Authors
Arbuckle, TE., Lin, Z., Mery, L.S.

Title
An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population.

Journal
Environmental Health Perspectives, 109: 851-857.2002.

Summary
The objective of this study was to explore the reproductive toxicity of specific pesticide active ingredients and their interaction with other known risk factors. This paper is of interest to toxicologists, regulatory agencies, chemical manufacturers, pesticide applicators, agricultural workers and the general public for several distinct reasons. First, municipalities and even Provincial governments are examining the pesticide issue and in some cases taking action to ban the use of pesticides for cosmetic purposes. Hence this study is timely and provides evidence in favor of restricting the use of pesticides. Secondly, several studies have demonstrated an association between pesticide exposure and decreased semen quality, increased time to pregnancy and an increased risk of spontaneous abortion. Finally, since the adverse effects documented in the literature are related to fertility and fetal development disruption of endocrine physiology is speculated although the authors themselves do not raise this issue. A strength of this paper is that it raises the hypothesis that there are critical periods during which exposure to pesticides can increase the risk of spontaneous abortions.

Arbuckle et al. investigated the risk of spontaneous abortion and pesticide exposure, as it relates to specific pesticide families and active ingredients, in pregnant farm women, during critical exposure windows. The sampling frame consisted of all farm operations in Ontario as reported in the 1986 Census. In order to make the sub-cohorts more comparable farms were restricted to family-run farms with reported sales of agricultural products of $50 000 or greater in 1986. Tobacco farms were excluded due to their small numbers and the very specific types of pesticides that they use. All farms meeting the criteria were contacted to determine eligibility of couples on the farms. Couples were eligible if they lived year round on the farm and the wife was 44 years of age or younger. Three questionnaires were then mailed to the farm family in order to gather information on health, as well as current and historical use of pesticides around the farm and home. The wife questionnaire asked women to recall her first 5 pregnancies and spontaneous abortions. For spontaneous abortions women were asked to state how many weeks they were pregnant. Before the analysis, the pesticide exposure information was pooled from the farm operator, husband, and wife questionnaires. From this, the active ingredient was identified for each pesticide reported and subsequently categorized into chemical families and four major classes of use: herbicides, fungicides, insecticides and miscellaneous. This resulted in 17 pesticide unit variables.

Exposures to pesticides were analyzed for two exposure windows: the pre-conception (3 months before conception and the conception month) and post-conception periods (3 months post conception). Exposures after pregnancy loss but in the period of interest were ignored. Pregnancy specific variables were created for other time-related factors that may have influenced the pregnancy loss such as parental age, smoking status, farm activities, and alcohol and caffeine intake. Three types of comparisons were examined in the analysis: (1) Exposed pregnancies in the pre- and post-conception period versus non-exposed pregnancies, to the pesticide unit of interest during the time window; (2) Pre- verses post-conception exposures, using post-conception exposure as the referent group and; (3) Early (<12 weeks gestation) vs. late (12-19 weeks gestation) spontaneous abortions, using late spontaneous abortions as the referent group.

In total there were 395 spontaneous abortions from 3936 pregnancies. The results suggested that the critical window of exposure for spontaneous abortion was in the pre-conception period. A moderate increase in risk of early spontaneous abortion (<12 weeks gestation) was seen for pre-conception exposures to phenoxy acetic acid (OR=1.5, CI=1.1-2.1), and herbicides (OR=1.4, CI=1.1-1.9). For late spontaneous abortions (12-19 weeks gestation) an increased risk was seen for preconception exposures to glyphosate (OR=1.7, CI=1.0-2.9), thiocarbamate (OR=1.8, CI=1.1-3.0), and miscellaneous pesticides (OR=1.5, CI=1.0-2.4). For exposures in the post-conception period, only the miscellaneous pesticide exposure showed an elevated risk (OR=1.9, CI=1.2-3.0) of late spontaneous abortion. When comparing pre- vs. post-conception exposures an elevated risk for early spontaneous abortion was seen for pre-conception exposures to the active ingredients 2,4-D (OR=2.9, CI=1.1-8.0) and 2,4-DB (OR=7.8, CI=1.0-62.3). As well elevated risks were seen for the chemical families phenoxy acetic acid (OR=3.1, CI=1.4-6.4), triazine (OR=1.9, CI=1.0-3.2), organophosphate (OR=2.2, CI=1.0-4.8) and thiocarbamate (OR=2.5, CI=1.1=5.8) exposure in the pre-conception period. Comparisons of early vs. late spontaneous abortions revealed that exposure to phenoxy acetic acid elevated the odds of early spontaneous abortion (OR=1.9, CI=1.1-3.3).

The Classification and Regression Tree (CART) was used to explore interactions between various pesticide units and other risk factors. Advanced maternal age was significantly associated with increased risk of spontaneous abortion (OR=2.6, CI=1.7-3.9). Using the CART method, a strong interaction was found between maternal age and pesticide exposure. Women over 35 years of age exposed in the pre-conception period to carbaryl had a 4-fold increase in risk compared to women of the same age who were unexposed. As well, women over 35 exposed to both carbaryl and 2,4-D in the pre-conception period were 27 times more likely to have a spontaneous abortion compared to unexposed women of the same age.

Due to some methodological limitations in this study, the results should be interpreted with caution. First, there is a possibility that women who had spontaneous abortions would have had better recall of their pesticide use resulting in differential misclassification of pesticide exposures. However, the authors state that most of the reporting of pesticide use was done by the farm operator and/or husbands, which would have limited the potential for recall bias by women. Second, pesticide exposures were not directly measured, making the exposure measurements less precise. There are several factors that could have contributed to the delivered dose of pesticides to farmers including: the type of pesticide formulation, application methods and conditions, handling practices, differences in absorption, distribution, metabolism, and excretion of products or metabolites. Finally, the incidence of spontaneous abortion is estimated to be close to 50% of all pregnancies. Thus, several spontaneous abortions may not have been recognized by the farm women and accounted for in the study. Overall this paper contributes to our knowledge base and extends the literature suggesting a link between exposure to specific pesticide active ingredients and spontaneous abortion.