Air pollution and female fertility: a systematic review of literature

Female infertility has increased in recent years [1]. It was estimated that this condition affects 1 in seven couples in developed countries [2]. Most cases of female infertility are related to specific disorders, namely, ovulatory disorders, endometriosis, chromosomal abnormalities and male factors [3–7]. There is also evidence that air pollutant could play a role in the pathogenesis of female infertility [8–10]. Air pollution appears to be a cause of concern for human health. For instance, it has been associated with an increased risk of cancer [11], and cardiovascular [12] and respiratory disorders in adults and children [13, 14]. In addition, air pollutants have been associated with adverse perinatal outcomes [15, 16].

Anthropogenic activities, namely traffic, industrial facilities and combustion of fossil fuels, which are particularly intense in large cities and in proximity of farms, are the main sources of health-related air pollutants. Air pollutants are in four main categories: gaseous pollutants (sulfur dioxide [SO₂], nitrate oxide [NO₂] and carbon monoxide [CO]), organic compounds (organic solvents or dioxins), heavy metals (lead and copper) and particulate matter (PM₁₀ PM_2.5-10and PM_2.5) [17]. Ingestion and inhalation are the most common routes of exposure [17]. Ingestion is also facilitated by the fact that air pollution contributes to the contamination of food and water [18]. Some air pollutants, namely Cu, Pb and diesel exhaust seem to exert endocrine activity [19] that could affect female reproduction. Moreover, these endocrine “disruptors” exert estrogenic, antiestrogenic and antiandrogenic activity and some could interfere with the thyroid axis and influence metabolic disorders, such as insulin resistance and obesity, which are strictly related to infertility [20–22]. The increase in female infertility seems to parallel the increase in toxic emissions, which suggests that the impact of air pollution on human health could increase in the next years [23, 24]. In an attempt to summarize current evidence, we carried out a systematic review of studies devoted to the impact of air pollutions on female infertility.

Only 11 studies have evaluated the potential effect of air pollutants on female reproduction.. In the IVF context, NO₂ and O₃ were associated with impaired live-birth rates. In addition, exposure to high levels of PM₁₀ (> 56.72 μg/m³) resulted in an increased miscarriage rate after IVF procedures. Consistently, no study reported a significant effect on other quantitative (i.e. number of oocytes retrieved, number of embryos transferred, and consumption of gonadotropin) and qualitative (embryo quality, and number of MII oocytes) IVF outcomes [28, 31, 32]. In natural conception, reduced fecundability was associated with solvents and SO₂ [33, 34]. Notably while abortion rate was associated with traffic pollutants [8, 35], and in particular SO₂ and NO₂ [30], no clear relation to coal combustion pollutants emerged [36]. Contrasting findings between infertility and PM_2.5–10 were reported [8, 9].

Only three retrospective studies evaluated the effects of air pollution on IVF [28, 31, 32]. Although Legro and colleagues studied a large IVF population, the heterogeneity of IVF protocols and the lack of information about male partners represent two important limitation factors [28]. Moreover, the two studies conducted by Perin et al., are limited by the fact that only one pollutant was investigated and by the low number of cases enrolled [31, 32].

Eight studies have been conducted on the general population. Of the three prospective studies, the one by Mahalingaiah et al. is the largest (more than 36,000 patients) and has the highest qualitative NOS score [8]. The quality of evidence was lowest in the study by Mohorovic et al. as was the number of observations, and the authors did not report effect size for each air pollutant separately [36]. The same weakness emerges in the Green et al. paper, which however analyzed such important factors as work exposure, residential history and employment status of the population studied [35]. Of the five retrospective studies conducted to-date, the quality of evidence is highest in two large studies conducted by Faiz and colleagues [30] and by Slama and colleagues [29] demonstrating that air pollutants significantly affect fertility and stillbirths rates. The remaining three retrospective studies have several limitations, namely a paucity of data regarding the population studied [9], a low number of pollutant analyzed [33] and the methods adopted to assess exposure [34].

The relationship between air pollutants and spontaneous fertility was first observed in an animal model [37]. In detail, Mohallem et al. observed an increased implantation failure rate and a significant reduction of births in mice exposed to polluted city air compared to non-exposed mice [38]. Similarly, Veras et al. found significantly fewer antral follicles and a lower fertility index in mice exposed to traffic pollutants versus non-exposed mice [39].

The effect of air pollutants on human spermatogenesis has also been investigated [40–43]. The largest study, conducted by Hammoud et al., reported that PM_2.5 exposure negatively correlated with sperm morphology and motility [40]. The negative effect of particulate matter was confirmed in a recent prospective cohort study that identified a significant association between PM₁₀ and PM_2.5 and sperm chromosomal abnormalities (i.e. disomy Y and disomy chromosome 21) [44].

The mechanism underlying the effect of air pollutants on female fertility is still a matter of debate. Several pathogenetic mechanisms have been proposed. Firstly, it was hypothesized that air pollutants could mimic the effect of androgens and estrogens in humans [45]. These endocrine-disrupting properties could exert their effect by interacting with nuclear receptor, the estrogen or androgen repertory or by interacting with specific targets in cytosol thus resulting in activation of the /Ras/Erk pathway [46]. Others have suggested that air pollutants could promote oxidative stress and inflammatory processes [17]. In this sense, we recently demonstrated that the addition of anti-oxidant factors to ovarian stimulation could improve reproductive outcome in women with polycystic ovarian syndrome [47]. However, whether antioxidant products could mitigate the effect of air pollutants on IVF outcomes remains to be determined. Finally, it has been suggested that air pollutants could exert a genotoxic effect. For instance, increased sperm DNA fragmentation was associated with exposure to elevated air pollution levels (at or above the upper limit of US air quality standards) [48]. Furthermore, DNA methylation seems to be significantly influenced by air pollutants [49]. Indeed, in a recent study of 777 men, an increase in air pollutant concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-γ and IL-6 hypermethylation [50].

Our review has several limitations. First, most of the studies included in our analysis are observational and retrospective, and hence more prone to bias. Second, exposure ascertainment was heterogeneous among studies. Most of the trials assessed air quality using a specific air monitoring station, others estimated exposure according to proximity to the potential source [8, 35, 36]. In addition, the reference levels of each pollutant varied significantly among studies. Lastly, the populations investigated as well as the definitions used to assess infertility and miscarriage were also heterogeneous. These factors render a meta-analytic and quantitative approach to this issue challenging.

In conclusion, our meta-analysis suggests there is a close association between female infertility and air pollution. However, a more robust meta-analytic approach is required before any definitive conclusion can be reached.