An overview of the science linking environmental contaminant exposure and Spontaneous Abortion

1. An overview of the science linking environmental contaminant exposure and Spontaneous Abortion Warren G. Foster, Ph.D. Department of Obstetrics & Gynecology McMaster University Hamilton, Ontario, Canada 8 December 2005

2. Objectives • Definitions; • Discuss the highlights of the literature; • Apply a weight of evidence approach; and • Illustrate the relationship between exposure to environmental contaminants and spontaneous abortion.

3. Definitions • Spontaneous abortion is defined as the loss of the products of conception prior to viability of the fetus at 20 weeks of gestation or below 500 gm. • A habitual aborter is a patient who serially miscarries 3 or more times.

4. Weight of evidence approach used in assessing the literature • Change in the prevalence of the disease or adverse outcome of interest; • Epidemiological literature establishing the association; • Consistency of the literature; • Temporality of the exposure; • Experimental evidence; • Biological plausibility of the proposed association; • Dose response; and • Reversibility

5. Established Risk Factors for Spontaneous abortion • Smoking • Advanced maternal age • Previous history of fetal death

6. Known causes of Spontaneous Abortion • Chromosomal abnormalities and occur in the first trimester; • Chemotherapy; • Radiation; • Anesthetic gases; and • Environmental contaminants.

7. Trend data • An electronic search of the literature using Pub Med, Medline and Toxnet was performed to identify articles relating to SA and incidence, prevalence, or frequency. • References from published articles on SA were also searched. • No published data in the peer reviewed literature that addresses this issue. • Therefore, the paucity of information on this topic represents a major data gap.

8. Epidemiological evidence • Paternal exposure is associated with increased risk of SA: • Paternal exposure to the pesticide 2,4D linked with an increase risk of SA (Aschengrau & Monson J. Occup Med. 31:618;1989; Am. J. Pub. Hlth. 80:1218;1990) • Savitz et al., (Am. J. Epidemiol. 146:1025;1997) demonstrated an increased risk of SA in couples who worked on a farm and had exposure to thiocarbamates, carbaryl and unclassified pesticides. The critical window of exposure was the three months prior to conception including the calendar month of conception. • Maternal exposure also associated with increased risk of SA: • Wives of workers exposed to organochlorine pesticides had an elevated risk of SA and stillbirth (Rupa et al., Environ. Res. 55:123;1991). • Bell and coworkers (Epidemiol. 12:148;2001) found that maternal pesticide exposure occurring during the 3rd to 8Th week of gestation had the greatest effect on SA. • Circulating levels of DDT higher in women with SA and stillbirths in India (Bercovici et al., Environ. Res. 30:169;1983; and Saxena et al., J. Toxicol. Environ. Hlth. 11:71;1983)

9. Epidemiological evidence • Drinking water byproducts also associated with an increased risk of SA (Waller et al., Epidemiol. 10:203;1999) whereas others have found no increased risk (Savitz et al., Environ. Hlth. Perspect. 103:592;1995) • Taken together the epidemiological literature shows that both paternal (3 months prior to and including month of conception) and maternal exposure to environmental contaminants (3rd to 8Th week of gestation) can increase risk of SA. • Weaknesses in the data include: (1) no direct measurement of exposure in the majority of studies; (2) based on subject recall of pesticide use prior to and during pregnancy; (3) inadequate methodology; (4) confounders; and (5) small sample sizes.

10. Experimental evidence • Foster and coworkers (Reprod. Toxicol. 9:541;1995)found the hexachlorobenzene (HCB) treatment reduced serum progesterone production in the luteal phase of Cynomolgus monkeys. • TCDD, TCDF and PCBs have been shown to be associated with abortions in rhesus monkeys (McNulty, Environ. Hlth. Perspect. 60:77;1985). • Greenlee and colleagues (Environ. Hlth. Perspect. 112:703;2004) demonstrated that several pesticides can attenuate embryo growth and increase programmed cell death in embryo cells. • In vitro experiments with o,p’-DDT reduced development to morula stage and increased blastomere apoptosis (Greenlee et al., Reprod. Toxicol. 13:555;2005). • Therefore, animal data suggests that environmental contaminants can affect physiological processes important in embryo development, implantation, and induce SA.

11. Biological plausibility • Animal models of the maternal-fetal-placental unit are lacking; • Evidence of contaminant induced changes in circulating progesterone levels and changes in cell proliferation and apoptosis of blastomeres suggests that these effects could occur with human embryos as well; • Emerging evidence from in vitro fertilization studies demonstrates that media changes can alter gene expression and could play a role in implantation failure.

12. Summary and Conclusions • Taken together evidence from (1) epidemiology, (2) animal studies, and (3) in vitro experiments provide a moderate level of support for the view that environmental contaminants, and pesticides in particular, can induce SA. • However, because few epidemiological studies have documented exposure it is not possible to establish a causal relationship. • Moreover, the relationship between environmental contaminants and spontaneous abortion, at the levels of contaminants measured in contemporary studies in North America, is at present speculative. • Never-the-less this is an area that requires further investigation at all levels. • Many important questions remain to be addressed before a the evidence can be considered to be strong.

13. Areas for future research To establish a strong link between environmental contaminant exposure and spontaneous abortion further research is needed: • Adequately powered epidemiological studies with direct measures of exposure and control for confounders; • Comparison of rates of SA in heavily polluted vs. relatively less polluted regions; • Identification of mechanism(s) of action will be important to establish biological plausibility; • Additional animal and in vitro studies focused on embryo development and implantation effects using environmentally relevant concentrations; and • Studies of the epigenetic (genetic programming) effects of environmentally relevant concentrations of environmental contaminants.