Prenatal folic acid supplementation and autism spectrum disorder in 3-year-old offspring: the Japan environment and children's study.

OBJECTIVE: We evaluated the relationship between prenatal folic acid supplementation and autism spectrum disorder (ASD) in 3-year-old offspring. METHODS: We used data from the Japan Environment and Children's Study, a nationwide prospective birth cohort study. We analyzed the data to determine the association between folic acid supplement use and the incidence of ASD in offspring, and classified participants into three groups based on the time of initiation of folic acid supplementation, as follows: (1) preconception users of folic acid supplements and (2) post-conception users, and (3) non-users. The dietary folate intake of study participants was also classified into three groups (<200 µg, 200 µg to <400 µg, ≥400 µg). RESULTS: Overall, 361 offspring of 96,931 participants with single pregnancies were diagnosed with ASD (0.37%). A total of 7,046 participants (7.3%) used folic acid supplements before conception, 29,984 (30.9%) took them after detection of pregnancy, and 59,901 (61.8%) never received them. Multivariate logistic regression analyses demonstrated no association between prenatal folic acid supplementation and ASD in offspring (preconception use: adjusted odds ratio [AOR], 1.189; 95% confidence interval [CI], 0.819-1.727 and post-conception use: AOR, 1.072; 95% CI, 0.840-1.368); additionally, no association was observed with the use of folic acid supplements and/or multivitamin supplements (preconception use: AOR, 1.273; 95% CI, 0.921-1.760 and post-conception use: AOR, 1.132; 95% CI, 0.885-1.449). Moreover, no significant association was observed in participants with combined prenatal supplement use and dietary folate intake. CONCLUSIONS: Maternal use of folic acid supplements from the pre- or post-conception period was not significantly associated with ASD in 3-year-old offspring in Japan. Evaluation of the dietary folate intake from preconception also showed no significant association.

Update on the prevalence and determinants of folic acid use in Japan evaluated with 91,538 pregnant women: the Japan Environment and Children's Study.

Objective: To provide the latest and most promising evidence on the prevalence and determinants for folic acid supplementation in pregnant women in Japan, including differences in prevalence between interview years and determinants across regions.Materials and methods: The study participants were enrolled from 15 regional centers across Japan between January 2011 and March 2014. Information on the use of folic acid supplementation before and during pregnancy and the characteristics of the participants were collected using questionnaires, medical chart reviews, and interviews by research coordinators.Results: Data for 91,538 women who provided sufficient data on folic acid supplementation were analyzed. The prevalence of adequate users was 8.0%, which, although low, tended to improve over the 4-year recruitment period. Various kinds of sociodemographic factors, lifestyle habits, and obstetrical and medication use history were significant and independent determinants for folic acid use. Associations between adequate preconception folic acid use and its major determinants tended to be similar across regions.Conclusions: Although the prevalence of adequate folic acid use was low, it increased from 2011 to 2014. Reproductive-aged women who have determinants for inadequate folic acid use should be informed about the need for preconception folic acid supplementation to help prevent neural tube defects.

Preconception folic acid supplementation use and the occurrence of neural tube defects in Japan: A nationwide birth cohort study of the Japan Environment and Children's Study.

We evaluated the relationship between preconception folic acid supplementation and the occurrence of neural tube defects (NTDs) in offspring, using data from the Japan Environment and Children's Study (a nationwide prospective birth cohort study) database. Of 92 269 participants with single pregnancies, 74 cases (offspring or fetuses) had NTDs, including 32 cases of spina bifida, 24 cases of anencephaly, and 19 cases of encephalocele. A total of 7634 participants (8.27%) used preconception folic acid supplementation, and of these, 621 (0.67%) also took in dietary folic acid at ≥480 µg/day. Multivariate logistic regression analyses demonstrated no association between preconception folic acid supplementation and NTDs in offspring or fetuses (odds ratio [OR] 0.622; 95% confidence interval [CI]: 0.226-1.713). Moreover, the participants who combined preconception folic acid supplement use with dietary folic acid intake ≥480 µg/day demonstrated no incidence of NTDs in offspring or fetuses. Our analysis is limited by the absence of the data on the daily amount of supplementary folic acid intake, requiring careful attention to the interpretation. Additional surveys are required in Japan to resolve those limitations for further comprehensive assessment.

Drug Use before and during Pregnancy in Japan: The Japan Environment and Children's Study.

Purpose: To elucidate drug use before and during pregnancy in Japan. Methods: The Japan Environment and Children's Study (JECS) is an ongoing nationwide birth cohort study. We analyzed data from JECS involving cases where drugs were used for 12 months before pregnancy was diagnosed, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy. Results: We analyzed data from 97,464 pregnant women. The percentages of pregnant women who had taken one or more drugs and supplements before diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy, were 78.4%, 57.1%, and 68.8% respectively. Excluding iron supplements, folic acid, and other vitamins and minerals, the percentages of women taking supplements were 75.3%, 36.0%, and 51.7% at each respective time point. The following drugs and supplements were frequently used for 12 months before pregnancy diagnosis: Commercially available antipyretics, analgesics, and/or medicine for treating common cold (34.7%), antipyretics, analgesics, and/or medicine for treating common colds, which were prescribed in hospitals (29.8%), antimicrobial drugs (14.0%), and anti-allergy drugs (12.5%). The following drugs and supplements were frequently used from the time of pregnancy diagnosis until week 12 of pregnancy, and after week 12 of pregnancy: folic acid (28.9% and 26.2%), antipyretics, analgesics and/or medicines for treating common cold, that were prescribed in hospitals (7.8% and 13.3%), Chinese herbal medicines (6.0% and 9.4%, and uterine relaxants (5.1% and 15.2%). Conclusions: The analysis of a nationwide cohort study showed that a high percentage of Japanese pregnant women were taking medicinal drugs. Further research is required to elucidate the relationship between drug use during pregnancy and birth defects in Japan.

Prevalence and determinants of inadequate use of folic acid supplementation in Japanese pregnant women: the Japan Environment and Children's Study (JECS).

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.

Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.

ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)