**5. Discussion**

To our knowledge, such a work, exploring the spatial association of neighborhood characteristics on geographical variations of PTB at such a small-scale level had never been performed. For this reason it is difficult to compare our findings with others. Our study shows that neighborhood socioeconomic deprivation and average NO2 concentrations over years need to be considered in the interpretation of the spatial disparities in PTB in the city of Paris.

First, not surprisingly, NO2 concentrations only explained a very small part of the spatial variations of PTB across different census blocks. While several studies [12,18] have suggested that maternal exposure to ambient air pollutants (PM10, PM2.5, NO2) are associated with various birth outcome, the evidence regarding preterm birth is mixed and not conclusive. Some studies reported significant associations between exposure during pregnancy to NO2 and PTB [14,60–63], while others

did not [20,64–68]. Recently, Estarlich et al. reported a suggestive association between residential exposure to NO2 during pregnancy and PTB among pregnan<sup>t</sup> women who spent more time at home [69]. They found that exposure during the second trimester and during the whole pregnancy was associated with a higher risk of PTB. Johnson et al. in 2016, did not confirm the association between NO2 exposure and PTB in New York City. Using the proximity to traffic as a proxy for air pollution exposure, several studies show that the risk of preterm birth infants is significantly higher among mothers who live near freeways or roadways or to major roads [70–75].

Several biological pathways emerge from the literature to explain the potential impact of exposure to NO2 on PTB. Potential etiologic factors for PTB include inflammation, oxidative stress and cardiovascular alterations [76,77]. Some studies sugges<sup>t</sup> that maternal exposures to NO2 can increase the risk of preterm delivery, via oxidative stress [78]. More recently, a second pathway through which NO2 could alter pregnancy outcomes was proposed. Some studies [61,73] sugges<sup>t</sup> that traffic-related air pollution can related to some cause of PTB such as Preterm premature rupture of membranes (PROM).

Secondly, our findings revealed that the spatial distribution of neighborhood socioeconomic deprivation index explained a grea<sup>t</sup> part of spatial repartition of the excess risk of PTB observed in the crude analysis. This finding is coherent with previous works documenting the existence of a social gradient of adverse pregnancy outcome including PTB. Majority revealed an inverse association between PTB and various socioeconomic measures such as income [79–83], unemployment [84], composite socio-economic score including Towsend, carstairs or other socioeconomic deprivation index [85–89].

Recent literature review and meta-analysis concluded that living in a deprived neighborhood is associated with risk of preterm birth [40,41]. Vo et al. in 2014 found that odds ratios for preterm delivery significantly increased in the most deprived neighborhood quintile compared with the least deprived quintile (odds ratio 1.23, (95% CI:1.18–1.28)) [41]. Ncube et al. in 2016 estimated an excess risk of PTB equal to 27% (95%CI: 16%, 39%) among the most disadvantaged neighborhoods compared with least disadvantaged [40].

Many hypotheses have been formulated explaining the pathways through which socioeconomic status could be a potential risk factor of adverse pregnancy outcome including PTB:


The accumulation of these risk factors which is more common in deprived neighborhood [99], can contribute to maternal stress in turn can lead to higher levels of corticotropin-releasing hormone and cortisol which could trigger contractions and/or the premature rupture of the membrane resulting in PTB [100].

Finally, interestingly, our findings showed that the combination of socioeconomic deprivation level and NO2 concentrations, tacking account the interaction, explain a larger part of the excess risk of PTB estimated in the north-eastern Paris in comparison with analysis considering only socioeconomic deprivation level or NO2 concentrations (even if the contribution of air pollution is marginal compared to the one of socioeconomic deprivation index). These findings are coherent with previous epidemiological studies. For instance, in the U.S. State of Georgia, Hao et al. in 2015 [101] found that the strength of association between NO2 and PTB is higher for low education pregnan<sup>t</sup> women. In California, Padula et al. 2014 confirmed a stronger association among pregnan<sup>t</sup> women living in low socioeconomic status neighborhoods [60].

Two main hypotheses are more likely to explain the spatial implication of both NO2 exposure and socio-economic deprivation in geographical distribution of PTB.


Some research sugges<sup>t</sup> that socioeconomic deprivation is spatially correlated with air pollution [103,104], and thus may have synergistic health effects through common biological pathways (e.g., chronic stress-induced inflammation, or dysregulation of immune and endocrine systems [105]). Clougherty et al. observed that a heightened susceptibility to pollution, associated with violence exposures or with fear thereof, may lead to synergistic health effects of social and physical environmental conditions. Bandoli et al. provide evidence of synergistic effects of air pollution and psychosocial stressors [106].
