{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:33:37Z","timestamp":1789835617675,"version":"4.0.1"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation","award":["CX2017-04"],"award-info":[{"award-number":["CX2017-04"]}]},{"name":"Shanghai Municipal Commission of Health and Family Planning","award":["201440636"],"award-info":[{"award-number":["201440636"]}]},{"name":"the Chongqing Science and Technology Bureau","award":["cstc2017shmsA130102"],"award-info":[{"award-number":["cstc2017shmsA130102"]}]},{"name":"the Health Commission of Chongqing Province","award":["2017ZDXM015"],"award-info":[{"award-number":["2017ZDXM015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>It is unclear whether periconceptional folic acid (FA) supplementation decreases the risk of spontaneous abortion (SA). The impact of supplementation initiation timing has not been ascertained. This cohort study aimed to investigate the association between maternal periconceptional FA supplementation and risk of SA, with due consideration of the supplementation initiation timing. Through the National Free Pre-conception Health Examination Project (NFPHEP), we identified 65,643 pregnancies on FA supplementation in Chongqing, China between 2010 and 2015. After adjusting for covariates, maternal periconceptional FA supplementation was associated with a lower risk of SA (adjusted risk ratio [aRR]: 0.52; 95% confidence interval [CI]: 0.48\u20130.56). Pregnant women with FA supplementation initiated at least 3 months before conception had a 10% lower risk of SA (aRR: 0.46; 95% CI: 0.42\u20130.50) than those with FA supplementation initiated 1\u20132 months before conception (aRR: 0.56; 95% CI: 0.50\u20130.62) or after conception (aRR: 0.56; 95% CI: 0.51\u20130.61). These associations might not thoroughly account for FA supplementation, and to some extent our findings confirm the role of the utilization of healthcare in preventing SAs. Women who initiated healthcare, including taking FA earlier during the periconceptional period, could have a lower risk of SA.<\/jats:p>","DOI":"10.3390\/nu12082264","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:31:45Z","timestamp":1596007905000},"page":"2264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Periconceptional Folic Acid Supplementation and the Risk of Spontaneous Abortion among Women Who Prepared to Conceive: Impact of Supplementation Initiation Timing"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-694X","authenticated-orcid":false,"given":"Yan-Yan","family":"Mao","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Xi","family":"Zhu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"He","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0958-2866","authenticated-orcid":false,"given":"Wei-Jin","family":"Zhou","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"ref_1","first-page":"1243","article-title":"Management of spontaneous abortion","volume":"72","author":"Griebel","year":"2005","journal-title":"Am. Fam. Physician"},{"key":"ref_2","first-page":"527","article-title":"Infertility and miscarriage: Common pathways in manifestation and management","volume":"11","author":"Agenor","year":"2015","journal-title":"Women\u2019s Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1055\/s-0028-1087105","article-title":"Miscarriage and its associations","volume":"26","author":"Brown","year":"2008","journal-title":"Semin. Reprod. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1056\/NEJM198807283190401","article-title":"Incidence of early loss of pregnancy","volume":"319","author":"Wilcox","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.psychres.2017.08.064","article-title":"Prevalence of depression, anxiety, and adjustment disorders in women with spontaneous abortion in Germany\u2014A retrospective cohort study","volume":"258","author":"Jacob","year":"2017","journal-title":"Psychiatry Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1053\/beog.2000.0124","article-title":"Genetic aspects of miscarriage","volume":"14","author":"Goddijn","year":"2000","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1081\/CRP-100108171","article-title":"Biochemical role of folate in cellular metabolism","volume":"18","author":"Wagner","year":"2001","journal-title":"Clin. Res. Regul. Aff."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40985-018-0079-6","article-title":"Public health failure in the prevention of neural tube defects: Time to abandon the tolerable upper intake level of folate","volume":"39","author":"Wald","year":"2018","journal-title":"Public Health Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.reprotox.2018.05.004","article-title":"Folic acid and primary prevention of neural tube defects: A review","volume":"80","author":"Hirche","year":"2018","journal-title":"Reprod. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S1701-2163(15)30230-9","article-title":"Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies","volume":"37","author":"Wilson","year":"2015","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S1028-4559(08)60002-9","article-title":"Chromosomal abnormalities associated with neural tube defects (I): Full aneuploidy","volume":"46","author":"Chen","year":"2007","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0140-6736(97)01342-1","article-title":"Can terathanasia explain the protective effect of folic-acid supplementation on birth defects?","volume":"350","author":"Hook","year":"1997","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/S0140-6736(01)05969-4","article-title":"Folic acid supplements during pregnancy and risk of miscarriage","volume":"358","author":"Gindler","year":"2001","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1515\/jpm-2012-0173","article-title":"Periconceptional use of folic acid and risk of miscarriage\u2014Findings of the Oral Cleft Prevention Program in Brazil","volume":"41","author":"Wehby","year":"2013","journal-title":"J. Perinat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S91","DOI":"10.1016\/S0140-6736(16)32018-9","article-title":"Folic acid supplementation, birth defects, and adverse pregnancy outcomes in Chinese women: A population-based mega-cohort study","volume":"388","author":"He","year":"2016","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/bdra.23368","article-title":"Plasma folate levels in early to mid pregnancy after a nation-wide folic acid supplementation program in areas with high and low prevalence of neural tube defects in China","volume":"103","author":"Liu","year":"2015","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1017\/S0007114515004663","article-title":"Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: A prospective cohort study","volume":"115","author":"Zheng","year":"2016","journal-title":"Br. J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e624","DOI":"10.1016\/S2214-109X(17)30142-0","article-title":"Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: A population-based cohort study","volume":"5","author":"Liu","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_19","unstructured":"National Health Commission of the People\u2019s Republic of China (2009, June 29). Project Management Plan on Folic Acid Supplement in Neural Tube Defects, Available online: http:\/\/www.nhc.gov.cn\/wjw\/gfxwj\/201304\/02c3c3d51117464aa054c08de04b0468.shtml."},{"key":"ref_20","unstructured":"Xie, X., Kong, B.H., and Duan, T. (2018). Pregnancy complication. Obstetrics and Gynecology, People\u2019s Medical Publishing House. [9th ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity Analysis in Observational Research: Introducing the E-Value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1749-6632.1993.tb26114.x","article-title":"Folic acid and the prevention of neural tube defects","volume":"678","author":"Wald","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S1701-2163(15)30444-8","article-title":"Prenatal screening, diagnosis, and pregnancy management of fetal neural tube defects","volume":"36","author":"Wilson","year":"2014","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_24","first-page":"890","article-title":"Risk Factors for Spontaneous Abortion of Chinese Married Women at Reproductive Age","volume":"18","author":"Liu","year":"2002","journal-title":"China Public Health"},{"key":"ref_25","unstructured":"Wang, L. (2018). Association between Periconception Environmental Risk Factors and Spontaneous Abortion among Reproductive Aged Couples in Rural China. [Ph.D. Thesis, Chinese Academy of Medical Sciences & Peking Union Medical College]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"g4554","DOI":"10.1136\/bmj.g4554","article-title":"Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model","volume":"349","author":"Crider","year":"2014","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/bdr2.1040","article-title":"Plasma folate levels and associated factors in women planning to become pregnant in a population with high prevalence of neural tube defects","volume":"109","author":"Ma","year":"2017","journal-title":"Birth Defects Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/aogs.12816","article-title":"Is pregnancy planning associated with background characteristics and pregnancy-planning behavior?","volume":"95","author":"Stern","year":"2016","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/ajmg.a.60699","article-title":"Periconceptional folic acid supplementation in Southern Brazil: Why are not we doing it right?","volume":"179","author":"Silveira","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5603\/GP.a2018.0036","article-title":"Demographic factors determining folic acid supplementation in pregnant and childbearing age women","volume":"89","author":"Kurzawinska","year":"2018","journal-title":"Ginekol. Polska"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1093\/humrep\/dep398","article-title":"Prevalence and predictors of periconceptional folic acid uptake--prospective cohort study in an Irish urban obstetric population","volume":"25","author":"McGuire","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.midw.2011.04.002","article-title":"Periconceptional folic acid supplementation among women attending antenatal clinic in Anhui, China: Data from a population-based cohort study","volume":"28","author":"Xing","year":"2012","journal-title":"Midwifery"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e12675","DOI":"10.1111\/mcn.12675","article-title":"Folate, vitamin B12, and homocysteine in smoking-exposed pregnant women: A systematic review","volume":"15","author":"Tuenter","year":"2019","journal-title":"Matern. Child Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.3945\/jn.111.142976","article-title":"Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications","volume":"141","author":"Bakker","year":"2011","journal-title":"J. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1038\/ncomms3889","article-title":"Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes","volume":"4","author":"Lambrot","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/ajmg.a.35796","article-title":"Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: A report from the National Down Syndrome Project","volume":"161","author":"Hollis","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"234","DOI":"10.2174\/1573402112666161010151632","article-title":"Evaluation of Homocysteine, Vitamin B12 and Folic Acid Levels During all the Trimesters in Pregnant and Preeclamptic Womens","volume":"12","author":"Kharb","year":"2016","journal-title":"Curr. Hypertens. Rev."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/8\/2264\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:52:30Z","timestamp":1760176350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/8\/2264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,29]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["nu12082264"],"URL":"https:\/\/doi.org\/10.3390\/nu12082264","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,29]]}}}