IJE vol.33 no.1 © International Epidemiological Association 2004; all rights reserved.
International Journal of Epidemiology 2004;33:74–86
DOI: 10.1093/ije/dyh049
Miscarriage, stillbirth and congenital
malformation in the offspring of UK veterans
of the first Gulf war
Pat Doyle,1 Noreen Maconochie,1 Graham Davies,1 Ian Maconochie,2 Margo Pelerin,3
Susan Prior1 and Samantha Lewis1
Accepted
14 October 2003
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
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
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: [email protected]
74
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
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.6–15 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.
75
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 interviewbased 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
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
76
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
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 Gulfdeployed 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 (midtrimester) 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 prevalence was calculated for livebirths only.
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.
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
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).
77
Results
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 nonresponder 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,
Table 1 Outcome of reported pregnancies conceived since the first Gulf wara
Reported by men
Total pregnancies
Reported by women
GWV
n (%)
NGWV
n (%)
GWV
n (%)
NGWV
n (%)
16 442 (100)
11 517 (100)
484 (100)
377 (100)
12 453 (76)
9309 (81)
341 (70)
271 (72)
183 (1)
105 (1)
7 (1)
3 (1)
51 (14)
Pregnancy type
Live birth:
Singleton
Multiple (1 livebirth and no fetal deaths)b
Fetal death:
First trimester miscarriagec
1928 (12)
958 (8)
68 (14)
Second trimester miscarriagec,d
901 (5)
567 (5)
22 (5)
22 (6)
Third trimester (stillbirth)c,d
74 (0.5)
59 (0.5)
2 (0.4)
1 (0.3)
Ectopic pregnancy
262 (2)
139 (1.2)
8 (2)
4 (1)
Hydatidiform mole
13 (0.1)
13 (0.1)
0 (–)
1 (0.3)
Termination for medical reasonse
105 (1)
40 (0.4)
1 (0.2)
2 (0.5)
Termination for non-medical reasons
523 (3)
327 (3)
35 (7)
22 (6)
2903 [100%]
1584 [100%]
92 [100%]
74 [100%]
645 [22]
279 [18]
24 [26]
12 [16]
8–11
1283 [44]
679 [43]
44 [48]
39 [53]
12–15
725 [25]
440 [28]
21 [23]
21 [28]
16–23
176 [6]
127 [8]
1 [1]
1 [1]
24–36
59 [2]
40 [3]
1 [1]
0 [0]
37
15 [1]
19 [1]
1 [1]
1 [1]
Reported gestation of fetal deaths (completed weeks)
All pregnancies ending in fetal death
8
a After first deployment to the Gulf (GWV), or after 1 January 1991 where Gulf deployment dates not known and among those not deployed to the Gulf
(NGWV); conceptions after 8 November 1997 (38 weeks before 1 August 1998) excluded; all analyses of fetal death include hydatidiform moles, ectotpic
pregnancies and pregnancies ending in termination.
b Liveborn multiple pregnancies reported by men include one liveborn-medical termination (GWV group). Among pregnancies reported by women, no
multiple births had different outcome types. No triplet pregnancies had different outcome types.
c First trimester: 12 completed weeks (early miscarriage); second trimester: 12–23 completed weeks (late miscarriage); third trimester: 24 weeks (stillbirth)
including missed abortion and blighted ova.
d 12 pregnancies having at least one second trimester fetal death reported by men were multiple: in 1 triplet and 3 twin pregnancies reported by GWV and
1 triplet and 4 twin pregnancies reported by NGWV both/all fetuses died; in 2 twin pregnancies reported by GWV and 1 twin pregnancy by NGWV one fetus
died and the other was liveborn. 10 pregnancies having at least one third trimester fetal death reported by men were multiple: in 3 twin pregnancies reported
by GWV and 1 twin pregnancy reported by NGWV both fetuses died; in 4 twin pregnancies reported by GWV and 1 twin pregnancy by NGWV one fetus died
and the other was liveborn; and one twin pregnancy (GWV ) combined an ectopic pregnancy and a late fetal death. No multiple pregnancies reported by
women had different outcome types.
e One of the medical terminations reported by male GWV was a twin pregnancy at 22 weeks. No other medical terminations were of multiple pregnancies.
1.5 (1.4, 1.7)
1070 (11)
44 (18)
1.2 (1.0, 1.3)
1.0
1.2 (1.1, 1.3)
1.0
Adjusted ORf
(95% CI)
12 (6)
14 (8)
22 (6)
22 (7)
114 (6)
72 (5)
0.7 (0.3, 1.7)
1.0
0.8 (0.4, 1.5)
1.0
1.2 (0.9, 1.7)
1.0
2 = 1.36, P = 0.72
559 (6)
363 (6)
901 (7)
567 (6)
n (risk %d)
Late miscarriaged
(Fetal deaths 12–23 weeks)
1.4 (1.3, 1.5)
1.0
1.4 (1.3, 1.5)
1.0
Adjusted ORf
(95% CI)
56 (23)
41 (21)
90 (20)
73 (21)
307 (15)
175 (11)
1.2 (0.7, 1.9)
1.0
1.0 (0.7, 1.4)
1.0
1.4 (1.2, 1.7)
1.0
2 = 2.34, P = 0.50
1629 (17)
889 (13)
2829 (18)
1525 (14)
n (risk %c)
All miscarriagec
(All fetal deaths 24 weeks)
0.9 (0.6, 1.4)
1.0
0.9 (0.7, 1.3)
1.0
Adjusted ORf
(95% CI)
3 (1.6)
0 (0)
3 (0.8)
1 (0.4)
13 (0.7)
5 (0.4)
∞
1.0
2.0 (0.3, 14.9)
1.0
1.9 (0.7, 5.1)
1.0
2 = 2.30, P = 0.51
53 (0.6)
42 (0.7)
77 (0.6)
60 (0.6)
n (risk %e)
Stillbirthe
(Fetal deaths 24 weeks)
additionally adjusted for multiple pregnancy. Pregnancies reported by NGWV form the baseline group for all analyses.
f All odds ratios adjusted for maternal age, paternal/maternal pregnancy order, year of pregnancy end, previous fetal loss, and service and rank at time of Gulf war. Analyses of late miscarriage and stillbirth
higher order births counted as individuals (see Methods).
e Denominator consists of all liveborn and all stillborn infants (singleton and multiple) (12 904 GWV and 9585 NGWV births reported by males; 358 GWV and 278 NGWV births reported by females). Twins and
males; 372 GWV and 297 NGWV pregnancies reported by females). Multiple pregnancies counted once only, regardless of number of fetuses (see Methods).
d Denominator consists of all liveborn pregnancies, and all pregnancies resulting in 1 fetal death at 12 weeks gestation (singleton and multiple) (13 611 GWV and 10 040 NGWV pregnancies reported by
440 GWV and 348 NGWV pregnancies reported by females). Multiple pregnancies counted once only, regardless of number of fetuses (see Methods).
c Denominator consists of all liveborn pregnancies, and all pregnancies resulting in fetal death at any gestation (singleton and multiple) (15 539 GWV and 10 998 NGWV pregnancies reported by males;
(38 weeks before 1 August 1998) excluded; all analyses of fetal death exclude hydatidiform moles, ectopic pregnancies, and pregnancies ending in termination.
b After first deployment to the Gulf (GWV), or after 1 January 1991 where Gulf deployment dates not known and among those not deployed to the Gulf (NGWV); conceptions after 8th November 1997
weeks) (see methods).
a Includes missed abortions and blighted ova. For miscarriage, the unit of analysis is a pregnancy with one or more fetal deaths (24 weeks), and for stillbirth the unit of analysis was a fetal death/infant (24
1.0
1.4 (0.8, 2.5)
27 (14)
1.0 (0.7, 1.6)
68 (15)
Mother GWV
1.0
Mother NGWV
All first pregnancies conceived since Gulf war
First pregnancy conceived since the Gulf war only
Mother GWV
Mother NGWV
All pregnancies conceived since the Gulf war
51 (15)
193 (9)
Women
1.0
1.5 (1.2, 1.9)
103 (7)
Father GWV
2 = 1.68, P = 0.64
1.0
526 (7)
1.0
1.5 (1.3, 1.6)
958 (9)
1928 (12)
Adjusted ORf
(95% CI)
Father NGWV
First pregnancy since Gulf war, conceived 1990–1991
2 test for interaction with year of conception (3 d.f.)
Father GWV
Father NGWV
All first pregnancies conceived since Gulf war
First pregnancy conceived since the Gulf war only
Father GWV
Father NGWV
All pregnancies conceived since the Gulf war
Men
n (risk %c)
Early miscarriagec
(Fetal deaths 12 weeks)
Table 2 Fetal deatha among all reported pregnancies conceived since the first Gulf warb by deployment status
78
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
and women 861 pregnancies (Table 1). Distributions by year of
conception are similar for GWV and NGWV (Table 1 of methods
paper16).
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).
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
NIFS19,28 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).
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
79
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).
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 musculoskeletal 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 nonchromosomal 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.
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
480 (11)
Father GWV
1.00
1.1 (0.9, 1.4)
0.7 (0.6, 0.9)
158 (7)
278 (7)
157 (5)
1.0
0.9 (0.6, 1.1)
0.6 (0.5, 0.8)
27 (0.7)
18 (0.6)
9 (0.4)
n (risk %g)
1.4 (0.4, 4.5)
1.2 (0.3, 4.2)
1.0
Adjusted ORh
(95% CI)
70 (0.5)
54 (0.6)
–
n (risk %d)
102 (81, 129)
106 (81, 139)
–
SRSRi
(95% CI)
i Standardized registered stillbirth ratio (SRSR) (observed risks compared with expected risks in England and Wales (SRSR = 100); standardized for year of pregnancy end and maternal age.
adjusted for multiple pregnancy. Pregnancies reported by NIFS participants form the baseline group for all analyses.
h All odds ratios (OR) adjusted for maternal age, paternal pregnancy order, year of pregnancy end, previous fetal loss, and service and rank at time of Gulf war. Analyses of late miscarriage and stillbirth additionally
counted as individuals (see Methods).
g Denominator consists of all liveborn and all stillborn infants (singleton and multiple) conceived 1990–1992 (2130 NIFS, 3634 GWV, and 2825 NGWV births reported by males). Twins and higher order births
pregnancies reported by males). Multiple pregnancies counted once only, regardless of number of fetuses (see Methods).
f Denominator consists of all liveborn pregnancies, and all pregnancies resulting in 1 fetal death of 12 weeks gestation (singleton and multiple) conceived 1990–1992 (2267 NIFS, 3855 GWV, and 2957 NGWV
males). Multiple pregnancies counted once only, regardless of number of fetuses (see Methods).
e Denominator consists of all liveborn pregnancies, and all pregnancies resulting in fetal death (singleton and multiple) conceived 1990–1992 (2469 NIFS, 4335 GWV, and 3194 NGWV pregnancies reported by
(12 897 GWV and 9 579 NGWV births reported by males). Twins and higher order births included as individuals.
d Registered stillbirths in England and Wales comprised fetal deaths 28 weeks to 1992, and 24 weeks from 1993 onwards. Denominator for risks consists of all (registered) live births and all registered stillbirths
to ionizing radiation at work on risk of fetal death and the data for both monitored (exposed) and non-monitored (unexposed) workers are combined here. Data only available for conceptions to 1992.
c Nuclear Industry Family Study (NIFS) was conducted using similar methods to those used in the Study of Reproductive Health in UK veterans of the Gulf War. The NIFS study did not find an effect of exposure
(38 weeks before 1 August 1998) excluded; all analyses of fetal death exclude hydatidiform moles, ectopic pregnancies, and pregnancies ending in termination.
a Includes missed abortions and blighted ova. Unit of analysis is a pregnancy for miscarriage (fetal death at 24 weeks), and a fetus for stillbirth (fetal death at 24 weeks) (see Methods).
b After first deployment to the Gulf (GWV), or after 1 January 1991 where Gulf deployment dates not known and among those not deployed to the Gulf (NGWV); conceptions after 8th November 1997
202 (8)
237 (7)
Father in Nuclear Industry Family Study
Adjusted ORh
(95% CI)
n (risk %f)
n (risk %e)
Adjusted ORh
(95% CI)
Late miscarriagef
(Fetal deaths 12–23 weeks)
Early miscarriagee
(Fetal deaths 12 weeks)
Father NGWV
Pregnancies
reported by men
Registered stillbirthd
(Fetal deaths 28 weeks
to 1992; 24 weeks
1993 onwards)
Comparison to Nuclear Industry Family Studyc:
Pregnancies conceived after the first Gulf war and before 1993
Stillbirthg
(Fetal deaths 24 weeks)
Comparison to England &
Walesd: pregnancies
conceived after the
first Gulf war
Table 3 Fetal deatha among pregnancies conceived since the first Gulf warb reported by men: comparison with external standards
80
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
81
Table 4 Reported congenital malformations in offspringa conceived since the first Gulf warb
Offspringa reported by GWV
Offspringa reported by NGWV
Live births
Fetal deaths
16 weeks
Medical
terminationsc
Total
offspringa
Live births
Fetal deaths
16 weeks
Medical
terminationsc
Total
offspringa
12 827
258
106
13 191
9525
193
40
9758
1 malformation
529 (4.1%)
19 (7.4%)
52 (49.0%)
600 (4.6%)
258 (2.7%)
10 (5.2%)
22 (55.0%)
290 (3.0%)
2 malformations
50 (0.4%)
1 (0.4%)
14 (13.2%)
65 (0.5%)
36 (0.4%)
1 (0.5%)
6 (15.0%)
43 (0.4%)
3 malformations
17 (0.1%)
1 (0.4%)
3 (2.8%)
21 (0.2%)
6 (0.1%)
2 (1.0%)
1 (2.5%)
9 (0.1%)
Any malformation (1) 596 (4.7%)
21 (8.1%)
69 (65.1%)
686 (5.2%)
300 (3.2%)
13 (6.7%)
29 (72.5%)
342 (3.5%)
355
4
1
360
277
3
2
282
1 malformation
14 (3.9%)
0 (–)
1 (100%)
15 (4.2%)
7 (2.5%)
0 (–)
2 (100%)
9 (3.2%)
2 malformations
4 (1.1%)
0 (–)
0 (–)
4 (1.1%)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
0 (–)
18 (5.1%)
0 (–)
1 (100%)
19 (5.3%)
7 (2.5%)
0 (–)
2 (100%)
9 (3.2%)
Men
No. offspringa
No. (%) with
Women
No. offspringa
No. (%) with
3 malformations
Any malformation (1)
a Liveborn children, fetuses 16 weeks dying in utero and fetuses in pregnancies terminated for medical reasons. Unit of analysis is a child/fetus (twins and
triplets included as individuals).
b After first deployment to the Gulf (GWV), or after 1 January 1991 where Gulf deployment dates not known and among those not deployed to the Gulf
(NGWV); infants conceived after 8 November 1997 (38 weeks before 1 August 1998) excluded; all analyses of congenital malformation exclude fetal deaths
at 16 weeks, hydatidiform moles, ectopic pregnancies, and pregnancies ending in non-medical termination.
c Medical terminations for complications of pregnancy and/or malformations in the fetus.
Table 5 Reported congenital malformationsa by system among offspringb conceived since the first Gulf warc
Adjustedd
OR (95% CI)
Reported by GWV
N ( Prevalence %)
Reported by NGWV
N ( Prevalence %)
686 (5.20)
342 (3.50)
1.5 (1.3, 1.7)
58 (0.44)
30 (0.31)
1.4 (0.9, 2.3)
Neural tube defects
25 (0.19)
17 (0.17)
1.1 (0.6, 2.1)
Hydrocephalusf
15 (0.11)
6 (0.06)
1.8 (0.7, 4.7)
Other CNSf
20 (0.15)
8 (0.08)
1.9 (0.8, 4.3)
Malformation grouping
MEN
Any malformation
Central nervous systeme
Eye, ear, face, necke,f
22 (0.17)
12 (0.12)
1.4 (0.6, 2.9)
Circulatory systeme
126 (0.96)
74 (0.76)
1.2 (0.9, 1.7)
113 (0.86)
65 (0.67)
1.3 (0.9, 1.7)
Congenital malformations of heartf
20 (0.15)
14 (0.14)
1.0 (0.5, 2.0)
Respiratory systeme
Other malformations of circulatory system
18 (0.14)
12 (0.12)
1.1 (0.5, 2.4)
Cleft lip/palatee,f
21 (0.16)
14 (0.14)
1.1 (0.5, 2.2)
Digestive systeme
72 (0.55)
37 (0.38)
1.4 (0.9, 2.2)
5 (0.04)
6 (0.06)
0.6 (0.2, 2.3)
TOF & other malformations of large intestine, rectum, anal canalg
69 (0.52)
31 (0.32)
1.6 (1.0, 2.5)
Genital systeme
Other malformations of digestive system
45 (0.34)
19 (0.19)
1.8 (1.0, 3.0)
Urinary systeme
103 (0.78)
48 (0.49)
1.6 (1.1, 2.3)
Renal anomalies
56 (0.42)
25 (0.26)
1.6 (1.0, 2.7)
Urinary tract anomalies
55 (0.42)
27 (0.28)
1.5 (1.0, 2.4)
82
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Table 5 continued
Malformation grouping
Reported by GWV
N ( Prevalence %)
Reported by NGWV
N ( Prevalence %)
Adjustedd
OR (95% CI)
194 (1.47)
78 (0.80)
1.8 (1.4, 2.4)
1.3 (0.4, 4.0)
Musculo skeletal systeme
Limb reduction
9 (0.07)
5 (0.05)
Polydactyly, syndactyly
17 (0.13)
10 (0.10)
1.3 (0.6, 2.8)
Other limb malformations
75 (0.57)
38 (0.39)
1.4 (1.0, 2.1)
Anomalies of diaphragm, exomphalos, gastrochisis
19 (0.14)
9 (0.09)
1.5 (0.6, 3.5)
Other musculo-skeletal anomalies
81 (0.61)
19 (0.19)
3.1 (1.9, 5.1)
45 (0.34)
19 (0.19)
1.7 (1.0, 3.0)
Specified syndromes (non-chromosomal)
15 (0.11)
13 (0.13)
0.8 (0.4, 1.9)
Remainder of other non-chromosomal malformations
30 (0.23)
6 (0.06)
3.5 (1.5, 8.4)
Other non-chromosomal malformationse
Chromosomal anomaliese
49 (0.37)
40 (0.41)
1.0 (0.6, 1.5)
Downs syndrome
23 (0.17)
19 (0.19)
0.9 (0.5, 1.7)
Other chromosomal
26 (0.20)
21 (0.22)
1.0 (0.5, 1.7)
Cranial neural creste,f
184 (1.39)
101 (1.04)
1.3 (1.0, 1.7)
22 (0.17)
8 (0.08)
2.0 (0.9, 4.8)
Metabolic and single gene defectse,h
WOMEN
Any malformation
19 (5.28)
9 (3.19)
1.7 (0.7, 3.9)
Central nervous systeme
4 (1.11)
3 (1.06)
1.0 (0.2, 5.5)
Eye, Ear, Face, Necke
1 (0.28)
1 (0.28)
0.7 (0.03, 18.9)
Circulatory Systeme
2 (0.56)
3 (1.06)
0.2 (0.03, 2.1)
Respiratory systeme
0 (–)
0 (–)
–
Cleft lip/palatee
0 (–)
0 (–)
–
Digestive systeme
1 (0.28)
0 (–)
–
Genital systeme
2 (0.56)
0 (–)
–
Urinary systeme
2 (0.56)
1 (0.35)
1.7 (0.1, 39.2)
Musculo-skeletal systeme
5 (1.39)
0 (–)
–
Other non-chromosomal malformationse
1 (0.28)
0 (–)
–
Chromosomal anomaliese
4 (1.11)
1 (0.35)
3.1 (0.3, 29.0)
Cranial neural creste,f
6 (1.67)
5 (1.77)
0.9 (0.2, 3.0)
0 (–)
0 (–)
–
Metabolic and single gene defectse,h
a Diagnosed at any time.
b Liveborn children, fetuses 16 weeks dying in utero and fetuses in pregnancies terminated for medical reasons (single and multiple). Unit of analysis is a
child/fetus (twins and triplets included as individuals).
c After first deployment to the Gulf (GWV), or after 1 January 1991 where Gulf deployment dates not known and among NGWV; conceptions after 8
November 1997 (38 weeks before 1 August 1998) excluded; all analyses of congenital malformation exclude fetal deaths at 16 weeks, hydatidiform moles,
ectopic pregnancies, and pregnancies ending in non-medical termination.
d All odds ratios (OR) adjusted for multiplicity, maternal age, paternal/maternal pregnancy order, year of pregnancy end, and service and rank at time of Gulf war.
e More than one malformation within a group in the same child/fetus counted once only. Number of malformations in sub-groups may not add up to group
total if more than one malformation was recorded within the group for the same child/fetus.
f Malformations within these groups make up the Cranial Neural Crest grouping: hydrocephalus; other Central Nervous System; eye, ear, face and neck;
congenital malformation of heart; and cleft lip/palate.
g Tracheo-oesophageal fistula, atresia and stenosis of oesophagus, large intestine, rectum, and anal canal.
h Among liveborn children only.
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
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
83
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.
a Adjusted for: multiplicity, year of pregnancy end, paternal pregnancy order, age of mother, service, rank, and serving status.
b Tracheo-oesophageal fistula, atresia, and stenosis of oesophagus, large intestine, rectum, and anal canal.
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.
84
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Discussion
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 if 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 lifethreatening 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.
REPRODUCTIVE OUTCOME IN UK VETERANS OF THE FIRST GULF WAR
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.
85
Acknowledgements
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 study was funded by the Ministry of
Defence and administered by the Medical Research Council.
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.
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