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9 Reproductive Effects
Pages 591-639

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From page 591...
... This section will expand on some of these issues as they relate specifically to reproductive epidemiology. Many of these issues are important in the interpretation of the findings of a number of studies of herbicides and reproductive outcomes in which the relative risk estimate is "weak" or "moderate," that is, between 1 and 2.
From page 592...
... In a cohort study evaluating herbicide exposure (e.g., among occupational groups or Vietnam veterans) and spontaneous abortion, approximately 266 total pregnancies would have to be studied to detect a doubling of risk (relative risk = 2, alpha = .05, beta = .80~.
From page 593...
... , further study of female veterans is called for; nonetheless, the majority of potentially exposed workers and veterans are men. This situation requires further general discussion, given the fact that the vast majority of animal and human data on adverse reproductive outcomes pertain to maternal preconceptional or in utero exposure not paternal exposure.
From page 594...
... A summary of the findings from epidemiologic studies is provided here. Paternal occupational exposure to vinyl chloride, anesthetic gases, dibromochloropropane, mercury, lead, other metals, and various solvents has been linked to an increased risk of fetal loss (spontaneous abortion)
From page 595...
... Because preimplantation and early postimplantation losses are difficult to ascertain for epidemiologic studies of pregnancy loss, the appropriate epidemiologic end point for these studies is not all spontaneous abortions but rather all clinically recognized spontaneous abortions-those that come to the attention of a woman or her physician. All subsequent discussions of pregnancy loss, miscarriage, or spontaneous abortion refer to clinically recognized outcomes unless otherwise specified.
From page 596...
... appear to have a higher proportion of chromosomally normal spontaneous abortions relative to their higher-SES counterparts. Other maternal medical conditions and exposures that have been associated, at least in some studies, with an increased risk of miscarriage include diabetes and epilepsy, a history of maternal fever during pregnancy, uterine and hormonal abnormalities, immunologic (e.g., Rh factor)
From page 597...
... The major limitation of this study was the small number of exposed and unexposed workers, which resulted in inadequate statistical power to detect anything other than a very large relative risk (RR)
From page 598...
... of 548 herbicide applicators in New Zealand did not find an increased risk of spontaneous abortion, with an odds ratio of 0.9 (CI 0.6-1.5) for the comparison of 2,4,5-T sprayers to men who were employed as agricultural workers without herbicide exposure.
From page 599...
... Spontaneous abortion increased in the sprayed area from 5.6 percent before the spraying to 13.9 percent after the time of spraying, and in the unsprayed area from 7.3 to 7.4 percent. An analysis of reproductive outcomes from 1952 to 1981 at a referral hospital in Ho Chi Minh City showed an increase in spontaneous abortion starting in 1967 (14.6 percent versus 4.1 percent in 1966)
From page 600...
... At present, from available reports, the studies from Vietnam, although suggesting an increased risk of spontaneous abortion, are of insufficient quality to weigh heavily in the final evaluation of an association with herbicides. Several studies conducted in Vietnam have also examined the risk for hydatidiform mole (Constable and Hatch, 1985; Huong et al., 1989; Phuong et al., 1989a)
From page 601...
... of 7,924 Vietnam veterans and 7,364 non-Vietnam veterans detected a significant, slightly increased relative risk estimate for spontaneous abortion (adjusted OR = 1.3, CI 1.2-1.4; CDC, 1989~. Veterans' self-reported herbicide exposure showed an apparent dose-response gradient, with an odds ratio of 1.2 (CI 1.0-1.4)
From page 602...
... A case-control study of spontaneous abortion in Massachusetts (Aschengrau and Monson, 1989) did not indicate an overall increased risk among women married to Vietnam veterans (adjusted OR = 0.9, CI 0.4-1.9~.
From page 603...
... The available epidemiologic studies of veterans are generally limited by inadequate sample sizes, potential bias, and other methodologic problems. There are some suggestive findings indicating an increased risk for Vietnam veterans, including a possible dose-response gradient of increasing risk with increasing estimated (self-reported or inferred)
From page 604...
... Vietnam veterans compared to: Vietnam-era veterans Low exposure Medium exposure High exposure Herbicide handlers Compared to low exposure: Medium exposure High exposure Aschengrau and Spontaneous abortion and husband's Monson, 1989 Vietnam service 231 1.4 (1.1 - 1.6)
From page 605...
... Studies of the potential reproductive toxicity of the herbicides are too limited to permit conclusions. Increased Risk of Disease in Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, the effects of selection, information, and confounding bias in these studies, and the lack of informatio needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
From page 606...
... Given the general frequency of major birth defects of 2 to 3 percent and the number of men who served in Vietnam (2.6 million) , and by assuming that they had at least one child, it has been estimated that 52,000 to 78,000 babies with birth defects have been fathered by Vietnam veterans, even in the absence of an increase due to exposure to herbicides or other toxic substances (Erickson et al., 1984a)
From page 607...
... . Epidemiologic Studies of Birth Defects Occupational Studies Four occupational epidemiology studies have examined the potential association between herbicide exposure of male workers and birth defects.
From page 608...
... These studies indicate an increased risk of birth defects including anencephaly, oral clefts, and a variety of other anomalies. Nonetheless, these studies generally suffer from poor reporting and a variety of methodologic problems such as limited control of confounding factors, use of a referral hospi
From page 609...
... An analysis of Vietnam veterans' self-reported herbicide exposure found a dose-response gradient, with an adjusted odds ratio for birth defects of 1.7 (CI 1.2-2.4) at the highest level of exposure.
From page 610...
... The number of defects was also too small for the analysis of specific individual defects. An analysis by race did indicate an elevated odds ratio (3.4, CI 1.5-7.6' for black Vietnam veterans.
From page 611...
... As an attempt to evaluate recall bias, two record validation studies of birth defects were conducted. Overall, the GBDS did not find any association with an increased risk of birth defects among offspring of Vietnam veterans.
From page 612...
... The results of this study were generally negative; that is, there was not a general pattern of increased risk for birth defects among the offspring of Vietnam veterans. However, the analysis of the Agent Orange EOIs based on military records found a significant trend for increased risk for spine bifida with increased exposure.
From page 613...
... The analyses compared the risk of malformations among children of 107 Vietnam veterans to that for children of 1,432 men without known military service; the risk in 313 non-Vietnam veterans compared to the 1,432 men without military service; and the 107 Vietnam veterans with the 313 nonVietnam veterans. There was a slight, nonsignificant increase in the odds ratio for all congenital anomalies for Vietnam veterans compared to men without known military service, (OR = 1.3, CI 0.9-1.9)
From page 614...
... Confidence intervals were not presented with the odds ratio estimates, but it was noted that they included 1.0, so elevated risks were not significantly increased. Further examination of specific anomaly diagnoses for the 18 infants of Vietnam veterans with major malformations did not reveal any pattern of association with potential herbicide exposure.
From page 615...
... There was a slight, statistically nonsignificant increase in the odds ratio for National Service Vietnam veterans versus National Service veterans who did not serve in Vietnam (OR = 1.3, CI 0.9-2.0~. It was found that the risk was independent of the length of Vietnam service and the time between service and conception.
From page 616...
... Moses et al., 1984 Follow-up of 2,4,5-T production workers 11 1.3 (0.5-3.4) Environmental Fitzgerald et al., Follow-up of an electrical transformer fire 1989 Total birth defects Hanify et al., 1981 Mastroiacovo et al., 1988 Stockbauer et al., 1988 Vietnam veterans All malformations All heart malformations Hypospadias, epispadias Talipes Anencephaly Spina bifida Cleft lip Isolated cleft palate Reproductive outcomes of Seveso, Italy, residents Zones A and B total defects Zones A, B
From page 617...
... Vietnam veterans vs. all other men 127 National Service veterans Vietnam service vs.
From page 618...
... Increased Risk of Disease in Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental and veterans studies that have been reviewed, the effects of selection and information bias and low statistical power in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH Introduction Definitions The use of the terms stillbirth and neonatal death can be confusing and
From page 619...
... The perinatal mortality rate of a population is often calculated as the sum of the number of stillbirths plus the number of deaths in the first week of life occurring per 1,000 live and stillbirths. Late neonatal death is usually defined as death of the infant after the first week but within the first 28 days of life, and infant death as death within the first year.
From page 620...
... The limitations of most of the occupational studies with respect to exposure assessment and statistical power have been described previously for other outcomes. Two environmental studies that have analyzed stillbirth have not reported an overall increased risk related to potential herbicide exposure (Stockbauer et al., 1988; White et al., 1988~.
From page 621...
... Vietnam Veterans Studies The Massachusetts veterans study did not report an increased risk of neonatal death for Vietnam veterans (OR = 1.1, CI 0.2-4.5) versus nonVietnam veterans or men without military service (OR = 1.2, CI 0.2-4.2)
From page 622...
... did not report an association with infant death. Self-reports of infant death from the interview study of the CDC's VES did not indicate an increased risk of deaths among children of Vietnam veterans relative to nonVietnam veterans (OR = 1.0, CI 0.8-1.3)
From page 623...
... 6 1.3 (0.4-4.2) Vietnam veterans Aschengrau and Neonatal death and paternal Vietnam service Monson, 1990 Vietnam veterans compared to men with no known military service3 1.2 (0.2-4.2)
From page 624...
... were limited by low statistical power, potential selection bias, and inadequate exposure classification. One study of veterans reported an association of infant death with self-reported herbicide exposure Nonetheless, other studies did not report an increased risk, but as noted for other outcomes, problems with exposure determination, statistical power, and potential bias limit interpretation.
From page 625...
... , the factors most strongly associated with reduced birthweight are maternal smoking during pregnancy, multiple births, and race/ethnicity. Other potential risk factors for low birthweight include SES, maternal size, birth order, maternal complications during pregnancy (e.g.,
From page 626...
... found similar rates of low birthweight among the offspring of Vietnam veterans and non-Vietnam veterans (OR = 1.1, CI 0.8-1.4~. Analysis by self-reported herbicide exposure did not indicate a pattern of increase with mid to high levels of exposure (CDC, 1989~.
From page 627...
... Studies of veterans were inconsistent; some indicated no increased risk, whereas others suggested an increased risk among certain subgroups. Future analyses of the Ranch Hand data may contribute important evidence regarding an increased risk for low birthweight among offspring of exposed Vietnam veterans.
From page 628...
... CHILDHOOD CANCER Introduction Definition and Descriptive Epidemiology In most epidemiologic studies, childhood cancer usually refers to cancer diagnosed from birth through age 15 years. Childhood cancers are usually classified by primary anatomic site or tumor cell type.
From page 629...
... Epidemiologic Studies of Childhood Cancer Occupational and Environmental Studies There were no studies that directly examined occupational or environmental exposure to herbicides or dioxin in relation to childhood cancer in offspring. Vietnam Veterans Studies The Field and Kerr (1988)
From page 630...
... Two studies of Vietnam veterans found some suggestion of an increased risk of cancer among offspring (see Table 9-6~. The evidence is, however, inadequate, given the lack of other studies, failure to exclude chance and bias, and problems with herbicide exposure assessment.
From page 631...
... . Men with sperm counts of less than 20 million/ml appear to be at an increased risk of infertility, although there is some uncertainty about the specific nature of the relationship between sperm number (or concentration)
From page 632...
... Vietnam Veterans Studies The Air Force study of 417 Ranch Hand veterans did not report decreased sperm count or increased percentage of abnormal sperm compared to the controls (AFHS, 19921. In fact, the reported relative risks were lower in the groups of exposed men.
From page 633...
... Vietnam veterans Stellman et al., 1988 CDC, 1989 Assessment of reproductive effects among American Legionnaires who served in Southeast Asia Difficulty having children Vietnam Experience Study Lower sperm concentration Proportion of abnormal sperm Reduced sperm motility 349 1.3, p ~ .01 42 51 83 NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval.
From page 634...
... Increased Risk of Disease in Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, effects of information bias in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
From page 635...
... 1988. Health status of Vietnam veterans.
From page 636...
... 1992. Semen Analysis in Vietnam Veterans with Respect to Presumed Herbicide Exposure.
From page 637...
... New Jersey Agent Orange Commission' Association of Birth Defect Children. Report submitted to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides.
From page 638...
... 1988. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam.
From page 639...
... 1985. Iowa Agent Orange Survey of Vietnam Veterans.


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