Our results indicate a modest but statistically significant lower mean birth weight among infants born to mothers that resided in areas with high concentrations of PFOS and PFOA in drinking water supplies. These findings are consistent with the majority of the prior literature that has evaluated these relationships [1, 12, 35]. We also found evidence that PFOS and PFOA exposure is linked to lower mean gestational age, a relationship that has found less consistent support in previous studies [5, 13, 14].
Associations between maternal PFAS exposure and birth weight and/or gestational age are of more concern if they entail a greater likelihood of clinically significant low birth weight (< 2500 g) or preterm birth (< 37 weeks), outcomes which have been associated with adverse long-term developmental consequences for the child [36, 37]. However, few studies have evaluated associations between PFAS and the likelihood of these adverse birth outcomes directly (exceptions include [10, 14, 38]), largely due to sample size constraints given the relative infrequency with which such outcomes occur.
Our analyses suggest that high levels of PFOA and PFOS exposure may lead to substantially increased odds of low birth weight, very low birth weight, pre-term birth, early pre-term birth, and a lower GFR. All of these outcomes are of substantial public health relevance [36,37,38]. We note, however, that these effects are not necessarily additive. In particular, pre-term birth may lead to an increased risk of low birth weight, such that these two outcomes are correlated. Part of the effect of PFAS exposure on the odds of low birth weight is thus already captured in the effect of PFAS exposure on pre-term birth. PFAS exposure may still be a causal factor in both outcomes though, and our estimates represent the overall effect of exposure on each outcome regardless of the mechanisms through which it acts.. In Oakdale, the area of highest and most consistent exposure before the installation of GAC water filtration, infants were 36% more likely to be born at a weight less than 2500 g and almost 45% more likely to be born prior to 32 weeks, relative to control communities unaffected by the contamination. These differences in outcomes between the highly exposed community and the control area moderated after municipal water filtration began and PFAS exposures were dramatically reduced.
Methodologically, the present study differs from the existing literature in several ways [39]. First, the contamination of drinking water supplies in our study area affected a large population, with approximately 19,000 (roughly 40%) of the birth records in our study being to mothers residing in affected areas. This large study population affords greater statistical power, a feature of particular importance in evaluating the probability of relatively rare birth outcomes such as early pre-term birth.
Second, with the exception of one C8 Science Panel study [14], prior studies have estimated only associations between individual serum-PFAS concentrations and birth outcomes. Such studies may be subject to concerns regarding the influence of unobserved confounding biological factors [25, 26]. For example, individuals with poor kidney function may be subject to slower removal of PFAS from the blood, leading to higher serum concentrations, and may also experience worse reproductive outcomes as a result of poor kidney function. Our proxy for exposure, however, does not rely on measured serum concentrations. By using a difference-in-differences approach, our analysis avoids this concern.
Third, the majority of prior studies are based on samples from general populations with more modest background levels of exposure to PFAS, limiting the range over which any relationships may be identified. Other studies that have estimated associations with high levels of PFAS exposure have been based on populations exposed primarily to PFOA [14, 40]. Residents of Oakdale and the other affected communities were highly exposed to both PFOS and PFOA. Animal-based toxicological studies indicate that PFOS is a significant determinant of adverse birth outcomes including decreased pup weight and survival [1]. The effects of exposure to PFOA and PFOS may also be additive, with certain health-based values specifying joint exposure limits [27].
Fourth, our use of all singleton live births in our study communities over the relevant time period enables a novel evaluation of the effects of PFAS exposure on fertility through analysis of the GFR and age-specific fertility rates. Unlike prior studies of TTP (time-to-pregnancy) that follow a self-selected set of individuals that succeed in conceiving, the research design in the present study does not implicitly omit the impact of PFAS exposure on infertility. Our results provide the first epidemiological evidence that elevated PFAS exposure affects fertility; the GFR in Oakdale was 15 to 25% lower among women in fertile age groups than rates observed in the control communities. While the post-filtration recovery in Oakdale appears to be slower or more modest for the general fertility rate than for the individual adverse birth outcomes evaluated, the estimated coefficients are still higher for the 2007–2011 period than for the 2002–2006 period. The rebound appears to be driven by 25–34-year-old women who represent the largest age category for mothers in our study.
While our study of the GFR cannot disentangle the particular mechanisms through which PFOA and/or PFOS exposure may affect the birth rate, it reflects the outcome of public health interest. Our study is, however, limited by lack of information on contraceptive use and other important choice-based determinants of fertility. To the extent that these variables are not captured by the demographic information included in the analysis and changed differently over time in Oakdale relative to the control communities, our estimates may be subject to confounding.
Fifth, the installation of the GAC filtration facility in Oakdale in 2006 effectively eliminated Oakdale residents’ exposure to non-background concentrations of PFAS. This population-wide change in exposure allows a difference–in-differences comparison that provides a stronger basis for causal inference than a standard cross-sectional cohort-based study, as all confounding factors that do not change over time are implicitly controlled for. A type I error will arise only if omitted factors change at the same time as the intervention. One conceivable confounding factor could be the presence of other contaminants in Oakdale’s municipal water supply with concentrations that were also reduced by GAC filtration. However, extensive monitoring and remediation to address the presence of known contaminants in groundwater in Washington County was undertaken in the 1980s [22].
Given the limitations on demographic information included in our data due to privacy concerns, it could also be the case that the composition of Oakdale’s population changed relative to the surrounding areas pre- and post-installation of the filtration system. Table 1, however, shows that the demographics of Oakdale changed in a similar way to the control zip codes suggesting that the results were not driven by temporal changes in race/ethnicity or income levels. Moreover, inclusion of these zip-code level variables in our models did not change our findings. Similarly, it is unlikely that significant differences in birth order emerged pre- and post-filtration in Oakdale relative to the control areas, especially since our analyses were adjusted for age.
Lastly, the present study is distinct due to the long study period. Exposure outcomes must be evaluated over a relatively long timeframe due to the fact that the half-lives of PFOA and PFOS in human blood have been estimated to be in the range of 2 to 4 years [41]. Maternal serum-PFAS concentrations in Oakdale would therefore remain elevated even after consumption of contaminated water ceased. Our binary classification of this gradual decline, using 2006 as a cutoff point, will tend to attenuate the magnitude and statistical significance of any relationships identified by introducing measurement error in the explanatory variable of interest [42]. Our data do, however, include mothers who moved into Oakdale and the other affected communities after 2006, and average serum concentrations across all residents of Oakdale may have declined at a faster rate than would be suggested by the elimination half-life only. In addition, transplacental passage of PFASs could be faster for recently absorbed PFASs than for accumulated PFAS stores that are bound to albumin or other ligands.
There are several important limitations of the present study. First, our data do not allow for the estimation of a dose-response relationship. Precise individual-level maternal exposure to PFAS in our study population is unknown, and our proxy for exposure is binary, although supported by analyses of serum samples thought to be representative for the community [31, 43]. Second, we were unable to disentangle the effects of PFOA and PFOS from one another, and from the potential effects of other PFASs. In particular, perfluorobutyrate (PFBA) contamination was also widespread in the Washington County area, although the prior literature does not suggest that PFBA is associated with the adverse reproductive outcomes observed. Third, drinking water is not the only exposure pathway for PFAS. Consumption of fish caught from contaminated water bodies is another local source of exposure, and fish consumption advisories due to the presence of PFOS in fish tissues were released only beginning in 2008 [44]. Lastly, our research design and potential annual variation in unobserved factors do not allow for a year-by-year analysis that explicitly accounts for the long half-lives of PFAS in the body. Further follow-up and extended access to covariates will be needed to establish the continued normalization of reproductive parameters in Oakdale.