12 levels and risk for neural tube defects in a Texas-Mexico border population. Ann. Epidemiol. 2003, 13, 81–88. [Google Scholar] [CrossRef]
  40. Neuhouser, M.L.; Beresford, S.A.A.; Hickok, D.E.; Monsen, E.R. Absorption dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls. J. Am. Coll. Nutr. 1998, 17, 625–630. [Google Scholar] [CrossRef]
  41. Van der Put, N.M.J.; Thomas, C.M.G.; Eskes, T.; Trijbels, F.J.M.; Steegers Theunissen, R.P.M.; Mariman, E.C.M.; De Graaf Hess, A.; Smeitink, J.A.M.; Blom, H.J. Altered folate and vitamin B-12 metabolism in families with spina bifida offspring. QJM-Int. J. Med. 1997, 90, 505–510. [Google Scholar] [CrossRef] [PubMed]
  42. Wright, M.E. A case-control study of maternal nutrition and neural tube defects in Northern Ireland. Midwifery 1995, 11, 146–152. [Google Scholar] [CrossRef] [PubMed]
  43. Steegers-Theunissen, R.P.; Boers, G.H.; Blom, H.J.; Nijhuis, J.G.; Thomas, C.M.; Borm, G.F.; Eskes, T.K. Neural tube defects and elevated homocysteine levels in amniotic fluid. Am. J. Obstet. Gynecol. 1995, 172, 1436–1441. [Google Scholar] [CrossRef] [PubMed]
  44. Steegers-Theunissen, R.P.M.; Boers, G.H.J.; Trijbels, F.J.M.; Finkelstein, J.D.; Blom, H.J.; Thomas, C.M.G.; Borm, G.F.; Wouters, M.G.A.J.; Eskes, T.K.A.B. Maternal hyperhomocysteinemia: A risk factor for neural-tube defects? Metabolism 1994, 43, 1475–1480. [Google Scholar] [CrossRef]
  45. Wild, J.; Schorah, C.J.; Sheldon, T.A.; Smithells, R.W. Investigation of factors influencing folate status in women who have had a neural tube defect-affected infant. Br. J. Obstet. Gynaecol. 1993, 100, 546–549. [Google Scholar] [CrossRef]
  46. Mills, J.L.; Tuomilehto, J.; Yu, K.F.; Colman, N.; Blaner, W.S.; Koskela, P.; Rundle, W.E.; Forman, M.; Toivanen, L.; Rhoads, G.G. Maternal vitamin levels during pregnancies producing infants with neural tube defects. J. Pediatr. 1992, 120, 863–871. [Google Scholar] [CrossRef]
  47. Molloy, A.M.; Kirke, P.; Hillary, I.; Weir, D.G.; Scott, J.M. Maternal serum folate and vitamin B12 concentrations in pregnancies associated with neural tube defects. Arch. Dis. Child. 1985, 60, 660–665. [Google Scholar] [CrossRef]
  48. Molloy, A.M.; Einri, C.N.; Jain, D.; Laird, E.; Fan, R.; Wang, Y.; Scott, J.M.; Shane, B.; Brody, L.C.; Kirke, P.N.; et al. Is low iron status a risk factor for neural tube defects? Birth Defects Res. A Clin. Mol. Teratol. 2014, 100, 100–106. [Google Scholar] [CrossRef]
  49. Gu, Q.; Li, Y.; Cui, Z.-L.; Luo, X.-P. Homocysteine, folate, vitamin B12 and B6 in mothers of children with neural tube defects in Xinjiang, China. Acta Paediatr. 2012, 101, e486–e490. [Google Scholar] [CrossRef]
  50. Cech, I.; Burau, K.D. Serological differences in folate/vitamin B12 in pregnancies affected by neural tube defects. South. Med. J. 2010, 103, 419–424. [Google Scholar] [CrossRef]
  51. Zhang, H.Y.; Luo, G.A.; Liang, Q.L.; Wang, Y.; Yang, H.H.; Wang, Y.M.; Zheng, X.Y.; Song, X.M.; Chen, G.; Zhang, T.; et al. Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism. Exp. Neurol. 2008, 212, 515–521. [Google Scholar] [CrossRef] [PubMed]
  52. Ratan, S.K.; Rattan, K.N.; Pandey, R.M.; Singhal, S.; Kharab, S.; Bala, M.; Singh, V.; Jhanwar, A. Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatr. Surg. Int. 2008, 24, 803–808. [Google Scholar] [CrossRef] [PubMed]
  53. Candito, M.; Rivet, R.; Herbeth, B.; Boisson, C.; Rudigoz, R.-C.; Luton, D.; Journel, H.; Oury, J.-F.; Roux, F.; Saura, R.; et al. Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: A multicenter case-control study. Am. J. Med. Genet. Part A 2008, 146A, 1128–1133. [Google Scholar] [CrossRef]
  54. Félix, T.M.; Leistner, S.; Giugliani, R. Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern brazil. Birth Defects Res. Part A Clin. Mol. Teratol. 2004, 70, 459–463. [Google Scholar] [CrossRef] [PubMed]
  55. Kirke, P.N.; Molloy, A.M.; Daly, L.E.; Burke, H.; Weir, D.G.; Scott, J.M. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. QJM-Int. J. Med. 1993, 86, 703–708. [Google Scholar]
  56. Yates, J.R.; Ferguson-Smith, M.A.; Shenkin, A.; Guzman-Rodriguez, R.; White, M.; Clark, B.J. Is disordered folate metabolism the basis for the genetic predisposition to neural tube defects? Clin. Genet. 1987, 31, 279–287. [Google Scholar] [CrossRef]
  57. Yadav, U.; Kumar, P.; Rai, V. Maternal biomarkers for early prediction of the neural tube defects pregnancies. Birth Defects Res. 2021, 113, 589–600. [Google Scholar] [CrossRef]
  58. Finer, S.; Saravanan, P.; Hitman, G.; Yajnik, C. The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. Diabet. Med. 2014, 31, 263–272. [Google Scholar] [CrossRef]
  59. Brito, A.; Hertrampf, E.; Olivares, M.; Gaitán, D.; Sánchez, H.; Allen, L.H.; Uauy, R. Folate, vitamin B12 and human health. Rev. Med. Chil. 2012, 140, 1464–1475. [Google Scholar] [CrossRef]
  60. Shane, B.; Stokstad, E.L. Vitamin B12-folate interrelationships. Annu. Rev. Nutr. 1985, 5, 115–141. [Google Scholar] [CrossRef]
  61. Smulders, Y.M.; Smith, D.E.; Kok, R.M.; Teerlink, T.; Swinkels, D.W.; Stehouwer, C.D.; Jakobs, C. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: A case for the methylfolate trap. Br. J. Haematol. 2006, 132, 623–629. [Google Scholar] [CrossRef] [PubMed]
  62. Paul, L.; Selhub, J. Interaction between excess folate and low vitamin B12 status. Mol. Asp. Med. 2017, 53, 43–47. [Google Scholar] [CrossRef]
  63. Deshmukh, U.; Katre, P.; Yajnik, C.S. Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring. In Nestlé Nutrition Institute Workshop Series; Karger Publishers: Basel, Switzerland, 2013; Volume 74, pp. 145–154, discussion 154–146. [Google Scholar] [CrossRef]
  64. Fofou-Caillierez, M.B.; Guéant-Rodriguez, R.M.; Alberto, J.M.; Chéry, C.; Josse, T.; Gérard, P.; Forges, T.; Foliguet, B.; Feillet, F.; Guéant, J.L. Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects. Am. J. Clin. Nutr. 2019, 109, 674–683. [Google Scholar] [CrossRef] [PubMed]
  65. Rebekah Prasoona, K.; Sunitha, T.; Srinadh, B.; Muni Kumari, T.; Jyothy, A. LRP2 gene variants and their haplotypes strongly influence the risk of developing neural tube defects in the fetus: A family-triad study from South India. Metab. Brain Dis. 2018, 33, 1343–1352. [Google Scholar] [CrossRef]
  66. Pangilinan, F.; Mitchell, A.; VanderMeer, J.; Molloy, A.M.; Troendle, J.; Conley, M.; Kirke, P.N.; Sutton, M.; Sequeira, J.M.; Quadros, E.V.; et al. Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects. J. Med. Genet. 2010, 47, 677–685. [Google Scholar] [CrossRef]
  67. Al-Batayneh, K.M.; Zoubi, M.S.A.; Shehab, M.; Al-Trad, B.; Bodoor, K.; Khateeb, W.A.; Aljabali, A.A.A.; Hamad, M.A.; Eaton, G. Association between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-control Study. J. Med. Biochem. 2018, 37, 141–147. [Google Scholar] [CrossRef]
  68. McCaddon, A.; Miller, J.W. Homocysteine-a retrospective and prospective appraisal. Front. Nutr. 2023, 10, 1179807. [Google Scholar] [CrossRef] [PubMed]
  69. Li, H.; Niswander, L. Does DNA methylation provide a link between folate and neural tube closure? Epigenomics 2018, 10, 1263–1265. [Google Scholar] [CrossRef]
  70. Mills, J.L.; McPartlin, J.M.; Kirke, P.N.; Lee, Y.J.; Conley, M.R.; Weir, D.G.; Scott, J.M. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995, 345, 149–151. [Google Scholar] [CrossRef]
  71. Eskes, T.K. Open or closed? A world of difference: A history of homocysteine research. Nutr. Rev. 1998, 56, 236–244. [Google Scholar] [CrossRef]
  72. Blom, H.J.; Shaw, G.M.; den Heijer, M.; Finnell, R.H. Neural tube defects and folate: Case far from closed. Nat. Rev. Neurosci. 2006, 7, 724–731. [Google Scholar] [CrossRef] [PubMed]
  73. Tyagi, N.; Sedoris, K.C.; Steed, M.; Ovechkin, A.V.; Moshal, K.S.; Tyagi, S.C. Mechanisms of homocysteine-induced oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H2649–H2656. [Google Scholar] [CrossRef] [PubMed]
  74. Finkelstein, J.L.; Fothergill, A.; Venkatramanan, S.; Layden, A.J.; Williams, J.L.; Crider, K.S.; Qi, Y.P. Vitamin B12 supplementation during pregnancy for maternal and child health outcomes. Cochrane Database Syst. Rev. 2024, 1, Cd013823. [Google Scholar] [CrossRef] [PubMed]
  75. Ray, J.G.; Goodman, J.; O’Mahoney, P.R.; Mamdani, M.M.; Jiang, D. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. QJM Int. J. Med. 2008, 101, 475–477. [Google Scholar] [CrossRef]
  76. Hopkins, S.M.; Gibney, M.J.; Nugent, A.P.; McNulty, H.; Molloy, A.M.; Scott, J.M.; Flynn, A.; Strain, J.J.; Ward, M.; Walton, J.; et al. Impact of voluntary fortification and supplement use on dietary intakes and biomarker status of folate and vitamin B-12 in Irish adults. Am. J. Clin. Nutr. 2015, 101, 1163–1172. [Google Scholar] [CrossRef]
  77. Molloy, A.M. Should vitamin B(12) status be considered in assessing risk of neural tube defects? Ann. N. Y. Acad. Sci. 2018, 1414, 109–125. [Google Scholar] [CrossRef]
  78. Mensink, G.B.M.; Barbosa, C.L.; Brettschneider, A.K. Prevalence of persons following a vegetarian diet in Germany. J. Health Monit. 2016, 1, 2–14. [Google Scholar] [CrossRef]
  79. Shaw, K.A.; Zello, G.A.; Rodgers, C.D.; Warkentin, T.D.; Baerwald, A.R.; Chilibeck, P.D. Benefits of a plant-based diet and considerations for the athlete. Eur. J. Appl. Physiol. 2022, 122, 1163–1178. [Google Scholar] [CrossRef]
  80. Selinger, E.; Kühn, T.; Procházková, M.; Anděl, M.; Gojda, J. Vitamin B12 Deficiency Is Prevalent Among Czech Vegans Who Do Not Use Vitamin B12 Supplements. Nutrients 2019, 11, 3019. [Google Scholar] [CrossRef]
  81. Sobiecki, J.G.; Appleby, P.N.; Bradbury, K.E.; Key, T.J. High compliance with dietary recommendations in a cohort of meat eaters, fish eaters, vegetarians, and vegans: Results from the European Prospective Investigation into Cancer and Nutrition-Oxford study. Nutr. Res. 2016, 36, 464–477. [Google Scholar] [CrossRef]
  82. Fernandes-Costa, F.; Metz, J. A comparison of serum transcobalamin levels in white and black subjects. Am. J. Clin. Nutr. 1982, 35, 83–86. [Google Scholar] [CrossRef] [PubMed]
  83. Dang, S.; Yan, H.; Zeng, L.; Wang, Q.; Li, Q.; Xiao, S.; Fan, X. The status of vitamin B12 and folate among Chinese women: A population-based cross-sectional study in northwest China. PLoS ONE 2014, 9, e112586. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Flow diagram of the study search and selection process.
Figure 1. Flow diagram of the study search and selection process.
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Figure 2. SMDs of vitamin B12 concentration (pmol/L) in the studies on NTDs [18,19,20,21,22,23,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56].
Figure 2. SMDs of vitamin B12 concentration (pmol/L) in the studies on NTDs [18,19,20,21,22,23,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56].
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Figure 3. Sensitivity analysis: SMD of vitamin B12 concentration (pmol/L) on NTDs after excluding studies that provided only the median and interquartile range [18,19,20,21,22,23,25,26,27,28,30,31,32,33,36,37,40,42,43,44,46,49,50,51,52,54,56].
Figure 3. Sensitivity analysis: SMD of vitamin B12 concentration (pmol/L) on NTDs after excluding studies that provided only the median and interquartile range [18,19,20,21,22,23,25,26,27,28,30,31,32,33,36,37,40,42,43,44,46,49,50,51,52,54,56].
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Figure 4. SMDs of vitamin B12 concentration (pmol/L) between the NTD and control groups: (A) among subjects with no significant differences in maternal folate between the NTD and control groups [19,20,21,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]; (B) among subjects with significant differences in maternal folate between the NTD and control groups [18,22,23,48,49,50,51,52,53,54,55,56].
Figure 4. SMDs of vitamin B12 concentration (pmol/L) between the NTD and control groups: (A) among subjects with no significant differences in maternal folate between the NTD and control groups [19,20,21,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]; (B) among subjects with significant differences in maternal folate between the NTD and control groups [18,22,23,48,49,50,51,52,53,54,55,56].
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Figure 5. Associations between the folate cycle, vitamin B12, and methylation.
Figure 5. Associations between the folate cycle, vitamin B12, and methylation.
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Table 1. Characteristics of the included studies (n = 38).
Table 1. Characteristics of the included studies (n = 38).
First AuthorPublication YearCountryNumber of Participants
(NTD/Non-NTD)
Time of Specimen Collection aFolate Between NTD and Control bMethod for Determination of B12
Chhabra2023India26/26Postpartum0ELISA
Hassan2023Egypt50/50Pre-pregnancy1ELISA
Kucha2022Ethiopia100/167Second or third trimester of pregnancy1ELISA
Turkyilmaz2020Turkey38/40Second trimester of pregnancy0Radioimmunoassay
Sirinoglu2018Istanbul/Turkey79/99Second trimester of pregnancy0Chemiluminescence immunoassay
Aydin2016Turkey35/38Second trimester of pregnancy0Chemiluminescence immunoassay
Yildiz2016Turkey26/48Pre-pregnancy0Chemiluminescence immunoassay
Peker2016Turkey92/102Postpartum1Competitive Immunoassay
Molloy2014Ireland64/207Second trimester of pregnancy1Microbiological assays
Gu2012China30/60Second or third trimester of pregnancy1ELISA
Lacasana2012Mexico99/91Postpartum0ELISA
Godbole2011India318/702All gestational weeks0Microbiological assays
Cech2010US–Mexico border107/275Not mentioned1Radioimmunoassay
Ceyhan2010Turkey31/32Second trimester of pregnancy0Radioimmunoassay
Mobasheri2010Northern Iran23/23Second trimester of pregnancy0Radioimmunoassay
Wang2010China32/36All gestational weeks0Competitive Immunoassay
Felkner2009US–Mexico border103/139Postpartum0Competitive Immunoassay
Shaw2009US80/409Second or third trimester of pregnancy0Mass spectrometry
Zeyrek2009Turkey74/70Second or third trimester of pregnancy0ELISA
Candito2008France77/61All gestational weeks1Radioimmunoassay
Ratan2008India35/24Postpartum1Chemiluminescence immunoassay
Zhang2008China46/44All gestational weeks1Chemiluminescence immunoassay
Gaber2007Egypt27/25Pre-pregnancy0Radioimmunoassay
Zhao2006China43/160Postpartum0Radioimmunoassay
Têmis Maria Félix2004southern Brazil41/44Pre-pregnancy1Radioimmunoassay
Groenen2004The Netherlands45/83Pre-pregnancy0Chemiluminescence immunoassay
Luo2004China38/22Second trimester of pregnancy0Chemiluminescence immunoassay
Suarez2003US–Mexico border157/186Postpartum0Competitive Immunoassay
Neuhouser1998US10/8Pre-pregnancy0Radioimmunoassay
Van der Put1997The Netherlands60/94Pre-pregnancy0Radioimmunoassay
Steegers-Theunissen1995The Netherlands27/31Second trimester of pregnancy0Radioimmunoassay
Wright1995Northern Ireland15/15Postpartum0Radioimmunoassay
Steegers-Theunissen1994The Netherlands41/50Postpartum0Radioimmunoassay
Kirke1993Ireland81/247All gestational weeks1Microbiological assays
Wild1993UK29/29Postpartum0Radioimmunoassay
Mills1992Finnish89/178All gestational weeks0Radioimmunoassay
Yates1987Scotland20/20Pre-pregnancy1Competitive Immunoassay
Molloy1985Dublin28/363All gestational weeks0Microbiological assays
a Time of specimen collection: pre-pregnancy refers to those who have a history of NTD-affected pregnancy. b Folate comparison between the NTD and control groups: 0 indicates no significant difference in maternal folate between the NTD and control groups, and 1 indicates a significant difference in maternal folate between the NTD and control groups.
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Nie, L.; Liu, X.; Li, X.; Ren, Z.; Cheng, X.; Wu, Y.; Li, Z.; Liu, J. Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development. Nutrients 2025, 17, 2040. https://doi.org/10.3390/nu17122040

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Nie L, Liu X, Li X, Ren Z, Cheng X, Wu Y, Li Z, Liu J. Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development. Nutrients. 2025; 17(12):2040. https://doi.org/10.3390/nu17122040

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Nie, Lirong, Xinru Liu, Xiaoxue Li, Ziyang Ren, Xiao Cheng, Yuwei Wu, Zhiwen Li, and Jufen Liu. 2025. "Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development" Nutrients 17, no. 12: 2040. https://doi.org/10.3390/nu17122040

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Nie, L., Liu, X., Li, X., Ren, Z., Cheng, X., Wu, Y., Li, Z., & Liu, J. (2025). Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development. Nutrients, 17(12), 2040. https://doi.org/10.3390/nu17122040

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