Table 1.
Quantitative synthesis of eligible positive associations for specific risk/protective factor and CHD
| Factor | Studies | Cases | Egger test | Random-effect | 95%PI | Heterogeneity | Excess significance bias | Fixed-effect | Random-effect | Gradea |
|---|---|---|---|---|---|---|---|---|---|---|
| p value | Summary effect size(95%CI) | I2(%) | p value | p value | p value | |||||
| Reproductive related and assistive technologies | ||||||||||
| Family genetic history | 5 | 7751 | 0.42 | 3.35 (2.70,4.14) | (2.37,4.73) | 0.00 | 0.24 | 1.02E-28 | 1.02E-28 | I |
| Abortion number | 4 | 2413 | 0.45 | 1.28 (1.18,1.40) | (1.06,1.56) | 55.24 | 0.34 | 1.89E-08 | 1.91E-08 | II |
| Maternal parity | 14 | 38,027 | 0.88 | 1.22 (1.09,1.36) | (0.83,1.78) | 82.65 | 0.94 | 3.80E-45 | 4.22E-04 | III |
| Singleton IVF/ICSI | 5 | 2159 | 0.11 | 1.56 (1.21,2.00) | (0.79,3.08) | 35.18 | 0.66 | 3.23E-05 | 5.89E-04 | III |
| ICSI/IVF pregnancies | 8 | 1047 | 0.61 | 1.45 (1.21,1.73) | (0.94,2.23) | 43.62 | 0.57 | 5.78E-08 | 4.69E-05 | III |
| History of spontaneous abortion | 9 | 5377 | 0.54 | 1.21 (1.12,1.31) | (1.10,1.34) | 11.15 | 0.64 | 2.57E-06 | 2.57E-06 | III |
| History of abortion | 13 | 7957 | 0.13 | 1.22 (1.11,1.34) | (1.00,1.48) | 45.77 | 0.03 | 3.75E-07 | 2.49E-05 | III |
| Gravidity number | 7 | 4381 | 0.09 | 1.15 (1.08,1.22) | (0.99,1.33) | 41.68 | 0.47 | 2.37E-08 | 7.12E-06 | III |
| Maternal or fetal abnormalities detected | 3 | 364 | 0.55 | 2.37 (1.25,4.49) | (0.02,296.12) | 18.79 | 0.10 | 3.86E-03 | 7.88E-03 | IV |
| Intermarriage | 3 | 467 | 0.36 | 2.88 (1.88,4.39) | (0.18,44.83) | 0.00 | 0.53 | 1.03E-06 | 1.03E-06 | IV |
| ICSI vs IVF (in fresh transplantation cycle) | 3 | 72 | 0.08 | 2.07 (1.28,3.36) | (0.09,47.47) | 0.00 | 1.00 | 3.05E-03 | 3.05E-03 | IV |
| History of induced abortion | 6 | 1566 | 0.03 | 1.68 (1.10,2.55) | (0.44,6.41) | 65.48 | 1.00 | 1.06E-03 | 1.64E-02 | IV |
| Gravidity | 10 | 5464 | 0.62 | 1.18 (1.03,1.36) | (0.77,1.81) | 62.10 | 1.00 | 1.11E-05 | 2.03E-02 | IV |
| MC twins without TTTS | 5 | 134 | 0.77 | 5.44 (3.66,8.08) | (2.86,10.34) | 0.00 | 0.94 | 5.57E-17 | 5.57E-17 | IV |
| MC twins with TTTS | 6 | 146 | 0.04 | 12.50 (8.66,18.04) | (7.43,21.03) | 0.00 | 0.68 | 2.06E-41 | 2.06E-41 | IV |
| MC twins | 6 | 141 | 0.03 | 5.88 (4.18,8.28) | (3.62,9.55) | 0.00 | 0.33 | 3.62E-24 | 3.62E-24 | IV |
| MC twins with TTTS vs. MC twins without TTTS | 4 | 123 | 0.67 | 2.40 (1.64,3.51) | (1.04,5.53) | 0.00 | 0.74 | 6.62E-06 | 6.62E-06 | IV |
| Parental age and BMI | ||||||||||
| Maternal severe obesity | 5 | 1497 | 0.10 | 1.38 (1.30,1.47) | (1.26,1.53) | 0.00 | 0.25 | 1.99E-26 | 1.99E-26 | I |
| Maternal moderate obesity | 5 | 3835 | 0.16 | 1.15 (1.10,1.20) | (1.05,1.27) | 33.84 | 0.24 | 1.37E-12 | 4.40E-10 | I |
| Maternal obesity | 20 | 58,926 | 0.01 | 1.33 (1.22,1.46) | (1.02,1.75) | 61.64 | 0.06 | 5.28E-42 | 6.93E-10 | II |
| Paternal age (≥40 years) | 11 | 7456 | 0.30 | 1.71 (1.31,2.23) | (0.68,4.29) | 94.33 | 0.00 | 1.46E-23 | 9.22E-05 | III |
| Paternal age (35–39 years) | 5 | 11,219 | 0.15 | 1.14 (1.06,1.22) | (0.98,1.32) | 16.64 | 0.94 | 8.50E-06 | 1.72E-04 | III |
| Advanced maternal age (≥35 years) | 9 | 19,212 | 0.26 | 1.15 (1.07,1.24) | (0.98,1.36) | 22.02 | 0.01 | 1.37E-06 | 2.66E-04 | III |
| Maternal overweight | 19 | 52,606 | 0.16 | 1.06 (1.01,1.12) | (0.93,1.21) | 58.58 | 0.05 | 1.21E-04 | 2.20E-02 | IV |
| Parental life habits, working and dwelling environment | ||||||||||
| Exposure to noise during pregnancy | 5 | 1218 | 0.03 | 2.80 (2.09,3.76) | (1.46,5.39) | 31.76 | 0.10 | 3.28E-14 | 6.68E-12 | II |
| Exposure to harmful chemicals during pregnancy | 13 | 3300 | 0.76 | 3.35 (2.19,5.13) | (0.88,12.81) | 63.80 | 0.01 | 2.34E-28 | 2.82E-08 | II |
| Exposure of decoration materials during pregnancy | 3 | 3090 | 0.46 | 4.21 (2.38,7.47) | (0.03,265.47) | 74.50 | 0.55 | 6.37E-49 | 9.68E-07 | II |
| Maternal educational attainment | 30 | 27,642 | 0.29 | 1.13 (1.05,1.21) | (0.90,1.42) | 57.14 | 0.39 | 4.95E-33 | 6.01E-04 | III |
| Paternal smoking | 10 | 8898 | 0.46 | 1.42 (1.17,1.73) | (0.72,2.82) | 84.85 | 1.00 | 8.41E-17 | 4.07E-04 | III |
| Paternal active smoking | 13 | 2099 | 0.44 | 1.43 (1.19,1.72) | (0.85,2.42) | 52.99 | 1.00 | 6.87E-12 | 1.18E-04 | III |
| Maternal passive smoking | 44 | 15,143 | 0.00 | 2.00 (1.65,2.43) | (0.61,6.55) | 89.51 | 0.03 | 9.58E-55 | 2.09E-12 | III |
| Maternal active smoking | 85 | 123,755 | 0.00 | 1.30 (1.17,1.44) | (0.57,2.97) | 88.20 | 0.18 | 3.39E-18 | 1.11E-06 | III |
| Paternal occupational exposure to adverse substances | 3 | 919 | 0.95 | 1.70 (1.19,2.43) | (0.17,17.30) | 0.00 | 0.57 | 3.81E-03 | 3.81E-03 | IV |
| Family income | 5 | 8150 | 0.72 | 1.05 (1.01,1.10) | (0.98,1.13) | 0.00 | 0.37 | 2.06E-02 | 2.06E-02 | IV |
| Solvents exposure | 6 | 2526 | 0.53 | 1.32 (1.06,1.63) | (0.97,1.78) | 0.00 | 1.00 | 1.15E-02 | 1.15E-02 | IV |
| Paternal heavy smoking (≥20cigarrette/day) | 5 | 1813 | 0.03 | 1.85 (1.01,3.40) | (0.19,18.04) | 85.41 | 0.00 | 1.22E-02 | 4.79E-02 | IV |
| Paternal light smoking (10–19 cigarette/day) | 4 | 1580 | 0.79 | 1.41 (1.13,1.76) | (0.64,3.11) | 43.08 | 0.01 | 4.70E-05 | 2.48E-03 | IV |
| High intake of caffeinated products | 4 | 320 | 0.29 | 1.32 (1.09,1.60) | (0.86,2.02) | 0.00 | 0.75 | 5.12E-03 | 5.12E-03 | IV |
| Lithium exposure (in the first trimester compared with patients with bipolar disorderd) | 3 | 59 | 0.39 | 1.96 (1.13,3.39) | (0.06,69.51) | 0.00 | 1.00 | 1.69E-02 | 1.69E-02 | IV |
| Lithium exposure (in the first trimester compared with general population) | 4 | 15,293 | 0.41 | 4.90 (1.72,13.96) | (0.07,322.10) | 69.14 | 0.08 | 2.70E-07 | 2.95E-03 | IV |
| Lithium exposure (in the first trimester compared with unexposed women) | 3 | 15,314 | 0.28 | 4.56 (1.59,13.12) | (0.00,627,861.00) | 71.78 | 0.06 | 1.41E-06 | 4.89E-03 | IV |
| Maternal drug exposure | ||||||||||
| SNRIs | 4 | 24,743 | 0.79 | 1.67 (1.40,1.98) | (1.09,2.55) | 24.27 | 0.60 | 9.48E-10 | 6.07E-09 | I |
| SSRIs | 16 | 43,170 | 0.78 | 1.26 (1.19,1.33) | (1.19,1.34) | 32.77 | 0.37 | 1.72E-16 | 1.73E-16 | I |
| Folic acid supplementation | 20 | 18,276 | 0.00 | 0.61 (0.51,0.73) | (0.30,1.22) | 79.76 | 0.00 | 2.35E-21 | 2.14E-08 | II |
| Any antidepressant (in the first trimester) | 20 | 61,539 | 0.50 | 1.28 (1.17,1.41) | (0.98,1.69) | 48.75 | 0.46 | 2.19E-22 | 2.07E-07 | II |
| Fluoxetine | 14 | 74,523 | 0.33 | 1.30 (1.13,1.50) | (0.98,1.72) | 28.25 | 0.19 | 3.90E-06 | 2.40E-04 | III |
| SSRIs (in the first trimester) | 19 | 74,191 | 0.63 | 1.26 (1.13,1.42) | (0.86,1.87) | 56.06 | 0.16 | 4.29E-15 | 8.23E-05 | III |
| Oral hormone pregnancy tests | 7 | 1003 | 0.76 | 1.90 (1.26,2.86) | (0.93,3.86) | 0.00 | 0.95 | 5.75E-04 | 2.11E-03 | IV |
| Sertraline | 13 | 74,598 | 0.26 | 1.44 (1.10,1.91) | (0.59,3.53) | 63.82 | 0.02 | 4.33E-06 | 9.22E-03 | IV |
| Nitrate (each additional daily 0.5 mg) | 3 | 826 | 0.56 | 1.02 (1.00,1.04) | (0.89,1.17) | 0.00 | 0.15 | 4.26E-02 | 4.26E-02 | IV |
| Citalopram | 11 | 67,622 | 0.21 | 1.26 (1.05,1.50) | (0.82,1.94) | 45.51 | 0.29 | 1.04E-03 | 1.12E-02 | IV |
| Nitrate (high vs low) | 4 | 912 | 0.14 | 1.20 (1.02,1.42) | (0.83,1.73) | 0.00 | 1.00 | 3.28E-02 | 3.28E-02 | IV |
| β-blockers (in the first trimester) | 8 | 59,756 | 0.72 | 1.57 (1.11,2.23) | (0.59,4.18) | 65.02 | 0.99 | 2.17E-06 | 1.08E-02 | IV |
| Bupropion | 3 | 6591 | 0.63 | 1.23 (1.01,1.49) | (0.35,4.31) | 0.00 | 1.00 | 3.58E-02 | 3.58E-02 | IV |
| Fluconazole (in the first trimester) | 5 | 6716 | 0.44 | 1.95 (1.18,3.21) | (0.35,10.78) | 78.00 | 0.11 | 1.18E-07 | 8.97E-03 | IV |
| Maternal diseases | ||||||||||
| Gestational hypertension | 23 | 138,067 | 0.13 | 1.73 (1.48,2.03) | (0.85,3.51) | 79.93 | 0.83 | 3.92E-128 | 1.19E-11 | II |
| GDM | 26 | 99,010 | 0.11 | 1.94 (1.59,2.35) | (0.82,4.57) | 88.99 | 0.01 | 3.24E-114 | 3.82E-11 | II |
| PGDM | 30 | 139,743 | 0.04 | 3.13 (2.65,3.69) | (1.42,6.88) | 79.39 | 0.79 | 0.00E+ 00 | 2.74E-41 | II |
| DM | 50 | 166,545 | 0.00 | 2.60 (2.65,3.01) | (1.09,6.24) | 97.66 | 0.00 | 8.18E-61 | 1.69E-38 | II |
| Fever | 16 | 37,269 | 0.00 | 1.46 (1.21,1.76) | (0.75,2.85) | 80.29 | 0.00 | 5.07E-05 | 7.76E-05 | III |
| Chronic diseases before pregnancy | 3 | 346 | 0.99 | 4.33 (2.28,8.23) | (0.07,227.22) | 0.00 | 0.45 | 7.40E-06 | 7.40E-06 | IV |
| Infection of the reproductive system | 3 | 2742 | 0.01 | 4.57 (1.10,18.92) | (0.00,3000.00) | 65.91 | 0.27 | 1.92E-03 | 3.61E-02 | IV |
| Respiratory infection | 5 | 653 | 0.28 | 3.79 (2.32,6.19) | (0.94,15.24) | 57.54 | 0.69 | 1.26E-16 | 1.02E-07 | IV |
| Malnutrition during pregnancy | 4 | 538 | 0.14 | 1.96 (1.33,2.88) | (0.46,8.42) | 48.51 | 0.01 | 2.51E-06 | 6.40E-04 | IV |
| Influenza | 8 | 6956 | 0.18 | 1.73 (1.10,2.71) | (0.59,5.03) | 52.16 | 0.99 | 2.36E-06 | 1.73E-02 | IV |
| Rubella virus | 7 | 332 | 0.46 | 3.30 (2.36,4.62) | (2.13,5.12) | 46.53 | 0.05 | 2.85E-12 | 2.86E-12 | IV |
| Cytomegalovirus infection | 4 | 119 | 0.42 | 3.95 (1.75,8.90) | (0.53,29.38) | 53.34 | 0.33 | 3.28E-04 | 9.43E-04 | IV |
| Viral infection | 17 | 6401 | 0.15 | 2.53 (1.40,4.56) | (0.23,27.47) | 77.67 | 0.38 | 1.91E-15 | 2.15E-03 | IV |
a Ioannidis’s five-class evidence grade
Abbreviation: CI Confidence interval, PI Predictive interval, IVF In-vitro-fertilization, ICSI Intracytoplasmic sperm injection, SSRI Selective serotonin reuptake inhibitor, SNRI serotonin-norepinephrine reuptake inhibitor, DM maternal diabetes mellitus, PGDM pregestational diabetes mellitus, GDM gestational diabetes mellitus, TTTS twin–twin transfusion syndrome, MC Monochorionic