Non-isolated neural tube defects with comorbid malformations are responsive to population-level folic acid supplementation in Northern China

Background Comorbid congenital malformation of multiple organs may indicate shared genetic/teratogenic causality. Folic acid supplementation reduces population-level prevalance of isolated neural tube defects (NTDs), but whether complex cases involving independent malformtions are also repsonsive 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. Methods Data from five counties in northern China were obtained between 2002 to 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, anaecephaly or encephalocele. Isolated NTDs included spina bifida cases with presumed secondary malformations (hydrocephalus, hip dislocation, talipes). Non-isolated NTDs were those with independent concomittant malformations. Results A total of 296,306 births and 2,031 cases of NTDs were recorded in 2002-2021. 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 or/and palate, limb reduction defects, hip dislocation, gastroschisis, omphalocele, hydrocephalus and urogenital system defects was significantly greater in infants with NTDs than 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 common etiology.