Infertility among male UK veterans of the 1990-1 Gulf war: reproductive cohort study
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《英国医生杂志》
1 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT
Correspondence to: N Maconochie noreen.maconochie@lshtm.ac.uk
Abstract
In late 1990 and early 1991 around 53 000 UK armed service personnel were deployed to the Gulf war. Compared with the many reports on adult health after service in the Gulf, relatively few epidemiological studies have been conducted on reproductive outcomes.1-9 Only two of these studies specifically examined infertility.5 8 The first study found no difference between Danish Gulf veterans and non-veterans in any of the reproductive hormones measured or with respect to fertility or adverse outcomes of pregnancy.5 The second study found that Australian Gulf veterans were more likely than non-veterans to report difficulties with fertility but were subsequently more likely to father a pregnancy, perhaps because more sought treatment.8 In both these studies, expected numbers were very small and power consequently low.
We now report findings relating to infertility from the only epidemiological survey of reproductive outcomes among UK Gulf veterans. Analyses of fetal death and congenital malformation have been reported elsewhere.9
Methods
Study population
In total, 10 465 Gulf veterans and 7376 non-Gulf veterans who had conceived or attempted to conceive a child after the Gulf war satisfied the eligibility criteria. Year of first post-Gulf conception or attempted conception was similar in the two groups (table 1).
Table 1 Characteristics of men included in the analysis. Values are numbers (percentages) unless stated otherwise
Infertility
Seven hundred and thirty two (7%) Gulf veterans and 370 (5%) non-Gulf veterans had consulted a doctor for fertility problems arising since the Gulf war (odds ratio 1.38, 95% confidence interval 1.20 to 1.60). More than 60% (n = 721) of these men had succeeded in fathering one or more pregnancy, and more than 50% (n = 580) had fathered one or more live birth by the time of survey (table 1). Prevalence of type I infertility was 2.5% (n = 259) in Gulf veterans and 1.7% (n = 122) in non-Gulf veterans; the equivalent figures for type II infertility were 3.4% (n = 356) and 2.3% (n = 166). For most men, this was primary infertility; only 45 (17%) Gulf veterans and 27 (22%) non-Gulf veterans with type I infertility had fathered one or more pregnancies before the war (table 1).
Among all participants reporting fertility problems we found no difference between Gulf veterans and non-Gulf veterans in total time trying unsuccessfully for a child—66% in each group (452/690 and 234/353) reported trying for more than two years (P = 0.80) (not tabulated). Nor did we find a difference in length of time between first trying for a pregnancy and consulting a doctor (mean 14.0 (SD 0.41) months among Gulf veterans and 13.6 (0.57) months among non-Gulf veterans, P = 0.53) (not tabulated). Slightly fewer Gulf veterans reported in vitro fertilisation or intracytoplasmic sperm injection treatment than non-Gulf veterans (107 (15%) 60 (16%)), but this difference was not statistically significant (P = 0.49) (not tabulated).
Table 2 describes the characteristics of men reporting type I infertility. Around 38% (n = 144) were diagnosed as having one or more male infertility factor; 26% (n = 67) of Gulf veterans and 25% (n = 30) of non-Gulf veterans had a male factor alone. The proportions with a clear diagnosis of female infertility were similar in the two groups (44% (n = 114) in Gulf veterans, 40% (n = 49) in non-Gulf veterans; P = 0.73 for difference).
Table 2 Characteristics of men classified as having type I infertility since Gulf war*. Values are numbers (percentages), percentages clinically confirmed
Type I infertility was higher among Gulf veterans (odds ratio 1.41, 95% confidence interval 1.05 to 1.89); the effect was stronger for type II infertility (odds ratio 1.50, 1.18 to 1.89) (table 3). The effect did not vary with time since the war (P values for interaction 1.00 for type 1 infertility and 0.56 for type II infertility) or with whether the infertility was primary (no previous conceptions) or secondary (P values for interaction 0.83 for type I and 0.82 for type II).
Table 3 Reported prevalence of infertility* after Gulf war. Values are numbers (percentages) unless stated otherwise
We found only weak evidence of an association of Gulf war service with a general diagnosis of male factor infertility (odds ratio for type I infertility 1.18, 0.68 to 2.03), though the effect was slightly stronger for type II infertility (odds ratio 1.45, 0.98 to 2.14) (table 3). Evidence was stronger for a more specific effect on risk of teratospermia (odds ratios 2.02, 0.79 to 5.14 for type I; 2.55, 1.03 to 6.30 for type II), and an association was also suggested between Gulf war service and risk of oligoasthenoteratospermia. The numbers of cases were, however, extremely small. Analyses using only clinically verified cases produced very similar results (table 4).
Table 4 Prevalence of infertility* after Gulf war—clinically confirmed cases only. Values are numbers (percentages) unless stated otherwise
We examined risk of infertility in relation to four self reported Gulf war exposures (vaccination against anthrax or plague, nerve agent pretreatment sets, depleted uranium, and pesticides) (table 5). A high proportion of men could not recall or did not know their exposure. Overall, the analyses revealed little or no evidence of an increased risk of infertility in relation to any specific exposure. We found some suggestion of an association between vaccination against anthrax or plague and infertility, particularly where a male factor was diagnosed, but numbers of unexposed cases for these analyses were extremely small, and all confidence intervals included 1.00.
Table 5 Exposures during the Gulf war—male Gulf veterans only
Time to pregnancy
The 9733 Gulf veterans and 7006 non-Gulf veterans who did not have fertility problems had fathered 15 593 and 11 023 pregnancies respectively since the Gulf war (table 6). Pregnancies fathered by Gulf veterans were more often reported as unplanned (adjusted odds ratio 1.12, 1.05 to 1.19). Among planned pregnancies, those fathered by Gulf veterans took longer to conceive; 9.1% (845) took more than a year compared with 7.8% (528) of those fathered by non-Gulf veterans (adjusted odds ratio 1.18, 1.04 to 1.34).
Table 6 Pregnancies fathered by Gulf war veterans (n=9733) and non-Gulf war veterans (n=7006) not reporting fertility problems. Values are numbers (percentages) unless stated otherwise
Discussion
Penman AD, Currier MM, Tarver RS. No evidence of increase in birth defects and health problems among children born to Persian Gulf veterans in Mississippi. Mil Med 1996;161: 1-6.
Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. The risk of birth defects among children of Persian Gulf veterans. N Engl J Med 1997;336: 1650-6.
Araneta MRG, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, et al. Goldenhar syndrome among infants born in military hospitals to Gulf veterans. Teratology 1997;56: 244-51.
Health study of Canadian forces personnel involved in the 1991 conflict in the Persian Gulf.Vol1. Canadian Department of National Defence, 1998. (Prepared for the Gulf War Illness Advisory Committee, Department of National Defence, by Goss Gilroy Inc. Management Consultants.) www.dnd.ca/site/reports/Health/vol1_TOC_e.htm (accessed 10 May 2004).
Ishoy T, Andersson AM, Suadicani P, Guldager B, Appleyard M. Major reproductive health characteristics in male Gulf veterans. Dan Med Bull 2001;48: 29-32.
Kang H, Magee C, Mahan C, Lee K, Murphy F, Jackson L, et al. Pregnancy outcomes among U.S. Gulf veterans: a population-based survey of 30,000 veterans. Ann Epidemiol 2001;11: 504-11.
Araneta MR, Schlangen KM, Edmonds LD, Destiche DA, Merz RD, Hobbs CA, et al. Prevalence of birth defects among infants of Gulf veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989-1993. Birth Defects Res Part A Clin Mol Teratol 2003;67: 246-60.
Sim M, Abramson M, Forbes A, Glass D, Ikin J, Ittak P, et al. Australian Gulf veterans' health study 2003. Vol 2. Commonwealth Department of Veterans' Affairs, 2003. www.dva.gov.au/media/publicat/2003/gulfwarhs (accessed 10 May 2004).
Doyle P, Maconochie N, Davies G, Maconochie I, Pelerin M, Prior S, et al. Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf war. Int J Epidemiol 2004;33: 74-86.
Maconochie N, Doyle P, Davies G, Lewis S, Pelerin M, Prior S, et al. The study of reproductive outcome and the health of offspring of UK veterans of the Gulf war: methods and description of the study population. BMC Public Health 2003;3: 4.
World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge, UK: Cambridge University Press on behalf of WHO, 1992.
Breslow NE, Day NE. Statistical methods in cancer research. Vol II. The analysis of cohort studies. Lyon: International Agency for Research on Cancer, 1980.
Huber PJ. The behaviour of maximum likelihood estimates under non-standard conditions. In: Proceedings of the fifth Berkeley symposium on mathematical statistics and probability. Berkley, CA: University of California Press, 1967;1: 221-33.
Korn EL, Graubard BI. Simultaneous testing of regression coefficients with complex data: use of Bonferoni t statistics. Am Stat 1990;44: 270-6.
Abou-Donia MB, Suliman HB, Khan WA, Abdel-Rahman AA. Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N-diethyl m-toluamide (DEET) and permethrin. J Toxicol Environ Health A. 2003;66: 57-73.
Military Health Research Advisory Group (MHRAG). MRC review of research into UK Gulf veterans' illnesses 2003. London: Medical Research Council, 2003. www.mrc.ac.uk/pdf-gulf-illness-review.pdf (10 May 2004).(Noreen Maconochie, senior)
Correspondence to: N Maconochie noreen.maconochie@lshtm.ac.uk
Abstract
In late 1990 and early 1991 around 53 000 UK armed service personnel were deployed to the Gulf war. Compared with the many reports on adult health after service in the Gulf, relatively few epidemiological studies have been conducted on reproductive outcomes.1-9 Only two of these studies specifically examined infertility.5 8 The first study found no difference between Danish Gulf veterans and non-veterans in any of the reproductive hormones measured or with respect to fertility or adverse outcomes of pregnancy.5 The second study found that Australian Gulf veterans were more likely than non-veterans to report difficulties with fertility but were subsequently more likely to father a pregnancy, perhaps because more sought treatment.8 In both these studies, expected numbers were very small and power consequently low.
We now report findings relating to infertility from the only epidemiological survey of reproductive outcomes among UK Gulf veterans. Analyses of fetal death and congenital malformation have been reported elsewhere.9
Methods
Study population
In total, 10 465 Gulf veterans and 7376 non-Gulf veterans who had conceived or attempted to conceive a child after the Gulf war satisfied the eligibility criteria. Year of first post-Gulf conception or attempted conception was similar in the two groups (table 1).
Table 1 Characteristics of men included in the analysis. Values are numbers (percentages) unless stated otherwise
Infertility
Seven hundred and thirty two (7%) Gulf veterans and 370 (5%) non-Gulf veterans had consulted a doctor for fertility problems arising since the Gulf war (odds ratio 1.38, 95% confidence interval 1.20 to 1.60). More than 60% (n = 721) of these men had succeeded in fathering one or more pregnancy, and more than 50% (n = 580) had fathered one or more live birth by the time of survey (table 1). Prevalence of type I infertility was 2.5% (n = 259) in Gulf veterans and 1.7% (n = 122) in non-Gulf veterans; the equivalent figures for type II infertility were 3.4% (n = 356) and 2.3% (n = 166). For most men, this was primary infertility; only 45 (17%) Gulf veterans and 27 (22%) non-Gulf veterans with type I infertility had fathered one or more pregnancies before the war (table 1).
Among all participants reporting fertility problems we found no difference between Gulf veterans and non-Gulf veterans in total time trying unsuccessfully for a child—66% in each group (452/690 and 234/353) reported trying for more than two years (P = 0.80) (not tabulated). Nor did we find a difference in length of time between first trying for a pregnancy and consulting a doctor (mean 14.0 (SD 0.41) months among Gulf veterans and 13.6 (0.57) months among non-Gulf veterans, P = 0.53) (not tabulated). Slightly fewer Gulf veterans reported in vitro fertilisation or intracytoplasmic sperm injection treatment than non-Gulf veterans (107 (15%) 60 (16%)), but this difference was not statistically significant (P = 0.49) (not tabulated).
Table 2 describes the characteristics of men reporting type I infertility. Around 38% (n = 144) were diagnosed as having one or more male infertility factor; 26% (n = 67) of Gulf veterans and 25% (n = 30) of non-Gulf veterans had a male factor alone. The proportions with a clear diagnosis of female infertility were similar in the two groups (44% (n = 114) in Gulf veterans, 40% (n = 49) in non-Gulf veterans; P = 0.73 for difference).
Table 2 Characteristics of men classified as having type I infertility since Gulf war*. Values are numbers (percentages), percentages clinically confirmed
Type I infertility was higher among Gulf veterans (odds ratio 1.41, 95% confidence interval 1.05 to 1.89); the effect was stronger for type II infertility (odds ratio 1.50, 1.18 to 1.89) (table 3). The effect did not vary with time since the war (P values for interaction 1.00 for type 1 infertility and 0.56 for type II infertility) or with whether the infertility was primary (no previous conceptions) or secondary (P values for interaction 0.83 for type I and 0.82 for type II).
Table 3 Reported prevalence of infertility* after Gulf war. Values are numbers (percentages) unless stated otherwise
We found only weak evidence of an association of Gulf war service with a general diagnosis of male factor infertility (odds ratio for type I infertility 1.18, 0.68 to 2.03), though the effect was slightly stronger for type II infertility (odds ratio 1.45, 0.98 to 2.14) (table 3). Evidence was stronger for a more specific effect on risk of teratospermia (odds ratios 2.02, 0.79 to 5.14 for type I; 2.55, 1.03 to 6.30 for type II), and an association was also suggested between Gulf war service and risk of oligoasthenoteratospermia. The numbers of cases were, however, extremely small. Analyses using only clinically verified cases produced very similar results (table 4).
Table 4 Prevalence of infertility* after Gulf war—clinically confirmed cases only. Values are numbers (percentages) unless stated otherwise
We examined risk of infertility in relation to four self reported Gulf war exposures (vaccination against anthrax or plague, nerve agent pretreatment sets, depleted uranium, and pesticides) (table 5). A high proportion of men could not recall or did not know their exposure. Overall, the analyses revealed little or no evidence of an increased risk of infertility in relation to any specific exposure. We found some suggestion of an association between vaccination against anthrax or plague and infertility, particularly where a male factor was diagnosed, but numbers of unexposed cases for these analyses were extremely small, and all confidence intervals included 1.00.
Table 5 Exposures during the Gulf war—male Gulf veterans only
Time to pregnancy
The 9733 Gulf veterans and 7006 non-Gulf veterans who did not have fertility problems had fathered 15 593 and 11 023 pregnancies respectively since the Gulf war (table 6). Pregnancies fathered by Gulf veterans were more often reported as unplanned (adjusted odds ratio 1.12, 1.05 to 1.19). Among planned pregnancies, those fathered by Gulf veterans took longer to conceive; 9.1% (845) took more than a year compared with 7.8% (528) of those fathered by non-Gulf veterans (adjusted odds ratio 1.18, 1.04 to 1.34).
Table 6 Pregnancies fathered by Gulf war veterans (n=9733) and non-Gulf war veterans (n=7006) not reporting fertility problems. Values are numbers (percentages) unless stated otherwise
Discussion
Penman AD, Currier MM, Tarver RS. No evidence of increase in birth defects and health problems among children born to Persian Gulf veterans in Mississippi. Mil Med 1996;161: 1-6.
Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. The risk of birth defects among children of Persian Gulf veterans. N Engl J Med 1997;336: 1650-6.
Araneta MRG, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, et al. Goldenhar syndrome among infants born in military hospitals to Gulf veterans. Teratology 1997;56: 244-51.
Health study of Canadian forces personnel involved in the 1991 conflict in the Persian Gulf.Vol1. Canadian Department of National Defence, 1998. (Prepared for the Gulf War Illness Advisory Committee, Department of National Defence, by Goss Gilroy Inc. Management Consultants.) www.dnd.ca/site/reports/Health/vol1_TOC_e.htm (accessed 10 May 2004).
Ishoy T, Andersson AM, Suadicani P, Guldager B, Appleyard M. Major reproductive health characteristics in male Gulf veterans. Dan Med Bull 2001;48: 29-32.
Kang H, Magee C, Mahan C, Lee K, Murphy F, Jackson L, et al. Pregnancy outcomes among U.S. Gulf veterans: a population-based survey of 30,000 veterans. Ann Epidemiol 2001;11: 504-11.
Araneta MR, Schlangen KM, Edmonds LD, Destiche DA, Merz RD, Hobbs CA, et al. Prevalence of birth defects among infants of Gulf veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989-1993. Birth Defects Res Part A Clin Mol Teratol 2003;67: 246-60.
Sim M, Abramson M, Forbes A, Glass D, Ikin J, Ittak P, et al. Australian Gulf veterans' health study 2003. Vol 2. Commonwealth Department of Veterans' Affairs, 2003. www.dva.gov.au/media/publicat/2003/gulfwarhs (accessed 10 May 2004).
Doyle P, Maconochie N, Davies G, Maconochie I, Pelerin M, Prior S, et al. Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf war. Int J Epidemiol 2004;33: 74-86.
Maconochie N, Doyle P, Davies G, Lewis S, Pelerin M, Prior S, et al. The study of reproductive outcome and the health of offspring of UK veterans of the Gulf war: methods and description of the study population. BMC Public Health 2003;3: 4.
World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge, UK: Cambridge University Press on behalf of WHO, 1992.
Breslow NE, Day NE. Statistical methods in cancer research. Vol II. The analysis of cohort studies. Lyon: International Agency for Research on Cancer, 1980.
Huber PJ. The behaviour of maximum likelihood estimates under non-standard conditions. In: Proceedings of the fifth Berkeley symposium on mathematical statistics and probability. Berkley, CA: University of California Press, 1967;1: 221-33.
Korn EL, Graubard BI. Simultaneous testing of regression coefficients with complex data: use of Bonferoni t statistics. Am Stat 1990;44: 270-6.
Abou-Donia MB, Suliman HB, Khan WA, Abdel-Rahman AA. Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N-diethyl m-toluamide (DEET) and permethrin. J Toxicol Environ Health A. 2003;66: 57-73.
Military Health Research Advisory Group (MHRAG). MRC review of research into UK Gulf veterans' illnesses 2003. London: Medical Research Council, 2003. www.mrc.ac.uk/pdf-gulf-illness-review.pdf (10 May 2004).(Noreen Maconochie, senior)