Anencephaly in Slovakia and Czech Republic: embryogenesis, risk factors, epidemiology and preventative approaches.

Anencephaly, a fatal anomaly of the central nervous system, belongs to the group of defects of the neural tube (NTDs). It is considered the most common congenital NTD, characterized by concurrent absence of a significant portion of the brain and cranial vault. This deformity occurs between days 23 and 26 after fertilization due to improper closure of the neural tube at its cranial end. Many genetic, epigenetic, and non-genetic factors (nutritional, environmental and geographical factors, parental socioeconomic status) contribute to the etiology of this disease. Despite significant advances in treatment and preventive measures, NTDs continue to pose a significant health and financial burden on patients and society as a whole. This study aimed to examine the incidence of anencephaly in Slovakia compared to the Czech Republic between 2012 and 2020. The authors seek to elucidate the reasons behind the higher incidence of this disease in Slovakia as compared to the Czech Republic, explore the male predominance of anencephaly in Slovakia, and investigate whether the prevention standards used in Slovakia differ from those employed in other countries (Tab. 1, Fig. 2, Ref. 129). Keywords: neural tube defects, anencephaly, risk factors, folic acid, food fortification.

Transitioning care for adolescents with spina bifida in the US: challenges for management.

Open spina bifida (OSB) is a common neural tube defect. Medical and surgical care involves addressing the baseline orthopedic, urologic, and neurological dysfunction as well as the changes or declines that may occur as the patient ages. Given the complexity of this disease, coordinated, multidisciplinary care involving specialists in neurosurgery, orthopedics, urology, rehabilitation and physical medicine, pediatrics, and psychology is necessary to establish and optimize baseline function. Traditionally in the US, pediatric multispecialty spina bifida clinics have provided the patient with a coordinated medical support system. Unfortunately, this coordinated, medical home has been difficult to establish during the transition from pediatric to adult care. Medical professionals must have a strong understanding of OSB to properly manage the disease and detect and prevent associated complications. In this manuscript, we (1) describe the changing needs and challenges of people living with OSB over a lifespan, (2) delineate current practices in the transition of care for people with OSB from childhood to adulthood, and (3) provide recommendations for best practices in navigating the transition process for clinicians who provide care for those afflicted with this most complex congenital abnormality of the nervous system compatible with long term survival.

Food Fortification With Folic Acid for Prevention of Spina Bifida and Anencephaly: The Need for a Paradigm Shift in Evidence Evaluation for Policy-Making.

Context-specific evidence evaluation is advocated in modern epidemiology to support public health policy decisions, avoiding excessive reliance on experimental study designs. Here we present the rationale for a paradigm shift in evaluation of the evidence derived from independent studies, as well as systematic reviews and meta-analyses of observational studies, applying Hill's criteria (including coherence, plausibility, temporality, consistency, magnitude of effect, and dose-response) to evaluate food fortification as an effective public health intervention against folic acid-preventable (FAP) spina bifida and anencephaly (SBA). A critical appraisal of evidence published between 1983 and 2020 supports the conclusion that food fortification with folic acid prevents FAP SBA. Policy-makers should be confident that with mandatory legislation, effective implementation, and periodic evaluation, food fortification assures that women of reproductive age will safely receive daily folic acid to significantly reduce the risk of FAP SBA. Current evidence should suffice to generate the political will to implement programs that will save thousands of lives each year in over 100 countries.

Optimization of folic acid supplementation in the prevention of neural tube defects.

Background: We examined the relationship between timing and duration of folic acid (FA) supplementation in achieving red blood cell (RBC) folate levels in early pregnancy which are optimal (>906 nmol/l) for the prevention of neural tube defects (NTDs). Methods: Clinical, FA supplementation and dietary folate details were computerized at the first antenatal visit. Maternal blood samples were analysed for RBC and serum folate. Results: Of the 502 women, 98.2% (n = 493) reported taking FA. There was a positive correlation between duration of supplementation and both RBC folate (r = 0.43, P < 0.001) and serum folate (rho = 0.29, P < 0.001). The optimal RBC folate level was achieved in 80.4% (n = 46) of women who started FA 400 µg 4-8 weeks before their LMP compared with only 53.6% (n = 153) in women who started 4-8 weeks after their LMP (P < 0.001). Conclusions: This study provides, for the first time, information on both the timing and duration of FA that will achieve the optimum RBC folate levels associated with the prevention of NTDs. Women who are taking FA (400 µg) need to start before they conceive.

An Audit of Neural Tube Defects in the Republic Of Ireland for 2012-2015.

Neural tube defects (NTD) are potentially preventable in two-thirds of cases by periconceptional maternal Folic Acid (FA) supplementation. A national audit for the years 2009-11 showed no decline in NTD rates over twenty years. The aim of this national audit was to determine trends/rates and inform revision of national FA supplementation and food fortification strategies. Of 274,732 live and stillbirths there were 121(42.0%) cases of anencephaly, 136(47.2%) cases of spina bifida and 31(10.8%) cases of encephalocoele giving a total of 288 and overall rate of 1.05/1000 compared with 1.04/1000 in 2009-11(NS). In the 184 women where the information was available, only 29.9%(n=55) reported starting FA before pregnancy. The number of cases diagnosed antenatally was 91%(n=262) and 53%(n=154) were live-born. This audit confirms that over a generation, healthcare interventions have not succeeded in decreasing the number of pregnancies in Ireland complicated by NTD, and that revised strategies need to be developed and implemented.

A 2015 global update on folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Spina bifida and anencephaly are two major neural tube defects. They contribute substantially to perinatal, neonatal, infant, and under-five mortality and life-long disability. To monitor the progress toward the total prevention of folic acid-preventable spina bifida and anencephaly (FAP SBA), we examined their global status in 2015. METHODS: Based on existing data, we modeled the proportion of FAP SBA that are prevented in the year 2015 through mandatory folic acid fortification globally. We included only those countries with mandatory fortification that added at least 1.0 ppm folic acid as a fortificant to wheat and maize flour, and had complete information on coverage. Our model assumed mandatory folic acid fortification at 200 µg/day is fully protective against FAP SBA, and reduces the rate of spina bifida and anencephaly to a minimum of 0.5 per 1000 births. RESULTS: Our estimates show that, in 2015, 13.2% (35,500 of approximately 268,700 global cases) of FAP SBA were prevented in 58 countries through mandatory folic acid fortification of wheat and maize flour. Most countries in Europe, Africa, and Asia were not implementing mandatory fortification with folic acid. CONCLUSION: Knowledge that folic acid prevents spina bifida and anencephaly has existed for 25 years, yet only a small fraction of FAP SBA is being prevented worldwide. Several countries still have 5- to 20-fold epidemics of FAP SBA. Implementation of mandatory fortification with folic acid offers governments a proven and rapid way to prevent FAP SBA-associated disability and mortality, and to help achieve health-related Sustainable Development Goals. Birth Defects Research (Part A) 106:520-529, 2016. © 2016 Wiley Periodicals, Inc.

When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence.

Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011.

In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying degrees of disability. The two most common NTDs are anencephaly and spina bifida. Beginning in 1998, the United States mandated fortification of enriched cereal grain products with 140 µg of folic acid per 100 g. Immediately after mandatory fortification, the birth prevalence of NTD cases declined. Fortification was estimated to avert approximately 1,000 NTD-affected pregnancies annually. To provide updated estimates of the birth prevalence of NTDs in the period after introduction of mandatory folic acid fortification (i.e., the post-fortification period), data from 19 population-based birth defects surveillance programs in the United States, covering the years 1999-2011, were examined. After the initial decrease, NTD birth prevalence during the post-fortification period has remained relatively stable. The number of births occurring annually without NTDs that would otherwise have been affected is approximately 1,326 (95% confidence interval = 1,122-1,531). Mandatory folic acid fortification remains an effective public health intervention. There remain opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States.

Preventable spina bifida and anencephaly in Europe.

BACKGROUND: Promotion of voluntary folic acid supplement use among women of reproductive age has been proven to be ineffective in lowering the risk of neural tube defects in Europe. METHODS: Using surveillance data from all births covered by the full member countries of the European Surveillance of Congenital Anomalies (EUROCAT), we estimated the total prevalence of spina bifida and anencephaly per 10,000 births between 2000 and 2010. We also estimated additional lifetime direct medical costs among individuals with spina bifida, compared with those without, in Germany for the year 2009. RESULTS: During the study period, there were 7478 documented cases of spina bifida and anencephaly among the 9,161,189 births, with an estimated average combined prevalence of 8.16 per 10,000 births (95% confidence interval, 7.98 - 8.35). For the 241 spina bifida-affected live births in 2009 in Germany, the estimated additional lifetime direct medical costs compared with non-spina bifida affected births were €65.5 million. Assuming a 50% reduction in the prevalence if folic acid has been provided to all women before pregnancy, 293 spina bifida cases could have been prevented in Germany in 2009. The estimated lifetime direct medical cost saving for the live births in 2009 was €32.9 million assuming a 50% reduction, or €26.1 million assuming a 40% risk reduction. CONCLUSION: Europe has an epidemic of spina bifida and anencephaly compared with countries with mandatory folic acid fortification policy. Primary prevention through mandatory folic acid fortification would considerably reduce the number of affected pregnancies, and associated additional costs.

Effects of a simple educational intervention in well-baby clinics on women's knowledge about and intake of folic acid supplements in the periconceptional period: a controlled trial.

OBJECTIVE: To test the hypothesis that a concise intervention to promote the preconception use of folic acid (FA) supplements among mothers who visit a well-baby clinic (WBC) for the 6-month check-up of their youngest child is effective. Effectiveness was measured as intention to use or actual use of FA supplements before a next pregnancy among women who expected to be pregnant within 0-12 months. DESIGN: Controlled intervention study with independent samples of intervention and control mothers. The intervention took place at the 6-month visit. A post-intervention measurement was done in the intervention group and a comparable measurement in the control group at the 11-month check-up visit. SETTING: The intervention, verbal and in writing, was implemented in four Dutch WBC and given by the WBC physician to the mothers who visited the WBC. SUBJECTS: All mothers visiting the WBC were eligible for inclusion, unless they were unable to complete a questionnaire. The intervention group consisted of 198 (68 %) mothers recruited from 291 6-month intervention visits and the control group of 215 (84%) mothers recruited from 255 11-month normal visits. RESULTS: In mothers who expected to be pregnant within 0-12 months, the proportion using or intending to use FA was 65% in the intervention group (n 49) v. 42% in the control group (n 43; difference 23%, 95% CI 4, 43%, P<0·05). CONCLUSIONS: Health education intervention at the 6-month WBC visit is an effective means to promote the use of FA supplements or the intention to do so.

Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies.

OBJECTIVE: To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies. This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy. EVIDENCE: Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Costs, risks, and benefits: The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy. These associations may require consideration before initiating folic acid supplementation. The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications. VALUES: The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Summary Statement In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) Recommendations 1. Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A) 2. All women in the reproductive age group (12-45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned, this applies to all women who may become pregnant. (III-A) 3. Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A) 4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A) 5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) 6. Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks' gestational age. (1-A) From 12 weeks' gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) 7. Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks' gestational age. From 12 weeks' gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A).

Objectif : Offrir des renseignements à jour sur l'utilisation pré et postconceptionnelle d'acide folique par voie orale, avec ou sans supplément de multivitamines / micronutriments, aux fins de la prévention des anomalies du tube neural et d'autres anomalies congénitales. Ces renseignements aideront les médecins, les sages-femmes, les infirmières et les autres professionnels de la santé à contribuer aux efforts de sensibilisation des femmes quant à l'utilisation et aux posologies adéquates de la supplémentation en acide folique / multivitamines, avant et pendant la grossesse. Résultats : La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, Medline, CINAHL et la Cochrane Library en janvier 2011 au moyen d'un vocabulaire contrôlé et de mots clés appropriés (p. ex. « folic acid ¼, « prenatal multivitamins ¼, « folate sensitive birth defects ¼, « congenital anomaly risk reduction ¼, « pre-conception counselling ¼). Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais entre 1985 et juin 2014. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en juin 2014. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. Coûts, risques et avantages : Les coûts financiers sont ceux de la supplémentation quotidienne en vitamines et de la consommation d'un régime alimentaire santé enrichi en folate. Les risques sont ceux qui sont liés à une association signalée entre la supplémentation alimentaire en acide folique et des modifications épigénétiques fœtales / la probabilité accrue d'obtenir une grossesse gémellaire. Ces associations pourraient devoir être prises en considération avant la mise en œuvre d'une supplémentation en acide folique. La supplémentation en acide folique par voie orale (ou l'apport alimentaire en folate combiné à un supplément de multivitamines / micronutriments) a pour avantage de mener à une baisse connexe du taux d'anomalies du tube neural et peut-être même des taux d'autres complications obstétricales et anomalies congénitales particulières. Valeurs : La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). Déclaration sommaire 1. Au Canada, les comprimés de multivitamines comptant de l'acide folique sont habituellement offerts en 3 formats : multivitamines régulières en vente libre comptant de 0,4 à 0,6 mg d'acide folique, multivitamines prénatales en vente libre comptant 1,0 mg d'acide folique et multivitamines d'ordonnance comptant 5,0 mg d'acide folique. (III) Recommandations 1. Les femmes devraient se voir conseiller de maintenir un régime alimentaire santé riche en folate; la mise en œuvre d'une supplémentation en acide folique / multivitamines s'avère cependant requise pour leur assurer l'obtention des taux érythrocytaires de folate qui sont associés à l'octroi d'une protection maximale contre les anomalies du tube neural. (III-A) 2. Toutes les femmes en âge de procréer (12-45 ans) qui sont toujours fertiles (la grossesse demeure possible) devraient se voir offrir, dans le cadre de leurs consultations gynécologiques de dépistage (renouvellement de la contraception, test de Pap, examen gynécologique annuel), des services de counseling au sujet des avantages de l'acide folique administré sous forme d'une supplémentation multivitaminique, et ce, qu'elles envisagent ou non de connaître une grossesse. Puisqu'un si grand nombre de grossesses se manifestent de façon inattendue, cette recommandation s'applique à toutes les femmes qui pourraient devenir enceintes. (III-A) 3. La supplémentation en acide folique est peu susceptible de masquer la carence en vitamine B12 (anémie pernicieuse). La tenue d'explorations (examen ou épreuves de laboratoire) n'est pas requise avant la mise en œuvre d'une supplémentation en acide folique chez les femmes exposées à des risques d'anomalies du tube neural (ou d'autres anomalies congénitales sensibles à l'acide folique) primaires ou récurrentes qui envisagent une grossesse. Il est recommandé que l'acide folique soit administré sous forme de multivitamines comptant également 2,6 µg/jour de vitamine B12, de façon à atténuer toutes les préoccupations (même celles qui sont théoriques). (II-2A) 4. Les femmes exposées à des RISQUES ÉLEVÉS (pour lesquelles une dose d'acide folique supérieure à 1 mg s'avère indiquée) qui prennent des multivitamines contenant de l'acide folique devraient être avisées de respecter les consignes d'utilisation du produit en question et de ne pas prendre plus d'une dose quotidienne de supplément multivitaminique; ces femmes devraient plutôt prendre des comprimés additionnels ne contenant que de l'acide folique pour obtenir la dose requise. (II-2A) 5. Pendant au moins les deux à trois mois précédant la conception, tout au long de la grossesse et pendant de quatre à six semaines à la suite de l'accouchement (ou tant et aussi longtemps que se poursuit l'allaitement), les femmes qui sont exposées à un FAIBLE RISQUE d'anomalie du tube neural ou d'autres anomalies congénitales sensibles à l'acide folique et qui comptent un partenaire masculin également exposé à un faible risque doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément multivitaminique oral quotidien contenant 0,4 mg d'acide folique. (II-2A) 6. À partir d'au moins trois mois avant la conception, les femmes qui sont exposées à un RISQUE MODÉRÉ d'anomalie du tube neural ou d'autres anomalies congénitales sensibles à l'acide folique et qui comptent un partenaire masculin également exposé à un risque modéré doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément multivitaminique oral quotidien contenant 1 mg d'acide folique. Ces femmes devraient poursuivre l'utilisation de cette posologie jusqu'à l'atteinte d'un âge gestationnel de 12 semaines. (1-A) À partir de 12 semaines d'âge gestationnel, tout au long du reste de la grossesse et pendant de quatre à six semaines postpartum (ou tant et aussi longtemps que se poursuit l'allaitement), la supplémentation quotidienne utilisée devrait être composée d'une multivitamine contenant de 0,4 à 1,0 mg d'acide folique. (II-2A) 7. Pendant au moins trois mois avant la conception et jusqu'à l'atteinte d'un âge gestationnel de 12 semaines, les femmes qui sont exposées à un RISQUE ÉLEVÉ ou accru d'anomalie du tube neural et qui comptent un partenaire masculin présentant des antécédents personnels d'anomalie du tube neural (ou encore en présence d'antécédents personnels ou familiaux de grossesse affectée par une anomalie du tube neural chez l'un ou l'autre des partenaires) doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément oral quotidien de 4 mg d'acide folique. À partir de 12 semaines d'âge gestationnel, tout au long du reste de la grossesse et pendant de quatre à six semaines postpartum (ou tant et aussi longtemps que se poursuit l'allaitement), la supplémentation quotidienne utilisée devrait être composée d'une multivitamine contenant de 0,4 à 1,0 mg d'acide folique. (I-A) Le même régime alimentaire et de supplémentation devrait être respecté en présence d'antécédents personnels ou familiaux de grossesse affectée par une anomalie du tube neural chez l'un ou l'autre des partenaires. (II-2A).

Impact of folate supplementation on the efficacy of sulfadoxine/pyrimethamine in preventing malaria in pregnancy: the potential of 5-methyl-tetrahydrofolate.

Malaria remains the leading cause of mortality and morbidity in children under the age of 5 years and pregnant women. To counterbalance the malaria burden in pregnancy, an intermittent preventive treatment strategy has been developed. This is based on the use of the antifolate sulfadoxine/pyrimethamine, taken at specified intervals during pregnancy, and reports show that this approach reduces the malaria burden in pregnancy. Pregnancy is also associated with the risk of neural tube defects (NTDs), especially in women with low folate status, and folic acid supplementation is recommended in pregnancy to lower the risk of NTDs. Thus, in malaria-endemic areas, pregnant women have to take both antifolate medication to prevent malaria and folic acid to lower the risk of NTDs. However, the concomitant use of folate and antifolate is associated with a decrease in antifolate efficacy, exposing pregnant women to malaria. Thus, there is genuine concern that this strategy may not be appropriate. We have reviewed work carried out on malaria folate metabolism and antifolate efficacy in the context of folate supplementation. This review shows that: (i) the folate supplementation effect on antifolate efficacy is dose-dependent, and folic acid doses required to protect pregnant women from NTDs will not decrease antifolate activity; and (ii) 5-methyl-tetrahydrofolate, the predominant form of folate in the blood circulation, could be administered (even at high dose) concomitantly with antifolate without affecting antifolate efficacy. Thus, strategies exist to protect pregnant women from malaria while maintaining adequate folate levels in the body to reduce the occurrence of NTDs.

A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2022.

BACKGROUND: Mandatory fortification of staple foods with folic acid is an effective public health strategy to prevent folic acid-preventable spina bifida and anencephaly (FAP SBA). We estimated the global proportion of FAP SBA prevented through mandatory folic acid fortification of cereal grains (i.e., wheat flour, maize flour, and rice). METHODS: We used year 2022 data from the Food Fortification Initiative to identify countries (n = 69) with mandatory fortification of grains that includes folic acid. Sixty-eight countries were eligible for analysis with complete data. Proportion of FAP SBA prevention was modeled assuming >150 mcg/day of folic acid fortification protects against FAP SBA, reducing post-fortification prevalence to a lowest achievable level of 0.5 cases per 1000 births. RESULTS: Our analysis found that a total of 63,520 cases of FAP SBA were prevented in the year 2022 in 68 countries implementing mandatory folic acid fortification of grains with folic acid. This translated to a 23.7% prevention of all possible FAP SBA prevention globally. An excess of 204,430 cases of FAPSBA still occurred in over 100 countries where mandatory staple food fortification with folic acid is not implemented. CONCLUSION: Our study showed that only a quarter of all FAP SBA cases were averted through mandatory folic acid fortification in the year 2022; many countries are not implementing the policy, resulting in a large proportion of FAP SBA cases that can be prevented. Fortification will help countries with achieving 2030 Sustainable Development Goals on neonatal- and under-five mortality, disability, stillbirths, and elective terminations prevention, from FAP SBA.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study.

OBJECTIVES: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored. DESIGN: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). SETTING: Regions of England with active registration in the time period. PARTICIPANTS: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD. MAIN OUTCOME MEASURES: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed. RESULTS: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time. CONCLUSIONS: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence.

Introducing reproductive life plan-based information in contraceptive counselling: an RCT.

STUDY QUESTION: Can reproductive life plan (RLP)-based information in contraceptive counselling before pregnancy increase women's knowledge of reproduction, and of the importance of folic acid intake in particular? SUMMARY ANSWER: The RLP-based information increased women's knowledge of reproduction including knowledge of folic acid intake. WHAT IS KNOWN ALREADY: Many women have insufficient knowledge of reproduction, including a health-promoting lifestyle prior to conception, and highly educated women in particular postpone childbearing until an age when their fertile capacity has started to decrease. STUDY DESIGN, SIZE, DURATION: The study was an randomized controlled trial with one intervention group (IG) and two control groups (CG1, CG2). A sample size calculation indicated that 82 women per group would be adequate. Recruitment took place during 3 months in 2012 and 299 women were included. The women were randomized in blocks of three. All groups received standard care (contraceptive counselling, Chlamydia testing, cervical screening). In addition, women in the IG were given oral and written RLP-based information about reproduction. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 299 out of 338 (88%) Swedish-speaking women visiting a Student Health Centre were included (mean age 23 years); response rate was 88%. Before the counselling, women in the IG and the CG1 completed a baseline questionnaire, including questions about lifestyle changes in connection to pregnancy planning, family planning intentions and knowledge of reproduction (e.g. the fecundity of an ovum). At follow-up 2 months after inclusion, a structured telephone interview was performed in all groups (n = 262, 88% participation rate). MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between the groups regarding the mean knowledge score at baseline. The IG scored higher at follow-up than at baseline (P < 0.001); the mean increased from 6.4 to 9.0 out of a maximum 20 points. The women in the CG1 scored no differently at follow-up than at baseline. The difference in the knowledge score between the IG and the two CGs was significant (P < 0.001), whereas no difference was shown between the two CGs. There was no difference between the groups at baseline regarding how many women could mention folic acid intake among the things to do when planning to get pregnant. At follow-up, 22% in the IG, 3% in CG1 and 1% in CG2 mentioned folic acid intake (P < 0.001). At follow-up, more women in the IG also wished to have their last child earlier in life (P < 0.001) than at baseline, while there was no difference in the CG1. LIMITATIONS, REASONS FOR CAUTION: As the study sample consisted of university students, it is possible that the effect of the intervention was connected to a high level of education and conclusions for all women of reproductive age should be drawn with caution. WIDER IMPLICATIONS OF THE FINDINGS: The provision of RLP-based information seems to be a feasible tool for promoting reproductive health. STUDY FUNDING/COMPETING INTEREST(S): Study funding was received from the Faculty of Medicine, Uppsala University, Sweden. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov Identifier NCT01739101.

2012 Update on global prevention of folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Folic acid was proven in 1991 to prevent most cases of spina bifida and anencephaly. In 2008, less than 10% of folic acid-preventable spina bifida and anencephaly (FAPSBA) was prevented through folic acid fortification programs. This study updates the global estimates of the proportion of FAPSBA prevented with various types of folic acid fortification as of 2012. METHODS: For each country, we estimated the annual birth prevalence of FAPSBA and the daily amount of folic acid consumed from mandatory folic acid fortification programs. Assuming in Model I (our original Bell and Oakley model) that it required 400 µg, and in Model II (a new model), 200 µg of folic acid daily for total prevention of FAPSBA, we estimated the percentage of FAPSBA being prevented in each country by fortification. RESULTS: Using the original model, we estimate that 15% of FAPSBA is being prevented in 2012, compared with 2006 (6.8%) and 2008 (9.1%). We estimate in our new model that 25% of FAPSBA is being prevented. CONCLUSION: We estimate an increasing prevention of FAPSBA in the world through folic acid fortification, yet the pace is slow. Our new model estimates that only 25% prevention and reminds us that there remains a lot of work to do in countries that do not implement mandatory fortification, which is key to achieving global and total prevention. If we are to prevent all FAPSBA, there is an urgent need to build the global political will to find sufficient resources to aid in this effort.

Estimate of the potential impact of folic acid fortification of corn masa flour on the prevention of neural tube defects.

BACKGROUND: Hispanics in the US have a higher prevalence of neural tube defect (NTD) -affected pregnancies than non-Hispanic whites, and lower median total folic acid (FA) intake. FA fortification of corn masa flour (CMF) is a policy-level intervention for NTD prevention; however, the impact on NTD prevalence has not been estimated. METHODS: We developed a model to estimate the percentage reduction in prevalence of spina bifida and anencephaly (NTDs) that could occur with FA fortification of CMF. Model inputs included estimates of the percentage reduction in United States NTD prevalence attributed to FA fortification of enriched cereal grain products (1995-1996 vs. 1998-2002), the increase in median FA intake after enriched cereal grain product fortification, and the estimated increase in median FA intake that could occur with CMF fortification at the same level as enriched cereal grain products (140 µg/100 g). We used Monte Carlo simulation to quantify uncertainty. We stratified analyses by racial/ethnic group and rounded results to the nearest 10. RESULTS: We estimated CMF fortification could prevent 30 Hispanic infants from having spina bifida (95% uncertainty interval: 0, 80) and 10 infants from having anencephaly (95% uncertainty interval: 0, 40) annually. The estimated impact among non-Hispanic whites and blacks was smaller. CONCLUSION: CMF fortification with FA could prevent from 0 to 120 infants, with the most likely value of approximately 40, from having spina bifida or anencephaly among Hispanics, the population most likely to benefit from the proposed intervention. While this estimated reduction is unlikely to be discernible using current birth defect surveillance methods, it still suggests an important benefit to the target population.

Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene.

The paired-class homeobox-containing gene, Cart1, is expressed in forebrain mesenchyme, branchial arches, limb buds and cartilages during embryogenesis. Here, we show that Cart1-homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth-a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect. Developmental studies suggest that Cart1 is required for forebrain mesenchyme survival and that its absence disrupts cranial neural tube morphogenesis by blocking the initiation of closure in the midbrain region that ultimately leads to the generation of lethal craniofacial defects. Prenatal treatment of Cart1 homozygous mutants with folic acid suppresses the development of the acrania/meroanencephaly phenotype.