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Real Prevalence of Neural Tube Defects in Japan: How many of such pregnancies have been terminated?
Abstract
The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311,000 deliveries obtained from 259 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.38 per 10,000 deliveries for the year 2014 and was 8.74 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20 % and 80 %, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking 5th among the 7 developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists.
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... In addition, studies have demonstrated incongruencies between reported NTD numbers; for example, a study in Japan reported a 50% greater prevalence of NTDs than that reported by the Japanese College of Obstetrics and Gynecology. 8 In this review, we identified the prevalence of NTDs from epidemiological studies in Nigeria, Iraq, Hawaii, Japan, India, Saudi Arabia, and South Africa (Table 3). [8][9][10][11][12][13][14] Numerous patterns and risk factors for NTDs emerged from these studies. ...
... 8 In this review, we identified the prevalence of NTDs from epidemiological studies in Nigeria, Iraq, Hawaii, Japan, India, Saudi Arabia, and South Africa (Table 3). [8][9][10][11][12][13][14] Numerous patterns and risk factors for NTDs emerged from these studies. Al-ani et al report on the geographic distribution of NTDs in Western Iraq, identifying population densities, sanitation, environmental contamination, and previous military activity as potential explanations for intranational variations. ...
BACKGROUND AND OBJECTIVES
Low- and middle-income countries (LMICs) face higher incidences and burdens of care for neural tube defects (NTDs) and hydrocephalus compared with high-income countries (HICs), in part due to limited access to neurosurgical intervention. In this scoping review, we aim to integrate studies on prenatal care, counseling, and surgical management for families of children with spinal dysraphism and hydrocephalus in LMICs and HICs.
METHODS
PubMed, Embase, Global Index Medicus, and Web of Science electronic databases were searched for English language articles pertaining to prenatal care, counseling, and surgical management for families of children with spinal dysraphism and hydrocephalus in HICs and LMICs. Identified abstracts were screened for full-text review. Studies meeting inclusion criteria were reviewed in full and analyzed.
RESULTS
Seventy studies met the inclusion criteria. Twelve studies (16.9%) were conducted in HICs only, 50 studies (70.4%) were conducted in LMICs only, and 9 studies (12.7%) encompassed both. On thematic analysis, seven underlying topics were identified: epidemiology, folate deficiency and supplementation/fortification, risk factors other than folate deficiency, prenatal screening, attitudes and perceptions about NTDs and their care, surgical management, and recommendations for guideline implementation.
CONCLUSION
NTDs have become a widely acknowledged public health problem in many LMICs. Prenatal counseling and care and folate fortification are critical in the prevention of spinal dysraphism. However, high-quality, standardized studies reporting their epidemiology, prevention, and management remain scarce. Compared with NTDs, research on the prevention and screening of hydrocephalus is even further limited. Future studies are necessary to quantify the burden of disease and identify strategies for improving global outcomes in treating and reducing the prevalence of NTDs and hydrocephalus. Surgical management of NTDs in LMICs is currently limited, but pediatric neurosurgeons may be uniquely equipped to address disparities in the care and counseling of families of children with spinal dysraphism and hydrocephalus.
... Folic acid combination in multivitamin supplements has been shown to reduce additional congenital anomalies. Case-control cohorts, after FA fortification, highlight the decrease in folate sensitive congenital anomaly frequencies (Czeizel, 1996;Jahanbin et al., 2018;Ingrid Goh et al., 2006;Goh and Koren, 2008;Johnson and Little, 2008;Lowry et al., 2019;Morris et al., 2018;Nishigori et al., 2019;Kondo et al., 2019;McDonnell et al., 2018;Mao et al., 2017;Kurdi et al., 2019;Poletta et al., 2018;Li et al., 2013;Godwin et al., 2008;Canfield et al., 2005;Canfield et al., 2009;Wilcox et al., 2007). Table 3 summarizes maternal counselling issues used to identify increased risk factors for fetal NTD and for low maternal folate status (Hurst et al., 2005;Briggs et al., 2017;Greene and Copp, 2014;Han et al., 2009;Eichholzer et al., 2006;Desrosiers et al., 2018;Werler et al., 2011;Chong and Lerman, 2016;Meijer et al., 2005). ...
... -vitamin B12 deficiency is considered at serum vitamin B12 level of < 150 pmol/L (Murphy et al., 2021), as holo-transcobalamin (HTC) is the functional form of B12 used by tissues, a HTC measurement can replace the standard total B12 test (Farrell, 2013) Table 8 summarizes the routine evidenced-based FA supplementation dosing alone, if no maternal serum FA monitoring is considered in the prevention process using Table 1 -2 (MRC Vitamin Study Research Group, 1991;Czeizel and Dudás, 1992;Shaw et al., 1995;Werler et al., 1993;Cawley et al., 2017;Castillo-Lancellotti et al., 2013;Moore et al., 2003;Bonnette et al., 1998;Caudill et al., 1997;Czeizel, 1996;Jahanbin et al., 2018;Ingrid Goh et al., 2006;Goh and Koren, 2008;Johnson and Little, 2008;Lowry et al., 2019;Morris et al., 2018;Nishigori et al., 2019;Kondo et al., 2019;McDonnell et al., 2018;Mao et al., 2017;Kurdi et al., 2019;Poletta et al., 2018;Li et al., 2013;Godwin et al., 2008;Canfield et al., 2005;Canfield et al., 2009;Wilcox et al., 2007). The Appendix provides additional detail for routine verses personalized FA supplementation dosing considerations. ...
More evidence is available for maternal intake, absorption, distribution, tissue specific concentrations, and pregnancy outcomes with folic acid (fortification / supplementation) during preconception - first trimester. This Quality Improvement prevention review used expert guidelines / opinions, systematic reviews, randomized control trials/controlled clinical trials, and observational case control / case series studies, published in English, from 1990 to August 2021. Optimization for an oral maternal folic acid supplementation is difficult because it relies on folic acid dose, type of folate supplement, bio-availability of the folate from foods, timing of supplementation initiation, maternal metabolism/genetic factors, and many other factors. There is continued use of high dose pre-food fortification ‘RCT evidenced-based’ folic acid supplementation for NTD recurrence pregnancy prevention. Innovation requires preconception and pregnancy use of ‘carbon one nutrient’ supplements (folic acid, vitamin B12, B6, choline), using the appropriate evidence, need to be considered. The consideration and adoption of directed personalized approaches for maternal complex risk could use serum folate testing for supplementation dosing choice. Routine daily folic acid dosing for low-risk women should consider a multivitamin with 0.4 mg of folic acid starting 3 months prior to conception until completion of breastfeeding. Routine folic acid dosing or preconception measurement of maternal serum folate (after 4-6 weeks of folate supplementation) could be considered for maternal complex risk group with genetic / medical / surgical co-morbidities. These new approaches for folic acid oral supplementation are required to optimize benefit (decreasing folate sensitive congenital anomalies; childhood morbidity) and minimizing potential maternal and childhood risk.
... However, recent studies reveal that folic acid supply before and in the early stages of pregnancy (1 to 3 months before pregnancy and up to 12 weeks of gestation) can dramatically prevent anencephaly and reduce its prevalence by 50-70% [18]. The U.S. Public Health Service and the Food and Nutrition Council of the Institute of Medicine, along with the National Research Council, recommend that all women of childbearing potential can take 0.4 mg of folic acid daily to reduce the risk of developing neural tube defects [19,20]. ...
Plain Language summary Anencephaly is a fatal congenital anomaly characterized by the absence of brain hemispheres and cranial arch. Cochran’s seven-step instructions were used as the guideline. Having determined the research question and inclusion and exclusion criteria, we studied MagIran, SID, Science Direct, WoS, Web of Science, Medline (PubMed), Scopus, and Google Scholar databases. Moreover, the search strategy in each database included using all possible keyword combinations with the help of “AND” and “OR” operators with no time limit to 2021. Out of 1141 initial articles found, and after excluding repetitive ones in various databases and those irrelevant to inclusion criteria, 360 studies with a sample size of 207,639,132 people were considered for the meta-analysis. Overall estimate of the prevalence, incidence and attenuation of anencephaly worldwide were 5.1 per ten thousand births (95% confidence interval 4.7–5.5 per ten thousand births), 8.3 per ten thousand births (95% confidence interval 5.5–9.9 per ten thousand births), 5.5 per ten thousand births (95% confidence interval 1.8–15 per ten thousand births) respectively the highest of which according to the subgroup analysis, belonged to the Australian continent with 8.6 per ten thousand births (95% confidence interval 7.7–9.5 per ten thousand births). The overall prevalence of anencephaly in the world is significant, indicating the urgent need for preventive and treating measures.
... The incidence of MMC is estimated to be 0.2-0.3 per 1000 live births in Japan. 68 At the lesion of MMC, the spinal cord is damaged, resulting in peripheral nerve injury distal to the lesion. The lesions are often located in the lumbar or sacral vertebrae resulting in limb disabilities, and bladder and rectal dysfunction. ...
Aim:
To review new challenges of fetal therapy in Japan after the establishment of four existing fetal therapies as standard prenatal care with National Health Insurance coverage over the past 20 years.
Methods:
Reported studies and our current research activities related to four fetal therapies newly performed in Japan were reviewed.
Results:
Fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) aims to occlude the trachea using a detachable balloon to promote lung growth. Following the recent successful completion of an international randomized controlled trial for CDH, in which we participated, FETO is offered for severe left CDH to perform balloon insertion at 27-29 weeks and removal at 34 weeks of gestation. Fetal cystoscopy (FC) for low urinary tract obstruction was introduced to overcome the demerits of vesicoamniotic shunting. FC may provide a proper diagnosis by visual observation of the urethra and physiological treatment of the posterior urethral valve. The effectiveness of open fetal surgery for myelomeningocele (MMC), direct surgery with laparotomy and hysterotomy, for ameliorating hindbrain herniation and the motor function was demonstrated, but it was also associated with substantial maternal and fetal risks. Fetal aortic valvuloplasty (FAV), ultrasound-guided fetal aortic balloon dilation for critical aortic stenosis with evolving hypoplastic left heart syndrome may improve left heart development and maintain biventricular circulation. Feasibility and safety studies for FC, MMC open fetal surgery, and FAV are currently ongoing.
Conclusions:
Clinical research on FETO, FC, MMC open fetal surgery, and FAV has proceeded with careful preparations in Japan.
... Termination of pregnancies in Japan is similar to those in North American countries or European countries and Kondo et al. mentioned in a study developed over two years (2014-2015) including more than 311 000 pregnant women, that half of the pregnancies with neural tube defects were terminated, 80% among those with anencephaly [54]. ...
Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium, with absence of the brain. Anencephaly has an incidence of 1 to 5 in every 1000 births, and the mortality rate is 100% during intrauterine life or within hours or days after birth. The etiology of anencephaly remains unclear, but various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins, genetic polymorphisms and mutations, as well as positive family history for neural tube defects. One of the most important nutritional factors in the development of anencephaly is folate deficiency. Methylenetetrahydrofolate reductase (MTHFR) gene codes the enzyme involved in the intracellular metabolism of folic acid; the 677C-T polymorphism of this gene causes the thermolability of the enzyme and decreased enzymatic activity, which is also dependent of folate plasmatic level. Etiopathogenesis of anencephaly includes several mutations in various other genes, such as: platelet-derived growth factor receptor alpha (PDGFRA), cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1), Vang-like 1 (VANGL1) and Vang-like 2 (VANGL2), the last two being involved in the process of neurulation. Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination. During the first trimester US screening, anencephaly is now detected in all cases, but in order to decrease the complication rate of pregnancy termination, the diagnosis should be established as soon as possible, during the pregnancy confirmation US. We conclude that given that anencephaly is a severe malformation of the CNS, morphological characterization could improve the screening by US that is mandatory in the first trimester in order to plan the best, safe and early management.
... In the year 2000, the Japanese government recommended that women who have the potential to be pregnant take 400 μg FA supplements daily starting from 1 month before pregnancy to up to 3 months of gestation [4]. However, despite this recommendation, the prevalence of NTDs in Japan has not declined [5,6]. ...
Objectives: Neural tube defects (NTDs) are major congenital anomalies. To establish new and effective strategies to prevent these defects, public-private partnerships (PPPs) were formed between a healthcare company in Japan and numerous local governments to create educational activities regarding the importance of folic acid supplementation.
Methods: Projects for promoting maternal and child health using healthcare products and services created by a healthcare company were proposed to local governments as PPPs.
Results: Nine municipalities distributed folic acid supplements together with a Mother and Child Handbook while seven municipalities conducted surveys to identify people's knowledge and behavior toward folic acid use.
Conclusions: Recent studies have shown that periconceptional folic acid use improves many pregnancy outcomes; therefore, establishing educational activities regarding the importance of folic acid supplementation through PPPs is a rational and effective measure to promote maternal and child health.
Objective
As the only hospital-based national surveillance spot of birth defects (BDs) in Changzhou city located in the economically developed eastern part of China, Changzhou Maternal and Child Health Care Hospital has encountered serious challenges in BD prevention. This study aimed to describe the epidemiology of total BDs born in the hospital from 2014 to 2018.
Methods
The data were collected from the national hospital-based birth defect surveillance system. BD prevalence was calculated by Poisson distribution. Trends of prevalence and the associations regarding information with BDs were analyzed by Poisson regression.
Results
The reported prevalence of total BDs was 313.92 (95% confidence interval [CI]: 299.59–328.76) per 10,000 perinatal infants (PIs), while the perinatal prevalence of BD was 160.19 (95% CI: 150.00–170.89) per 10,000 PIs. A remarkable uptrend in the prevalence of BDs was noticed with a prevalence rate ratio (PRR) of 1.09 (95% CI: 1.04–1.14) and 1.13 (95% CI: 1.09–1.16), respectively. Congenital heart disease (CHD), cleft lip with or without cleft palate (CL/P), congenital malformation of the kidney (CMK), polydactyly, Down syndrome (DS), cystic hygroma, neural tube defect (NTD), and congenital talipes equinovarus (CTE) were common types of total BDs. Mothers living in the urban area (PRR = 1.67, 95% CI:1.50–1.87), male fetuses (PRR = 1.16, 95% CI: 1.05–1.28), and maternal age younger than 20 (PRR = 2.28, 95% CI: 1.60–3.25) and 25 years (PRR = 1.41, 95% CI: 1.22–1.63) or older than 35 years (PRR = 1.18, 95% CI: 1.00–1.40) were risk factors for BD occurrence.
Conclusion
The reported prevalence of total BDs was nearly two times higher than the perinatal prevalence of BDs in PIs, and the ranks of total BDs and BDs in PIs were different. Mothers living in the urban area, male fetuses, and maternal ages younger than 25 or older than 35 years were risk factors for BD incidence. Thus, improving prenatal examination technology, expanding the surveillance time quantum of BDs, and keeping maternal health may be warranted.
Background and objectives:
Evolving technologies have influenced the practice of myelomeningocele repair (MMCr), including mandatory folic acid fortification, advances in prenatal diagnosis, and the 2011 Management of Myelomeningocele Study (MOMS) trial demonstrating benefits of fetal over postnatal MMCr in select individuals. Postnatal MMCr continues to be performed, especially for those with limitations in prenatal diagnosis, health care access, anatomy, or personal preference. A comprehensive, updated national perspective on the trajectory of postnatal MMCr volumes and patient disparities is absent. We characterize national trends in postnatal MMCr rates before and after the MOMS trial publication (2000-2010 vs 2011-2019) and examine whether historical disparities persist.
Methods:
This retrospective, cross-sectional analysis queried Nationwide Inpatient Sample data for postnatal MMCr admissions. Annual and race/ethnicity-specific rates were calculated using national birth registry data. Time series analysis assessed for trends relative to the year 2011. Patient, admission, and outcome characteristics were compared between pre-MOMS and post-MOMS cohorts.
Results:
Between 2000 and 2019, 12 426 postnatal MMCr operations were estimated nationwide. After 2011, there was a gradual, incremental decline in the annual rate of postnatal MMCr. Post-MOMS admissions were increasingly associated with Medicaid insurance and the lowest income quartiles, as well as increased risk indices, length of stay, and hospital charges. By 2019, race/ethnicity-adjusted rates seemed to converge. The mortality rate remained low in both eras, and there was a lower rate of same-admission shunting post-MOMS.
Conclusion:
National rates of postnatal MMCr gradually declined in the post-MOMS era. Medicaid and low-income patients comprise an increasing majority of MMCr patients post-MOMS, whereas historical race/ethnicity-specific disparities are improving. Now more than ever, we must address disparities in the care of MMC patients before and after birth.
Background:
Neural tube defects (NTDs) encompass a variety of distinct types. We assessed if the preventive effect of folic acid (FA) varied by NTD type and infant sex.
Methods:
We examined all pregnancies with NTD status confirmation from a pregnancy-monitoring system in selected locations in northern and southern regions of China between 1993 and 1996. Women who took 400 μg of FA daily during 42 days after last menstrual period were considered FA users. We analyzed NTD prevalence by FA use status, NTD type, geographic region, and infant sex.
Results:
Among 626,042 pregnancies, 700 were affected by an NTD. Among FA nonusers, 65 pregnancies (8.8 per 10,000) in the north and 51 pregnancies (1.2 per 10,000) in the south were affected by one of the two rare NTDs, that is, craniorachischisis, iniencephaly. FA use prevented occurrence of these two rare NTDs and reduced the prevalence of spina bifida (SB) by 78% (from 17.9 to 3.9 per 10,000) in the north and 51% (from 2.4 to 1.2 per 10,000) in the south. Among FA users, SB prevalence, including SB with high lesion level, was significantly reduced in both geographic regions. FA use reduced prevalence of anencephaly and encephalocele by 85% and 50%, respectively in the north, while it did not reduce the prevalence of these two NTDs in the south. There was a greater reduction in NTD prevalence in female than in male infants and fetuses.
Conclusions:
This is the first study to show that FA prevents the entire spectrum of NTD types.
This chapter focuses on the use of amniotic fluid (AF) for the prenatal diagnosis of neural tube defects (NTDs). Both the kidneys and the placenta may produce trace amounts of AFP but the fetal liver dominates Human β‐fetoprotein (AFP) synthesis. AFP in the fetal plasma enters the fetal urine and from there the AF. A raised AFAFP without the concomitant presence of AChE poses increased risks for that pregnancy. In normal pregnancy, AFP reaches the AF mostly by fetal urination. The assay for neuronal‐derived acetylcholinesterase (AChE) is a critical adjunct in the prenatal diagnosis of open NTDs. In developed countries, first‐ and second‐trimester high‐resolution ultrasound has largely replaced the need for AChE assay. In developed countries, the use of ultrasound and maternal serum screening has made the unexpected birth of a child with anencephaly a relatively rare event. The option of fetal surgery introduces maternal, fetal, and neonatal mortality and morbidity risks and ethical challenges.
Aim
Fetal surgery for myelomeningocele (MMC) has yet not been performed in Japan, and the clinical backgrounds of fetal MMC in Japan remain poorly described. We examined the prenatal characteristics and perinatal outcomes of fetal MMC to prepare for the introduction of fetal surgery.
Methods
A nationwide questionnaire survey was conducted on fetuses with MMC between January 2012 and December 2014 at perinatal centers in Japan.
Results
Among 50 tertiary centers, 188 cases of MMC were included, and 126 (67%) were isolated cases. Only half of cases were referred to tertiary centers with a diagnosis of MMC. The median time point for a prenatal diagnosis was 26 weeks’ gestation (range 12‐38); 54% of cases were diagnosed after 26 gestational weeks, which is over the limit for fetal surgery for MMC. Furthermore, 22% of cases were diagnosed before 22 gestational weeks, and three‐quarters of these cases elected to terminate the pregnancy. No fetal or neonatal deaths were observed among isolated MMC cases. MMC repairs, ventriculoperitoneal shunts and clean intermittent catheterization were required after birth in 100%, 73% and 55% of isolated cases, respectively. In total, 96% of the tertiary centers cared for <5 cases of fetal MMC per year.
Conclusions
The gestational age at the MMC diagnosis was late mid‐gestation, so earlier detection is essential when considering fetal treatment of MMC in Japan. Although the survival rate was excellent, three‐quarters of isolated MMC cases required ventriculoperitoneal shunts. Early detection and centralization of MMC cases at specialized centers should be considered.
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Since 2000, preconceptional folic acid supplementation has been recommended in Japan. In Japan, lack of active campaign and attitude of women for folic acid intake has retained behind situation as compared to western countries. In the present review, we traced past and present practice and discuss the issues surrounding folate intake both before and after conception.
For the last 25 years, it has been proven that the occurrence or recurrence of neural tube defects can be prevented with the administration of folic acid before and early pregnancy. At present, over 80 countries in the world, except Japan, have mandated the fortification of wheat flour and/or rice with folic acid, which has resulted in a significant reduction in the prevalence of neural tube defects. In 2000, the Japanese government recommended folic acid 400 µg daily for young women of childbearing age and women who are planning to conceive. In 2002, the government started to present information about the importance of folic acid in the development of fetuses in the Mother-Child Health Booklet annually. Despite these endeavors, the prevalence of neural tube defects has remained unchanged. We discuss the risk factors of neural tube defects and propose preventive measures to decrease the number of neonates with neural tube defects. We believe that the government should implement the fortification of staple food with folic acid very soon, which will eventually decrease not only the neonatal mortality and morbidity, but also the economic burden on our health care system.
The introduction of mandatory fortification of grains with folate in 1998 in the United States resulted in 767 fewer spina bifida cases annually and a cost savings of $603 million per year. However, far more significant medical cost savings result from preventing common diseases, including myocardial infarction, stroke, dementia and osteoporosis. A cost-effectiveness analysis showed a gain of 266,649 quality-adjusted life-years and $3.6 billion saved annually, mainly due to the reduction of cardiac infarction. The recommended folate intake in Japan is 240 µg//d whereas it is 400 µg//d internationally. Our Sakado Folate Project targeted individuals with genetic polymorphism of methylenetetrahydrofolate reductase or with hyperhomocysteinemia. Using, for example, folate-fortified rice, resulted in an increase in serum folate and a decrease in serum homocysteine in the participants, and reduced medical costs were achieved by decreasing myocardial infarction, stroke, dementia and fracture. Due to the small population of Sakado City (about 101,000) and small number of births (693) in 2015, a decrease in spina bifida could not be confirmed but there was a significant decrease in the number of very low birth weight infants. The genome notification of subjects was effective in motivating intake of folate, but the increase in serum folate (from 17.4 to 22.5 nmol/L, 129%) was less than that observed following compulsory folic acid fortification of cereals in the USA (from 12.1 to 30.2 nmol/L, 149.6%). Mandatory folic acid fortification is cheap in decreasing medical costs and is thus recommended in Japan.
The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended women planning pregnancy to take FA supplements of 400 μg/d in 2000, but the incidence of spina bifida has not decreased. We aimed to evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between an increase in supplement use and possible promoters for the increase. This is a case-control study which used 360 case women who gave birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0·48 in the first period, and 0·53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan.
Folate is involved in DNA synthesis and methylation and may reduce breast cancer risk, particularly among women with greater alcohol consumption.
To assess the association between folate intake and risk of breast cancer and whether higher folate intake may reduce excess risk among women who consume alcohol.
Prospective cohort study performed in 1980, with 16 years of follow-up.
A total of 88818 women who completed the dietary questionnaire section of the Nurses' Health Study in 1980.
Incidence of invasive breast cancer by levels of folate and alcohol intake.
A total of 3483 cases of breast cancer were documented. Total folate intake was not associated with overall risk of breast cancer. However, among women who consumed at least 15 g/d of alcohol, the risk of breast cancer was highest among those with low folate intake. For total folate intake of at least 600 microg/d compared with 150 to 299 microg/d, the multivariate relative risk (RR) was 0.55 (95% confidence interval [CI], 0.39-0.76; P for trend = .001). This association was only slightly attenuated after additional adjustment for intake of beta carotene, lutein/zeaxanthin, preformed vitamin A, and total vitamins C and E. The risk of breast cancer associated with alcohol intake was strongest among women with total folate intake of less than 300 microg/d (for alcohol intake > or =15 g/d vs <15 g/d, multivariate RR, 1.32; 95% CI, 1.15-1.50). For women who consumed at least 300 microg/d of total folate, the multivariate RR for intake of at least 15 g/d of alcohol vs less than 15 g/d was 1.05 (95% CI, 0.92-1.20). Current use of multivitamin supplements, the major source of folate, was associated with lower breast cancer risk among women who consumed at least 15 g/d of alcohol (for current users of supplements vs never users, RR, 0.74; 95% CI, 0.59-0.93).
Our findings suggest that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.
Background
Periconceptional use of multivitamins containing folic acid can reduce a woman's risk of having a baby with a neural-tube defect.
Methods
As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy.
Results
Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the northern region and 1.0 per 1000 in the southern region. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.0 per 1000 in the northern region and 0.6 per 1000 in the southern region. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took folic acid pills more than 80 percent of the time. In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95 percent confidence interval, 3 to 64 percent).
Conclusions
Periconceptional intake of 400 μg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas with low rates.
In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented.
The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented.
A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively).
Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.
Folate functions as a coenzyme to transfer one-carbon units that are necessary for deoxythymidylate synthesis, purine synthesis, and various methylation reactions. Ingested folate becomes a functional molecule through intestinal absorption, circulation, transport to cells, and various modifications to its structure. Associations between nutritional folate status and chronic diseases such as cardiovascular disease, cancer, and cognitive dysfunction have been reported. It has also been reported that maternal folate nutritional status is related to the risk of neural tube defects (NTDs) in the offspring. It has also been recommended that folate be consumed in the diet to promote the maintenance of good health. To reduce the risk of NTDs, supplementation with folic acid (a synthetic form of folate) during the periconceptional period has also been recommended. This paper describes the basic features and nutritional role of folate.
To reduce the risk of neural tube defects, studies have been conducted on female students of medical services, nutritional science, and nursery education that investigated the awareness of folic acid by using questionnaires. Many investigators have suggested the need to provide detailed information about the awareness of folic acid and knowledge about folic acid intake and neural tube defect risk reduction. The dietary habits of female students showed a positive correlation with their estimated folic acid intake, suggesting that improvements in dietary habits are associated with the consumption of folic acid. The importance of folic acid intake must be more aggressively promoted among female students. Thus, many learning opportunities should be provided for such students to help increase their folic acid intake.
Objective:
The aim of the study was to clarify the prevalence and determinants of inadequate use of folic acid supplementation in pregnant Japanese women.
Methods:
This study was part of the Japan Environment and Children's Study, a nationwide and government-funded birth cohort study. We collected information on the use of folic acid supplementation before and during pregnancy and characteristics of participants using self-administered questionnaire.
Results:
Among 9849 women who completed the data collection for this study, the prevalence of inadequate users was 92.6% of the total population and varied from 84.5% to 96.2% among regions. On the basis of multivariate logistic regression analysis, younger age, not married, lower family income, multipara, natural conception and no history of spontaneous abortion were found to be determinants for inadequate users of folic acid supplementation.
Conclusion:
Most Japanese pregnant women show inadequate folic acid supplementation use. Japanese women of child-bearing age need to be specifically informed about the need for periconceptional intake of folic acid to prevent neural tube defects.
It is clear that women who take multivitamins that include folic acid lower their risk of having an infant with a neural tube defect (NTD). As part of a public health campaign carried out in the mid-1990s in China, pregnancy outcomes were examined when women were asked to take a pill containing 400 μg of folic acid daily from the time of the premarital examination to the end of the first trimester. The study focused on two regions, one with high and one with low rates of NTDs. In all, NTDs were sought in the fetuses or infants of 130,142 women who took folic acid any time before or during pregnancy and in 117,689 others whose mothers had no taken folic acid at all. A total of 102 NTDs were found when folic acid had been taken, and 173 were found when women did not take folic acid. For fetuses or infants of women who registered before their last menses and did not take any folic acid, NTDs occurred at a rate of 4.8 per 1000 pregnancies (of 20 weeks’ or more gestation) in the high-NTD area and 1.0 per 1000 in the low-NTD region. The rates when women used folic acid periconceptionally were 1.0 and 0.6 per 1000 pregnancies, respectively. The risk of an NTD was lowered the most, 85 percent, for offspring of women in the high-NTD region who took more than 80 percent of their folic acid pills. In the low-NTD area, the risk reduction was 40 percent. The rates of NTD were 0.7 and 0.6 per 1000 pregnancies, respectively. In the high-risk region, the chance of an NTD was half of that for offspring of women who were compliant no more than 80 percent of the time. The implication of the results of this survey is that the intake of 400 μg of folic acid daily during the periconceptional period can lower the risk of NTDs regardless of whether the risk level in a given geographic area is high or low. N Engl J Med 1999;341:1485–1490
A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups--namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.
The prevalence of neural tube defect (NTD)-affected pregnancies ranges between 0.4 and 2/1000 pregnancies in EU. NTDs result in severe malformations and sometimes miscarriages. Children born with NTD suffer for the rest of their life of disability and chronic healthcare issues, and many women therefore choose termination of pregnancy if NTD is diagnosed prenatally. Women planning for pregnancy are recommended to eat 400 μg folic acid/d, whereas average figures across Europe indicate intakes of ∼250 μg/d for women of fertile age, a gap that could be bridged by implementation of folic acid fortification. The results of mandatory folic acid fortifications introduced in USA and Canada are a decrease between 25 and 45% of NTD pregnancies.
Conclusion: Evidence-based NTD prophylaxis is now practised in more than 60 countries worldwide. EU countries worry over possible cancer risks, but ignore a wealth of studies reporting decreasing cancer risks with folate intakes at recommended levels. Currently, there are indications of a U-shaped relationship, that is, higher cancer risks at low folate intakes (<150 μg/day) and highly elevated folate intakes (>1 mg/day), respectively. However neither the global World Cancer Research review nor EU’s European Food Safety Authority report present data on increased cancer risk at physiological folate intake levels. Therefore, EU should act to implement folic acid fortification as NTD prophylaxis as soon as possible.
To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them.
Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk.
Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration.
There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies.
The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%).
This article has no abstract; the first 100 words appear below.
In 1991, a randomized trial funded by the Medical Research Council demonstrated that folic acid supplementation before pregnancy and during its early stages markedly reduced the risk of neural-tube defects in newborns.¹ This finding — which indicated that neural-tube defects may be considered to represent a vitamin-deficiency disorder — led to the recommendation that all women who are planning to become pregnant should take folic acid supplements beginning before pregnancy is recognized and continuing through its early stages. Once a pregnancy has been confirmed, it is probably too late for supplemental folic acid to be protective. In this issue of . . .
Source Information
From the Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, University of London, London.
Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50-70 years with raised plasma total homocysteine and normal serum vitamin B12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance.
Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 mug daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov with trial number NCT00110604.
Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0.132, 95% CI 0.032 to 0.233), information processing speed (0.087, 0.016 to 0.158) and sensorimotor speed (0.064, -0.001 to 0.129) were significantly better in the folic acid group than in the placebo group.
Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.
Mandatory vitamin B12 fortification of enriched grain products is long overdue in the United States and Canada. Fortification would help provide the 2.4 mug of synthetic vitamin B12 that the US Institute of Medicine recommends for all persons 50 years and older. The findings of Ray and colleagues in this issue suggest that B12 may also help to prevent neural tube defects. If recommendations for B12 fortification were followed, it is possible that cases of spina bifida and anencephaly would be prevented. Two hundred twenty thousand children each year acquire folic acid-preventable spina bifida because many governments, including all in Europe, have yet to implement mandatory folic acid fortification. Fortification with folic acid and vitamin B12 is safe and should be implemented in all countries.
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