Reproductive health of Gulf War veterans

In this review we summarize the scientific literature on reproductive health following deployment to the first Gulf war by armed service personnel. All the studies examined had methodological limitations, making interpretation difficult. Nonetheless we conclude that for male veterans there is no strong or consistent evidence to date for an effect of service in the first Gulf war on the risk of major, clearly defined, birth defects or stillbirth in offspring conceived after deployment. Effects on specific rare defects cannot be excluded at this stage since none of the studies had the statistical power to examine them. For miscarriage and infertility, there is some evidence of small increased risks associated with service, but the role of bias is likely to be strong. For female veterans, there is insufficient information to make robust conclusions, although the weight of evidence to date does not indicate any major problem associated specifically with deployment to the Gulf. None of the studies have been able to examine risk according particular exposures, and so possible associations with specific exposures for smaller groups of exposed veterans cannot be excluded.We suggest that the way forward to address the question of veterans' reproductive health with confidence in the future is prospective surveillance following deployment. Anything less will result in further problems of interpretation and continued anxiety for parents, as well as prospective parents, in the armed forces.     

Clinical findings for the first 1000 Gulf war veterans in the Ministry of Defence’s medical assessment programme

ObjectiveTo review the clinical findings in the first 1000 veterans seen in the Ministry of Defence’s Gulf war medical assessment programme to examine whether there was a particular illness related to service in the Gulf.DesignCase series of 1000 veterans who presented to the programme between 11 October 1993 and 24 February 1997.SubjectsGulf war veterans.Results588 (59%) veterans had more than one diagnosed condition, 387 (39%) had at least one condition for which no firm somatic or psychological diagnosis could be given, and in 90 (9%) veterans no other main diagnosis was made. Conditions characterised by fatigue were found in 239 (24%) of patients. At least 190 (19%) patients had a psychiatric condition, which in over half was due to post-traumatic stress disorder. Musculoskeletal disorders and respiratory conditions were also found to be relatively common (in 182 (18%) and 155 (16%) patients respectively).ConclusionMany Gulf war veterans had a wide variety of symptoms. This initial review shows no evidence of a single illness, psychological or physical, to explain the pattern of symptoms seen in veterans in the assessment programme. As the veterans assessed by the programme were all self selected, the prevalence of illness in Gulf war veterans cannot be determined from this study. Furthermore, it is not known whether the veterans in this study were representative of sick veterans as a group.

Key messages

• Many Gulf war veterans present with a wide variety of symptoms
• No single cause has been found to explain these symptoms
• From a clinical standpoint the variety and multiplicity of symptoms makes it unlikely that any single cause will be found to underlie Gulf war illness
• Some of the illnesses may be an example of a postwar syndrome

     

Paternité après traitement du cancer du testicule: enquête sur 136 patients

We sent a questionnaire to 136 patients, treated between 1981 and 1993, to try to evaluate, retrospectively, fertility amongst patients following treatment for testicular cancer. From the 76 complete questionnaires, 56% of patients had fathered at least one child. After treatment, approximately 35% of patients were steriles. Treatment, in wich ever form, does not seem to influence fertility. Only 3 couples resorted to infertility treatment. There were 46 pregnancies in total, one of wich resulted from IVF, on average 4 years after the end of treatment for testicular cancer. A prospective study carried out in conjonction with the centre for study and conservation of sperm would seem to be neceessary to consolidate these findings.     

Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study

ObjectivesTo explore the relation between ill health after the Gulf war and vaccines received before or during the conflict. To test the hypothesis that such ill health is limited to military personnel who received multiple vaccines during deployment and that pesticide use modifies any effect.DesignCross sectional study of Gulf war veterans followed for six to eight years after deployment.Setting UK armed forces.ParticipantsMilitary personnel who served in the Gulf and who still had their vaccine records.Results The response rate for the original survey was 70.4% (n=3284). Of these, 28% (923) had vaccine records. Receipt of multiple vaccines before deployment was associated with only one of the six health outcomes (post-traumatic stress reaction). By contrast five of the six outcomes (all but post-traumatic stress reaction) were associated with multiple vaccines received during deployment. The strongest association was for the multisymptom illness (odds ratio 5.0; 95% confidence interval 2.5 to 9.8).ConclusionAmong veterans of the Gulf war there is a specific relation between multiple vaccinations given during deployment and later ill health. Multiple vaccinations in themselves do not seem to be harmful but combined with the “stress” of deployment they may be associated with adverse health outcomes. These results imply that every effort should be made to maintain routine vaccines during peacetime.     

Multi-symptom illnesses, unexplained illness and Gulf War Syndrome

Explanatory models for the increased prevalence of ill health in Gulf veterans compared to those not deployed to the Gulf War 1990-1991 remain elusive. This article addresses whether multi-symptom reporting in Gulf veterans are types of medically unexplained symptoms and whether the alleged Gulf War Syndrome is best understood as a medically unexplained syndrome. A review of the epidemiological studies, overwhelmingly cross-sectional, describing ill health was conducted including those that used factor analysis to search for underlying or latent clinical constructs. The overwhelming evidence was that symptoms in Gulf veterans were either in keeping with currently defined psychiatric disorders such as depression and anxiety or were medically unexplained. The application of factor analysis methods had varied widely with a risk of over interpretation in some studies and limiting the validity of their findings. We concluded that ill health in Gulf veterans and the alleged Gulf War Syndrome is best understood within the medically unexplained symptoms and syndromes constructs. The cause of increased reporting in Gulf veterans are still not clear and requires further inquiry into the interaction between sociological factors and symptomatic distress.     

Lifestyle and fertility: the influence of stress and quality of life on male fertility

Background

Male infertility is a widespread condition among couples. In about 50% of cases, couple infertility is attributable to the male partner, mainly due to a failure in spermatogenesis. In recent times, the crucial role that modifiable lifestyle factors play in the development of infertility have generated a growing interest in this field of study, i.e. aging, psychological stress, nutrition, physical activity, caffeine, high scrotal temperature, hot water, mobile telephone use. Several studies have investigated associations between semen quality and the presence of lifestyle stressors i.e. occupational, life events (war, earthquake, etc.) or couple infertility; overall, these studies provide evidence that semen quality is impaired by psychological stress. In this review, we will discuss the impact of quality of life (modifiable lifestyle factors) and psychological stress on male fertility. In addition, the role that increased scrotal temperature along with inappropriate nutritional and physical exercise attitudes exert on male fertility will be presented.

Conclusion

The decline of male fertility, particularly associated with advancing age, incorrect lifestyles and environmental factors plays an important role on natality, and its consequences on the future on human population makes this an important public health issue in this century. Thus, modification of lifestyle through a structured program of educational, environmental, nutritional/physical exercise and psychological support, combined with the use of nutraceutical antioxidants can prevent infertility and therefore, may help couples to obtain better quality of life and improved possibility to conceive spontaneously or optimize their chances of conception.

     

Use of somatic cell nuclear transfer to study meiosis in female cattle carrying a sex-dependent fertility-impairing X-chromosome abnormality

Animal models have played an important part in establishing our knowledge base on reproduction, development, and the occurrence and impact of chromosome abnormalities. Translocations involving the X chromosome and an autosome are unique in that they elicit sex-dependent infertility, with male carriers rendered sterile by synaptic anomalies during meiosis, whereas female carriers conceive but repeatedly abort. Until now the limited access to relevant fetal oocytes has precluded direct study of meiotic events in female carriers. Because somatic cell nuclear transfer (SCNT) circumvents meiotic problems associated with fertility disturbances in translocation carriers, we used SCNT to generate embryos, fetuses, and calves from a cell line derived from a deceased subfertile X-autosome translocation carrier cow to study the meiotic configurations in carrier oocytes. Data from 33 replicates involving 2470 oocyte-donor-cell complexes were assessed for blastocyst development and of these, 42 blastocysts were transferred to 21 recipients. Fourteen pregnancies were detected on day 35 of gestation. One of these was sacrificed for ovary retrieval on day 94 and three went to term. Features of oocytes from the fetal ovary and from the newborn ovaries were examined. Of the pachytene spreads analyzed, 16%, 82%, and 1.5% exhibited quadrivalent, trivalent/univalent, and bivalent/univalent/univalent structures, respectively, whereas among the diakinesis/metaphase I spreads, 16% ring, 75% chain, and 8.3% bivalent/bivalent configurations were noted, suggesting that the low fertility among female carriers may be related to synaptic errors in a predominant proportion of oocytes. Our results indicate that fibroblasts carrying the X-autosome translocation can be used for SCNT to produce embryos, fetuses, and newborn clones to study such basic aspects of development as meiosis and to generate carriers that cannot easily be reproduced by conventional breeding.     

Parental fertility and infant hypospadias: an international case-control study.

The authors have performed an international case-control study on the significance of exogenous hormones for the origin of hypospadias (K?llén et al., 1991 a,b). Using data from this study on 846 infants with isolated hypospadias and equally many controls (next male infant born in the same hospital as the case), variables that might indicate an increased rate of fertility problems in couples who had a boy with hypospadias were studied. Cases had slightly fewer previous pregnancies, there was practically no difference in the rate of previous induced abortions, and no demonstrable difference in menstrual history. Infertility periods of at least 6 months were more likely among cases than controls but the difference did not reach statistical significance in a two-tailed test. There was no demonstrable difference in the time to conceive between cases and controls. The difficulties of directly studying subfertility problems are stressed.     

Birth defects prevalence among infants of Persian Gulf War veterans born in Hawaii, 1989-1993

BACKGROUND: Gulf War veterans (GWVs) have expressed concern about possible teratogenic exposures. However, epidemiologic studies on birth defects prevalence among their progeny have been limited to military hospitals, anomalies diagnosed among newborns, or self-reported data. To measure the prevalence of selected birth defects among infants of GWVs and nondeployed veterans (NDVs) in Hawaii, using birth defects surveillance records. METHODS: Personal identifiers of 684,645 GWVs and 1,587,102 NDVs and their families were matched against birth certificate records of 99,545 live births reported to the State of Hawaii Department of Health between 1989 and 1993 to identify births to military personnel. These births were matched with records from the Hawaii Birth Defects Program. RESULTS: A total of 17,182 military infants (3,717 GWV infants and 13,465 NDV infants) were identified. Of these, 367 infants (2.14/100 live births) were identified with one or more of 48 major birth defects diagnoses. The prevalence of the 48 birth defects were similar for GWV and NDV infants during the prewar and postwar periods, and among GWV infants who were conceived before and after the Gulf war. CONCLUSIONS: The results must be interpreted with caution because of the small number of affected infants in each birth defects category. This study demonstrated the feasibility of measuring birth defects prevalence among military infants through multiple data linkage. Further, it included live births to parents who had separated from the military, births in civilian hospitals, and birth defects diagnosed through the first year of life.     

Gulf War illness: a view from Australia

Australia sent a small, mostly naval, deployment to the 1991 Gulf War. When papers and media concerns arose about unexplained Gulf War illnesses in Gulf War troops from other countries, Australia decided to undertake its own study of Australian veterans. Undertaking a later study, more than 10 years after the Gulf War, allowed us to incorporate some methodological improvements on previous research, such as the inclusion of a face-to-face health assessment where more objective health data could be collected in addition to using a postal questionnaire. Despite the different Gulf War experience for the mostly naval Australian group, there were remarkable consistencies in the patterns of multiple symptom reporting found in overseas studies, including the fact that no unique symptom clusters were identified. In general, this excess symptom reporting was not found to occur with excesses in more objective measures of physical health. These objective physical measures included a wide range of haematological, biochemical and serological markers, a physical examination, spirometry and a step test of fatigability. In contrast, several psychological disorders, including anxiety, post-traumatic stress disorder, depression and substance abuse, were found to occur in excess in the Australian Gulf War group and were associated with Gulf War psychological stressors. These findings have helped raise awareness in Australia of psychological health problems in deployed military personnel.     

Healthcare utilization and mortality among veterans of the Gulf War

The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the 1990-1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149728 (19.8%) of 756373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.     

Prevention of multiple pregnancy during ovulation induction.

Gonadotrophin ovulation induction is currently used for a heterogeneous group of ovulation disorders and unexplained infertility. In the United States it is reported that multiple pregnancy rates of greater than 30% occur as a result of ovulation induction, most commonly after controlled ovarian hyperstimulation and intrauterine insemination. Treatment strategies to reduce the incidence of multiple pregnancies on ovulation induction programs can be targeted to reducing multiple follicular development and subsequent ovulation by a more aggressive cancellation policy, follicle reduction by fine needle aspiration or conversion to IVF; or dealing with the problem of multiple gestation after it has occurred (i.e., multifetal pregnancy reduction). The procedures and abilities exist to resolve this problem. What is needed are appropriate treatment guidelines and well constructed trials to demonstrate that higher order multiple pregnancies can be substantially reduced and/or eliminated without compromising a couple's chances to conceive.     

Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-Caribbean women in Trinidad with and without systemic lupus erythematosus

The objective of the study was to examine pregnancy outcomes in women with systemic lupus erythematosus (SLE) and population controls in Trinidad. We performed a cross-sectional analysis of adverse outcomes in pregnancies of Afro-Caribbean women with SLE and without SLE. One hundred and twenty-two female adult cases of SLE and 203 neighbourhood age-matched women without SLE were interviewed concerning details of their reproductive history, and the anticardiolipin antibody (ACL) status was established for women with SLE. A total of 1,029 pregnancies were reported (356 by women with SLE, 673 by women without SLE). In women with ≥ 1 pregnancy the total number of pregnancies was similar in women with a diagnosis of SLE and women without; however, a lower proportion of women with SLE had ever been pregnant compared with women without SLE (80% versus 91%, P = 0.002). In multivariate logistic regression analyses adjusted for maternal age, district of residence, pregnancy order and smoking, SLE pregnancies were more than twice as likely to end in foetal death than non-SLE pregnancies (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2–4.7). This effect was driven by a large increase in the odds of stillbirth (OR, 8.5; 95% CI, 2.5–28.8). The odds of early miscarriage (OR, 1.4; 95% CI, 0.6–3.1) and of mid-trimester miscarriage (OR, 1.9; 95% CI, 0.4–9.5) were higher, but were not statistically significantly different, in SLE pregnancies than in non-SLE pregnancies. The odds of ectopic pregnancy (OR, 7.5; 95% CI, 0.9–62.5) and of preterm birth (OR, 3.4; 95% CI, 1.2–10.0) were higher in SLE pregnancies conceived after diagnosis than in non-SLE pregnancies. There was no evidence of raised levels of IgG or IgM ACL among the majority (93/97 women, 96%) of SLE cases who reported sporadic mid-trimester miscarriage or stillbirth, although there was evidence of high levels of IgM and IgG ACL among women reporting three or more miscarriages and three consecutive miscarriages, and of raised IgG ACL among those experiencing ectopic pregnancy. In conclusion, we found evidence for a large increase in risk of stillbirth in the pregnancies of Afro-Caribbean Trinidadian women with SLE (not accounted for by high ACL status). There was some evidence of an increased risk of preterm delivery and ectopic pregnancy in pregnancies conceived after a diagnosis of maternal SLE.     

The challenges of exposure assessment in health studies of Gulf War veterans

A variety of exposures have been investigated in Gulf War veterans' health studies. These have most commonly been by self-report in a postal questionnaire but modelling and bio-monitoring have also been employed. Exposure assessment is difficult to do well in studies of any workplace environment. It is made more difficult in Gulf War studies where there are a number and variety of possible exposures, no agreed metrics for individual exposures and few contemporary records associating the exposure with an individual. In some studies, the exposure assessment was carried out some years after the war and in the context of media interest. Several studies have examined different ways to test the accuracy of exposure reporting in Gulf War cohorts. There is some evidence from Gulf War studies that self-reported exposures were subject to recall bias but it is difficult to assess the extent. Occupational exposure-assessment methodology can provide insights into the exposure-assessment process and how to do it well. This is discussed in the context of the Gulf War studies. Alternative exposure-assessment methodologies are presented, although these may not be suitable for widespread use in veteran studies. Due to the poor quality of and accessibility of objective military exposure records, self-assessed exposure questionnaires are likely to remain the main instrument for assessing the exposure for a large number of veterans. If this is to be the case, then validation methods with more objective methods need to be included in future study designs.     

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness

Gulf War Illness (GWI) has been reported in 25%–35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.     

Expression of genes associated with immunity in the endometrium of cattle with disparate postpartum uterine disease and fertility

Background  

Contamination of the uterine lumen with bacteria is ubiquitous in cattle after parturition. Some animals develop endometritis and have reduced fertility but others have no uterine disease and readily conceive. The present study tested the hypothesis that postpartum cattle that develop persistent endometritis and infertility are unable to limit the inflammatory response to uterine bacterial infection.     

Population genetics study of the differential fertility in urban populations

In an urban population with widespread birth control practice the distribution of the number of pregnancies, births and abortions was studied in a cohort of women of completed fertility. The mean number of pregnancies per woman was 4.03 +/- 0.08 (sigma = = 2.98); the mean number of births - 1.12 +/- 0.02 (sigma = 0.77). 7.4% of women which had completed their reproductive performance had no pregnancies and 19.5% - no births. The Crow's Index of the Opportunity for Selection and its components connected with differential fertility and differential mortality were estimated. In the population under study two components of selection - selection at the prenatal stages and selection associated with infertility - are shown to be still significant. Such type of selection is exemplified by investigation of couples suffering from repeated spontaneous abortions.     

The case of an infertile male with an uncommon reciprocal X-autosomal translocation: how does this affect male fertility?

Infertility is defined as the inability to conceive after one year of regular unprotected intercourse. Constitutional numerical and/or structural chromosomal aberrations like sex-chromosome aberrations are one of the possible factors involved in fertility problems. Reciprocal translocations between an X-chromosome and an autosome are rarely seen in men. Male carriers of an X-autosome translocation are invariably sterile, regardless of the position of the breakpoint in the X-chromosome. Breakpoints in autosomal chromosomes could also be involved in male infertility. In this paper, we describe a 31-year-old male with azoospermia. GTG banding with high resolution multicolor-banding (MCB) techniques revealed a karyotype 46,Y,t(X;1)(p22.3;q25), and we discuss how the breakpoint of this translocation could affect male infertility. As a conclusion, cytogenetic evaluation of infertile subjects with azoospermia should be considered in the first place before in vitro fertilisation procedures are planned.     

Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide,Population-Based Case-Control Study

Background

An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls.

Methods

We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden.

Results

1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89–1.02), nor for any risk category, OR 0.97 (95% CI 0.84–1.12) for low-risk disease, and OR 1.04 (95% CI 0.90–1.22) for metastatic disease.

Conclusion

The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.     

MPA given orally during the first trimester for threatened miscarriage carries no specific risk for foetal abnormalities albeit the rate is higher than non-threatened pregnancies

This observational study examines the outcomes of pregnancies arising in women referred for infertility, where those who experienced threatened miscarriage were treated with medroxyprogesterone acetate (MPA) tablets. The 14-year study period covers comprehensive real-time data entries into the validated electronic database including details of the infertility management, pregnancy outcomes and any foetal anomalies among the infants, each being tracked and recorded. Of 4057 clinical pregnancies, 1343 received MPA for threatened miscarriage; 934 (69.6 %) of which continued to livebirths. These were compared with the remaining 2714 clinical pregnancies without threatened miscarriage or MPA and which resulted in 2075 (76.5 %) livebirths. There were 134 developmental abnormalities recorded among the 3009 livebirths of which 78 (2.6 %) were categorised appropriate for the Western Australian Developmental Abnormalities Register; WARDA. These comprised 55 in the MPA group, 36 of which were categorised as serious (being 2.7 % of clinical pregnancies and 3.9 % of births). In the group without MPA, there were 79 abnormalities, of which 42 were categorised as serious (being 1.7 % of clinical pregnancies and 2.2 % of births). Specifically, there were no cases of androgenisation noted among the female infants. The abnormality rates were low overall and well within the annual WARDA ranges. We cautiously suggest that oral MPA can be considered for studies throughout pregnancy including the early first trimester to assess a potential role in reducing miscarriage, as well as advanced pregnancies to evaluate a potential role in reducing stillbirths and preterm delivery.