Abstract
The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.
Highlights
According to the WHO, globally more than 300 000 deaths during the first 28 d of life were attributable to birth defects in 2015, with neural tube defects (NTD) being one of the most serious of these defects[1]
During the years 1999–2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) termination of pregnancies due to fetal anomaly (TOPFA) were registered in the Medical Birth Registry of Norway (MBRN) (Fig. 1)
Use of folic acid supplements before and during pregnancy was associated with higher maternal age, marriage/cohabitation, lower parity and nonsmoking
Summary
According to the WHO, globally more than 300 000 deaths during the first 28 d of life were attributable to birth defects in 2015, with neural tube defects (NTD) being one of the most serious of these defects[1]. In the early 1990s, two randomised controlled studies demonstrated that periconceptional folic acid supplementation prevented the recurrence and occurrence of NTD[12,13]. Because of these studies, many authorities worldwide implemented policies to fortify flour with folic acid, starting in the USA from 1998(14). Folic acid and birth defects in Norway supplement of 0·4 mg folic acid from 1 month before conception and until the 12th week of gestation to reduce the risk of NTD[16]. Associations between folic acid supplements and major birth defect categories have not previously been investigated in nationwide cohorts in the Nordic countries. As our main objective, we compared the risks of organ-specific major birth defects in live- and stillborn infants of mothers who did or did not use folic acid and/or multivitamin supplements
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