Table 4.
Relative Risk of Congenital Heart Defecta (Overall), Severe Heart Defectb, Conotruncal Defect,c and Septal Defectd by Maternal Intake of Folic Acid Supplements in the Periconceptional Period, Combining 94 228 Births in the DNBC, Denmark, 1996–2003, and 102 985 Births in MoBa, Norway 1999–2009
| Total Births, N=186 861e | Any Congenital Heart Defect,an=2130 | Severe Heart Defect,bn=551 | Conotruncal Heart Defect,cn=187 | Septal Defect,dn=1139 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n (%) | n | Adjusted RRf(95% CI) | n | Adjusted RRf(95% CI) | n | Adjusted RRf(95% CI) | n | Adjusted RRf(95% CI) | |||||
| Supplement use (4 wk before to 8 wk after conception) | |||||||||||||
| None | 52 401 (28.0) | 569 | 1 | Reference | 157 | 1 | Reference | 55 | 1 | Reference | 296 | 1 | Reference |
| Other supplements, no folic acid | 9414 (5.0) | 104 | 0.99 | 0.80–1.22 | 25 | 0.92 | 0.61–1.41 | 8 | 0.84 | 0.40–1.77 | 61 | 1.06 | 0.80–1.39 |
| Folic acid only | 22 695 (12.2) | 279 | 1.08 | 0.93–1.25 | 68 | 1.10 | 0.82–1.48 | 22 | 0.98 | 0.59–1.64 | 155 | 1.03 | 0.84–1.26 |
| Folic acid plus other supplementation | 102 351 (54.8) | 1178 | 1.07 | 0.97–1.19 | 301 | 1.02 | 0.84–1.25 | 102 | 0.93 | 0.66–1.31 | 627 | 1.06 | 0.92–1.22 |
| Initiation of folic acidg (4 wk before to 12 wk after conception) | |||||||||||||
| None | 53 142 (28.4) | 577 | 1 | Reference | 158 | 1 | Reference | 57 | 1 | Reference | 301 | 1 | Reference |
| Weeks −4 to −1 | 62 924 (33.7) | 753 | 1.11 | 1.00–1.25 | 192 | 1.08 | 0.87–1.34 | 65 | 0.95 | 0.66–1.38 | 397 | 1.08 | 0.92–1.26 |
| Weeks 0–4 | 28 961 (15.5) | 348 | 1.09 | 0.95–1.25 | 82 | 1.01 | 0.77–1.33 | 29 | 0.93 | 0.59–1.48 | 199 | 1.11 | 0.92–1.33 |
| Weeks 5–8 | 33 161 (17.8) | 356 | 0.98 | 0.86–1.12 | 95 | 1.00 | 0.77–1.30 | 30 | 0.85 | 0.54–1.33 | 186 | 0.93 | 0.77–1.11 |
| Weeks 9–12h | 8673 (4.6) | 96 | 0.97 | 0.78–1.20 | 24 | 0.97 | 0.63–1.50 | 6 | 0.68 | 0.29–1.58 | 56 | 1.00 | 0.75–1.32 |
APVR indicates anomalous pulmonary venous return; ASD, atrial septal defect; AVSD, atrioventricular septal defect; DNBC, Danish National Birth Cohort; LVOTO, left ventricle outflow tract obstruction; MoBa, Norwegian Mother and Child Cohort Study; PDA, patent ductus arteriosus; RR, risk ratio; RVOTO, right ventricle outflow tract obstruction; VSD, ventricular septal defect.
Congenital heart defects: Heterotaxia, conotruncal defects, AVSD, APVR, LVOTO, RVOTO, VSD, ASD, VSD plus ASD, complex defects; patent ductus arteriosus (PDA) in live births at term (gestational age ≥37 weeks); other specified heart defects; unspecified heart defects.
Severe heart defects: heterotaxia, conotruncal defects (see below), AVSD, APVR, LVOTO, RVOTO, complex defects.
Conotruncal defects: truncus arteriosus, transposition of the great arteries, tetralogy of Fallot, pulmonary atresia with ventricular septal defect (tetralogy of Fallot type), double‐outlet right ventricle, conoventricular septal defect, interrupted aortic arch type B or C, supravalvular aortic stenosis, aortopulmonary window.
Septal defects: VSD, ASD, VSD plus ASD.
Individuals with missing values of covariates were excluded in the adjusted analyses (total births n=10 352 [5.2% of 197 213]; any heart defect n=117 [5.2% of 2247]; severe defects n=32; conotruncal defects n=14; septal defects n=52); see country‐specific numbers in Tables S2 and S3.
Relative risk with 95% CI comparing supplement use with no use (reference) 4 weeks before to 8 weeks after conception (upper panel) or comparing initiation of folic acid supplements with no use or non–folic acid supplements (reference) 4 weeks before to 12 weeks after conception (lower panel). RRs adjusted for interaction between country (Denmark/Norway) and the following factors: year of birth (Denmark: 1996–1997, 1998, 1999, 2000, 2001, 2002–2003; Norway: 1999–2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008–2009), maternal age (≤24, 25–29, 30–34, ≥35 years), birth order (first, second, third or higher), maternal body mass index (<20, 20–24, 25–29, 30–34, ≥35), maternal heart defect (yes/no), maternal epilepsy before pregnancy (yes/no). Categories for adjustment variables combined for severe and conotruncal defects.
The 4 exposure categories in supplement use collapsed into no/yes; no is no folic acid use (no supplements and other supplements, no folic acid), and yes is folic acid use (folic acid only and folic acid plus other supplementation.
In DNBC, including week 11.