Women enrolled in the AHS who reported activities involving agricultural pesticide exposures during the first trimester of their most recent pregnancy had a twofold increased risk of developing GDM. GDM risk was not increased among women who reported using pesticides only in the home and garden or who reported working in the fields. Prior analysis has shown that women in the AHS are involved in many aspects of farm work (22
). Only mixing and applying pesticides during the first trimester of pregnancy was associated with GDM. Thus, the association we observed is unlikely to be due to some uncontrolled correlate of participation in general farm activities. We had no information on specific pesticide use during pregnancy. For completeness, however, we examined the association between having ever mixed or applied individual pesticides at some time before enrollment and GDM only among women who reported agricultural exposures during the index pregnancy. These analyses are, however, limited by the small sample sizes. An elevated risk of GDM was associated with ever-use of four herbicides, two organophosphate insecticides, and one carbamate insecticide. Since we do not have information on the timing of exposure relative to pregnancy, any resulting misclassification is likely to have biased these estimates toward null values.
Although our findings of an association between 2,4,5-T and 2,4,5-TP and GDM are based on small numbers, they are of particular interest given the potential for contamination with dioxin in these pesticides (23
). Several biologic mechanisms have been proposed for the effects of dioxin-like compounds on glucose metabolism (24
). In general, most effects are thought to be mediated through interactions between aryl hydrocarbon receptors and peroxisome proliferator-activated receptor-γ–mediated signaling pathways (24
), resulting in an increase in insulin resistance (14
) and reduction in glucose transporter activity (15
). Epidemiologic studies have also indicated an association between dioxin-like compounds and glucose metabolism (7
). However, because these studies measured serum levels of TCDD (2,3,7,8 tetrachlorodibenzo-p
-dioxin) after disease onset, it is possible that the disease process influenced TCDD metabolism. An advantage of questionnaire data in this instance is that our measure of pesticide exposure is unlikely to be influenced by disease processes.
Laboratory data have suggested a possible effect of malathion (an organophosphate) on glucose metabolism, including increases in insulin and blood glucose concentration and changes in key enzymes involved in gluconeogenesis, glycogenolysis, and glycolysis. Similar mechanisms may be involved for other organophosphates (16
). In our study we did not find an increased risk of GDM among women who reported agricultural exposures during pregnancy and ever-use of malathion (). Malathion is widely used for home and garden as well as for crop applications, and its purchase does not require a pesticide license (20
). It is possible that we missed an association with malathion by focusing solely on women who reported mixing or applying pesticides to crops during the first trimester of the pregnancy. However, when we examined women reporting home and garden use of pesticides during the first trimester we still failed to see an association.
We saw an increased risk of GDM associated with two other organophosphate insecticides (diazinon and phorate) and one carbamate insecticide (carbofuran). Interestingly, there have been several case reports of glycosuria with and without hyperglycemia following pesticide poisoning with organophosphate insecticides and carbamates (10
This study provides data on a large number of women who reported performing specific tasks during the first trimester of their most recent pregnancy. Even though GDM in this study was self-reported, the reported frequency of 4.5% is in the expected range for the U.S. (3–5%) (4
). Although our analysis excluded women with diabetes diagnosed aged <20 years, we were unable to exclude preexisting type 2 diabetes for all women, since age at diagnosis of type 2 diabetes was asked in broad categories. Our GDM question asked specifically about “diabetes only during pregnancy” to facilitate more accurate reporting. Even so, bias from self-reported GDM may be a concern. Several studies in diverse populations have shown that maternal recall of rare obstetric complications (including GDM) is relatively accurate when compared with medical records (26
). These studies report high sensitivity, which suggests that there are not likely to be unreported cases among the control subjects. While some women who report GDM may not have it, this would tend to bias our results toward the null.
The data on reported pesticide exposure during pregnancy span 25 years, which may affect accuracy of exposure reporting. However, we have previously found that farmers and their families tend to reliably report pesticide exposure history (29
). Furthermore, our estimates were unchanged when we restricted the analysis to pregnancies that occurred within 12 years of enrollment. Unfortunately, the sample size was too small to focus on a shorter interval.
Our estimates may be affected by reporting bias if women who had GDM tended to over-report agricultural pesticide use during pregnancy or if women who had been exposed were more likely to report GDM. This is unlikely since GDM was not the primary focus of the questionnaire, and we characterized the exposure by aggregating responses to several individual questions. Furthermore, the increased risk observed in our estimates was associated only with activities with a greater potential for exposure to farm pesticides, while we saw no increase in risk with other activities.
Although adjusting for BMI had little effect on risk estimates, our ability to control for it was limited by the fact that we relied on weight reported at enrollment rather than before the index pregnancy. Even though BMI tends to track over time, BMI at enrollment will be a better surrogate for recent pregnancies than for those more distant in time. It was, however, reassuring that restricting the analysis to more recent pregnancies did not change the results. Furthermore, although BMI was not a confounder in our analysis, it was significantly associated with GDM. Due to small sample size, we were unable to explore whether race modified the association between agricultural exposure and GDM.
Pregnancy is a known diabetogenic state resulting from decreased insulin sensitivity (32
). The inability to compensate for the decreased insulin sensitivity results in hyperglycemia above the normal pregnancy ranges. Although much is known about common risk factors for GDM, our understanding of whether and how environmental exposures may affect risk is still limited. Research shows that 20–50% of women with GDM will develop type 2 diabetes within 5–10 years (34
). Thus, understanding any potential effect of environmental exposures on glucose tolerance during pregnancy may have substantial public health importance beyond the direct effects on GDM.