Theoretically at least (Colie 1993
; Schrader & Kesner 1993
; Skakkebaek et al. 1993
), exposure to one or more toxicants of the type thought to be present in the Gulf war could affect spermatogenesis, either temporarily through direct damage to spermatozoa, or more permanently through damage to the spermatogenic stem cells or testicular cells responsible for spermatogenesis. These effects would be manifest as increased levels of infertility. A laboratory-based study published in 2003 which reported extensive damage to rats' testes when given insecticides and NAPS of the type used in the Gulf War, which worsened when the rats were subjected to moderate levels of stress, would seem to strengthen this hypothesis (Abou-Donia et al. 2003
). Further plausibility arises from the adverse effect on semen quality seen among veterans of the Vietnam War (which included potential exposure to herbicides such as Agent Orange), such as an almost tripling in risk of poor sperm concentration (less than 20 million per ml) compared with a similar group of armed service personnel not deployed to Vietnam (DeStefano et al. 1989
). Despite demonstrating that depleted uranium (DU) mobilizes and translocates to the gonads in rats, and hence is potentially toxic to reproductive tissues (Domingo 2001
), studies of implanted DU in male rats have however found no evidence of a detrimental effect of DU on mating success, sperm concentration or sperm velocity (Arfsten et al. 2006
Only three epidemiological studies (Ishoy et al. 2001
; Sim et al. 2003
; Maconochie et al. 2004
) have specifically examined fertility in relation to Gulf War service in general, while a further set of overlapping surveillance studies have examined reproductive health in a small number of US GWV who were victims of ‘friendly fire’ involving DU weapons (McDiarmid et al. 2000
). These studies are summarized in . Notably, no studies have examined this outcome among US GWV in general.
Summary of published papers—infertility.
The first epidemiological study relating to fertility was an interview-based study of 661 male Danish GWVs and a matched comparison group of 215 military servicemen not deployed to the Gulf, which included taking a blood sample (Ishoy et al. 2001
). Semen samples were not taken, but instead reproductive hormones were used as serum markers of male reproductive health status. A serum inhibin B level of less than or equal to 80
combined with a serum follicle stimulating hormone (FSH) of greater than or equal to 10
was used as a validated indicator of oligospermia (sperm count less than 20 million per ml). The study found no difference between GWVs and controls with respect to any of the reproductive hormones measured, including the proportions with FSH and inhibin B levels indicating suspected oligospermia, which were identical (1.6%) in the two groups. Nor did the study find a difference in proportions reporting ‘treatment due to childlessness after 1990’ (2.8% in GWV versus 2.6% in NGWV, p
>0.05). No attempt was made to validate the self-reported reproductive histories, however, and expected numbers were small, hence power was consequently low.
The second study examined self-reported fertility status among Australian veterans, using a postal questionnaire. Among males who responded to the questionnaire and had achieved or tried to achieve conception since 1991 (1313 GWV and 1412 NGWV), GWV were slightly more likely than the comparison group to report difficulties with fertility (defined as difficulties fathering a pregnancy despite trying for at least 12 months) following the Gulf War. There was no evidence of a difference in identifying a cause of infertility, however, and GWV with reported fertility difficulties appeared more likely subsequently to father a successful pregnancy. This latter finding could be related to the fact that slightly more GWV sought treatment than NGWV (4.0% versus 3.3%), though since there was no clinical validation of the self-reported reproductive histories, the possibility of recall (reporting) bias is perhaps more likely, with NGWV being less likely to report fertility difficulties if they had subsequently fathered a liveborn child. Expected numbers for men in this study were also small and power consequently low. Among women, identical proportions (10%: three GWV, four NGWV) reported fertility difficulties commencing 1991 or later, but with only 32 (out of 38) female Australian GWV and 40 NGWV participating in the study, the numbers in analyses were too small to draw meaningful conclusions.
The largest epidemiological study of infertility in GWV was the UK study (Maconochie et al. 2004
), which examined failure to achieve any conceptions (type I infertility) or livebirths (type II infertility) after the Gulf War, having tried for more than 1 year and consulted a doctor, among 10
465 male UK GWV and 7376 NGWV who had fathered or tried to father pregnancies after the Gulf War. Time to conception among pregnancies fathered by men not reporting fertility problems was also examined. Again, this study used a self-administered postal questionnaire to obtain details of reproductive history, but unlike the other studies, an attempt was made to verify and obtain further information on all reported fertility problems, including diagnostic details and a copy of the semen analysis results, if available, by contacting both male and female partners' General Practitioner or relevant clinician. The study found a small increased risk of reported infertility associated with Gulf War service, which was strengthened when the definition was extended to include men reporting fertility problems who had fathered only pregnancies ending in foetal death. This effect was regardless of whether or not the men had fathered pregnancies before the war, and was constant over time, which argues in favour of either paternal germ cell mutation or other damage to spermatogenic stem cells or the testicular cells necessary for supporting spermatogenesis. Furthermore, the results were similar when analyses were restricted to clinically confirmed diagnoses. The evidence for an adverse effect of Gulf war service on fertility was also strengthened by the finding that pregnancies fathered by GWV not
reporting fertility problems also took longer to conceive.
These findings were consistent with the Australian study, but conflicted with that of Danish veterans. The UK study had a fairly low response rate (53% for GWV and 42% for NGWV), but a study of non-responders provided no evidence of bias with respect to infertility, the prevalence of (self-reported) infertility among GWV and NGWV being almost identical in responders and non-responders. Differential recall of infertility problems by GWV is a possibility in all three studies, and it could be argued that GWV had more incentive to report details relating to this highly sensitive issue, even if minor, if they perceived that it could be associated with their Gulf War service. The similarity in results when restricted to clinically confirmed infertility provides little evidence of this kind of biased reporting in the UK study, however.
Four rounds of medical surveillance (1994, 1997, 1999, 2001) have been conducted on a small number of US veterans exposed to DU during friendly fire incidents in the Gulf War when their vehicles were hit with munitions containing DU penetrators (McDiarmid et al. 2000
). The numbers participating at each time point varied in size, but all are extremely small, between 29 and 50 GWV. The four overlapping studies involved GWV only, comparing either DU-exposed GWV having high (greater than or equal to 10
creatinine) urinary uranium concentrations with DU-exposed GWV having low (less than 10
creatinine) urinary uranium concentrations (McDiarmid et al. 2000
), or DU-exposed GWV with non-DU-exposed GWV (McDiarmid et al. 2000
). Overall, despite persistent urine uranium elevations in these DU-exposed GWV for more than 10 years, no clinically significant difference in semen characteristics (volume, count, concentration) and motility was found between groups at any of the time points.
In conclusion, epidemiological evidence for an effect of Gulf war service on risk of infertility is sparse, and the majority of studies lack statistical power. In particular, the numbers of female GWV in the populations studied are too small to produce meaningful analyses. Nevertheless, evidence from animal studies suggests that the possibility of sperm damage resulting from exposure to toxicants of the type present in the 1991 Gulf War is at least plausible, and the Australian and UK studies provide some evidence of a consistent, if small, effect of Gulf War service on risk of infertility. This is strengthened by findings of increased time to conception among UK GWV not reporting fertility problems, and by previous findings of increased risk of miscarriage among pregnancies fathered by GWV, but the possibility of reporting bias cannot be ruled out. Overall, this is a difficult outcome to study, and the epidemiological evidence is too sparse to draw firm conclusions.