Concerns about the effects of harmful environmental exposure on birth outcomes have existed for decades. Great advances have been made in understanding the effects of smoking and air pollution, among others, yet research on the effects of pesticides has remained inconclusive. While environmental contaminants generally share the ethical and legal problems of evaluating the health consequences of exposure in a controlled setting and the difficulties associated with rare outcomes, pesticides present an additional challenge. Unlike smoking, which is observable, or even air pollution, for which there exists a robust network of monitors, publicly available pesticide use data are lacking for most of the world. As a result, studies have typically been either highly correlative at coarse resolutions or have included a small number of subjects. Both constraints make it difficult to assess whether residential agricultural pesticide exposure has no effect or whether logistical and analytical barriers have obfuscated the identification of important effects.

Our study bridges the gap between detail and scale by leveraging vast pesticide and birth data for the San Joaquin Valley, CA. Our study has far stronger statistical power to identify effects than previous studies owing to over a hundred thousand birth observations, individual maternal and birth characteristics, and the inclusion of fine-scale regional and temporal fixed effects (PLS Township-year and birth month indicator variables). As a result of our statistical design, we have the analytical power to identify extremely small, but statistically significant negative effects of pesticide exposure on several birth outcomes, if they occur.

Furthermore, our study design and extensive pesticide data enable us to evaluate many details of the nature of pesticide exposure. For example, we can evaluate whether pesticide exposure in different trimesters or pesticides of different toxicity levels affected birth outcomes in different ways. Fetal susceptibility to environmental exposure varies through development37. Similarly, different chemical toxicity can have different expected health outcomes. Here we focused on aggregate chemicals grouped into high and low toxicity pesticides by their EPA Signal Word, which reflects acute toxicity. Acute toxicity does not necessarily indicate impacts from long-term exposure. As such, chemicals suspected to cause negative birth outcomes, such as organophosphates or atrazine would be classified as low toxicity. Nevertheless, we consistently find effects of less than a 10% increase in adverse outcomes for individuals in the top 5% of exposure regardless of timing or toxicity of exposure, even though which effects are statistically significant depends on the model.

Pesticide exposure has a highly skewed distribution in the San Joaquin Valley, where over half of births received no pesticides, the top quarter received about 250 kg and the top 5% received over 16 times that amount. Further, exposure to the top 25% levels had virtually no detectable effect whereas exposure to the top 1% had effects that were up to double the magnitude of effects observed for the top 5% of exposure. In other words, for most births, there is no statistically identifiable impact of pesticide exposure on birth outcome. Yet, for individuals in the top 5 percent of exposure, pesticide exposure led to 5–9% increases in adverse outcomes. The magnitude of effects were further enlarged for the top 1%, where these extreme exposures (>11 000 kg over gestation) led to an 11% increased probability of preterm birth, 20% increased probability of low birth weight, and ~30 g decrease in birth weight.

For perspective, other environmental conditions such as air pollution and extreme heat generally report a 5–10% increase in adverse birth outcomes, but from less extreme exposure13, 15, 38. Similar magnitudes of effects are also observed for other, non-exposure conditions of pregnancy. For example, stress during pregnancy may increase the probability of low birth weight by ~6%39, while enrollment in supplemental nutrition programs is estimated to reduce the probability of low birth weight by a similar amount40.

The significance of the negative effects of extreme pesticide exposure on birth outcomes is heightened by the fact that birth outcomes are persistent and costly. Reducing the incidence of adverse birth outcomes has obvious benefits for individuals, but also for society. Healthier babies require less intensive care as infants, have better long term health and are higher achieving in terms of earnings and employment10, 41. Thus, even small reductions in adverse outcomes can economically offset societal investment in programs such as supplemental nutrition programs offered to millions of low-income women41.

Due to the concentration of negative outcomes at the very highest pesticide exposures, policies, and interventions that target the extreme right tail of the pesticide exposure distribution could largely eliminate the adverse birth outcomes associated with agricultural pesticide exposure documented in this study. As such, valuable and pressing future directions for research should focus on identifying the extreme pesticide users near human development and on the underlying causes for their extreme quantities of use. These insights are critical to designing appropriate and adaptive interventions for the population living nearby.

For instance, crops vary dramatically in their average pesticide use. Commodities such as grapes receive nearly 50 kg ha−1 per year of insecticides alone in the San Joaquin Valley region42, while other high value crops such as pistachios receive barely on third of that amount. Within these broad differences, there are also relevant differences among crops with regard to the chemical composition and seasonal timing of pesticide application. Finally, not all agricultural fields are in proximity to human settlement. Rather, as we illustrate, areas with consistent births and pesticides are a small fraction of the San Joaquin Valley. Thus, if extreme pesticide areas and vulnerable populations could be identified, strategies or interventions could be developed to mitigate the likelihood of extreme exposures.

One further difficulty is isolating the roles of individual chemicals and their mixtures in driving the negative outcomes. Doing so is extremely challenging, because many chemicals are used in conjunction or in close spatial or temporal windows. Using a large-scale data-driven approach could provide a starting point from which individual or community based studies could be built. For example, statewide birth certificate data could enable the identification of potential hot spots of negative (and rare) birth outcomes while the Pesticide Use Reports provide a large sample of different pesticide mixtures. This could yield valuable information for targeting more detailed studies of individual exposures and difficult to observe outcomes (e.g., time to pregnancy, fetal deaths) towards regions and months of the highest concern.

There are some important limitations to our study. As with other environmental contaminants, controlled experiments evaluating the effects of pesticide exposure on birth outcomes are impossible due to clear ethical and legal constraints. This presents challenges both for interpretation and estimation. With regard to interpretation, we cannot observe all individual adaptive responses to pesticide use, such as staying indoors to avoid exposure to pesticide. Further, we can only observe the effects on live births. As a result, our estimates reflect both the direct effect of exposure on live births and the mitigating effects of avoidance behaviors. With regard to identification and estimation, establishing causality without random assignment into pesticide exposure relies on quasi-experimental approaches, such as the panel data models used here with observational data43. While there is no way to formally test if our methods have eliminated all sources of bias that preclude causal interpretation of the regression coefficients, our results are robust to multiple modeling approaches, including controlling for other environmental contaminants such as ambient concentration of pollutants and extreme temperatures. Similarly, we find no significant placebo effects of exposure in the 3 months following birth.

Birth records do not fully capture adverse outcomes such as abnormalities that are difficult to observe at birth nor are they comprehensive with regards to socio-demographics. Measurement error on the outcome variable would not bias our estimates of the effects of pesticide exposure unless it was somehow correlated with pesticide use, yet it could reduce our precision and thus the likelihood of finding statistical significance. With respect to sociodemographic factors, mothers that are exposed to extreme levels of pesticide are more likely to be minorities and have lower education than the sample population as a whole. While we control for these factors, there is potential for the high exposure sample to differ in other unobserved ways (e.g., unobserved maternal health behaviors) that could yield a higher likelihood of adverse birth outcomes. If so, this would result in overestimates of the effects of pesticide exposure on adverse birth outcomes.

Additionally, we measure pesticide exposure as all pesticide use (active ingredients) on production agriculture in the 2.6 km2 PLS Section encompassing mothers’ addresses. We do so because the diversity of chemicals applied in the San Joaquin Valley is extensive and the cumulative effects of multiple exposures are not well understood. However, some chemicals or combinations of chemicals may not be relevant to reproductive risk. Thus, our coefficients are likely underestimates for individuals exposed to a disproportionately high fraction of chemicals of reproductive concern for their PLS Section, year and birth month.

There is some indication that closer proximity to agricultural fields (<1000 m) results in increased odds of adverse birth outcomes7, 20, 44. For a study of this spatial and temporal breadth it is infeasible to directly measure distance from a sprayed field. However, for the San Joaquin Valley, PLS Sections that have any agriculture generally are agriculturally dominated45. Furthermore, the PLS Section is roughly 2276 m on a diagonal. Thus it is highly likely that the vast majority of households in PLS Sections with pesticide use are within 1000 m of a treated agricultural field. If pesticides dissipate much more rapidly, such that the effect is concentrated within 100 m of pesticide use, our study design would underestimate this relationship due to dilution with individuals living farther away from fields but still within the same PLS Section exposure. However, for this to be occurring, the population residing on-farm or adjacent to fields must be much smaller than the broader population residing in the San Joaquin Valley for us to observe such small coefficients. Indeed, this makes intuitive sense for California, where farmworkers overwhelmingly report living independent of their employers in houses or rental units, particularly if they have a spouse or children (93%)46. However, our results may under predict adverse birth outcomes in regions where a larger proportion of workers reside in employer-provided housing on or adjacent to fields, where a larger fraction of pesticide are applied aerially, or where permissible chemicals are more environmentally persistent or toxic to humans.

We also lack information on residence time at mother’s address and employment. Much of the San Joaquin Valley economy is driven by the agricultural industry. If farmworkers were mostly migratory and followed the harvest, our measure of residential pesticide exposure would be inaccurate for this subset of the population. Yet, according to the National Agricultural Workers Surveys for 1996–2011, California farmworkers, especially if they have a spouse or children in their household, are settled (~98%)46. Our measure of exposure would also be artificially high if women were applying agricultural pesticides during pregnancy. While ~18% of California farmworkers are women, only 1.5% of women reported using pesticides in the past 12 months and 0% of women with a spouse or children had reported doing so46. Women could get additional exposure via their spouses, and ~16% of male farm workers reported loading, mixing or applying pesticides in the past year46.

Finally, the San Joaquin Valley is well known to have substandard environmental quality, frequently exceeding EPA contamination levels for air quality. If such exposures co-vary with pesticide use and vary at small spatial and temporal scales, the coefficient on pesticide exposure could capture additional contamination despite our PLS Township-year and birth month controls. While we cannot be certain we have eliminated all sources of contamination that co-vary with pesticides, including a rich set of ambient air quality and temperature metrics did not change the basic results of this paper.

In conclusion, there is a growing literature on the relationship between pesticide exposure and adverse birth outcomes. Yet, evidence of a causal link between infant health and agricultural pesticide exposure remains uncertain due to small samples and lack of maternal or birth characteristics. Our study is the most comprehensive to date, bringing together the largest data file ever compiled on street-address level birth outcomes and fine scale exposure to agricultural pesticides. We provide robust evidence that there are multiple negative effects of residential agricultural pesticide exposure on adverse birth outcomes, but only for births exposed to very high levels of pesticides during gestation. The documented concentration of impacts in the extreme upper tail of the pesticide exposure distribution may explain why previous studies fail to consistently detect effects of pesticides on birth outcomes. Furthermore, the concentration of impacts in the extreme tail of the pesticide exposure distribution provides policy challenges and public health opportunities to balance these potentially serious but rare outcomes with the societal benefits of continued pesticide use.