The cases of stillbirth were evenly distributed in the four seasons for all pollutants, with seasonal variability in the mean concentrations of the pollutants ranging from 12.6 to 17.9 µg/m3 for PM2.5, 10.2 to 12.7 ppb for NO2, 4.2 to 8.3 ppb for SO2, and 7.6 to 9.6 ppm for CO. Apparent temperature showed much larger variability within seasons, ranging from 1°C during winter to 25°C during summer (Supplementary Table, http://links.lww.com/EDE/A679).
The only pollutant with strongly correlated values on successive lag days was CO (r = 0.91 for lag day 2 vs. 3; r = 0.52 for lag day 2 vs. 6). We also assessed correlations between pollutants on lag day 2. NO2 was moderately correlated with SO2 (r = 0.51) and CO (r = 0.59). SO2 was moderately correlated with CO (r = 0.49). The correlations between other pollutants for the mean concentrations on lag day 2 were low (r = 0.31 to 0.37). The mean apparent temperature on lag day 2 was moderately correlated with PM2.5 (r = 0.45) and inversely correlated with NO2, SO2, and CO (r = −0.28 to −0.07) (Table 3).
In unadjusted analyses, we found increased relative odds of stillbirth associated with IQR increases in the mean CO, SO2, and NO2 concentrations on lag day 2, lag days 2 to 3, lag days 2 to 4, and lag days 2 to 5. We also found increased relative odds of stillbirth associated with IQR increases in the mean concentrations of CO and SO2 on lag days 2 to 6, although the increase in relative odds was small for SO2. There was also a small increased relative odds of stillbirth associated with IQR increases in mean PM2.5 concentrations on all lag days (Table 4). After adjusting for mean apparent temperature, effect estimates were little changed (Table 4).
The relative odds of stillbirth associated with each pollutant appeared independent of the other pollutants. The relative odds of stillbirth associated with individual pollutants were similar in two-pollutant and single-pollutant models on the same subjects (Table 5).
Last, we evaluated whether maternal risk factors modified the associations, focusing on lag day 2. There were no clear pattern of increasing or decreasing risk within categories of maternal age, maternal race, and maternal education. The associations of pollutant concentrations with stillbirth were stronger among those with some prenatal care and among nonsmokers (Table 6).
When we defined lag day 1 as the case period, the relative odds of stillbirth were reduced. For example, for SO2 on lag day 1 the OR was 1.04 (95% CI = 0.95–1.13) compared with 1.11 (95% CI = 1.02–1.22) on lag day 2. This pattern of attenuated risk was similar for other pollutants (data not shown).
Our relative odds estimates for CO and NO2 concentrations on lag day 2 were not changed after restricting to only those stillbirths with a maternal residence within 5 km from a monitoring station (CO: OR = 1.21, 95% CI = 1.00–1.47; NO2: OR = 1.05, 95% CI = 0.89–1.24) (Table 4). Patterns were also similar for other moving average NO2 and CO concentrations (data not shown).
We found increased relative odds of stillbirth associated with increases in the mean concentrations of NO2, SO2, CO, and PM2.5 in the immediate few days preceding stillbirth. These risks appeared independent of ambient temperature changes. Non–time varying characteristics of the mother, such as demographic characteristics, maternal health history, socioeconomic status, maternal residence, neighborhood characteristics, etc, could not have confounded these associations because these variables were controlled by the case-crossover design. We did not observe effect modification with maternal age, race/ethnicity, or maternal education. However, the associations of pollutants with stillbirth risk were stronger among the relatively low-risk women with some prenatal care and among nonsmokers.
Our findings of increased stillbirth with increases in NO2, SO2, CO, and PM2.5 concentrations in the immediate few days before delivery are broadly consistent with our previous study, in which we reported 13% to 26% increases in the risk of stillbirth associated with IQR increases in 1st, 2nd, and 3rd trimester mean NO2, SO2, and CO concentrations.15
Our findings are also similar to results of several recent studies that reported acute effects (from 6 weeks to 2 days before birth) between short-term increases in ambient air pollution and preterm birth.7,14,26–28 Only a few studies8,13,14 have examined the association between ambient air pollution and stillbirth, and the findings are inconsistent. Bobak and Leon8 found an increased risk of stillbirth in a study in Czech Republic associated with each 50 µg/ m3 increase in the annual mean concentrations of NO2 (OR = 1.21, 95% CI= 0.89–1.64), but Landgren13 did not find any association between stillbirth and levels of air pollution in Swedish municipalities. However, both these studies were ecological by design, and long-term time trends, season, day of week, temperature, and other potential confounding factors were not adjusted in these studies. Our findings are consistent with the results of a study conducted in Sao Pãulo, Brazil, by Periera et al,14 in which they used a time-series design and reported an association between daily counts of intrauterine mortality and NO2, SO2, and CO concentrations after adjusting for weather and seasons. These associations were observed at short time lags (not greater than 5 days before delivery), which is similar to our findings.
An acute association between short-term increases in ambient air pollution and the risk of stillbirth may suggest that ambient air pollutants can acutely compromise the fetus, leading to stillbirth in the next few days. Our previous and current findings collectively provide evidence for harmful effects of ambient air pollutants on the growing fetus. It may be possible for these pollutants to cross the uteroplacental barrier and trigger hypoxic or immune-mediated injury, causing irreversible damage to the fetus leading to fetal death. However, the biological mechanisms causing fetal demise are not understood for either long-term or short-term effects of these pollutants.
We used a time-stratified case-crossover design, which is the recommended referent selection method for a case-crossover design and controls by design for confounding by time trends (weekday, long-term time trend, and season) and any interaction between them.29–31 There was a strong short-term autocorrelation in our exposure data for CO (autocorrelation in 6-day period) but not for other pollutants. This autocorrelation may have biased our results toward the null, in that it suggests that the exposure of the case period is similar to that of the control periods. As discussed by Janes et al32 and Mittleman,33 bias due to incorrect use of the conditional maximum likelihood was minimal in our study because the time-stratified referent selection strategy divides the time period a priori into fixed strata (ie, months), which allows control/referent periods to be matched to the case period by day of the week within that calendar month, thereby minimizing possible overlap bias.
Although our study had several strengths including a statewide dataset of linked stillbirths and hospital discharge data, there are a few limitations that should be considered. First, we assigned mean daily pollutant concentrations to each pregnancy based on the closest pollutant monitor within 10 km of the maternal residence at birth, regardless of the time spent at other locations, time spent indoors versus outdoors, etc., resulting in exposure error (ie, difference between ambient concentration and true pollutant exposure). However, this exposure error was not likely to be different for each subject’s case and control periods, therefore resulting in underestimates of the relative odds of stillbirth associated with increased pollutant concentration. Second, the true date of fetal death was not known, but it was estimated using the date of delivery recorded on the fetal death certificate. Because this is estimated to be, on average, 48 hours after the fetal death,24 matching air pollution data to the case and control periods based on this delivery date likely resulted in some exposure error as well. However, this misclassification would occur for both case and control periods, likely resulting in bias toward the null.
In summary, we found an increased risk of stillbirth associated with short-term increases in mean concentrations of NO2, SO2, CO, and PM2.5 in the previous a few days. Further studies (with a larger sample size, better measurement of the stillbirth date/time, and improved exposure assessment methods) are needed to confirm these findings and to investigate the biological mechanisms underlying these associations.
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