Table 1.
Assessment across the 63 associations of environmental risk factors with CHD.
| Outcomes | Sample size (number of cases) | Significance threshold reached (under the random-effects model) | 95% prediction interval rule | Estimate of heterogeneity* | Small-study effects or excess significance bias | Random-effects summary effect size (95% CI) | |
|---|---|---|---|---|---|---|---|
| Associations supported by convincing evidence | |||||||
| Severe obesity | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Neither | 1.38 (1.30–1.47) |
| Associations supported by highly suggestive evidence | |||||||
| Lithium (pregnancy) | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Small-study effects/excess significance bias | 2.14 (1.67–2.75) |
| Lithium (in the first trimester) | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Small-study effects/excess significance bias | 2.16 (1.69–2.75) |
| Maternal alcohol consumption | CHD | >1,000 | <10−6 | Excluding the null value | Very large | Small-study effects | 1.28 (1.17–1.39) |
| Obesity | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.18 (1.14–1.22) |
| Moderate obesity | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.15 (1.09–1.21) |
| Obesity | Outflow tract defects | >1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.39 (1.26–1.54) |
| Obesity | ASD | >1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.38 (1.21–1.57) |
| Maternal fever | CHD | >1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.56 (1.31–1.85) |
| Associations supported by suggestive evidence | |||||||
| SSRI (in the first trimester) | CHD | >1,000 | <10−3 | Excluding the null value | Large | Neither | 1.26 (1.11–1.37) |
| Maternal folate supplementation | CHD | >1,000 | <10−6 | Including the null value | Very large | Neither | 0.72 (0.63–0.89) |
| Fluoxetine (pregnancy) | CHD | >1,000 | <10−3 | Excluding the null value | Not large | Neither | 1.60 (1.32–1.95) |
| Overweight | Outflow tract defects | >1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.19 (1.09–1.31) |
| Moderate obesity | ASD | >1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.26 (1.13–1.40) |
| Severe obesity | ASD | >1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.72 (1.35–2.20) |
| IVF/intracytoplasmic sperm injection | CHD | >1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.45 (1.20–1.75) |
| Singleton IVF/intracytoplasmic sperm injection | CHD | >1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.55 (1.21–1.99) |
| Gravidity number | CHD | >1,000 | <10−3 | Excluding the null value | Not large | Small-study effects/excess significance bias | 1.15 (1.08–1.22) |
| Paternal age 35–39 | CHD | >1,000 | <10−3 | Excluding the null value | Not large | Neither | 1.14 (1.06–1.22) |
| Paternal smoking | CHD | >1,000 | <10−3 | Including the null value | Very large | Neither | 1.42 (1.17–1.74) |
| Associations supported by weak evidence | |||||||
| Fluoxetine (in the first trimester) | CHD | >1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.39 (1.12–1.73) |
| Paroxetine | CHD | >1,000 | <0.05 | Including the null value | Not large | Neither | 1.25 (1.01–1.54) |
| Nitrofurantoin | HLHS | <1,000 | <0.05 | Excluding the null value | Not large | Excess significance bias | 3.07 (1.59–5.93) |
| Fluconazole | CHD | >1,000 | <0.05 | Excluding the null value | Not large | Excess significance bias | 1.29 (1.05–1.59) |
| Valproic acid | CHD | <1,000 | <10−6 | Excluding the null value | Not large | Neither | 2.24 (1.65–3.03) |
| Multivitamin | CHD | >1,000 | <0.05 | Including the null value | Large | Neither | 0.83 (0.70–0.97) |
| Oral hormone pregnancy tests | CHD | >1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.89 (1.32–2.72) |
| Air pollution (NO2) | COA | <1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.20 (1.02–1.41) |
| Maternal alcohol consumption | TOF | >1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.19 (1.07–1.33) |
| Secondhand smoking | CHD | >1,000 | <0.05 | Excluding the null value | Very large | Small-study effects | 2.10 (1.32–3.35) |
| Smoking | Septal defect | >1,000 | <0.05 | Excluding the null value | Large | Neither | 1.21 (1.01–1.46) |
| Smoking | Cardiovascular/ heart defects | >1,000 | <0.05 | Excluding the null value | Large | Neither | 1.10 (1.02–1.17) |
| Smoking | Heart defect | >1,000 | <0.05 | Excluding the null value | Large | Neither | 1.09 (1.00–1.18) |
| Overweight | CHD | >1,000 | <0.05 | Including the null value | Large | Neither | 1.06 (1.02–1.11) |
| Overweight | HLHS | <1,000 | <0.05 | Including the null value | Not large | Small-study effects | 1.31 (1.08–1.60) |
| Moderate obesity | HLHS | <1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.54 (1.21–1.95) |
| Severe obesity | HLHS | <1,000 | <0.05 | Including the null value | Not large | Neither | 1.60 (1.11–2.31) |
| Obesity | HLSH | <1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 1.52 (1.23–1.88) |
| Severe obesity | TOF | <1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 1.95 (1.50–2.52) |
| Obesity | TOF | <1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.27 (1.07–1.51) |
| Obesity | Conotruncal defects | >1,000 | <0.05 | Including the null value | Not large | Neither | 1.23 (1.08–1.40) |
| Severe obesity | AVSD | <1,000 | <0.05 | Including the null value | Not large | Neither | 1.44 (1.03–2.00) |
| Severe obesity | VSD | >1,000 | <0.05 | Excluding the null value | Not large | Excess significance bias | 1.23 (1.07–1.41) |
| Moderate obesity | COA | <1,000 | <0.05 | Including the null value | Not large | Neither | 1.29 (1.03–1.61) |
| Obesity | COA | <1,000 | <0.05 | Including the null value | Not large | Neither | 1.25 (1.02–1.53) |
| Obesity | All septal anomalies | >1,000 | <0.05 | Excluding the null value | Not large | Small-study effects | 1.24 (1.04–1.49) |
| Chlorination by-products | VSD | <1,000 | <0.05 | Excluding the null value | Not large | Excess significance bias | 1.59 (1.21–2.07) |
| Monochorionic twins vs. singletons | CHD | <1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 5.88 (4.18–8.28) |
| Monochorionic twins with TTTS vs. singletons | CHD | <1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 12.50 (8.66-18.05) |
| Monochorionic twins without TTTS vs. singletons | CHD | <1,000 | <10−6 | Excluding the null value | Not large | Excess significance bias | 5.44 (3.66–8.08) |
| Monochorionic twins with TTTS vs. Monochorionic twins without TTTS | CHD | <1,000 | <10−3 | Excluding the null value | Not large | Excess significance bias | 2.40 (1.64–3.51) |
| Maternal fever | VSD | <1,000 | <0.05 | Including the null value | Not large | Neither | 1.34 (1.02–1.78) |
| Maternal fever | Right obstructive defects | <1,000 | <10−3 | Excluding the null value | Not large | Small-study effects/excess significance bias | 2.06 (1.47–2.88) |
| Occupational exposure to solvents | CHD | >1,000 | <0.05 | Including the null value | Not large | Neither | 1.31 (1.06–1.63) |
| Gravidity (ever vs. nulligravidity) | CHD | >1,000 | <0.05 | Excluding the null value | Large | Neither | 1.18 (1.03–1.34) |
| History of spontaneous abortion | CHD | >1,000 | <0.05 | Including the null value | Not large | Neither | 1.18 (1.07–1.31) |
| History of induced abortion | CHD | >1,000 | <0.05 | Including the null value | Large | Small-study effects | 1.58 (1.12–2.22) |
| Abortion number | CHD | >1,000 | <0.05 | Excluding the null value | Large | Excess significance bias | 1.31 (1.12–1.52) |
| Parity number | CHD | >1,000 | <0.05 | Excluding the null value | Very large | Neither | 1.06 (1.02–1.09) |
| Paternal age ≥40 | CHD | >1,000 | <0.05 | Excluding the null value | Very large | Neither | 1.20 (1.05–1.38) |
| Paternal medium smoking (10–19 cigarettes per day) | CHD | >1,000 | <0.05 | Excluding the null value | Not large | Neither | 1.41 (1.12–1.77) |
| Paternal heavy smoking (≥20 cigarettes per day) | CHD | >1,000 | <0.05 | Including the null value | Very large | Small-study effects | 1.76 (1.10–2.80) |
| Paternal wine drinking | CHD | >1,000 | <0.05 | Including the null value | Very large | Neither | 1.48 (1.05–2.07) |
*
Heterogeneity was categorized as not large (I2 < 50%), large (I2 ≥ 50% but I2 ≤ 75%), and very large (I2 > 75%).
ASD, atrial septal defect; AVSD, atrioventricular septal defect; CHD, congenital heart disease; COA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; IVF, in-vitro fertilization; SSRI, selective serotonin reuptake inhibitor; TOF, tetralogy of Fallot; TTTS, twin-twin transfusion syndrome; VSD, ventricular septal defect.