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Paternal exposure to Agent Orange and spina bifida: a meta-analysis

  • REPRODUCTIVE EPIDEMIOLOGY
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Abstract

The objective of this study is to conduct a meta-analysis of published and unpublished studies that examine the association between Agent Orange (AO) exposure and the risk of spina bifida. Relevant studies were identified through a computerized literature search of Medline and Embase from 1966 to 2008; a review of the reference list of retrieved articles and conference proceedings; and by contacting researchers for unpublished studies. Both fixed-effects and random-effects models were used to pool the results of individual studies. The Cochrane Q test and index of heterogeneity (I 2) were used to evaluate heterogeneity, and a funnel plot and Egger’s test were used to evaluate publication bias. Seven studies, including two Vietnamese and five non-Vietnamese studies, involving 330 cases and 134,884 non-cases were included in the meta-analysis. The overall relative risk (RR) for spina bifida associated with paternal exposure to AO was 2.02 (95% confidence interval [CI]: 1.48–2.74), with no statistical evidence of heterogeneity across studies. Non-Vietnamese studies showed a slightly higher summary RR (RR = 2.22; 95% CI: 1.38–3.56) than Vietnamese studies (RR = 1.92 95% CI: 1.29–2.86). When analyzed separately, the overall association was statistically significant for the three case–control studies (Summary Odds Ratio = 2.25, 95% CI: 1.31–3.86) and the cross sectional study (RR = 1.97, 95% CI: 1.31–2.96), but not for the three cohort studies (RR: 2.11; 95% CI: 0.78–5.73). Paternal exposure to AO appears to be associated with a statistically increased risk of spina bifida.

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Abbreviations

AO:

Agent Orange

CDC:

Centers for disease control and prevention

CI:

Confidence interval

EOI:

Exposure opportunity index

OR:

Odds ratio

RR:

Relative risk

References

  1. Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS. Spina bifida. Lancet. 2004;364:1885–95.

    Article  PubMed  Google Scholar 

  2. Northrup H, Volcik KA. Spina bifida and other neural tube defects. Curr Probl Pediatr. 2000;30:313–32.

    Article  CAS  PubMed  Google Scholar 

  3. Institute of Medicine. Veterans and Agent Orange—update. Washington DC: National Academy Press; 2003.

    Google Scholar 

  4. Barker E, Saulino M, Caristo AM. Spina bifida. RN. 2002;65:33–8.

    PubMed  Google Scholar 

  5. Erickson JD, Mulinare J, McClain PW, et al. Vietnam veterans’ risks for fathering babies with birth defects. JAMA. 1984;252:903–12.

    Article  CAS  PubMed  Google Scholar 

  6. Centers for Disease Control. Health status of Vietnam veterans. III. Reproductive outcomes and child health. The Centers for Disease Control Vietnam Experience Study. JAMA. 1988;259:2715–9.

    Article  Google Scholar 

  7. Wolfe WH, Michalek JE, Miner JC, et al. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology. 1995;6:17–22.

    Article  CAS  PubMed  Google Scholar 

  8. Centers for Disease Control and Prevention. Vietnam veterans’ risks for fathering babies with birth defects. MMWR. 1984;33:457–9.

    Google Scholar 

  9. Ngo AD, Taylor R, Roberts CL, Nguyen TV. Association between Agent Orange and birth defects: systematic review and meta-analysis [see comment]. Int J Epidemiol. 2006;35:1220–30.

    Article  PubMed  Google Scholar 

  10. Stern J, Braburn MJ, Egger M, Smith GD, Altman DG. Meta-analysis in StataTM. In: Altman DG, editor. Systematic reviews in health care, meta-analysis in context. London: BMJ; 2001. p. 357.

    Google Scholar 

  11. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1995;22:719–48.

    Google Scholar 

  12. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control ClinTrials. 1986;7:177–88.

    Article  CAS  Google Scholar 

  13. Pettiti D, editor. Meta analysis, decision analysis and cost effectiveness analysis. New York: Oxford University Press; 1999.

    Google Scholar 

  14. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  15. Egger M, Davey SG, Schneider M, Minder CE. Bias in metaanalysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    CAS  PubMed  Google Scholar 

  16. del Junco DJ, Sweeney AM, Papke O. Paternal blood dioxin, CYP1A1 and nural tube defects in children of Vietnam Veterans. Houston: Texas A & M Health Science Center; 2006.

    Google Scholar 

  17. Donovan JW, MacLennan R, Adena M. Vietnam service and the risk of congenital anomalies. A case-control study. Med J Aus. 1984;140:394–7.

    CAS  Google Scholar 

  18. Can N, Xiem NT, Hong TT, Tong NK, Duong DB. An epidemiological survey of pregnancies in the North of Vietnam. In: Proceedings of the first international conference of Agent Orange/dioxin. 1983. Hanoi.

  19. Hung TM, Cuc PTK, Cau HD. Spina Bifida investigated by Spinal X-ray among children of veterans exposed to defoliant in the war in consequences of chemicals used in Vietnam war 1961–1971. Hanoi: 10–80 Committee; 2000. p. 50–9.

    Google Scholar 

  20. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301:636–50.

    Article  CAS  PubMed  Google Scholar 

  21. Institute of Medicine. Veterans and Agent Orange—update. Washington DC: National Academy Press; 2004.

    Google Scholar 

  22. Glass GV. Primary, secondary, and meta-analysis of research. Educ Res. 1976;5:3–8.

    Google Scholar 

  23. Glass CV. Integrating findings: the meta-analysis of research. Rev Res Educ. 1978;5:351–79.

    Google Scholar 

  24. Wolfe WH, Michalek JE, Miner JC, Rahe AJ. An epidemiologic investigation of health effects in air force personnel following exposure to herbicides. Armstrong: Epidemiology Research Division; 1992.

    Google Scholar 

  25. Knafl KJ, Schwartz, LS. Assessment of evidence for an impact of dioxin exposure on birth defects occurrence in offspring of Ranch Hand study participants. In: Third international conference of Agent Orange/dioxin. Hanoi; 2001.

  26. Hatch MC, Stein ZA. Agent Orange and risks to reproduction: the limits of epidemiology. Teratog Carcinog Mutagen. 1987;7:423–4.

    Article  CAS  PubMed  Google Scholar 

  27. Theobald HM, Peterson RE. Developmental and reproductive toxicity of dioxins and other ah receptor agonists. In: Schecter A, editor. Dioxin and health. New York: Plenum Press; 1984. p. 319–32.

    Google Scholar 

  28. Giri AK. Mutagenic and genotoxic effects of 2, 3, 7, 8- tetrachlorodibenzo-p-dioxin, a review. Mutat Res. 1986;168:241–8.

    CAS  PubMed  Google Scholar 

  29. Couture LA, Harris MW. Characterization of the peak period of sensitivity for the induction of hydronephrosis in C57BL/6N mice following exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol. 1990;15:142–50.

    Article  CAS  PubMed  Google Scholar 

  30. Nessel CS, Gallo MA, Lippmann M. Dioxins and related compounds. In: Lippmann M, editor. Environmental toxicants. New York: Van Nostrand Reinhold; 1992.

    Google Scholar 

  31. DeVito MJ, Birnbaum LS. Dioxins: model chemicals for assessing receptor-mediated toxicity. Toxicology. 1995;102:115–23.

    Article  CAS  PubMed  Google Scholar 

  32. Bryant PL, Reid LM, Schmid JE, Buckalew AR, Abbott BD. Effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) on fetal mouse urinary tract epithelium in vitro. Toxicology. 2001;162:34.

    Article  Google Scholar 

  33. Hansen DA. Parental environment exposures and gene expression during spermatogenesis: research review to research framework. Birth Defects Res Part C. 2008;84:155–63.

    Article  CAS  Google Scholar 

  34. Schultz R, Suominen J, Varre T. Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear transporter messenger ribonucleic acids and proteins in rat and human testis. Endocrinology. 2003;144:767–76.

    Article  CAS  PubMed  Google Scholar 

  35. Dwernychuk LW, Cau HD, Hatfield CT. Dioxin reservoirs in southern Viet Nam—a legacy of Agent Orange. Chemosphere. 2002;47:117–37.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Anh Duc Ngo.

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Ngo, A.D., Taylor, R. & Roberts, C.L. Paternal exposure to Agent Orange and spina bifida: a meta-analysis. Eur J Epidemiol 25, 37–44 (2010). https://doi.org/10.1007/s10654-009-9401-4

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