First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Data Collection
2.3. Classification of CHD Phenotypes
2.4. CHD Risk Factors
2.5. First-Trimester Maternal FAS
2.6. Covariates
2.7. Statistical Analysis
3. Results
4. Discussion
4.1. Interaction Effects of FAS/Non-FAS, Viral Infection, and Fever on CHDs
4.2. Synergistic Effects of Non-FAS and Maternal Risk Factors on CHD Categories
4.3. Synergistic Effects of Non-FAS and Living in a Newly Renovated Home on CHDs
4.4. Dose Response and Joint Effects of Non-FAS and Risk Factors Exposures on CHDs
4.5. Strengths and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Maternal Exposures | Total | CHD Case, n (%) | Control, n (%) | OR (95% CI) * |
---|---|---|---|---|
Total | 15297 | 8379 | 6918 | - |
Maternal FAS † | ||||
Yes | 1877 (12.3) | 928 (11.1) | 949 (13.7) | 0.69 (0.62-0.76) |
No | 13,420 (87.7) | 7451 (88.9) | 5969 (86.3) | 1.00 (ref) |
Maternal disease † | ||||
Fever | ||||
Yes | 371 | 306 (3.7) | 65 (0.9) | 2.41 (1.81–3.20) |
No | 14,926 | 8073 (96.3) | 6853 (99.1) | 1.00 (Ref) |
Viral infection | ||||
Yes | 1114 | 885 (10.6) | 229 (3.3) | 3.00 (2.56–3.52) |
No | 14,183 | 7494 (89.4) | 6689 (96.7) | 1.00 (Ref) |
Hypertension | ||||
Yes | 148 | 115 (1.4) | 33 (0.5) | 2.37 (1.52–3.70) |
No | 15,149 | 8264 (98.6) | 6885 (99.5) | 1.00 (Ref) |
Threatened abortion | ||||
Yes | 727 | 546 (6.5) | 181 (2.6) | 1.95 (1.62–2.35) |
No | 14,567 | 7831 (93.5) | 6736 (97.4) | 1.00 (Ref) |
Reproductive history | ||||
Previous pregnancies with birth defects | ||||
Yes | 106 | 95 (1.1) | 11 (0.2) | 6.55 (3.48–12.35) |
No | 15,191 | 8284 (98.9) | 6907 (99.8) | 1.00 (Ref) |
Spontaneous/elective abortion history | ||||
Yes | 1037 | 644 (7.7) | 393 (5.7) | 1.28 (1.12–1.47) |
No | 14,260 | 7735 (92.3) | 6525 (94.3) | 1.00 (Ref) |
Maternal lifestyle and environmental factors | ||||
Alcohol consumption † | ||||
Yes | 87 | 65 (0.8) | 22 (0.3) | 1.65 (0.99–2.73) |
No | 15,210 | 8314 (99.2) | 6896 (99.7) | 1.00 (Ref) |
Active Smoking † | ||||
Yes | 141 | 119 (1.4) | 22 (0.3) | 1.38 (0.82–2.32) |
No | 15,156 | 8260 (98.6) | 6896 (99.7) | 1.00 (Ref) |
Living in newly renovated home ‡ | ||||
Yes | 392 | 317 (3.8) | 75 (1.1) | 2.28 (1.74–2.99) |
No | 14,905 | 8062 (96.2) | 6843 (98.9) | 1.00 (Ref) |
Residing within 50 m of a high traffic roadway ‡ | ||||
Yes | 1721 | 1076 (12.8) | 645 (9.3) | 1.16 (1.04–1.30) |
No | 13,576 | 7303 (87.2) | 6273 (90.7) | 1.00 (Ref) |
With FAS | Without FAS | ||||
---|---|---|---|---|---|
Strata of Maternal Exposures | CHD Cases/ Participants | OR * (95% CI) | CHD Cases/ Participants | OR * (95% CI) | p-Value for Multiplicative Interaction |
Total | 928/1877 | - | 7451/13,420 | - | - |
Maternal disease † | |||||
Fever (>38 °C) | |||||
Yes (n = 371) | 44/60 | 1.19 (0.59–2.42) | 262/311 | 2.72 (1.97–3.76) | 0.01 |
No (n = 14,926) | 884/1817 | 1.00 (ref) | 7189/13,109 | 1.00 (ref) | |
Viral infection ‡ | |||||
Yes (n = 1114) | 157/218 | 2.45 (1.73–3.47) | 728/896 | 3.21 (2.68–3.85) | 0.01 |
No (n = 14,183) | 771/1659 | 1.00 (ref) | 6723/12,524 | 1.00 (ref) | |
Hypertension | |||||
Yes (n = 148) | 12/18 | 3.17 (0.94–10.69) | 103/130 | 2.34 (1.44–3.82) | 0.90 |
No (n = 15,149) | 916/1859 | 1.00 (ref) | 7348/13,290 | 1.00 (ref) | |
Threatened abortion | |||||
Yes (n = 727) | 96/152 | 1.60 (1.08–2.39) | 450/575 | 2.07 (1.67–2.56) | 0.05 |
No (n = 14,570) | 832/1725 | 1.00 (ref) | 7001/12,845 | 1.00 (ref) | |
Reproduction history | |||||
Previous pregnancies with birth defects | |||||
Yes (n = 106) | 13/15 | 4.85 (1.01–23.24) | 82/91 | 6.60 (3.28–13.28) | 0.61 |
No (n = 15,191) | 915/1862 | 1.00 (ref) | 7369/13,329 | 1.00 (ref) | |
Spontaneous/elective abortion history | |||||
Yes (n = 1037) | 123/226 | 1.10 (0.78–1.54) | 521/811 | 1.23 (1.05–1.45) | 0.44 |
No (n = 14,260) | 805/1651 | 1.00 (ref) | 6930/12,609 | 1.00 (ref) | |
Maternal lifestyle and environmental factors | |||||
Alcohol consumption † | |||||
Yes (n = 87) | 9/10 | 5.45 (0.67–44.74) | 56/77 | 1.46 (0.86–2.47) | 0.11 |
No (n = 15,210) | 919/1867 | 1.00 (ref) | 7395/13,343 | 1.00 (ref) | |
Active smoking † | |||||
Yes (n = 141) | 2/9 | 1.43 (0.26–7.75) | 20/132 | 1.34 (0.77–2.32) | 0.82 |
No (n = 15,156) | 947/1868 | 1.00 (ref) | 5949/13,288 | 1.00 (ref) | |
Living in newly renovated home ‡ | |||||
Yes (n = 392) | 20/30 | 1.02 (0.42–2.51) | 297/360 | 2.54 (1.91–3.38) | 0.93 |
No (n = 14,905) | 908/1847 | 1.00 (ref) | 7154/13,058 | 1.00 (ref) | |
Residing within 50 m of a high traffic roadway ‡ | |||||
Yes (n = 1721) | 94/158 | 1.29 (0.89–1.89) | 982/1563 | 1.13 (1.00–1.27) | 0.93 |
No (n = 13,576) | 834/1719 | 1.00 (ref) | 6469/11,857 | 1.00 (ref) |
Maternal Exposures | OR00 (ref) (FAS, No Exposure) | OR10 (95% CI) (Non-FAS, No Exposure) | OR01 (95% CI) (FAS, Exposure) | OR11 (95% CI) (Non-FAS, Exposure) | RERI (95% CI) | AP (95% CI) | S (95% CI) |
---|---|---|---|---|---|---|---|
Maternal disease † | |||||||
Fever | 1.00 | 1.53 (1.37–1.72) | 1.08 (0.58–2.00) | 4.30 (3.08–6.01) | 2.69 (1.18–4.21) | 0.63 (0.43–0.82) | 5.43 (1.65–17.83) |
Viral infection | 1.00 | 1.50 (1.34–1.69) | 1.97 (1.42–2.73) | 4.73 (3.85–5.80) | 2.26 (1.22–3.29) | 0.48 (0.32–0.64) | 2.53 (1.56–4.10) |
Gestational hypertension | 1.00 | 1.56 (1.39–1.75) | 1.82 (0.65–5.15) | 3.05 (1.92–4.85) | 0.67 (−1.67–3.00) | 0.22 (−0.49–0.93) | 1.48 (0.32–6.79) |
Threatened abortion | 1.00 | 1.52 (1.36–1.71) | 1.33 (0.92–1.91) | 3.08 (2.43–3.90) | 1.23 (0.43–2.03) | 0.40 (0.20–0.60) | 2.45 (1.27–4.73) |
Reproductive history | |||||||
Previous pregnancy with birth defect | 1.00 | 1.40 (1.23–1.58) | 4.49 (0.96–21.05) | 9.78 (4.83–19.82) | 4.90 (−4.83–14.63) | 0.00 (−0.29–1.29) | 2.26 (0.32–15.8) |
Spontaneous/elective abortion history | 1.00 | 1.39 (1.22–1.57) | 1.17 (0.86–1.58) | 1.80 (1.49–2.18) | 0.24 (−0.20–0.69) | 0.14 (−0.10–0.37) | 1.44 (0.69–3.00) |
Maternal lifestyle and environmental factors | |||||||
Alcohol consumption † | 1.00 | 1.57 (1.40–1.76) | 8.23 (1.02–66.39) | 2.28 (1.34–3.90) | −6.51 (−23.72–10.7) | −2.85 (−10.63–4.92) | 0.16 (0.02–1.80) |
Active smoking † | 1.00 | 1.40 (1.24–1.59) | 1.23 (0.23–6.66) | 1.77 (1.01–3.09) | 1.43 (−2.17–5.02) | 0.47 (0.09–0.84) | 3.25 (1.07–9.86) |
Living in newly renovated home ‡ | 1.00 | 1.54 (1.38–1.73) | 0.87 (0.39–1.93) | 3.92 (2.89–5.32) | 2.51 (1.19–3.84) | 0.64 (0.44–0.84) | 7.14 (1.20–42.34) |
Residing within 50 m of a high traffic roadway ‡ | 1.00 | 1.56 (1.39–1.75) | 1.07 (0.75–1.54) | 1.70 (1.46–1.99) | 0.07 (−0.36–0.50) | 0.04 (−0.21–0.29) | 1.11 (0.57–2.17) |
Exposures | n | OR (95% CI) * |
---|---|---|
FAS + No risk factor exposure | 1381 | 1.00 (Reference) |
Non-FAS + Viral infection + Living in newly renovated home | 30 | 4.45 (1.74–11.40) |
Non-FAS + Viral infection + Threatened abortion | 42 | 4.87 (2.17–10.92) |
Non-FAS + Fever + Living in newly renovated home | 6 | 5.63 (0.61–52.35) |
Non-FAS + Threatened abortion + Living in newly renovated home | 94 | 6.19 (2.77–13.86) |
Non-FAS + Fever + Viral infection | 92 | 6.33 (3.47–11.56) |
Non-FAS + Fever + Threatened abortion | 17 | 7.19 (1.58–32.62) |
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Qu, Y.; Lin, S.; Bloom, M.S.; Wang, X.; Nie, Z.; Ou, Y.; Mai, J.; Gao, X.; Wu, Y.; Chen, J.; et al. First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring. Life 2021, 11, 724. https://doi.org/10.3390/life11080724
Qu Y, Lin S, Bloom MS, Wang X, Nie Z, Ou Y, Mai J, Gao X, Wu Y, Chen J, et al. First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring. Life. 2021; 11(8):724. https://doi.org/10.3390/life11080724
Chicago/Turabian StyleQu, Yanji, Shao Lin, Michael S. Bloom, Ximeng Wang, Zhiqiang Nie, Yanqiu Ou, Jinzhuang Mai, Xiangmin Gao, Yong Wu, Jimei Chen, and et al. 2021. "First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring" Life 11, no. 8: 724. https://doi.org/10.3390/life11080724
APA StyleQu, Y., Lin, S., Bloom, M. S., Wang, X., Nie, Z., Ou, Y., Mai, J., Gao, X., Wu, Y., Chen, J., Justino, J., Tan, H., Zhuang, J., & Liu, X. (2021). First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring. Life, 11(8), 724. https://doi.org/10.3390/life11080724