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Folic acid supplementation reduces the population-level prevalence of isolated neural tube defects (NTDs), but whether complex cases involving independent malformations are also responsive is unknown. We aimed to describe the epidemiology of NTDs with comorbid malformations in a Chinese population and assess the impact of folic acid supplementation. Study Design: Data from five counties in Northern China were obtained between 2002 and 2021 through a population-based birth defects surveillance system. All live births, stillbirths, and terminations because of NTDs at any gestational age were recorded. NTDs were classified as spina bifida, anencephaly, or encephalocele. Isolated NTDs included spina bifida cases with presumed secondary malformations (hydrocephalus, hip dislocation, talipes). Non-isolated NTDs were those with independent concomitant malformations. Results: A total of 296,306 births and 2031 cases of NTDs were recorded from 2002\u20132021. A total of 4.8% of NTDs (97\/2031) had comorbid defects, which primarily affected the abdominal wall (25\/97), musculoskeletal system (24\/97), central nervous system (22\/97), and face (15\/97). The relative risk of cleft lip and\/or palate, limb reduction defects, hip dislocation, gastroschisis, omphalocele, hydrocephalus, and urogenital system defects was significantly greater in infants with NTDs than in the general population. Population-level folic acid supplementation significantly reduced the prevalence of both isolated and non-isolated NTDs. Conclusion: Epidemiologically, non-isolated NTDs follow similar trends as isolated cases and are responsive to primary prevention by folic acid supplementation. Various clinically-important congenital malformations are over-represented in individuals with NTDs, suggesting a common etiology.<\/jats:p>","DOI":"10.3390\/biology11091371","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T21:47:27Z","timestamp":1663624047000},"page":"1371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Non-Isolated Neural Tube Defects with Comorbid Malformations Are Responsive to Population-Level Folic Acid Supplementation in Northern China"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1421-251X","authenticated-orcid":false,"given":"Xiaoyu","family":"Che","sequence":"first","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5844-8973","authenticated-orcid":false,"given":"Jufen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Galea","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1E, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-5248","authenticated-orcid":false,"given":"Nicholas","family":"Greene","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1E, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3254-9105","authenticated-orcid":false,"given":"Lei","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2033-9277","authenticated-orcid":false,"given":"Linlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-5638","authenticated-orcid":false,"given":"Aiguo","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Child Health\/Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Peking University, Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of 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