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Veterans and Agent Orange: Update 2012 (2014)

Chapter: 9 Fertility and Gestational Outcomes

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Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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9


Fertility and Gestational Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and fertility or gestational outcomes. Current evidence supports the findings of earlier studies that

•    None of the fertility or gestational outcomes had sufficient evidence of an association with the chemicals of interest.

•    None of the fertility or gestational outcomes had limited or suggestive evidence of an association between the chemicals of interest.

•    There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and endometriosis; decreased sperm counts or sperm quality, subfertility, or infertility; spontaneous abortion, stillbirth, neonatal death, or infant death; and low birth weight or preterm delivery.

•    There is limited or suggestive evidence of no association between paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and spontaneous abortion.

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2010, hereafter referred to as Update 2010 (IOM, 2011), on the association between exposure to herbicides and adverse effects on fertility and during gestation. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, 2004, 2006, and 2008 [IOM, 1996,

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

1999, 2001, 2003, 2005, 2007, 2009] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to TCDD. Because some polychlorinated biphenyls (PCBs), some polychlorinated dibenzofurans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs). Although all studies reporting TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization’s revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006).

The adverse outcomes evaluated in this chapter include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth), neonatal and infant mortality, and the adverse gestational outcomes of low birth weight or preterm delivery. In this update, consideration of the possibility of adverse health outcomes at any time during the lives of all progeny of Vietnam veterans has been moved to a separate chapter: Chapter 10, “Effects on Future Generations.”

Because the vast majority of Vietnam veterans are men, the primary focus of the VAO series has been on potential adverse effects of herbicide exposure on men, and the etiologic importance of the exposed party’s sex does not play the dominant role in nonreproductive outcomes that it does in reproductive outcomes. However, about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so findings relevant to female reproductive health, such as endometriosis, are also included in the present chapter. Whenever the information was available, an attempt was made to evaluate the effects of exposure on adult men and women separately.

The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. To reduce repetition throughout the report, Chapter 6 characterizes study populations and presents design information related to new publications that report findings on multiple health outcomes or that revisit study populations considered in earlier updates.

BIOLOGIC PLAUSIBILITY OF EFFECTS ON FERTILITY AND REPRODUCTION

This chapter opens with a general discussion of factors that influence the plausibility of adverse reproductive effects of TCDD and the four herbicides used in Vietnam. There have been few reproductive studies of the four herbicides in

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the preponderance of the following discussion concerns TCDD, which other than in controlled experimental circumstances usually occurred in a mixture of dioxins (dioxin congeners in addition to TCDD).

TCDD is stored in fat tissue and has a long biologic half-life, so internal exposure at generally constant concentrations may continue after episodic, highlevel exposure to external sources ceases. If a person had high exposure, high amounts of dioxins may still be stored in fat tissue and be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid.

Dioxin exposure has the potential to disrupt male reproductive function by altering gene expression that is pertinent to spermatogenesis and by altering steroidogenesis (Wong and Cheng, 2011) and to disrupt female reproductive function by altering gene expression pertinent to ovarian follicle growth and maturation, uterine function, placental development, and fetal morphogenesis and growth.

A father’s direct contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg; those contents had long been thought to consist of greatly condensed, transcriptionally inert deoxyribonucleic acid (DNA) constituting half the paternal genome (a haploid set of chromosomes). Consequently, it was believed that paternally-derived damage to the embryo or offspring could only result from changes in sperm DNA, but dioxins have not been shown to mutate DNA sequence. More recently, however, it has been recognized that sperm also carry a considerable collection of ribonucleic acid (RNA) fragments (Kramer and Krawetz, 1997; Krawetz et al., 2011). Although ribosomal and messenger RNAs have been detected, as yet, demonstration of an active role has been limited to several of the small RNAs found in mature sperm (Krawetz, 2005), in such functions as fertilization itself (Amanai et al., 2006), early embryonic development (Hamatani, 2012; Suh and Blelloch, 2011), and epigenetic determinations (Kawano et al., 2012). Epigenetic effects are ones that result in permanent (heritable) changes in gene expression without a change in DNA sequence arising from modification to DNA (usually involving methylation) or to other cellular components such as histones and RNAs (Jirtle and Skinner, 2007). Therefore, male infertility or fetal loss associated with exposure to the chemicals of interest (COIs) might be mediated by epigenetic modifications to components of sperm other than their DNA (Krawetz, 2005).

A mother’s contribution to a pregnancy is obviously more extensive, and damage to an embryo or offspring can result from epigenetic changes of the egg DNA or from direct effects of exposure on placenta formation and the fetus during gestation. Mobilization of dioxin during pregnancy may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus. TCDD has been measured in human circulating maternal blood, cord

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

blood, and placenta. Thus, dioxin in the mother’s bloodstream could cross the placenta and expose the developing embryo and fetus. Data indicate that dioxin can accumulate in placental tissue, but the amount of TCDD that can transfer to the fetus appears to be very limited—TCDD’s transfer index was the lowest of 13 environmental toxicants evaluated in perfusion studies of human placentas (Mose et al., 2012).

On the basis of laboratory animal studies, TCDD can affect reproduction, so a connection between TCDD exposure and human reproductive and gestational effects is biologically plausible. However, definitive conclusions based on animal studies about the potential for TCDD to cause reproductive and gestational toxicity in humans are complicated by differences in sensitivity and susceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences between laboratory animals and humans in the toxicokinetics of TCDD. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that they have subcellular effects that could constitute a biologically plausible mechanism for reproductive and gestational effects. However, the preponderance of evidence from animal studies indicates that they do not have reproductive effects. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their reproductive or gestational effects.

The sections on biologic plausibility of the specific outcomes considered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed.

ENDOMETRIOSIS

Endometriosis (International Classification of Diseases, Ninth Revision [ICD-9], code 617) affects 5.5 million women in the United States and Canada at any given time (NICHD, 2007). The endometrium is the tissue that lines the inside of the uterus and is built up and shed each month during menstruation. In endometriosis, endometrial cells are found outside the uterus—usually in other parts of the reproductive system, in the abdomen, or on surfaces near the reproductive organs. The ectopic tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with the menstrual cycle. Unlike blood released during normal shedding of the endometrium, blood released from endometrial lesions has no way to leave the body and results in inflammation and internal bleeding. The degeneration of blood and tissue can cause scarring, pain, infertility, adhesions, and intestinal problems.

There are several theories of the etiology of endometriosis, including a genetic contribution, but the cause remains unknown. Estrogen dependence and im-

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

mune modulation are established features of endometriosis but do not adequately explain its cause. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those who have immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis, diagnosis is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure.

Conclusions from VAO and Previous Updates

Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies. Additional studies considered in later updates have not changed the conclusion that the evidence is inadequate or insufficient to support an association with herbicide exposure. Table 9-1 provides a summary of relevant studies that have been reviewed.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and endometriosis have been published since Update 2010.

Environmental Studies

Cai et al. (2011) recruited 17 women who were undergoing diagnostic laparoscopy for infertility in Japan during October 2004–March 2007. Of those women, 10 were found to have endometriosis, and 7 were not. Serum and peritoneal fluid were collected from each participant during her follicular phase and analyzed for 7 PCDDs, 10 PCDFs, and 12 dioxin–like PCBs. Concentrations adjusted for lipids were measured with gas chromatography–mass spectrometry, and from them, TEQs attributable to dioxins, to furans, and to PCBs and an overall total in serum and peritoneal fluid were calculated for each participant. There were no differences in lipid–adjusted TEQ for any of the categories in either serum or peritoneal fluid between women who had endometriosis and women who did not. The authors noted that in women who had high PCDD and PCDF simultaneously in the peritoneal fluid, there was an association with endometriosis (odds ratio [OR] = 2.5, 95% confidence interval [CI] 1.17–5.34). Although this finding achieved statistical significance by usual standards, the sample studied was very small and the biologic importance of this isolated result is unclear.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 9-1 Selected Epidemiologic Studies—Endometriosis (Shaded Entry Is New to This Update)


Study Population Study Results Reference

ENVIRONMENTAL
 
Studies Conducted in the United States
 

Case-control study of women in Atlanta, Georgia, with endometriosis; 60 cases and 64 controls

Results for cases vs controls:
Total TEQ (determined by GC/MS): OR = 01.0 (95% CI 0.9–1.1)
Niskar et al., 2009
 
Studies Conducted in Belgium
 

88 matched triads (264 total); patients with deep endometriotic nodules, pelvic endometriosis, controls matched for age, gynecologic practice in Belgium; routes of exposure to DLCs examined

Results for pelvic endometriosis vs controls:

Dietary fat: OR = 1.0 (95% CI 1.0–1.0)

BMI: OR = 1.0 (95% CI 0.9–1.0)

Occupation: OR = 0.5 (95% CI 0.2–1.1)

Traffic: OR = 1.0 (95% CI 0.3–2.8)

Incinerator: OR = 1.0 (95% CI 1.0–1.1)

Heilier et al., 2007
 

Serum DLC and aromatase activity in endometriotic tissue from 47 patients in Belgium

No association between TEQs (determined by GC/MS) of DLCs in serum and aromatase activity by regression analyses p-values = 0.37–0.90 for different endometriosis subgroups Heilier et al., 2006
 

Endometriosis in Belgian women with overnight fasting serum levels of PCDD, PCDF, PCB

50 exposed cases, risk of increase of 10 pg/g lipid of TEQ compounds (determined by GC/MS); OR = 2.6 (95% CI 1.3–5.3) Heilier et al., 2005
 

Belgian women with environmental exposure to PCDDs, PCDFs; compared analyte concentrations in cases vs controls

Mean concentration of TEQ (determined by GC/MS) Cases (n = 10), 26.2 (95% CI 18.2–37.7) Controls (n = 132), 25.6 (95% CI 24.3–28.9) No significant difference Fierens et al., 2003
 

Patients undergoing infertility treatment in Belgium; compared number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay)

Six exposed cases: OR = 4.6 (95% CI 0.5–43.6) Pauwels et al., 2001
 
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Study Population Study Results Reference

Studies Conducted in Italy
 

Case-control study of Italian women with endometriosis; 80 cases and 78 controls (TEQs determined by CALUX bioassay)

Results for endometriosis vs controls: dl PCB118 compared to ≤ 13.2 ng/g: 13.3–24.2 ng/g; OR = 3.17 (95% CI 1.36–7.37) ≥ 24.3 ng/g; OR = 3.79 (95% CI 1.61–8.91) Total TEQ compared to ≤ 15.6 pgC-TEQ/g fat: 15.7–29.5 pgC-TEQ/g fat; OR = 0.52 (95% CI 0.18–1.48) ≥ 29.6 pgC-TEQ/g fat; OR = 0.73 (95% CI 0.26–2.01) Porpora et al., 2009
 

Case-control study of Italian women with endometriosis, measured serum PCBs

Mean total PCBs (ng/g) Cases, 410 ng/g Control, 250 ng/g All PCB congeners: OR = 4.0 (95% CI 1.3–13) Porpora et al., 2006
 

Pilot study of Italian, Belgian women of reproductive age; compared concentrations of TCDD, total TEQ (determined by GC/MS) in pooled blood samples from women who had diagnosis of endometriosis with controls

Mean concentration of TCDD (ppt of lipid):

Italy:

Controls (10 pooled samples), 1.6

Cases (2 sets of 6 pooled samples), 2.1, 1.3

Belgium:

Controls (7 pooled samples), 2.5

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 2.3, 2.3

De Felip et al., 2004
 
  Mean concentration of TEQ (ppt of lipid):

Italy:

Controls (10 pooled samples), 8.9 ± 1.3 (99% CI 7.2–11.0)

Cases (2 sets of 6 pooled samples), 10.7 ± 1.6; 10.1 ± 1.5

Belgium:

Controls (7 pooled samples), 24.7 ± 3.7 (99% CI 20–29)

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 18.1 ± 2.7; 27.1 ± 4.0

 
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Study Population Study Results Reference

Residents of Seveso Zones A and B up to 30 yrs old in 1976; populationbased historical cohort comparing incidence of endometriosis across serum TCDD concentrations

≤ 20 (n = 2 cases), RR = 1.0 (reference) 20.1–100, (n = 8), RR = 1.2 (90% CI 0.3–4.5) > 100, (n = 9), RR = 2.1 (90% CI 0.5–8.0) Eskenazi et al., 2002a
 
Studies Conducted in Israel
 

Residents of Jerusalem being evaluated for infertility; compared number of women with high TCDD who had (n = 44), did not have (n = 35) a diagnosis of endometriosis

8 exposed cases: OR = 7.6 (95% CI 0.9–169.7) Mayani et al., 1997
 
Studies Conducted in Japan
 

17 women undergoing diagnostic laparoscopy for infertility, 10 were found to have endometriosis and 7 were not

TEQ calculated for each person based on PCDDs, PCDFs, and 12 dl-PCBs. No difference in lipid-adjusted exposure levels between those with and without endometriosis. Association was seen with endometriosis and women with high PCDD and PCDF (OR = 2.5, 95% CI 1.2–5.3) Cai et al., 2011
 

138 infertility patients in Japan; laproscopically confirmed casecontrol status, serum dioxin, PCB TEQ (determined by GC/MS); P450 genetic polymorphism

Results for advanced endometriosis: Total TEQ: OR = 0.5 (95% CI 0.2–1.7) Genotype-specific: ORs = 0.3–0.6 No significant interaction between genotype, dioxin TEQ Tsuchiya et al., 2007

NOTE: BMI, body mass index; CALUX, chemical activated luciferase gene expression; CI, confidence interval; dl, dioxin-like; DLC, dioxin-like compound; GC/MS, gas chromatography/mass spectrometry; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetra-chloro dibenzo-p-dioxin; TEQ, (total) toxic equivalent.

Biologic Plausibility

Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. Genetic polymorphisms in the aryl hydrocarbon receptor (AHR) signaling complex have recently been associated with susceptibility to advanced endometriosis in humans (Wu et al., 2012). The first suggestion that TCDD exposure may be linked to endometriosis came as a secondary finding of a study that exposed female rhesus

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

monkeys (Macaca mulatta) chronically to low concentrations of dietary TCDD for 4 years (Rier et al., 1993). Ten years after the exposure ended, the investigators documented an increased incidence of endometriosis in the monkeys that correlated with the TCDD exposure concentration. The sample was too small to yield a definitive conclusion that TCDD was a causal agent of endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of preexisting endometriotic lesions.

There are a number of mechanisms by which TCDD may promote endometrial lesions, which constitute additional support of biologic plausibility of a link between TCDD and endometriosis. Human endometrial tissue and cultured human endometrial epithelial cells both express the AHR; its dimerization partner, the aryl hydrocarbon nuclear translocator (Khorram et al., 2002); and three AHR target genes—CYP1A1, 1A2, and 1B1 (Bulun et al., 2000; Willing et al., 2011). That suggests that endometrial tissue is responsive to TCDD. Recently, it was shown that CYP1A1 expression is greater in ectopic endometrial tissue than in eutopic uterine tissue in the absence of TCDD exposure; this suggests that CYP1A1 may play a role in disease etiology (Singh et al., 2008). Other mechanisms by which TCDD may promote endometriosis include altering the ratio of progesterone receptor A to B and blocking the ability of progesterone to suppress matrix metalloproteinase expression—actions that promote endometrial-tissue invasion and that are observed in women who have endometriosis (Igarashi et al., 2005).

TCDD also induces changes in gene expression that mirror those observed in endometrial lesions. In addition to the induction of CYP1A1 noted above, TCDD can induce expression of histamine-releasing factor, which is increased in endometrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). Similarly, TCDD stimulates expression of RANTES (regulated on activation, normal T-cell-expressed, and secreted protein) in endometrial stromal cells, and RANTES concentration and bioactivity are increased in women who have endometriosis (Zhao et al., 2002). The two CC-motif chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory protein 1α (MIP-1a), have been identified as potential contributors to the pathogenesis and progression of endometriosis. Previous studies showed that the combination of 17β-estradiol and TCDD increased the secretion of RANTES and MIP-1α in endometrial stromal cells (Yu et al., 2008), and a more recent study showed that the same combination suppressed the expression of tetraspanin CD82, a tumor-metastasis suppressor, and thus promoted the invasion of endometrial stromal cells (Li et al., 2011). Those results support the idea that TCDD in combination with estradiol may contribute to the development of endometriosis by increasing invasiveness of endometrial cells. Despite that compelling evidence, chronic exposure of rats to TCDD, PCB153, dioxin-like PCB118 or PCB126, or 2,3,4,7,8-PeCDF (the furan congener with the highest TEF) individually or to various mixtures of these chemicals fails to alter endometrial histology in a consistent manner (Yoshizawa

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

et al., 2009). Differences between rodent and human endometrium could account for the lack of observed effects in rats.

In summary, experimental studies, particularly ones that used human eutopic and ectopic endometrial tissue, provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis.

Synthesis

The studies linking dioxin exposure with endometriosis are few and inconsistent. The single new epidemiologic study since Update 2010 found no substantive pattern of dioxin-like activity in serum or in peritoneal fluid that would distinguish infertile women who do and do not have endometriosis; however, this study was very small and involved a large number of statistical tests. Although animal studies support the biologic plausibility of an association, contemporary human exposures may be too low to show an association consistently.

Conclusion

On the basis of the evidence reviewed here, in VAO, and in the previous VAO updates, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and human endometriosis.

FERTILITY

Male reproductive function is under the control of several components whose proper coordination is important for normal fertility. Several of the components and some health outcomes related to male fertility, including reproductive hormones and sperm characteristics, can be studied as indicators of fertility. The reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both are secreted into the circulation in episodic bursts by the anterior pituitary gland and are necessary for normal spermatogenesis. In the testis, LH interacts with receptors on Leydig cells, where it stimulates increased testosterone synthesis. FSH and the testosterone from the Leydig cells interact with Sertoli cells in the seminiferous tubule epithelium to regulate spermatogenesis. More detailed reviews of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde and Giwercman, 1995; Tas et al., 1996). Recent reviews on the effects of various environmental toxicants, including TCDD, on testicular steroidogenesis and

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

spermatogenesis provide insights into potential underlying mechanisms, including reducing testosterone production in Leydig cells and inhibiting the formation of cyclic adenosine monophosphate (Mathur and D’Cruz, 2011; Svechnikov et al., 2010).

Studies of the relationship between chemicals and fertility are less common in women than in men. Some chemicals may disrupt the female hormonal balance necessary for proper functioning. Normal menstrual-cycle functioning is also important in the risk of hormonally related diseases, such as osteopenia, breast cancer, and cardiovascular disease. Chemicals can have multiple effects on the female system, including modulation of hormone concentrations that result in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and menopause, and impairment of fertility (Bretveld et al., 2006a,b).

Conclusions from VAO and Previous Updates

The committee responsible for the original VAO report (IOM, 1994) concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and alterations in sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change the conclusion that exposure to the COIs had not been found to be associated with impaired fertility in either men or women. Reviews of the relevant studies are presented in the earlier reports. Tables 9-2 and 9-3 summarize the studies related to male and female fertility, respectively.

Update of the Epidemiologic Literature

Male Fertility

No new epidemiologic studies of exposure to the COIs and effects on male fertility have been published since Update 2010.

Female Fertility

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and female fertility have been published since Update 2010.

Environmental Studies

The literature searches for Update 2012 identified several studies relating menstrual-cycle characteristics to exposures that might have included COIs.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 9-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted) All COIs

AFHS (964 Ranch Hands, 1,259 comparisons)

Coefficient (p-value) for In(Testosterone) vs In(TCDD) in 1987 Gupta et al., 2006

Comparison TCDD quartile I (mean, 2.14 ppt)

nr 0 (referent)

Comparison TCDD quartile II (mean, 3.54 ppt)

nr –0.063 (0.004)

Ranch Hand TCDD quartile I (mean, 4.14 ppt)

nr 0.002 (0.94)

Comparison TCDD quartile III (mean, 4.74 ppt)

nr –0.048 (0.03)

Comparison TCDD quartile IV (mean, 7.87 ppt)

nr –0.079 (< 0.001)

Ranch Hand TCDD quartile II (mean, 8.95 ppt)

nr –0.052 (0.03)

Ranch Hand TCDD quartile III (mean, 18.40 ppt)

nr –0.029 (0.22)

Ranch Hand TCDD quartile IV (mean, 76.16 ppt)

nr –0.056 (0.02)

Effects on specific hormone concentrations or sperm count in Ranch Hands

Henriksen et al., 1996

Low testosterone

High dioxin (1992)

18 1.6 (0.9–2.7)

High dioxin (1987)

3 0.7 (0.2–2.3)

Low dioxin (1992)

10 0.9 (0.5–1.8)

Low dioxin (1987)

10 2.3 (1.1–4.9)

Background (1992)

9 0.5 (0.3–1.1)

High FSH

High dioxin (1992)

8 1.0 (0.5–2.1)

Low dioxin (1992)

12 1.6 (0.8–3.0)

Background (1992)

16 1.3 (0.7–2.4)

High LH

High dioxin (1992)

5 0.8 (0.3–1.9)

Low dioxin (1992)

5 0.8 (0.5–3.3)

Background (1992)

8 0.8 (0.4–1.8)

Low sperm count

High dioxin

49 0.9 (0.7–1.2)

Low dioxin

43 0.8 (0.6–1.0)

Background

66 0.9 (0.7–1.2)
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed All COIs

Detailed description of cohort

CDC, 1989a

Lower sperm concentration

42 2.3 (1.2–4.3)

Proportion of abnormal sperm

51 1.6 (0.9–2.8)

Reduced sperm motility

83 1.2 (0.8–1.8)
US American Legion Cohort All COIs

American Legionnaires who served in SEA

Stellman et al., 1988

Difficulty in having children

349 1.3 (p < 0.01)
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

NIOSH Cross-sectional Medical Study—248 chemical workers employed at plants in Newark, New Jersey (1951–1969), and Verona, Michigan (1968–1972), vs 231 nonexposed neighborhood referents, measured in 1987

Dioxins, phenoxy herbicides

Testosterone (< 10.4 nmol/L)

Egeland et al., 1994

Referents (TCDD < 20 ppt)

11 1.0

Workers

25 2.1 (1.0–4.6)

Quartile I (TCDD < 20 ppt)

2 0.9 (0.2–4.5)

Quartile II (TCDD 20–75 ppt)

7 3.9 (1.3–11.3)

Quartile III (TCDD 76–240 ppt)

6 2.7 (0.9–8.2)

Quartile IV (TCDD 241–3,400 ppt)

10 2.1 (0.8–5.8)

FSH (> 31 IU/L)

20 1.5 (0.7–3.3)

LH (> 28 IU/L)

23 1.6 (0.8–3.3)
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

Canada—Sawmill Workers in British Columbia; 26,487 workers for ≥ 1 yr at 14 mills using chlorophenates 1950–1985

Chlorophenates, not TCDD

Workers having a live birth within 1 yr after the initiation of employment

Heacock et al., 1998

Standard fertility ratio

18,016 (births) 0.7 (0.7–0.8)b

Mantel-Haenszel rate-ratio estimator

18,016 (births) 0.9 (0.8–0.9)b
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Cumulative exposure (hours)

120–1,999

7,139 0.8 (0.8–0.9)b

2,000–3,999

4,582 0.9 (0.8–1.0)b

4,000–9,999

4,145 1.0 (0.9–1.1)b

≥ 10,000

1,300 1.1 (1.0–1.2)b (p < 0.01 overall)

Denmark—Danish farmers (n = 1,146), 18–50 yrs of age, who used any potentially spermatotoxic pesticides, including 2,4-D

Herbicides Larsen et al., 1998

Farmers using pesticides vs organic farmers

523 1.0 (0.8–1.4)c

Used three or more pesticides

nr 0.9 (0.7–1.2)c

Used manual sprayer for pesticides

nr 0.8 (0.6–1.1)c
ENVIRONMENTAL
Seveso, Italy, Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Men exposed in Seveso, Zone A, vs age-matched men residing outside the contamination zone, measured semen characteristics, estradiol, FSH, testosterone, LH, inhibin B

Mocarelli et al., 2008
Author’s evaluation (data not shown)

Age at 1976 exposure:

Infant/prepuberty (1–9 yrs), n = 71 vs 176

Sensitive Intermediate response

Puberty (10–17 yrs), n = 44 vs 136

Adult (18–26 yrs), n = 20 vs 60

No associations
Other International Environmental Studies

Belgian men in general population

PCBs, dioxin Dhooge et al., 2006

Association with 2-fold increase in

Change (p-value)

CALUX-TEQ

Sperm concentration

25.2% (p = 0.07)

Semen volume

–16.0% (p = 0.03)

Total testosterone

–7.1% (p = 0.04)

Free testosterone

–6.8% (p = 0.04)

Belgium—Adolescent girls (17 yrs of age) in communities close to industrial sources of heavy metals, PCBs, VOCs, and PAHs—delays in sexual maturity

PCBs, DLCs Staessen et al., 2001
200

In Hoboken, Belgium

8 4.0 (nr)

In Wilrik, Belgium

15 1.7 (nr)

Polish, Greenlandian, Ukranian, Swedish men in general population; AHR binding measured with CALUX assay

dl activity Toft et al., 2007
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Measurement of semen quality (concentration, motility, percentage normal)

No consistent associations
CASE-CONTROL STUDIES

US Case-Control Studies

Missouri—men with or without low sperm quality (21–40 yrs of age)

2,4-D Swan et al., 2003

Increased urinary metabolite markers for 2,4-D

5 0.8 (0.2–3.0)

International Case-Control Studies

Argentinean farmers exposed to 2,4-D (n = 32) vs 25 nonexposed controls, March–July 1989

2,4-D Lerda and Rizzi, 1991

Sperm count (millions/mL)

exposed: 49.0 vs control: 101.6

Motility (%)

exposed: 24.8 vs control: 70.4

Sperm death (%)

exposed: 82.9 vs control: 37.1d

Anomalies (%)

exposed: 72.9 vs control: 33.4

Canada—study of erectile dysfunction in urology patients in Ontario

PCBs/Highest vs lowest PCB groups Polsky et al., 2007

PCB-118 (TEF = 0.0001)

1.0 (0.5–2.1)

PCB-118 (TEF = 0.0001)

0.9 (0.5–1.6)

PCB-170

0.6 (0.3–1.2)

PCB-180

0.7 (0.4–1.4)

Greenland Inuit men (n = 53) and European men (n = 247), DNA sperm integrity among Inuit men

POPs Krüger et al., 2008

Median % DNA fragmentation index

Inuits

6.8

Europeans

12

Median % DNA stainability

Inuits

11

Europeans

8.9

Korean male waste incinerator workers (n = 6) vs controls (n = 8), dioxin measured by air monitoring

Phenoxy herbicides Oh et al., 2005

Reduced number of sperm (106/ml)

(p = 0.050)

Workers

42.9 ± 18.0

Controls

56.1 ± 44.5
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

DNA-damaged sperm (%)

(p = 0.001)

Workers

1.40 ± 0.08

Controls

1.26 ± 0.03

Turkey (Ankara)—Adipose-tissue samples from fertile and infertile men (21–46 yrs of age) assayed for PCB-118, April 2002–June 2007

DLCs Cok et al., 2010
21 fertile 68.8 ng/g lipid
25 infertile 21.7 ng/g lipid (p = 0.003)

Turkey (Ankara)—Adipose-tissue samples from fertile and infertile men (21–45 yrs of age) assayed for dioxin, furans, dl PCBs, June 2003–September 2005

DLCs Cok et al., 2008
22 fertile 9.4 TEQ pg/g lipid
(p = 0.003)
23 infertile 12.5 TEQ pg/g lipid
(p = 0.065)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHR, aryl hydrocarbon receptor; CALUX, assay for determination of dioxin-like activity; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemicals of interest; dl, dioxin-like; DLC, dioxin-like chemical; DNA, deoxyribonucleic acid; FSH, follicle-stimulating hormone; IARC, International Agency for Research in Cancer; ICD-9, International Classification of Diseases, 9th Revision; IU, international unit; LH, luteinizing hormone; nr, not reported; NIOSH, National Institute for Occupational Safety and Health; PAH, polycyclic aromatic hydrocarbon; PCB, polychlorinated biphenyl; POP, persistent organic pollutants; ppt, parts per trillion; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxicity equivalency factor; TEQ, (total) toxic equivalent; VOC, volatile organic compound.

aGiven when available; results other than estimated risk explained individually.

bFor this study, relative risk has been replaced with standardized fertility ratio, for which value less than 1.0 indicates adverse effect.

cFor this study, relative risk has been replaced with fecundability ratio, for which value less than 1.0 indicates adverse effect.

dTable 1 in reference reverses these figures—control, 82.9%; exposed, 37.1%—but text (“The percentages of asthenospermia, mobility, necrosperma and teratospermia were greater in the exposed group than in controls…”) suggests that this is a typographical error.

Yang et al. (2011) examined the relation between exposure to PCB and PCDF-contaminated cooking oil (“Yucheng exposure”) in Taiwan and self-reported menstrual-cycle characteristics in 197 Yucheng-exposed women and 218 neighborhood referents. There was no association between Yucheng exposure and cycle irregularity or dysmenorrhea, but results based only on group membership without further characterization of exposure with respect to the COIs do not

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 9-3 Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

UNITED STATES

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

8,038 premenopausal women age 30–55 at enrollment

Farr et al., 2006

Pesticide exposure

5,013 0.9 (0.8–1.0)

Herbicide exposure

3,725 0.9 (0.7–1.1)

Phenoxy herbicide exposure

1,379 0.9 (0.7–1.1)

Menstrual-cycle characteristics of 3,103 premenopausal women age 21–40

Farr et al., 2004

Reported at enrollment had used herbicides

1,291

Short menstrual cycle

0.6 (0.4–1.0)

Long menstrual cycle

1.0 (0.5–2.0)

Irregular

0.6 (0.3–0.9)

Missed period

1.4 (1.0–2.0)

Intermenstrual bleeding

1.1 (0.8–1.7)
ENVIRONMENTAL
Seveso (Italy) Women’s Health Study—Industrial accident July 10, 1976; 981 women between infancy and 40 yrs of age at the time of the accident, who resided in Zones A and B TCDD

Time to pregnancy and infertility in women from Zones A and B who attempted pregnancy after 1976

Eskenazi et al., 2010

20-yr followup to 1996—men and women

Time to pregnancy (adjusted fecundability OR)

Log10 TCDD

278 0.8 (0.6–1.0)

Categorical TCDD (ppt)

≤ 20

52 1.0 (reference)

20.1–44.4

76 0.8 (0.5–1.3)

44.5–100

75 0.7 (0.5–1.1)

> 100

75 0.6 (0.4–1.0)
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Infertility (adjusted OR)

Log10 TCDD

49 1.9 (1.1–3.2)

Categorical TCDD (ppt)

≤ 20

6 1.0 (reference)

20.1–44.4

9 1.1 (0.4–3.6)

44.5–100

16 2.5 (0.8–7.3)

> 100

18 2.8 (1.0–8.1)

Fibroids among women from Zones A and B who were newborn to age 40 in 1976

Eskenazi et al., 2007

Uterine fibroids (age-adjusted HR)

Log10 TCDD (ppt)

251 0.8 (0.7–1.1)

Categorical TCDD (ppt)

≤ 20

62 1.0 (reference)

20.1–75.0

110 0.6 (0.4–0.8)

> 75

79 0.6 (0.4–0.9)

Ovarian function in women from Zones A and B who were newborn to age 40 in 1976; results are for a 10-fold increase in serum TCDD

Warner at al., 2007

Ovarian follicles (age-adjusted OR):

in follicular phase

65 1.0 (0.4–2.2)

Ovulation (age-adjusted OR):

in luteal phase

87 1.0 (0.5–1.9)

in midluteal phase

55 1.0 (0.4–2.7)

Estradiol (age-adjusted ß):

slopes for Log10
TCDD

in luteal phase

87 −1.8 (−10.4–6.8)

in midluteal phase

55 −3.1 (−14.1–7.8)

Progesterone (age-adjusted ß):

in luteal phase

87 −0.7 (−2.4–1.0)

in midluteal phase

55 −0.8 (−3.7–2.0)

Age at menopause in women from Zones A and B who were newborn to age 40 in 1976

Eskenazi et al., 2005

Onset of natural menopause (unadjusted HR)

Log10 TCDD

169 1.0 (0.8–1.3)

Menopause category

Serum TCDD median (IQR)

Premenopause

260 43.6 (0.2–0.9)

Natural menopause

169 45.8 (0.3–1.0)

Surgical menopause

83 43.4 (0.3–1.0)

Impending menopause

13 43.8 (0.2–1.1)

Perimenopause

33 36.5 (0.2–0.9)

Other

58 39.6 (0.2–0.9)

Age at menarche in women from Zones A and B who were premenarcheal in 1976

282 1.0 (0.8–1.1) Warner et al., 2004
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

All premenarcheal women in 1976 (unadjusted HR)

Log10 TCDD

282 1.0 (0.8–1.1)

Women < 8 yrs in 1976 (unadjusted HR)

Log10 TCDD

158 1.1 (0.9–1.3)

Menstrual-cycle characteristics in women from Zones A and B who were premenopausal, less than age 44, and not recently pregnant, breastfeeding, or using hormonal medications

Eskenazi et al., 2002b

Menstrual-cycle length (adjusted ß)

Log10 TCDD

277 0.4 (−0.1–0.9)

Premenarcheal at explosion

0.9 (0.0–1.9)

Postmenarcheal at explosion

0.0 (−0.6–0.5)

Days of menstrual flow (adjusted ß)

Log10 TCDD

301 0.2 (−0.1–0.4)

Premenarcheal at explosion

0.2 (−0.2–0.5)

Postmenarcheal at explosion

0.2 (−0.2–0.5)

Heaviness of flow (scanty vs moderate/heavy; adjusted OR)

Log10 TCDD

30 0.8 (0.4–1.6)

Premenarcheal at explosion

0.3 (0.1–1.1)

Postmenarcheal at explosion

1.4 (0.7–2.6)

Irregular cycle (vs regular; adjusted OR)

Log10 TCDD

24 0.5 (0.2–1.0)

Premenarcheal at explosion

0.5 (0.2–1.4)

Postmenarcheal at explosion

0.4 (0.2–1.2)
Other International Environmental Studies

Taiwanese pregnant women (18–40 yrs of age); placental TEQ concentrations of TCDDs, TCDFs, PCBs

Dioxin/ Regression adjusted for maternal age, Chao et al., 2007
BMI, parity

≥ 18 yrs old, “regular menstrual cycle”

Dioxin TEQ

p = 0.032

PCB TEQ

p = 0.077

Women with “longest menstrual cycle”

Dioxin TEQ

p = 0.269

PCB TEQ

p = 0.006
CASE-CONTROL STUDIES

US Case-Control Studies

Women in Wisconsin with or without infertility (maternal exposure)—incidence

Phenoxy herbicides Greenlee et al., 2003
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Mixed or applied herbicides

21 2.3 (0.9–6.1)

Used 2,4,5-T

9 9 cases (2.7%) 11 controls (3.4%)

Used 2,4-D

4 4 cases (1.2%)
4 controls (1.2%)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BMI, body mass index; CATI, computer-assisted telephone interviewing; CI, confidence interval; HR, hazard ratio; IARC, International Agency for Research on Cancer; IQR, inter-quartile range; OR, odds ratio; PCB, polychlorinated biphenyl; ppt, parts per trillion; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total) toxic equivalent.

aGiven when available; results other than estimated risk explained individually.

meet this committee’s criteria for consideration. However, women exposed to contaminated oil who also reported skin manifestations of exposure (chloracne, hyperkeratosis, or abnormal nails)—highly indicative of exposure to dioxin-like chemicals (DLCs)—did report menstrual cycles shorter than those of community referents by about 1.2 days (95% CI 1.7–0.7).

Buck Louis et al. (2011) provided associations in relation to summed concentrations of multiple PCB congeners, only some of which exhibit dioxin-like activity. They reported an association between increased concentrations of estrogenic PCBs (which do not include dioxin-like PCBs) and increased cycle length but no such relationship for the sum of eight anti-estrogenic PCBs (six of which are dioxin-like).

Uterine leiomyomas (fibroids) are also recognized as a contributor to infertility. In 2001–2004, Lambertino et al. (2011) contacted 580 women who had participated in the Great Lakes Fish Consumption Study, which had been initiated in the early 1990s. Updated information on health, reproductive history, and fish consumption was gathered from these subjects and merged with existing data. Blood samples were provided by 197 of them and analyzed for serum concentrations of various persistent organic pollutants, including a number of PCBs. The exposure measure for the category “dioxin-like PCBs” consisted of the summed concentrations of only the mono-ortho PCBs 118 and 167. There was no difference in the concentrations for the exposure category between women who had and had not self-reported the occurrence of these benign tumors, but because this result is based solely on mono-ortho PCBs, which typically contribute only a small percentage to total TEQs, no conclusions can be drawn.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Since Update 2010, there have been no additional studies of time to pregnancy (TTP) with sufficient exposure specificity to add to the evidence from the previous literature. Burdorf et al. (2011) examined TTP among 8,880 women enrolled in a prospective birth cohort in the Netherlands (Generation R Study) as part of an assessment of occupational exposures based on a job exposure matrix. They found no association between occupational exposure to “pesticides” and increased TTP, but the exposure classification of “pesticides” is insufficiently specific to determine whether any compounds related to Agent Orange exposure were among those included.

Biologic Plausibility

Although a recent study reported that doses of 2,4-D greater than 50 mg/kg/day produces acute testicular toxicity in male rats (Joshi et al. 2012), there is little evidence that lower doses of either 2,4-D or 2,4,5-T (when free of TCDD contamination) given chronically have substantial effects on reproductive organs or fertility (Charles et al., 2001; Munro et al., 1992) and the no-observed-adverse-effect level for 2,4-D is recognized as 15 mg/kg/day (Gervais et al., 2008). In contrast, many diverse laboratory studies have provided evidence that TCDD can affect reproductive-organ function and reduce fertility in both males and females.

The administration of TCDD to male animals elicits reproductive toxicity by affecting testicular, epididymal, prostate, and seminal vesicle weight and function and by decreasing the rate of sperm production. The mechanisms underlying those effects are not known, but primary hypotheses are that they are mediated through dysregulation of testicular steroidogenesis, altered Sertoli cell function, and increases in oxidative stress. Studies published since Update 2010 have reinforced those possibilities. Exposure of cultured testicular Leydig cells to 25 nM TCDD markedly alters gene expression (Naville et al., 2011), and exposure of cultured Sertoli cells to 5 nM TCDD decreases viability and increases markers of oxidative stress (Aly and Khafagy, 2011). Exposure of adult rats or mice to TCDD (2–7 μg/kg/week for 45–60 days) reduces testicular and reproductive function, and these effects can be attenuated by co-treatment with various antioxidants (Beytur et al., 2012; Ciftci et al., 2012; Sönmez et al., 2011; Yin et al., 2012). The results of those studies are supported by the transgenic mouse model that harbors a constitutively active AHR in which testicular and ventral prostate weights and sperm number are reduced (Brunnberg et al., 2011).

Many studies have examined the effects of TCDD on the female reproductive system. Two primary mechanisms that probably contribute to abnormal follicle development and decreased numbers of ova after TCDD exposure are “cross-talk” of the AHR with the estrogen receptor and dysregulation of the hypothalamic-pituitary-gonadal axis. Oocytes are directly responsive to TCDD, so TCDD’s effects on hormone concentrations, hormone-receptor signaling, and ovarian responsiveness to hormones all probably contribute to TCDD-induced

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

female reproductive toxicity. Since Update 2008, additional work addressing TCDD’s effects on female reproduction in animal models has been published. The data of Jung et al. (2010) in rats show that a single gavage treatment of 32 μg/kg TCDD reduces the proliferation of granulosa cells and thus attenuates cell-cycle progression and potentially contributes to the reduction in ovulation rates observed in other studies. In contrast, Karman et al. (2012) found that 1 nM TCDD exposure in vitro did not reduce rates of growth of murine antral follicles, but did reduce secretion of progesterone and estradiol by the follicles. Concentrations of those hormones could be restored by the addition of the precursor pregnenolone, and this suggests that TCDD acts upstream of pregnenolone formation. That would be consistent with previous observations in zebrafish that 10, 40, and 100 ppb TCDD in food depressed estradiol biosynthesis (Heiden et al., 2008).

Since Update 2010, studies of TCDD in rodents have provided additional evidence that dioxin has effects on early embryo development and effects on placenta formation. A recent study that used a rat in vitro fertilization model demonstrated that 100 nM TCDD perturbs chromatin and cytoskeletal remodeling at the earliest stages of embryo development, but these changes failed to result in any apparent morphologic changes at later stages of development (Petroff et al., 2011). The long-term potential effects of those early changes on pregnancy outcome are unknown. It has previously been shown that TCDD may have direct effects on human trophoblast formation at 0.2–2 nM in vitro and thus the capacity to influence the developing fetus (Chen et al., 2010). That idea is supported by a recent study that showed the ability of 5 nM TCDD to activate the AHR signaling pathway in both rat and human placental trophoblasts (Stejskalova et al., 2011). Finally, a study has demonstrated that TCDD at 0.1, 1, and 10 nM reduces in a dose-dependent fashion the ability of trophoblastic spheroids (which constitute an embryo surrogate) to attach to endometrial epithelial cells (Tsang et al., 2012). The more recent literature continues to support the biologic plausibility of effects of TCDD on male and female reproduction.

Sex Ratio

Although it would not constitute an adverse health outcome in an individual veteran, the perturbations in the sex ratio of children born to an exposed population suggest the exposure has an impact on the reproductive process. As shown in Table 9-4, studies of the sex ratios observed among children born to people exposed during the 1976 Seveso accident (Mocarelli et al., 1996, 2000) suggested that paternal exposure to dioxin may result in a lower sex ratio (that is, a smaller-than-expected proportion of male infants at birth), particularly when the father was exposed early in his life (sex ratio [SR] = 0.382). Consideration all 481 singleton births in 1994–2005 to women who resided in Zones A and B and were less than 28 years old at the time of the Seveso accident (18–46 years old at the beginning of period when births were identified), however, generated crude

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 9-4 Selected Epidemiologic Studies—Sex Ratioa (Shaded Entry Is New for This Update)

Study Population Sex Ratio of Offspring (boys/total)b Comments Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

Births from service through 1993 in AFHS

Michalek et al., 1998b

Comparison group

0.504 Not formally analyzed

Dioxin level in Ranch Hand personnel

Background

0.502

Low

0.487

High

0.535
OCCUPATIONAL—INDUSTRIAL
NIOSH Cross-Sectional Study

Workers producing trichlorophenol and derivatives, including 2,4,5-T

No difference on basis of Schnorr et al., 2001

Serum TCDD in fathers

age at first exposure

Neighborhood controls (< 20 ppt)

0.544 Referent

Working fathers

< 20 ppt

0.507 None significantly decreased (or increased)

20–255 ppt

0.567

255– < 1,120 ppt

0.568

≥ 1,120 ppt

0.550

Other Studies of Industrial Workers (not related to NIOSH phenoxy cohort)

Austrian chloracne cohort—157 men, 2 women; exposed to TCDD during 2,4,5-T production

Moshammer and Neuberger,

Children born after starting TCDD exposure in 1971

0.464 (26 boys: 30 girls) Fewer sons, especially if father was less than 20 yrs old when exposed: SR = 0.20 (1 boy: 4 girls) 2000

Children born before 1971

0.613 (19 boys: 12 girls)

Russian workers manufacturing 2,4,5,-trichlorophenol (1961–1988) or 2,4,5-T (1964–1967)

Ryan et al., 2002

Either parent exposed

0.401 (91 boys: 136 girls) p < 0.001

Only father exposed

0.378 (71 boys: 117 girls) p < 0.001
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Sex Ratio of Offspring (boys/total)b Comments Reference

Only mother exposed

0.513 (20 boys: 19 girls) ns
OCCUPATIONAL—PAPER AND PULP WORKERS

Canada—British Columbian sawmill workers (n = 26,487)

Heacock et al., 1998

Chlorophenate-exposed workers

0.515

Nonexposed workers

0.519

Province overall

0.512
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

Canadian OFFHS fathers’ exposure during 3 mo before conception:

Savitz et al., 1997

No chemical activity

0.503 Referent

Crop herbicides (some phenoxy herbicides)

0.500 ns

Protective equipment used, not used

0.510 ns

No protective equipment

0.450 ns
ENVIRONMENTAL
Seveso, Italy, Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)

Births 1994–2005 in women 0–28 yrs old at time of Seveso accident

Baccarelli et al., 2008

Zone A

0.571

Zone B

0.508

Zone R

0.495

Births 1977–1996 in people from Zones A, B, R, 3–45 yrs old at time of 1976 Seveso accident

Mocarelli et al., 2000
0.514 Referent

Neither parent exposed

0.608 ns

Father exposed (whether or not mother exposed)

0.440 p = 0.03

Father < 19 yrs old in 1976

0.382 p = 0.002

Father at least 19 yrs old in 1976

0.469 ns

Only mother exposed

0.545 ns

Parent (either sex) from Seveso Zone A

Mocarelli et al., 1996

Births 1977–1984

0.351 (26 boys: 48 girls) p < 0.001, related to parental TCDD serum

Births 1985–1994

0.484 (60 boys: 64 girls) ns
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Sex Ratio of Offspring (boys/total)b Comments Reference
Ecological Study of Residents of Chapaevsk, Russia

Residents near chemical plant in operation 1967–1987 in Chapaevsk, Russia

Revich et al., 2001

1983–1997

0.507 No clear pattern

Minimum in 1989

0.401

Maximum in 1987

0.564

Maximum in 1995

0.559
Other International Environmental Studies

JAPAN—Yusho incident

Parents (one or both) exposed to PCBs, PCDFs (not TCDD) in 1968

Yoshimura et al., 2001

All Japan in 1967

0.513 Referent

Births 1967 (before poisoning incident)

0.516 ns

Births 1968–1971 (after incident)

0.574 ns

Births 1968–2009

Tsukimori et al., 2012a

Father exposed (whether or not mother exposed)

0.505 p = 0.74

Father < 20 yrs old in 1967

0.465 p = 0.15

Mother exposed (whether or not father exposed)

0.501 p = 0.62

Mother < 20 yrs old in 1967

0.450 p = 0.06

TAIWAN

Taiwanese pregnant women (18–40 yrs of age); placental TEQ concentrations of TCDDs, TCDFs, PCBs

nr No association Chao et al., 2007

Births in individuals exposed to PCBs, PCDFs, PCDDs in 1979 Yucheng incident

vs unexposed with same demographics del Rio Gomez et al., 2002

Father exposed (whether or not mother exposed)

0.490 p = 0.037

Father < 20 yrs old in 1979

0.458 p = 0.020

Father at least 20 yrs old in 1979

0.541 p = 0.60

Mother exposed (whether or not father exposed)

0.504 p = 0.45

Mother < 20 yrs old in 1979

0.501 p = 0.16

Mother at least 20 yrs old in 1979

0.500 p = 0.40
UNITED STATES

San Francisco Bay area—serum concentrations in pregnant women during 1960s

OR for male birth (not SR) Hertz-Picciotto et al., 2008

90th percentile vs 10th percentile

SRs all < 0.5

Total PCBs

0.4 (0.3–0.8) p = 0.007

dl PCBs

PCB 105

0.6 (0.4–0.9) p = 0.02
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Sex Ratio of Offspring (boys/total)b Comments Reference

PCB 118

0.7 (0.5–1.2) p = 0.17

PCB 170

0.6 (0.4–0.9) p = 0.02

PCB 180

0.8 (0.5–1.2) p = 0.32

Births after 1963 to Michigan fish-eaters with serum PCBs in both parents

Karmaus et al., 2002

Paternal PCBs > 8.1 μg/L

0.571 p < 0.05 (but for more sons)

Maternal PCBs > 8.1 μg/L

0.494 ns

NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; dl, dioxin-like; NIOSH, National Institute for Occupational Safety and Health; ns, not significant; nr, not reported; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; ppt, parts per trillion; SEA, Southeast Asia; SR, sex ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total) toxic equivalent.

aVAO reports before Update 1998 did not address association between perturbations in sex ratio of offspring and exposure to chemicals of interest.

bGiven when available.

SRs showing that male births slightly exceeded female births in Zones A and B (SR = 0.516) and that an increase (SR = 0.571) was more pronounced for the 56 births in Zone A (Baccarelli et al., 2008).

A similar depression in the SR concentrated in fathers who were less than 20 years old at the time of the Yucheng poisoning with oil contaminated with PCBs, PCDFs, and PCDDs was reported by del Rio Gomez et al. (2002). On the other hand, Yoshimura et al. (2001) found a nonsignificant increase in the SR (SR =0.574) of children born in the 4 years following the similar 1967 Yusho poisoning by rice oil contaminated with PCBs and PCDFs (but not TCDD) when at least 1 parent was exposed. Following up on the Yusho cohort, however, Tsukimori et al. (2012a) did note modest nonsignificant decreases in the SR when either the mother (SR = 0.450) or the father (SR = 0.465) was less than 20 years old at the time of the poisoning. In considering the second generation of Yusho offspring, Tsukimori et al. (2012a) found no effect on SR in the grandchildren of the exposed men, but the daughters of exposed women showed a tendency toward decreased SRs, especially if the grandmother had been young when exposed (results not tabled).

Chao et al. (2007) mentioned that they did not find an association between SR of offspring and the TEQ concentrations of dioxins, furans, or PCBs in the placentas from 119 Taiwanese women. Hertz-Picciotto et al. (2008) found evi-

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

dence of an effect on SR in an analysis of the serum concentrations of nine PCB congeners (of which the two dioxin-like congeners were the mono-ortho PCBs 105 and 118) in blood gathered during the 1960s from 399 pregnant women in the San Francisco Bay area. The adjusted odds of male birth were significantly decreased when the 90th percentile of the total concentration of all nine PCBs was compared with the 10th percentile (OR = 0.45, 95% CI 0.26–0.80, p = 0.007). The proportion of male births was significantly reduced for only two of the PCBs when analyzed separately: dioxin-like, mono-ortho PCB 105 and non-dioxin-like PCB 170 (p = 0.02 for each).

Reductions in the expected number of male offspring have also been reported in cohorts of men who were occupationally exposed to dioxin (Moshammer and Neuberger, 2000; Ryan et al., 2002), but other such cohorts did not manifest this relationship (Heacock et al., 1998; Savitz et al., 1997; Schnorr et al., 2001). In the single report relevant to this outcome in Vietnam veterans, however, the SR was increased in the Operation Ranch Hand group that had the highest serum dioxin concentrations (Michalek et al., 1998b), but no formal analysis of this outcome was reported.

A population-level finding of a paternally mediated effect would be a strong indicator that dioxin exposure can interfere with the male reproductive process. James (2006) has interpreted perturbation of SRs by dioxins and other agents as being an indicator of parental endocrine disruption. If James’s hypothesis were demonstrated to hold, it would be concordant with a reduction in testosterone in exposed men. Another pathway to an altered SR might involve male embryos’ experiencing more lethality with induction of mutations due to their unmatched X chromosome. A genotoxic mechanism has not been expected to apply to TCDD, but sex-specific adverse consequences of modified imprinting of gametes might be a possible mechanism leading to observation of altered SRs at birth. To date, however, results regarding the proportion of sons among the children of fathers exposed to dioxin-like chemicals do not present a clear pattern of reduction.

There has been no work with experimental animals that has specifically examined the effects of TCDD on SRs of offspring, nor have any alterations in SR been reported in animal studies that examined developmental effects of TCDD on offspring.

Synthesis

Reproduction is a sensitive toxic endpoint of TCDD and DLCs in rodents. It is clear that the fetal rodent is more sensitive than the adult rodent to adverse effects of TCDD. The sensitivity of those endpoints in humans is less apparent. There is little evidence that exposure to dioxin is associated with a reduction in sperm quality or a reduction in fertility. However, the committee for Update 2008 noted that the evidence that TCDD exposure reduces serum testosterone in men is consistent across several epidemiologic studies with appropriate consideration

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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of confounders, including one of Vietnam veterans that found a dose–response relationship. The biologic plausibility of such a relationship is supported by concomitant increases observed in gonadotropins and the results of animal studies. Human populations that have shown evidence of reduced testosterone with exposure to DLCs include a general population sample (Dhooge et al., 2006), occupationally exposed people (Egeland et al., 1994), and Vietnam veterans in the Air Force Health Study (Gupta et al., 2006). The evidence that DLCs may modify the SR lends credence to the hypothesis that these chemicals have an effect on male reproductive functioning.

Despite the relative consistency of the finding of a reduction in testosterone, the testosterone concentrations observed even in the highest-exposure groups studied are well within the normal range. The small reduction in testosterone is not expected to have adverse clinical consequences. There is evidence of compensatory physiologic mechanisms. The occupational study by Egeland et al. (1994) found increased gonadotropins in addition to reduced testosterone. Gonadotropins stimulate the production of testosterone in men.

The first published study to examine dioxin exposure in women and association with TTP and infertility was reviewed in Update 2010. A dose–response relationship between TCDD exposure and TTP and infertility was observed and is consistent with published observations of the rat model. However, there have been no additional studies of dioxin exposure specifically and TTP since Update 2010. Epidemiologic studies have not provided data sufficient to interpret the effects of dioxin specifically on menstrual-cycle function in humans.

Conclusions

On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the present committee concludes that there is inadequate or insufficient evidence of an association between exposure to the COIs and decreased sperm counts or sperm quality, subfertility, or infertility.

SPONTANEOUS ABORTION, STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Spontaneous abortion is the expulsion of a nonviable fetus, generally before 20 weeks of gestation, that is not induced by physical or pharmacologic means. The background risk of recognized spontaneous abortion is generally 7–15% (Hertz-Picciotto and Samuels, 1988), but it is established that many more pregnancies terminate before women become aware of them (Wilcox et al., 1988); such terminations are known as subclinical pregnancy losses and generally are not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Studies have included cohorts of women asked retrospectively about pregnancy history,

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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cohorts of pregnant women (usually those receiving prenatal care), and cohorts of women who are monitored for future pregnancies. The value of retrospective reports can be limited by loss of memory, particularly of spontaneous abortions that took place long before the interview. Studies that enroll women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for differences in the times at which women seek medical care during pregnancy. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it can attract nonrepresentative study groups because the study protocols are demanding for the women.

Countries and US states have different legal definitions of the age of fetal viability and apply these terms differently, but typically stillbirth or late fetal death refers to the delivery at or after 20 weeks of gestation of a fetus that shows no signs of life, including a fetus that weighs more than 500 g regardless of gestational age (Kline et al., 1989); neonatal death refers to the death of a live-born infant within 28 days of birth; and infant death to a death that occurs before the first birthday.

The causes of stillbirth and early neonatal death overlap considerably, so they are commonly analyzed together in a category referred to as perinatal mortality (Kallen, 1988). Stillbirths make up less than 1% of all births (CDC, 2000). The most common causes of perinatal mortality (Kallen, 1988) in low-birth-weight (500–2,500 g) live-born and stillborn infants are placental and delivery complications—abruptio placenta, placenta previa, malpresentation, and umbilical-cord conditions. The most common causes of perinatal death of infants weighing more than 2,500 g at birth are complications of the cord, placenta, and membranes, and congenital malformations (Kallen, 1988).

Conclusions from VAO and Previous Updates

The committee responsible for the original VAO report concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and spontaneous abortion or perinatal death. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion.

The committee responsible for Update 2002, however, found that there was enough evidence available concerning paternal exposure specifically to TCDD to conclude that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion. That conclusion was based primarily on the National Institute for Occupational Safety and Health study (Schnorr et al., 2001), which investigated a large number of pregnancies fathered by workers whose serum TCDD concentrations were extrapolated back to the time of conception; no association was observed up to the highest-exposure group (1,120 ppt or higher). Indications of positive association were seen in studies of Vietnam veterans (CDC, 1989a,b; Field and Kerr, 1988; Stellman et al., 1988),

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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but the committee for Update 2002 asserted that these might be due to exposure to phenoxy herbicides rather than to TCDD and concluded that there was insufficient information to determine whether there is an association between maternal exposure to TCDD and the risk of spontaneous abortion or between maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion.

The additional information (none of which concerned paternal exposure) reviewed by the committees responsible for Update 2004, Update 2006, Update 2008, and Update 2010 did not change these conclusions.

The relevant studies concerning perinatal death are reviewed in the earlier reports, and Table 9-5 summarizes the findings of studies concerning spontaneous abortion.

Update of the Epidemiologic Literature

No studies of exposure to the COIs and spontaneous abortion or perinatal death have been published since Update 2010.

Biologic Plausibility

Laboratory animal studies have demonstrated that TCDD exposure during pregnancy can alter concentrations of circulating steroid hormones and disrupt placental development and function and thus contribute to a reduction in survival of implanted embryos and to fetal death (Huang et al., 2011; Ishimura et al., 2009; Wang et al., 2011). There is no evidence of a relationship between paternal or maternal exposure to TCDD and spontaneous abortion. Exposure to 2,4-D or 2,4,5-T causes fetal toxicity and death after maternal exposure in experimental animals. However, that effect occurs only at high doses and in the presence of maternal toxicity. No fetal toxicity or death has been reported to occur after paternal exposure to 2,4-D.

Laboratory studies of maternal TCDD exposure during pregnancy have demonstrated the induction of fetal death; neonatal death, however, is only rarely observed and is usually the result of cleft palate, which leads to an inability to nurse. Studies addressing the potential for perinatal death as a result of paternal exposure to TCDD or herbicides are inadequate to support conclusions.

Synthesis

No epidemiologic evidence concerning the COIs and spontaneous abortion, stillbirth, neonatal death, or infant death has been published since Update 2010, and toxicologic studies do not provide clear evidence of biologic plausibility of an association. Furthermore, given the ages of the Vietnam-veteran cohort, pub-

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 9-5 Selected Epidemiologic Studies—Spontaneous Abortiona

Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs Southeast Asia veterans (unless otherwise noted)

All COIs

Air Force Ranch Hand veterans

157 Wolfe et al., 1995

Background

57 1.1 (0.8–1.5)

Low exposure

56 1.3 (1.0–1.7)

High exposure

44 1.0 (0.7–1.3)

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Overall

1,566 1.3 (1.2–1.4) CDC, 1989a

Self-reported low exposure

489 1.2 (1.0–1.4)

Self-reported medium exposure

406 1.4 (1.2–1.6)

Self-reported high exposure

113 1.7 (1.3–2.1)

US VA Cohort of Female Vietnam Veterans

All COIs

Female Vietnam-era veterans (maternal exposure)

1.0 (0.82–1.21) Kang et al., 2000

Vietnam veterans (1,665 pregnancies)

278 nr

Vietnam-era veterans who did not serve in

317 nr

Vietnam (1,912 pregnancies)

US National Vietnam Veterans

All COIs

Female Vietnam veterans (maternal exposure)

Schwartz, 1998

Women who served in Vietnam

113 nr

Women who did not serve in the war zone

124 nr

Civilian women

86 nr

US American Legion Cohort

All COIs

American Legionnaires with service 1961–1975

Stellman et al., 1988

Vietnam veterans vs Vietnam-era veterans

All Vietnam veterans

231 1.4 (1.1–1.6)

Low exposure

72 1.3 (1.0–1.7)

Medium exposure

53 1.5 (1.1–2.1)

High exposure

58 1.7 (1.2–2.4)

Vietnam-era veterans vs herbicide handlers

9 1.6 (0.7–3.3)

Vietnam veterans

Low exposure

72 1.0

Medium exposure

53 1.2 (0.8–1.7)

High exposure

58 1.4 (0.9–1.9)
State Studies of US Vietnam Veterans
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Massachusetts—Wives of Vietnam veterans presenting at Boston Hospital for Women

Aschengrau and

27 weeks of gestation

10 0.9 (0.4–1.9) Monson,

13 weeks of gestation

nr 1.2 (0.6–2.8) 1990
International Vietnam-Veteran Studies

Tasmanian Veterans with Service in Vietnam

All COIs

Followup of Australian Vietnam veterans

199 1.6 (1.3–2.0) Field and Kerr, 1988
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates Dioxins, phenoxy herbicides

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers, 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Wives and partners of men in NIOSH cohort

Schnorr et al., 2001

Estimated paternal TCDD serum at time of conception

< 20 ppt

29 0.8 (0.5–1.2)

20 to < 255 ppt

11 0.8 (0.4–1.6)

255 to < 1120

11 0.7 (0.3–1.6)

≥ 1120 ppt

8 1.0 (0.4–2.2)

Dow Workers with Potential TCDD Exposure and reproductive outcomes studied in offspring of 930 men working with chlorophenol, 1939–1975

Dioxins, phenoxy herbicides Townsend et al., 1982

Wives of men employed involved in chlorophenol processing at Dow Chemical Co.

85 1.0 (0.8–1.4)

Monsanto workers in Nitro, West Virginia, occupationally exposed and potentially exposed after 1949 explosion (1948–1969)

Dioxins, phenoxy herbicides

Followup of current and retired 2,4,5-T production workers (n = 235; 117 with chloracne exposure), 1948–1969

14 0.9 (0.4–1.8) Moses et al., 1984

Followup of 2,4,5-T production workers (204 exposed, 163 unexposed), 1948–1969

69 0.9 (0.6–1.2) Suskind and Hertzberg, 1984
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

New Zealand—Followup of 2,4,5-T sprayers vs nonsprayers (n = 989)

Herbicides 90% CI Smith et al., 1982
43 0.9 (0.6–1.3)
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

US Forest Service

Herbicides

Women employed by US Forest Service—miscarriages (maternal exposure)

141 2.0 (1.1–3.5) Driscoll et al., 1998
ENVIRONMENTAL
Seveso, Italy, Women’s Health Study—Industrial accident July 10, 1976; 981 women between infancy and 40 yrs of age at the time of the accident, who resided in Zones A, B) TCDD

SWHS participants living in Zones A, B in 1976 (maternal exposure)

Eskenazi et al., 2003

Pregnancies 1976–1998

97 0.8 (0.6–1.2)

Pregnancies 1976–1984

44 1.0 (0.6–1.6)
Ecological Study of Residents of Chapaevsk, Russia TCDD

Residents of Samara Region, Russia (maternal and paternal exposure)

Revich et al., 2001

Chapaevsk

nr 24.4% (20.0–29.5%)c

Samara

nr 15.2% (14.3–16.1%)c

Toliatti

nr 10.6% (9.8–11.5%)c

Syzran

nr 15.6% (13.4–18.1%)c

Novokuibyshevsk

nr 16.9% (14.0–20.3%)c

Other small towns

nr 11.3% (9.4–13.8%)c
Ontario Farm Family Health Study Phenoxy herbicides

Ontario farm families (maternal, paternal exposures)

Arbuckle et al., 2001

Phenoxyacetic acid herbicide exposure in preconception period, spontaneous-abortion risk

48 1.5 (1.1–2.1)
Other International Environmental Studies

Japan—Spontaneous abortions among pregnancies (excluding induced abortions) of women in 1968 Yusho incident (maternal exposure)

PCBs, PCDFs Tsukimori et al., 2008

10 yrs after vs 10 yrs before

nr 2.1 (0.8–5.2)

10-fold increase in maternal blood concentration (drawn 2001–2005) of

PeCDF

nr 1.6 (1.1–2.3)

PCB 126 (TEF = 0.1)

nr 2.5 (0.9–6.9)

PCB 169 (TEF = 0.01)

nr 2.3 (1.1–4.8)
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Taiwanese pregnant women (18–40 yrs of age); placental TEQ concentrations of PCDDs, PCDFs, PCBs

PCDD, PCBs nr, but reported Chao et al., 2007
ns

Vietnamese women who were, or whose husbands were, exposed to herbicides sprayed during Vietnam War

nr COIs/nr, anecdotal reports of miscarriage in pilot study Tuyet and Johansson, 2001
CASE-CONTROL STUDIES

US Case-Control Studies

Washington, Oregon—wives of men occupationally exposed to 2,4-D; all reported work exposure to herbicides (high and medium)

2,4-D Carmelli et al., 1981
90% CI
63 0.8 (0.6–1.1)

Farm exposure

32 0.7 (0.4–1.5)

Forest and commercial exposure

31 0.9 (0.6–1.4)

Exposure during conception period

Farm exposure

15 1.0 (0.5–1.8)

Forest and commercial exposure

16 1.6 (0.9–1.8)

Fathers 18–25 yrs old

Farm exposure

1 0.7 (nr)

Forest and commercial exposure

3 4.3 (nr)

Fathers 26–30 yrs old

Farm exposure

4 0.4 (nr)

Forest and commercial exposure

8 1.6 (nr)

Fathers 31–35 yrs old

Farm exposure

10 2.9 (nr)

Forest and commercial exposure

5 1.0 (nr)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant (usually refers to p < 0.05); PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; PCB, polychlorinated biphenyl; PCDF, polychlorinated dibenzofuran; ppt, parts per trillion; SWHS, Seveso Women's Health Study; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

aUnless otherwise indicated, results are for paternal exposure.

bGiven when available; results other than estimated risk explained individually.

cSpontaneous abortion rate per 100 full-term pregnancies for 1991-1997.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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lication of additional information on this outcome in the target population of the VAO series is not likely.

Conclusions

On the basis of the evidence reviewed to date, the committee concludes that paternal exposure to TCDD is not associated with risk of spontaneous abortion and that insufficient information is available to determine whether there is an association between maternal exposure to TCDD or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion. The committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and stillbirth, neonatal death, or infant death.

BIRTH WEIGHT AND PRETERM DELIVERY

Birth weight and the length of the gestation period can have important effects on neonatal morbidity and mortality and on health over the life span. Defined by the World Health Organization as a birth weight under 2,500 g (Alberman, 1984), low birth weight (LBW) has two distinct causes. Intrauterine growth retardation (IUGR) occurs when fetal growth is diminished and a fetus or baby fails to attain a normal weight or is small for gestational age (SGA). The concept of IUGR represents birth weight, adjusted for gestational age, that is lower than average according to local or national fetal-growth graphs (Romo et al., 2009). LBW can also be secondary to preterm delivery (PTD), which is delivery at less than 259 days, or 37 completed weeks, of gestation, calculated on the basis of the date of the first day of the last menstrual period (Bryce, 1991). LBW due to either cause occurs in about 7% of live births. When no distinction is made between the causes of LBW (IUGR or PTD), the factors most strongly associated with it are maternal tobacco use during pregnancy, multiple births, and race or ethnicity. Other potential risk factors are low socioeconomic status, malnutrition, maternal weight, birth order, maternal complications during pregnancy (such as severe pre-eclampsia or intrauterine infection) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Alexander and Slay, 2002; Alexander et al., 2003; Ergaz et al., 2005; Kallen, 1988; Peltier, 2003). Established risk factors for PTD include race (black), marital status (single), low socioeconomic status, previous LBW or PTD, multiple gestations, tobacco use, and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993).

Birth weight is a strong and consistent predictor of infant mortality and, to a smaller extent, of health problems later in life, including adverse neurodevelopmental outcomes and adult-onset chronic diseases (Wilcox, 2001). However, the importance and interpretation of associations with birth weight or, by extension, with common classifications of birth weight—such as LBW, IUGR, and SGA—

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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are often unclear and a subject of controversy among researchers. Across populations, the frequency distribution of birth weight is Gaussian, with an extended lower tail, or “residual distribution,” that includes preterm and LBW infants. The predominant, normal distribution corresponds largely to term births. In general, shifts in the predominant distribution do not tend to correspond to notable shifts in infant mortality (Wilcox, 2001). A number of factors may result in shifts in the predominant distribution; altitude, race or ethnicity, and maternal smoking are among the better studied, thereby producing a larger (or smaller) percentage of LBW babies. However, populations that have a larger percentage of LBW infants do not always have higher infant mortality (Wilcox, 2001).

Population trends in birth weight are tracked internationally to identify opportunities for intervention and to understand country-specific infant mortality (UNICEF, 2004). Being born at the lower tail of the birth-weight distribution may have significant and immediate health and economic consequences. Pregnancies afflicted by fetal growth restriction incur greater medical expenses in the prenatal and immediate postnatal period and higher risks of hospitalization in the first year of life (NRC, 2003). Thus, although an exogenous factor exerts an effect at all points in the birth-weight growth curve, the economic and clinical consequences of that effect might be borne disproportionately by those at the lower end of the birth-weight distribution.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and LBW or PTD.

Update 2010 considered three studies of prenatal exposure to DLCs and birth weight. In a prospective cohort study of 514 women in Sapporo, Japan, Konishi et al. (2009) reported that a significant reduction in birth weight was associated with total TEQs (-220.5 g per 10-fold increase in TEQ; 95% CI–399.2 to –41.9) in maternal blood. A significant reduction in birth weight was also observed in connection separately with dioxin-like PCDD TEQs and PCDF TEQs and marginally with TEQs based on all dioxin-like PCBs. When stratified on infant sex, the association remained statistically significant for males but not females. In a coastal area of Japan (where consumption of seafood is common), Tawara et al. (2009) found that the concentrations of several individual dioxin-like PCDD and PCDF congeners and of total TEQs in maternal breast milk were inversely related to newborn length, but none was related to birth weight. Similarly, in a nested study of fatty-fish consumption in the Danish National Birth Cohort, Halldorsson et al. (2009) did not find that total maternal serum TEQs derived with the AHR-CALUX assay were associated with birth weight.

Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006,

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Update 2008, and Update 2010 did not change that conclusion. Reviews of the relevant studies are presented in the earlier reports. The most relevant findings on birth weight after paternal and maternal exposure to the COIs are summarized in Tables 9-6 and 9-7, respectively.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and LBW or PTD have been published since Update 2010.

Environmental Studies

Nishijo et al. (2012) examined the association between dioxin exposure and infant growth among 210 mother-infant pairs residing in dioxin-contaminated districts near the Da Nang airbase in Vietnam. Full-term babies from uncomplicated deliveries were recruited in 2008 and 2009. Breast milk was collected 1 month after birth and analyzed for 7 PCDDs and 10 PCDFs. Maternal interviews provided detailed covariate data, and pregnancy and delivery information was obtained from the obstetricians. All infants were breastfed until 4 months after birth. Length of residence in the contaminated districts was directly related to PCDD/F-TEQ exposure quartile and maternal age. However, overall, breast-milk concentrations 1 month after birth were not excessively increased, even given the proximity of the subjects to the contaminated districts. Body weight of 4-month-old boys whose breast-milk PCDDs/F-TEQ (pg/g of fat) was in the fourth quartile (highest exposure) was significantly lower than that of boys whose breast-milk exposure was in the first quartile (lowest exposure) (6,562 g vs 6,927 g), as was their body mass index (15.9 kg/m2 vs 16.5 kg/m2). Body weight, however, did not decline linearly with increasing quartile of exposure. No effect was found in girls, and the overall sample of this study was small.

Tsukimori et al. (2012b) examined the association of maternal exposure to PCDDs, PCDFs, and PCBs in relation to birth weight among women who were accidentally exposed to rice oil contaminated with PCBs, PCDDs, or PCDFs in western Japan (in the Yusho incident of 1968). A nationwide health examination of Yusho survivors has been conducted annually since 1986. As of 2009, 737 women were registered with the Study Group for Yusho; to qualify, they had to have signs and symptoms of Yusho oil disease, a history of consumption of contaminated oil, or the characteristic profile of PCBs and polychlorinated quarterphenyls in their blood. The 2009 mailed questionnaire included questions about maternal and infant outcomes. Date of delivery, gestational age at delivery, and birth weight were obtained from the record of pregnancy care provided by each patient. Of the 737 women registered, 206 gave birth after the Yusho incident. The analysis was based on 190 births after the Yusho incident to 101 women who provided blood samples collected in 2001 or later for measurement of PCDDs,

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 9-6 Selected Epidemiologic Studies—Birth Weight Following Paternal Exposure

Reference Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans; births from service through 1993 in AFHS
Michalek et al., 1998a Ranch Hands 2,082 births No association with IUGR Adjusted by stratification for father’s race, mother smoking during pregnancy, mother’s alcohol use, mother’s age, father’s age, father’s military occupation
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed
CDC, 1989a,b Military service in VA 1,771 Vietnam; 1,561 non-Vietnam LBW/RR 1.1 (0.8–1.4) Maternal age and gravidity. Also model with smoking history, alcohol use, educational attainment, marital status, illicit drug use in military
US American Legion Cohort—American Legionnaires with service 1961–1975
Stellman et al., 1988 US men deployed to SEA during Vietnam War, and other deployed men during same time period 2,858 in SEA 3,933 deployed elsewhere (n = 6,081) “no difference between the birthweight of boys born to servicemen stationed in SEA compared to those born to controls, nor did girls’ birthweight differs between two groups” Sex, age of father at time of child’s birth, age of mother, mother smoking during pregnancy, military service in SEA and exposure to combat and AO—these were not multivariate adjusted models, so strong smoking effect might have had an influence. These appear to have all been independent models
Tasmanian Veterans with Service in Vietnam—Followup of Australian Vietnam veterans
Field and Kerr, 1988 Military service in Vietnam ~550 LBW/RR 1.6 (1.0–2.5) RR calculated by committee member
OCCUPATIONAL—INDUSTRIAL
Lawson et al., 2004 Wives of chemical workers highly exposed to TCDD-contaminated chemicals ~500 exposed 600 referents No association with birth weight overall Adjusted for sex, education, parity, smoking, length of gestation, no stratification by sex
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Reference Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates
OCCUPATIONAL—HERBICIDE-USING WORKERS
DimichWard et al., 1996 Chlorophenate, wood preservative in sawmill industry 19,675 births No association (ORs for SGA ~1) Sex, maternal and paternal age, birth yr, matching

NOTE: AFHS, Air Force Health Study; AO, Agent Orange; CDC, Centers for Disease Control and Prevention; IUGR, intrauterine growth restriction; LBW, low birth weight; OR, odds ratio; RR, relative risk; SEA, Southeast Asia; SGA, small for gestational age; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

PCDFs, and non-ortho PCBs. A simple decay model was used to estimate chemical concentration at the time of delivery. Models were adjusted for important predictors of fetal growth, including gestational age at delivery. Increased maternal exposure to PCDDs and PCDFs was strongly associated with reduced birth weight overall, which appeared to be driven by strong effects in male infants. For each 10-fold increase in total-PCDDs TEQ, male infant birth weight was decreased by about 200 g (95% CI -33 to -70 g), which was statistically significant (p = 0.003). A similar magnitude of association was found for non-ortho PCBs TEQ, whereas the total-PCDFs TEQ and total TEQ were 130–170 g. All the individual congeners, including 2,3,7,8-TCDD and 1,2,3,7,8-pentachloro-dibenzodioxin, were associated with significant decrements in birth weight in males. There were no significant associations in females overall or for individual congeners despite the fact that there were no significant differences in exposure levels between sexes of the infants. In addition, the odds of delivering a LBW infant (birth weight < 2,500 g) increased significantly with each 10-fold increase in total exposure to PCDD TEQ (OR = 8.1, 95% CI 1.67–38.86), total non-ortho PCB TEQ (OR = 9.32, 95% CI 1.40–62.03), and total TEQ (OR = 4.36, 95% CI 1.21–15.72). This study has many strengths, but there was some concern with respect to the accuracy of the exposure extrapolation model, specifically with respect to the treatment of births and breastfeeding events that occurred in the period between the index pregnancy and the blood collection. Using the historical serum samples available, the study did not explicitly measure non-dioxin-like PCBs. Given the complex nature of the Yusho exposure, which was predominantly a PCB exposure with PCDF contaminants, it is not possible with these data to disentangle the effects of the non-dioxin-like PCB exposures. Although the Yusho cohort does have higher TEQs than the general population, the toxic effects of the Yusho exposure were driven predominantly by PCDFs, not TCDD.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 9-7 Selected Epidemiologic Studies—Birth Weight Following Maternal Exposure (Shaded Entries Are New Information for This Update)

Reference Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates
VIETNAM VETERANS
US VA Cohort of Female Vietnam Veterans
H. Kang, personal correspondence, February 27, 2013 Military service 2,689 BW girls = + 0.5 oz BW boys = –0.8 oz (difference in boys comes to –22.7 g Unadjusted differences and major uncontrolled confounders (smoking, parity, race)
Kang et al., 2000 Military service 4,140 LBW (OR = 1.06, 95% CI 0.8–1.5) Maternal age, education, race, marital status, military characteristics, smoking, drinking, average number of hours worked during pregnancy, complications during pregnancy
ENVIRONMENTAL
Seveso, Italy, Women’s Health Study—Industrial accident July 10, 1976 (981 women who were between infancy and 40 yrs old, who resided in Zones A or B)
Baccarelli et al., 2008 Seveso 51 No association with LBW None
Eskenazi et al., 2003 (B. Eskenazi, personal correspondence, January 30, 2013—researchers checked for effect modification by sex but found none) Seveso 608 overall Birth weight (nonsignificant negative coefficients). SGA—ORs between 1.2–1.8; none are technically significant. OR = 1.2, 0.8–1.8 is overall Gestational age, sex, parity, history of LBW, maternal height, maternal BMI, maternal age, maternal education, smoking
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Reference Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates
Vietnamese Studies
Nishijo et al., 2012 People living around contaminated airbase in Vietnam 210 At birth no effect, but birth-weight discrepancy grows with months from delivery. Significant at 4 months. Effect only seen in boys Parity, maternal age, weight, educational period, alcohol use, family income, family smoking, gestational weeks, infant age on the day of examination
Times Beach and Quail Run Cohorts
Stockbauer et al., 1988 TCDD soil contamination in Missouri Matched sets, ~400 (2:1) LBW: 1.5 (95% CI 0.2–2.3) Sex, maternal education, parity, marital status, prepregnancy weight, smoking, history of previous SAB and fetal deaths
Yusho, Japan, Cohort—population exposed to PCDDs, PCDFs, and PCBs in contaminated cooking oil
Tsukimori et al., 2012b Yusho 190 ~ –200g birthweight reduction with PCDD TEQ (p = 0.003) in males, also overall effect but driven by effect in boys Gestational age, maternal age, parity, smoking, duration breastfeeding, seafood consumption
Kuratsune et al., 1972 Yusho 11 None calculated
Other Environmental Studies
Japan
Konishi et al., 2009 Sapporo, Japan; contemporary cohort 514 BW (–220.5 g per 10-fold increase in TEQ, 95% CI –399.2 to –41.9); effect driven by males Gestational age, maternal age, maternal height, maternal weight before pregnancy, parity, smoking, inshore fish intake, blood sampling period, infant sex
Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Reference Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates
Tawara et al., 2009 Coastal Japan; contemporary cohort 75 Some weak negative correlations Unadjusted; Spearman correlations
Nishijo et al., 2008 Breast-milk dioxin levels 42 Negative correlation for TEQ-PCDD and TEQ, PCDF, but not “significant” Spearman correlations
Finland
Vartiainen et al., 1998 Random sampling of mother/infant pairs from urban/rural Finland 167 Birth weight decreased with increasing concentrations of I-TEQ, especially among boys Unadjusted; effect goes away when restricted to primiparas
Netherlands
Patandin et al., 1998 Dutch children—PCB 118 exposure (only total) 207 Birth weight = –119 (53.7); p = 0.03 Smoking, alcohol, gestational age, target height, parity
United States
Kezios et al., 2012 California Child Health and Human Development Study 600 No association with birth weight Race, age, smoking status, BMI, sex, length of gestation, lipids
Sagiv et al., 2007 PCB 118 722 Negative birthweight effects with increasing exposure quartile, nonsignificant—0, –18, –72, –69.5 Gestational age, infant size, birth year, maternal age, race parity, height, prepregnancy BMI, smoking, local fish consumption

NOTE: BMI, body mass index; BW, birth weight; CI, confidence interval; I-TEQ, international (total) toxic equivalent; LBW, low birth weight; OR, odds ratio; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofurans; SAB, spontaneous abortion; SGA, small for gestational age; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

It is also noteworthy that serum TCDD was not higher in the Yusho mothers than in the general population. Nonetheless, the results raise concerns and in theory would provide some plausibility of later associations with diseases in offspring, from neurodevelopmental impairment to adult-onset chronic diseases.

Finally, Kezios et al. (2012) examined the association of maternal exposure to PCBs and infant growth measures in 600 infants (born in 1960–1963) participating in the Child Health and Development Studies in northern California. Eleven PCB congeners were measured in postpartum maternal seruma, including dioxin-like, mono-ortho PCB 118. Overall, there was no association between PCB 118 concentration and infant birth weight, and no interaction related to infant sex. There was also no association with length of gestation.

Biologic Plausibility

The available evidence from experimental animal studies indicates that TCDD exposure during pregnancy can reduce body weight at birth but only at high doses. Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are inadequate to support conclusions. TCDD and herbicides are known to cross the placenta, and this leads to direct exposure of the fetus. Data from studies of experimental animals also suggest that the preimplantation embryo and developing fetus are sensitive to the toxic effects of 2,4-D and TCDD after maternal exposure.

Synthesis

Three studies provide some evidence of deficit in birth weight in relation to maternal exposure to DLCs—Konishi et al. (2009, reviewed in Update 2010), Nishijo et al. (2012), and Tsukimori et al (2012b)—some with notably stronger effects in male infants. LBW itself was examined overall only in the Tsukimori study, in which it was found to be significantly increased in association with exposure. None of the studies found associations with prematurity or gestational length continuously. In Tsukimori et al. (2012b), the magnitude of birth weight decrease associated with a 10-fold increase in total TEQ exposure is comparable with that found for maternal active smoking (about a 200-g birth-weight deficit). The implication of this finding is unclear—animal evidence indicates that in utero TCDD exposure can reduce birth weight at high doses in both male and female pups, but there are insufficient data to support conclusions about any sex-specific effects of TCDD.

Two older studies had addressed this outcome without reporting separate results by infant sex, and the committee asked researchers from each team whether they could make such a comparison. Both responded to the inquiries, but the information they provided did little to support the hypothesis that there tended

Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

to be a lowering of birth weight in male infants. The one previous Vietnam-era study (Kang et al., 2000) reported no association with LBW in 4,140 female military veterans, and Kang replied that a reanalysis showed that the average birth weight of the boys was only slightly lower than that of the girls (see Table 9-7) (H. Kang, US Department of Veterans Affairs, personal communication, February 27, 2013). Eskenazi et al. (2003), in their analysis of the Seveso population that had high TCDD exposures, reported no overall association with SGA and birth weight, although they did not report the results of any analyses that considered effect modification by infant sex; Eskenazi replied to the committee’s question by reporting that the researchers had made the comparison by infant sex but they found nothing of interest and so did not report details (B. Eskenazi, Seveso Women’s Health Study, personal communication, January 30, 2013).

There are a number of challenges in conducting these types of epidemiologic studies in a rigorous way. First, the prenatal and immediate postpartum period is not a stable pharmacokinetic state, involving substantial changes in body volume and fat mobilization. Biomarker measures during pregnancy may be substantially affected by weight change during pregnancy. Moreover, extrapolation of a more recent biomarker measure back many years to a more relevant period is complicated by intervening pregnancy and breastfeeding events, which result in substantial uncertainty in the index exposure level. Overall, although the committee notes that the animal literature does support an effect of TCDD exposure on birth weight, the epidemiologic literature is insufficiently robust to allow a final determination. However, the committee is concerned about a potential association of maternal exposure with birth weight.

Conclusions

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and low birth weight or preterm delivery.

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Suggested Citation:"9 Fertility and Gestational Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences (NAS) was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations are conducted every two years to review newly available literature and draw conclusions from the overall evidence.Veterans and Agent Orange: Update 2012 reviews peer-reviewed scientific reports concerning associations between health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published in October 2010--September 2012 and integrates this information with the previously established evidence database. This report considers whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association; the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

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