Reproductive health and pregnancy outcomes among French gulf war veterans

In late 1990 and early 1991, approximately 20,000 French troops were deployed in the First Gulf War. Since 1993, many studies on the health of Persian Gulf War veterans (PGWVs) have been undertaken, mainly in the USA and the UK. US and UK mortality studies have shown a lower mortality from all illnesses among Gulf War veterans in comparison to non-deployed veterans and an increased mortality from external causes consistent with patterns of postwar mortality observed in veterans of previous wars [1‐4]. Compared to non-deployed veterans, PGWVs have been reported to have no excess of recognized diseases [5‐17] but were 2–3 times more likely to report fatigue, cognitive difficulties, headaches, myalgia and arthralgia, mood disturbances, and sleep problems [5‐17].

Several studies have been conducted on reproductive outcomes [18‐31], mainly focused on pregnancy outcomes and birth defects [18‐25, 27, 29‐31], but no specific studies on spermatogenesis anomalies.

One study did not find any difference between the reproductive hormones measured in Gulf War veterans and in controls [24]. However, compared with non-deployed controls, Gulf War veterans had a significantly higher risk of reported infertility (OR: 1.4 to 1.5 according to the fertility type) [28] and a higher risk of self-reported sexual problems (OR: 3.5 – p < 0,001) [24].

Pregnancies fathered by Gulf War veterans took longer to conceive [28]. Conceptions of exposed and nondeployed veterans have similar outcomes [20, 23, 26], and no differences in pre-term deliveries are described [25, 29, 30]. Female Gulf War veterans had a higher risk of ectopic pregnancies than non-deployed veterans [20]. The increase of miscarriage or spontaneous abortion was not consistent between the different studies [20, 22‐26]. Compared with non-deployed veterans, Gulf War veterans reported the same risk of stillbirth [23, 25, 26] or infant mortality [25].

Most of the studies on the children of Gulf War veterans found no evidence of an increase in the risk of birth defects [18, 21, 22, 24, 29, 31] or congenital diseases [22, 24]. Some authors reported a higher prevalence of reported birth defects in babies of Gulf War veterans conceived after the Gulf War [22, 23, 25]. When looking at specific defects, only Araneta et al [19] observed a higher prevalence of renal agenesis and hypoplasia among children conceived postwar to GWV men, adjusted for prenatal alcohol exposure and intrauterine growth retardation. The other birth defects described (cardiac valve disorder among children conceived postwar to GWV men and hypospadias among children conceived postwar to GWV women) were no longer significant after adjustment for maternal parameters, branch of military service, and military rank [19].

For Doyle et al [32], there is no strong or consistent evidence in the literature of an effect of paternal service in the first Gulf War on the risk of major birth defects or stillbirth in offspring conceived after deployment, even if effects on specific rare defects cannot be excluded. There is some evidence of small increased risks of miscarriage or infertility associated with service, but the role of bias cannot be ruled out [32]. Finally, with regards to female veterans, firm conclusions cannot be drawn due to lack of sufficient information [32].

The present study reports findings relating to the reproductive outcome and health of offspring of French Gulf War veterans. The French Study on the Persian Gulf War and its Health Consequences is an exhaustive investigation into all French PGWVs conducted from 2002 to 2004. The aim of this descriptive study was, mainly, to examine self-reported symptom data among Gulf War veterans and to describe the main exposures reported in the theater, the symptoms and diseases that appeared during and after the Persian Gulf mission, and children's health.

In this study, 1% of the Gulf veterans reported fertility disorders and 12% of male veterans reported at least one miscarriage among their partners after the PGW mission. Overall, 4.2% of fathers reported at least one child born with a birth defect after the mission. No PGW-related exposure was associated with any birth defect in children fathered after the PGW mission. Concerning the reported health of children born after the PGW mission, 1.0% of children were born with pre-term delivery and 2.7% presented a birth defect. The main birth defects reported were musculoskeletal malformations (0.5%) and urinary system malformations (0.3%). Birth defect incidence in PGWV children conceived after the mission was similar to birth defect incidence described by the Paris Registry; except for Down syndrome, where the incidence in PGWV children was lower than the Paris Registry incidence.

Results are reported with several reservations. Although we sent out two reminders, our study did not have a high response rate, which suggests selective participation by respondents according to health outcome. The French Study on the Persian Gulf War and its Health Consequences aimed to be exhaustive, offering a free medical examination to all veterans provided by the French Government. The media in foreign countries gave massive coverage to complaints lodged due to the health consequences of the Gulf War, so respondents with health disorders, or at least worried about them, were more willing to participate in our study. However, this bias could be partly compensated for by the fact that 71% of respondents were still in service.

Data were gathered retrospectively and were based on veterans' self-reported data and were not validated against medical records for healthy veterans or their children. However, it is probable that symptoms or serious diseases requiring specific care or of unusual frequency or intensity were reported more often than events considered as slight or benign.

Recall bias can be a serious problem in case-control studies; when pre-recorded written exposure information is unavailable, controls with identical stimuli should be selected (e. g. a control series of children with malformations other than the one under study) [38]. We conducted a case-control study including controls matched for age and who reported one hospitalization for at least one symptom in order to minimize the recall bias.

A direct relationship of birth defects to characteristics of the PGW mission could not be shown because i) data were collected retrospectively on a 10-year period, ii) information was based on the declarations of the PGW veterans (most were men, with no information on the children's mother), and iii) this study can only highlight associations between exposures and diseases and not evidence. Moreover, many children were conceived long after the war itself, personal risk factors (i.e., family history or history of another child with a birth defect) were not examined, and there is a potential for misreporting. No information was available on the use of medication. Results must be interpreted with caution due to the small number of case children for specific birth defects. Despite these major limitations, frequencies shown in French PGWVs were similar to frequencies in the French general population, except for the low frequency of Down syndrome. In our study, dates of birth of the unaffected children were not available and fathers' ages at birth were not known. However, 82% of fathers were 25 to 35 years old during the period covered by the study. Paternal age is related to maternal age and the risk of infecundity, miscarriage, and birth defects seems to increase with paternal age [39, 40]. In the registry, 22% of mothers were above 35 years of age [37]. The analysis could not be controlled for mothers' age or parity.

The results of fertility studies on Gulf War veterans are controversial. The first studies published [24, 28] did not find any effect of Gulf War service on markers of male fertility (hormone measurements, oligospermia, azoospermia, asthenospermia, teratospermia, sexual problems). However, some authors described an increased risk of infertility reaching 7% to 14% [25, 26], mainly due to an increase of teratospermia and oligoasthenospermia [28]. The low estimation (0.9%) in our study could be explained by the self-reported infertility data collected in this study. Besides these sperm anomalies, pregnancies fathered by PGWVs seemed to take longer to conceive [27].

Authors reported an increased risk of miscarriage among partners of PGWVs, compared to a control group [22, 23, 25‐27], ranging from 12% to 60% among first pregnancies conceived after the PGW mission [25]. In our study, this miscarriage rate was 12% after the mission.

Concerning children's health in our study, the frequency of pre-term delivery (1.0%) was lower than frequencies described in other studies on PGW veterans (ranging from 0.6% to 10.9%) [18, 19, 23, 25, 26, 30].

In our study, the frequency of birth defects was slightly lower (2.7%) than the frequencies described in other studies (ranging from 3.6 to 9.0%) [21‐23, 25, 26]. The rate of birth defects among the French general population is estimated at 3.2% of all births for the period 1981–2000 [37]. No specific birth defect was highlighted in our study. Moreover, as one hypothesis was that wartime exposures adversely affected spermatogenesis, it was therefore reasonable to evaluate conceptions that occurred 70–90 days after leaving the war environment. The assessment of conceptions that occurred 3–10 years after the PGW mission would be more a reflection of non-war exposures and advanced paternal age than of distant wartime exposures. Since the number of live births per year was not available, in order to show a statistical difference between the birth defect rates of each of the two periods (1991–1992 vs 1993–2001), we estimated by simulation that fewer than 700 live births were needed in 1991–1992 (i.e. 13% of all children born after the PGW mission). However, this figure did not seem plausible in view of the context (a return home after an overseas mission). Specific birth defect frequencies were lower in our study than frequencies described by Doyle [22] in UK PGWVs: malformations of the musculoskeletal system (8.0‰ in Doyle's study vs 4.6‰ in our study), or malformations of the urinary system (4.9‰ in Doyle's study vs 3.5‰ in our study). The frequency of renal anomalies (1.4‰) was similar to that described by Araneta [19] in US PGWVs (1.1‰), and chromosomal anomalies were similar to those previously described (2.7‰ in our study, 0.2‰ to 2.6‰ in the literature) [19, 25]. Since 1970, the increase in malformations of the urinary, central nervous, and cardiac systems could be explained by the widespread use of ultrasound, (particularly in antenatal diagnosis), which can identify malformations even without clinical symptomatology.

A combination of genetic and environmental factors may be responsible for 20 to 25% of congenital anomalies [41]. US Gulf veterans were exposed to many chemical, biological, and physical agents suspected of being reproductive toxins [42]. Constant infertility over time of UK veterans, described by Maconochie [28], argues in favor of either paternal germ cell mutation or other damage to spermatogenic stem cells necessary for supporting spermatogenesis. Combined exposure to pyridostigmine bromide, the insect repellent DEET, and the insecticide permethrin seemed to induce apoptosis in rat testicular germ cells, Sertoli cells, and Leydig cells [43]. However, Arfsten [44] showed that implantation of depleted uranium in adult rats does not have an adverse impact on male reproductive success, sperm concentration, or sperm velocity. Our case-control analysis did not highlight the role of PGW-related exposures in birth defects among PGWV children.

In conclusion, this study found the same frequencies of fertility disorders, miscarriage, and health disorders among PGWV children as those described among foreign PGWVs and the French general population. No PGW-related exposure was associated with any birth defect in children fathered after the PGW mission. Our findings are limited by the reliability of self-reported data concerning exposures and health and pregnancy outcomes. This study highlights the importance of prospective data collection for exposures during future foreign operations and epidemiological surveillance of servicemen and women.

However, if the fertility disorders and birth defects remain constant over time, a more detailed and focused survey would be required to examine fertility and other aspects of reproduction more thoroughly.