Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf war

Pat Doyle1, Noreen Maconochie1, Graham Davies1, Ian Maconochie2, Margo Pelerin3, Susan Prior1 and Samantha Lewis1

1 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
2 Department of Paediatric Accident and Emergency, St Mary's Hospital, London W2 1NY, UK
3 Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK

Correspondence: Dr Pat Doyle, Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. E-mail: pat.doyle{at}lshtm.ac.uk


    Abstract
 Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Objectives To assess whether the offspring of UK veterans of the first Gulf war are at increased risk of fetal death or congenital malformation.

Method This was a retrospective reproductive cohort study of UK Gulf war veterans and a demographically similar comparison group who were in service at the time but were not deployed to the Gulf. Reproductive history was collected by means of a validated postal questionnaire between 1998 and 2001.

Results In all, 27 959 pregnancies reported by men and 861 pregnancies reported by women were conceived after the first Gulf war and before November 1997. The risk of reported miscarriage was higher among pregnancies fathered by Gulf war veterans than by non-Gulf war veterans (OR = 1.4, 95% CI: 1.3, 1.5). Stillbirth risk was similar in both groups. Male Gulf war veterans reported a higher proportion of offspring with any type of malformation than the comparison cohort (OR = 1.5, 95% CI: 1.3, 1.7). Examination by type of malformation revealed some evidence for increased risk of malformations of the genital system, urinary system (renal and urinary tract), and ‘other’ defects of the digestive system, musculo-skeletal system, and non-chromosomal (non-syndrome) anomalies. These associations were weakened when analyses were restricted to clinically confirmed conditions. There was little or no evidence of increased risk for other structural malformations, specific syndromes, and chromosomal anomalies. Among female veterans, no effect of Gulf war service was found on the risk of miscarriage. The numbers of stillbirths and malformations reported by women were too small to allow meaningful analyses.

Conclusion We found no evidence for a link between paternal deployment to the Gulf war and increased risk of stillbirth, chromosomal malformations, or congenital syndromes. Associations were found between fathers' service in the Gulf war and increased risk of miscarriage and less well-defined malformations, but these findings need to be interpreted with caution as such outcomes are susceptible to recall bias. The finding of a possible relationship with renal anomalies requires further investigation. There was no evidence of an association between risk of miscarriage and mothers' service in the gulf.


Keywords Gulf war, miscarriage, stillbirth, congenital malformation

Accepted 14 October 2003

In late 1990 and early 1991 the UK deployed over 53 000 armed service personnel to the first Gulf war. Subsequent media reports of apparent clusters of birth defects among children of Gulf war veterans (GWV) raised concern about possible prenatal effects of hazardous exposures during the war.1–4 A report by the US General Accounting Office in 1994 identified 21 potential reproductive toxicants present during the Gulf war.5 In addition, a high proportion of deployed personnel were exposed to multiple vaccinations, including those for plague and anthrax, and some also took pyridostigmine bromide (anti-chemical warfare nerve agent prophylaxis, or NAPS) tablets.

Compared with the many reports on adult health following service in the Gulf, relatively few epidemiological studies have been conducted on reproductive outcome.6–14 The first published report found no marked physiological or psychological impairment, or excess congenital malformations, in the children of Mississippi National Guardsmen deployed to the Gulf war.6 However, the numbers in this study were small (children of <300 men) and there was no armed service comparison group. A comparison of the prevalence of birth defects among over 80 000 children born to USA GWV and non-Gulf veterans (NGWV) found no differences in the prevalence of major birth defects diagnosed at birth.7 Although large and with a suitable control group, this study was of live births only and did not include infants born in non-military hospitals.8

Media reports of increased numbers of infants suffering with Goldenhar syndrome (characterized by abnormal development of facial structures) born to GWV led to an in-depth study of US military hospital discharge data.9 The prevalence of likely cases of Goldenhar syndrome was higher in GWV compared with NGWV, but the numbers with this rare condition were small (seven cases overall) and the difference was not statistically significant. In an attempt to address criticism that previous studies of birth defects in the US excluded children born in non-military hospitals, in particular children born to parents who had left the armed services, a large study linking routinely collected state-wide birth defects surveillance data to military databases was undertaken. For the state of Hawaii prevalence of the 48 birth defects studied was found to be similar for children of GWV and NGWV, and also for GWV infants who were conceived before and after the Gulf War.10 But when data for six states were combined, a higher prevalence of specific heart defects in infants conceived post-war by GWV fathers, and of hypospadias in infants conceived by GWV mothers, compared with infants conceived by NGWV parents was found.11 This study also reported a higher prevalence of aortic valve stenosis and renal agenesis or hypoplasia in infants conceived by GWV fathers after the war compared with that in infants conceived by GWV fathers before the war.11 However, as noted by the authors, this study involved multiple testing and the role of chance in these findings could not be ruled out.

Another study from the US was a large postal survey of health and reproductive outcome in over 30 000 GWV and NGWV.12 Higher rates of miscarriage, and to some extent stillbirth, were reported in the first pregnancies conceived after the Gulf war by both male and female veterans compared with a non-deployed group. This study also found higher reported rates of congenital malformation in liveborn children of both male and female Gulf veterans. The authors concluded that the risk of birth defects was significantly associated with military service in the Gulf War, but noted that self-reported conditions needed to be confirmed to rule out possible reporting bias.

Three non-US studies of reproductive outcome in relation to military service in the Gulf war have been published to date. The first was an anonymous health survey of over 6500 Canadian veterans, finding higher rates of congenital anomalies in the children of GWV than the children of NGWV.13 However, GWV reported higher rates for children born before, during and after the Gulf War, as well as a higher proportion of minor anomalies, indicating possible biased reporting. The proportion of pregnancies ending in spontaneous abortion was also higher for pregnancies conceived by GWV than by NGWV, but post-war rates were not reported separately. Rates of stillbirth did not differ between pregnancies conceived by GWV and NGWV.13 The second study was an interview-based study of the reproductive outcomes of 661 male Danish GWV and 215 NGWV.14 No evidence of an increase in prevalence of congenital malformations in the offspring reported by the two groups was found. Finally, the recent Australian veteran's health report did not find increased adverse pregnancy outcome in 1448 pregnancies reported by GWV and 1555 pregnancies by NGWV.15

We now report findings from the first epidemiological survey of reproductive outcome and the health of offspring of UK GWV. It is also the first large study of reproductive health in veterans of the first Gulf war to investigate congenital malformations in late fetal deaths and medical terminations in live births, and to attempt medical confirmation of all reported congenital malformations.


    Methods
 Top
 Abstract
 Methods
 Results
 Discussion
 References
 
The survey
This was a retrospective cohort study of reproduction and pregnancy outcome. Information about the study is reported in detail elsewhere.16 In brief, the Gulf cohort consisted of all UK armed services personnel who served in the Gulf area at some time between August 1990 and June 1991. The randomly selected comparison cohort comprised a similar number of armed services personnel who were in service on 1 January 1991 and were appropriately fit but were not deployed to the Gulf (NGWV). This group was stratum-matched to the GWV on Service (Royal Navy [RN], Army, and Royal Air Force [RAF]), sex, age (in 5-year groups), serving status at the time of the Gulf war (regular, reservist), and rank (officer, other ranks). The Ministry of Defence (MoD) supplied name, date of birth, sex, Service, date of joining and leaving (for discharged personnel) the armed forces, and last known address for all surviving cohort members. The total number of eligible people in the cohorts was 52 811 GWV and 52 924 NGWV.

Data collection was by means of a postal questionnaire which the authors had developed in previous large-scale cohort studies of reproductive outcome.17–19 From August 1998 packages containing a questionnaire and accompanying information leaflet were sent to both in-service and discharged personnel. Up to two reminders were sent to each new address after 6 weeks had elapsed, with mailing continuing to 2001. In order to promote the study, posters were placed within all armed forces units and British Legion establishments, and numerous radio and television programmes advertised the launch of the study. Throughout the study we maintained close liaison with Gulf war veteran groups, armed forces welfare groups, and resettlement programmes, and a freephone helpline was maintained by a nurse.

The postal questionnaire requested details of all liveborn children, including name, sex, date and place of birth, gestation, birthweight, any congenital defects or serious medical conditions ever experienced, and date of death if appropriate. Also requested were details about infertility and any adverse pregnancy outcomes (miscarriage, stillbirth, ectopic pregnancy, hydatidiform mole, missed abortion) or terminations of pregnancy, including date of pregnancy end, gestation, whether any abnormalities were detected in the fetus and sex of fetus if known.

Dates of conception for each pregnancy were estimated as the date of pregnancy end minus gestation plus 14 days. Where gestational age was not given (2% live births, 3% fetal deaths, and 10% other outcomes among post-Gulf/1991 conceptions) it was estimated by the median for all other pregnancies of that type, for example 40 weeks (live birth), 10 weeks (miscarriage), and 32 weeks (stillbirth). Pregnancies reported by Gulf-deployed personnel were assigned pre- or post-deployment status using dates of employment and estimated dates of conception. Analyses were restricted to post-deployment conceptions only for GWV and pregnancies conceived on or after 1 January 1991 for NGWV (referred to collectively as conceptions since the Gulf war). Pregnancies conceived after 8 November 1997 (<38 weeks before the first mailing) were excluded to avoid truncation effects.

Among pregnancies conceived after the Gulf war we attempted to obtain clinical confirmation, and information on congenital malformations, for all fetal deaths at 16 weeks or more, or of unknown gestation. In addition, we attempted clinical verification for post-Gulf liveborn children where a congenital abnormality, cancer, other serious childhood medical condition, or death was reported. Study subjects were asked for details of their own general practitioner (GP) or armed forces medical officer (MO), those of the mother of all reported pregnancies (men), and those of their children. They were also asked for details of the hospital and consultant treating the mother, fetus, or child for any serious medical condition reported in any of the pregnancies or children. For parents who provided the relevant permission, attempts were made to verify reported conditions by contacting the GP or other relevant clinician using standard postal forms. Up to two reminder letters were sent.

Fetal death analyses
All pregnancies <16 weeks were treated as singleton, regardless of number of fetuses/sacs reported because antenatal scanning (hence confirmation of multiple pregnancy) is not universal before that gestation. Multiple pregnancies >=16 weeks gestation were included in all analyses, with adjustment for this in all statistical models. To be certain that they were not biasing the results, analyses were repeated with singleton pregnancies only, producing virtually identical results. Fetal death (including blighted ova and missed abortions) was divided into three categories according to the reported gestation at pregnancy end: early (first trimester) miscarriage (<12 weeks); late (mid-trimester) miscarriage (12–23 weeks) (multiple pregnancy with at least one fetal death being allocated to this category, regardless of the outcome of the other fetus/es); and stillbirth (>=24 weeks gestation). In analyses of early miscarriage the number at risk was taken to be all pregnancies ending in one or more livebirths and all pregnancies ending in fetal death; for late miscarriage the denominator included all pregnancies surviving 12 or more weeks (multiple pregnancies counted only once in the analysis); for stillbirth, the number at risk consisted of all live- and stillborn babies (twins and triplets counted as individuals). Ectopic pregnacies, hydatidiform moles, and terminations were excluded from all analyses of fetal death. Ectopic pregnancies, hydatidiform moles, and terminations were excluded from all analyses of fetal death.

Congenital malformation analyses
Livebirths, fetal deaths of >=16 weeks gestation, and terminations for medical reasons were included in these analyses, each child/fetus being counted as an individual. Adjustment was made for multiplicity (single or multiple birth) in all analyses. Cases were conditions diagnosed in-utero, at birth, or at any time after birth. Coding was based on information received from the clinician unless either the clinical verification process had not been possible (usually because there was no consent, or no relevant GP/other clinician details) or nothing relating to the condition was found in the clinical notes, when coding was based on the parental description only. Conditions were coded to the 10th Revision of the International Classification of Diseases (ICD-10)20 and individual codes were grouped for analysis based on the classification system used by the European Registry of Congenital Anomalies (EUROCAT),21 with additional groupings consisting of malformations in tissues originating from the embryonic cranial-neural crest and metabolic/single gene defects. Minor anomalies were excluded.16 Children (or fetuses) with more than one malformation were counted more than once if they had malformations in more than one group, but were counted only if the malformations were all in the same group. Prevalence was calculated as the number of offspring with a particular malformation divided by the total number of reported offspring liveborn, dying in utero at 16 weeks or more, or terminated for medical reasons, for metabolic and single gene defects.

In order to investigate the possible role of poor recall of more minor conditions in older children, the analyses were repeated restricting diagnoses to children aged <5 at survey only.

Statistical methods
All analyses were performed using Stata statistical software.22 All P-values quoted are two-sided and values <0.05 were taken to indicate statistical significance. All comparisons related to reproductive history were adjusted for age at survey. The effect of service in the Gulf on risk of fetal death or congenital malformation was estimated using logistic regression analysis,23 taking NGWV pregnancies as the baseline for all odds ratios (OR). The unit of analysis was a pregnancy for miscarriage and a fetus/infant for stillbirth and congenital malformations. When more than one pregnancy reported by the same subject could be in the analysis a robust method based on the ‘sandwich estimate’24,25 was used to compute standard errors and Wald tests were used to test statistical significance of parameters.26,27 This was to account for possible clustering of exposure. Otherwise standard errors and tests of significance were based on the (binomial) likelihood.23 OR for all analyses were adjusted for year of pregnancy end, paternal/maternal pregnancy order (as appropriate), age of mother, Service, and rank. Additionally, analyses of any type of fetal death were adjusted for previous fetal death, and analyses of late miscarriage, stillbirth, and congenital malformation for multiplicity. None of these covariates appeared to confound the effect of interest (none changed the estimate by more than 1–2%), but all were included for completeness. Though it was a significant risk factor for late miscarriage, smoking at the time of conception was not included in the models, because this information was missing for around 2.4% of pregnancies, and after adjustment the effect of interest (Gulf war deployment) remained unchanged, hence providing no evidence of confounding.

To investigate possible bias we compared reported fetal death rates with rates in two external populations. First, we obtained miscarriage and stillbirth risks for 1990–1992 by single year of conception, paternal age, and pregnancy order from a similar cohort study of nuclear industry workers (the Nuclear Industry Family Study: NIFS).19,28 The methods of NIFS, which had a very high response rate, were similar to those used here and were developed by the authors. NIFS did not find an effect of exposure to ionizing radiation at work and the data were combined for both monitored (‘exposed’) and non-monitored (‘unexposed’) workers. Logistic regression analysis, with robust standard errors as described above, was used to compare the risk of miscarriage and stillbirth with those of GWV and NGWV. Secondly, we obtained annual registered stillbirth risks by maternal age for England and Wales, 1991–1998.29 Logistic regression analysis, offsetting the log odds of the population risk, was used to calculate standardized registered stillbirth ratios (SRSR).


    Results
 Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Response rates, characteristics of respondents, and outcome of reported pregnancies are reported elsewhere.16 Briefly, completed questionnaires were received from 42 818 men and 1269 women, representing response rates of 53% for GWV men, 72% for GWV women, 42% for NGWV men, and 60% for NGWV women, after adjusting for undelivered mail. Given the relatively low response rate for men, we conducted a non-responder study to investigate possible selection bias.16 Data from this study showed that failure to respond to the main survey was unrelated to reproduction. Indeed, 90% of the reasons given by both GWV and NGWV related to such things as not remembering receiving a questionnaire, thinking they had sent it back, intending to send it back but not doing so, or being generally mistrustful of the MoD.16 Male participants reported a total of 27 959 pregnancies conceived since the war, and women 861 pregnancies. Distributions by year of conception are similar for GWV and NGWV (Table 1 of methods paper16).


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Table 1 Outcome of reported pregnancies conceived since the first Gulf wara

 
Analysis of fetal death by deployment status
Miscarriage
Overall, there was a 40% increased risk of miscarriage among pregnancies reported by male GWV (OR = 1.4, 95% CI: 1.3, 1.5). The effect was stronger for early miscarriage (OR = 1.5, 95% CI: 1.3, 1.6) but was still present for late miscarriage (OR = 1.2, 95% CI: 1.1, 1.3) (Table 2). The effect was robust to confounding (all adjusted OR within 1% of the crude estimates), and persisted when either all miscarriages <8 weeks gestation were excluded (OR for all miscarriage = 1.4, 95% CI: 1.3, 1.5), or when miscarriages not reported as being confirmed by a doctor were excluded (OR for all miscarriage = 1.4, 95% CI: 1.3, 1.6). Among pregnancies reported by women there was no evidence of an effect of deployment to the Gulf on risk of miscarriage (OR for all miscarriage = 1.0, 95% CI: 0.7, 1.4; P = 0.82).


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Table 2 Fetal deatha among all reported pregnancies conceived since the first Gulf warb by deployment status

 
Restricting the analysis to the first conception following service in the Gulf war (or 1 January 1991) produced similar results (Table 2). Furthermore, the effect of service in the first Gulf war on these conceptions was constant over time since the war (all P >= 0.50 for interaction with year of conception). Further restriction to pregnancies reported by cohort members whose reproductive history started only after the first Gulf war also had little impact on the results (OR for early, late, and all miscarriage respectively among pregnancies reported by men = 1.5 [95% CI: 1.3, 1.6], 1.1 [95% CI: 1.0, 1.3], and 1.3 [95% CI: 1.2, 1.5]).

Stillbirth
Overall, there was no evidence of an increased risk of stillbirth among pregnancies reported by male GWV (OR = 0.9, 95% CI: 0.7, 1.3) (Table 2). The risk appeared higher for pregnancies conceived soon after the war (OR = 1.9, 95% CI: 0.7, 5.1) (Table 2) but this result was driven by the low prevalence of stillbirth (and small number of events) in the NGVW group, and was not statistically significant (P = 0.21). The numbers of stillbirths reported by women (3 by GWV, 1 by NGWV) were too small to allow meaningful analysis.

Comparison with external standards (pregnancies reported by men only)
Among pregnancies conceived by male GWV between 1990 and 1992, there was no evidence of a difference in risk of early or late miscarriage, or of stillbirth, compared with the risk among NIFS25,26 pregnancies (all P > 0.23). Among pregnancies reported by NGWV, however, the risk of early miscarriage was 30% lower (P = 0.004), and of late miscarriage 40% lower (P = 0.001), than that in NIFS, although there was no evidence of a difference in risk of stillbirth (P = 0.78) (Table 3). SRSR were consistent with national expectation in both groups (P = 0.85 and 0.67 for GWV and NGWV respectively) (Table 3).


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Table 3 Fetal deatha among pregnancies conceived since the first Gulf warb reported by men: comparison with external standards

 
Analysis of congenital malformation by deployment status
Pregnancies with malformations
Male GWV reported 801 malformations in a total of 686 affected offspring conceived after the Gulf war. Male NGWV reported 411 malformations in 342 affected offspring. The overall prevalence of any malformation was 5.2 per 100 offspring reported by GWV compared with 3.5 per 100 offspring reported by NGWV (P < 0.0001)(Table 4). Female GWV reported 23 malformations in 19 affected offspring and female NGWV 9 malformations in 9 offspring. The overall prevalence of any malformation was 5.3 per 100 offspring reported by female GWV compared with 3.2 per 100 offspring reported by female NGWV (P = 0.20) (Table 4).


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Table 4 Reported congenital malformations in offspringa conceived since the first Gulf warb

 
Analysis by type of malformation
Overall, the risk of any malformation among pregnancies reported by men was 50% higher in GWV compared with NGWV (OR = 1.5, 95% CI: 1.3, 1.7). Although some of the OR were above one, there was no strong statistical evidence for an effect of Gulf deployment on risk of malformations of the central nervous system, eye/ear/face/neck, circulatory system, or respiratory system, nor for cleft lip and palate or chromosomal anomalies; the P-values ranging from 0.11 (CNS) to 0.85 (chromosomal anomalies) (Table 5). The risk of malformation within the digestive system as a whole was 40% higher among offspring of GWV, the effect being driven by the subgroup ‘other malformations of the digestive system’ (OR = 1.6, 95% CI: 1.0, 2.5). The three commonest diagnoses in this subgroup were pyloric stenosis, congenital hiatus hernia, and unspecified anomalies of the digestive system. The risk of genital malformations was 80% higher in offspring of GWV compared with NGWV (P = 0.04), the most common diagnosis being hypospadias (24 GWV/10 NGWV). Risks of one or more malformation within the urinary system (OR = 1.6, 95% CI: 1.1, 2.2), and of musculo-skeletal system malformations (OR = 1.8, 95% CI: 1.4, 2.4), were statistically significantly associated with paternal Gulf war service. Within the urinary system, the risk of renal anomaly was approximately 60% higher in the offspring of GWV and the commonest diagnosis within this subgroup was vesico-uretero-renal reflux (32 GWV/17 NGWV). For musculo-skeletal malformations, the significant association with Gulf war service was largely driven by the ‘other musculo-skeletal malformations’ subgroup (OR = 3.1, 95% CI: 1.9, 5.1). The commonest diagnoses within this subgroup include codes related to head size and shape (plagiocephaly/macrocephaly/ craniosynostosis) (33 GWV/9 NGWV). The risk of ‘other non-chromosomal malformations’ was 70% higher among GWV, and this was driven wholly by the group of malformations remaining when specified syndromes were removed (OR = 3.5, 95% CI: 1.5, 8.4). Diagnoses under this subgroup were mainly non-specific malformations where the parent reported that the fetus or child had an anomaly but no further details were supplied (15 GWV/2 NGWV). The pattern of results did not change when analyses were restricted to diagnoses in children aged <5 at survey.


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Table 5 Reported congenital malformationsa by system among offspringb conceived since the first Gulf warc

 
For women there was no evidence of an association between malformation risk and mothers' deployment to the Gulf (Table 5), but analyses were severely limited by small numbers.

Clinically verified conditions only
Although we were able to obtain additional medical information for only 55% of affected pregnancies, there was no significant variation in this proportion between GWV and NGWV for any system or subgroup.16 Thus we were able to use malformations where we received additional information as an unbiased sample of the total reported malformations. Where we received information from GPs or other relevant clinicians, 330 (91%) of 362 affected pregnancies reported by male GWV had their condition(s) confirmed, compared with 196 (98%) of 201 affected pregnancies reported by male NGWV. For malformations reported by females all conditions where further information was received were confirmed.16 Adjusted OR for clinically verified malformations only are presented in Figure 1. The numbers of malformations were reduced and the CI consequently widened, but overall the effect of the restriction was a general shift of the point estimates towards the null. Risk of urinary system anomalies continued to show weak evidence of an increased risk with Gulf deployment (OR = 1.6, 95% CI: 1.0, 2.5). Musculo-skeletal system malformations as a whole also showed weak evidence of an association with Gulf deployment (OR = 1.5, 95% CI: 1.0, 2.2), the latter again driven largely by the subgroup ‘other musculo-skeletal anomalies’ (OR = 2.0, 95% CI: 1.0, 4.1). Of the 41 confirmed anomalies in this subgroup, 19 (14 GWV/5 NGWV) related to unusual head shape and size. Fourteen (11 GWV/3 NWV) of these latter anomalies were isolated i.e. the parent reported no further congenital anomalies in that child or fetus, and there was no evidence for the presence of a syndrome in the other five cases.



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Figure 1 Clinically confirmed congenital malformations by system among pregnancies

Bars indicate odds ratios (OR) and 95% CI. Area of rectangles proportional to numbers in analysis.

aAdjusted for: multiplicity, year of pregnancy end, paternal pregnancy order, age of mother, service, rank, and serving status.

bTracheo-oesophageal fistula, atresia, and stenosis of oesophagus, large intestine, rectum, and anal canal.

 

    Discussion
 Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Miscarriage and stillbirth
We found no effect of Gulf war service on the risk of stillbirth in pregnancies reported by male veterans, or of miscarriage in pregnancies reported by female veterans (too few stillbirths were reported by women to perform meaningful analyses). In contrast, we report a 40% increased risk of miscarriage among pregnancies fathered by men who served in the first Gulf war, compared with that in pregnancies fathered after 1 January 1991 by the comparison cohort. This finding is consistent with that reported in a study of similar design by Kang et al.12 who found an increased risk of miscarriage of 60% in the first pregnancy conceived by GWV after the war. However, as noted by the authors, the potential for biased participation in a survey of this kind is a major concern since Gulf veterans may have been more likely to participate if they had had an adverse outcome. As discussed in a previous report16 our study does have a fairly low response rate, raising the possibility of selective participation according to pregnancy outcome. However, 90% of reasons given by both GWV and NGWV in a study of non-responders were unrelated to adverse outcome.16 Furthermore, we have shown that stillbirth rates in both GWV and NGWV groups were similar to that expected using two external standards: England and Wales and a similar study of reproduction in a male workforce, with a very high response rate, NIFS.19,28 These findings together provide evidence that participation in the study by both GWV and NGWV was not strongly influenced by their experience of adverse reproductive outcome.

Could differential recall of miscarriage, in particular early miscarriage, explain this finding? It is unlikely that GWV misreported the timing of events in relation to the Gulf war, since the observed effect was constant over time since the war. It is also unlikely that GWV reported miscarriages that did not in fact occur. The alternative—that NGWV under-reported early fetal death—is possibly more likely. The raised risk associated with US Gulf war service in pregnancies reported by men in Kang et al.'s paper appeared to be driven by a low reported risk for NGWV (7.7%) rather than a high risk of miscarriage for pregnancies reported by GWV (11.9%).12 The data reported here show a similar pattern, and comparison with NIFS data confirmed this, finding a significantly lower than expected miscarriage rate for NGWV. It is thus possible that at least some of the observed excess in miscarriage risk for male GWV can be explained by under-reporting by male NGWV. We estimate that the observed 40% increased risk could have been produced in the absence of any true association of NGWV underreported between 25% and 40% of early miscarriage cases.

The possibility that there is a real increased risk of miscarriage, over and above that resulting from reporting bias must, however, be considered. The observed increases in risk do not decline with time since the Gulf, which would argue in favour of a genetic effect resulting from exposures experienced during Gulf war service. Since we have not observed any clear increase in genetic syndromes and chromosomal anomalies in the offspring of GWV reaching >=16 weeks gestation this possible genetic effect would need to be specific to early fetal loss. The presence of lethal abnormalities would explain such a phenomenon,30 although epidemiological evidence for a genetic influence of male origin on early fetal loss in humans is limited.31 The existence of an increase in reported infertility resulting from very early, unrecognized, fetal loss32 would add important information to the observations noted here, and the authors are currently investigating the prevalence of infertility in these cohorts.

Congenital malformations
In contrast to the findings from recent US studies,11,12 we did not find increases in heart malformations or chromosomal malformations in GWV offspring. However, Araneta et al.11 reported a highly raised risk of renal agenesis and hypoplasia in GWV offspring conceived post-war versus pre-war, and, although not statistically significant for validated anomalies, our finding of a modestly raised risk for renal anomalies overall is consistent with this. Although Araneta et al.11 did not report a statistically significant raised risk of these conditions in GWV versus NGWV offspring conceived post-war, this result is potentially important and we are currently investigating this group of defects further.

Overall, male UK GWV reported a 50% higher prevalence of malformations than the NGWV comparison group. With the exception of the urinary system, this result was not due to increases in clearly defined structural malformations within the major system groups. We observed that associations with Gulf war service tended to be found for less specific conditions or groups of conditions, and in some cases less serious or life-threatening conditions, in particular conditions in ‘other’ and ‘unspecified’ categories. Subgroups where a clear effect was found include malformations coded in ‘other’ (non-specific) categories. These codes were used by necessity in cases where parents reported a problem without a formal diagnosis, for example an ‘abnormality of the skull’, where we were unable to obtain further medical documentation. When analysis was restricted to clinically verified malformations, there was a general shift of the point estimates towards the null, indicating that at least a proportion of these unspecified malformations were not confirmed by medical documentation.

Once again we need to consider reporting bias as an explanation for these results. Study participants were asked about medical problems in their children and were not given a list of pre-defined conditions. Observations that the prevalence of ‘harder’ outcomes are mostly reported at a similar prevalence in GWV and NGWV, and that the less specific or ‘softer’ outcomes are not, suggests possible biased reporting of the latter type of outcome. Attenuation of effects when the analyses are restricted to clinically verified conditions lends further support to this argument. But how might such a bias operate? Media articles concerning genetic effects of hazardous exposures in the first Gulf war would have alerted at least a proportion of GWV to their children's health. GWV thus had more reason to think about the health of their offspring and would be more likely to report all problems than NGWV, even if they were more minor and the children were now well. The fact that a lower proportion of conditions reported by GWV compared with NGWV was verified (where documentation was available)16 may reflect the fact that some of the conditions were not recorded and/or treated by GPs.

Notwithstanding these cautionary comments, it is important that these findings, and the findings of other studies, are investigated further. Recent experimental studies on the effects of radiation and chemical exposure on mouse spermatogonia have demonstrated subtle alterations in gene expression and instability in certain repeat sequences in offspring DNA.33,34 It is possible that health effects resulting from these alterations have ‘softer’, or more minor, diagnoses, which are difficult to recognize and measure. Our observation of higher incidence of more minor and less well-defined structural malformations, especially within the musculo-skeletal system, in the offspring of fathers deployed to the Gulf, may be of relevance to this emerging story. However, there are severe limitations on what can be interpreted from data gathered retrospectively with little or no contemporaneous individual exposure information. To avoid the many problems associated with retrospective studies, prospective surveillance of the reproductive health of veterans, and the health of their offspring, is strongly recommended. The second Gulf war now presents a timely opportunity to implement such a surveillance programme.


KEY MESSAGES

  • Offspring of male UK veterans of the first Gulf war were not found to have increased risks of stillbirth, chromosomal malformations, or syndromes.
  • Fathers' service in the first Gulf war was associated with an increased risk of miscarriage and some groups of malformations.
  • These results need to be interpreted with caution and we cannot at this stage conclude that the associations are causal.
  • For female veterans there was no increased risk of miscarriage in pregnancies conceived since the war. Stillbirths and malformations were too few to analyse.

 


Crown copyright 2004, images from www.photos.mod.uk. Reproduced with permission of the Controller of Her Majesty's Stationery Office. This image must not be downloaded from the website by third parties without permission.


    Acknowledgments
 
We would like to thank the many people who supported the conduct of this study: Representatives of the Armed Services, the British Legion in particular Col Terry English, National Gulf Veterans and Families Association, Gulf Veterans Association, Professor Malcolm Hooper and, most importantly, the study members themselves for taking the time and effort to participate. We also acknowledge the skills and commitment of those who worked on the study, particularly Patrick Sampson, Tommy Clarke, Haydon Hughes, Juliet Jain, Darren Reed and Janet Sullivan. We are grateful to Mike Kenward and Chris Frost at London School of Hygiene and Tropical Medicine for statistical advice. For supplying cohort data and for invaluable help with queries, we thank all members of the Gulf Veterans Illness Unit at the Ministry of Defence, in particular Nick Blatchley, John Graham, Philip Bolton, Linda Walpole and Chris Baker. We appreciate the work of Steve McManus and colleagues at the British Forces Post Office for providing valuable serving status and address information on a regular basis. The Medical Research Council funded the study.


    References
 Top
 Abstract
 Methods
 Results
 Discussion
 References
 
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