http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2015; 31(1): 7–13 ! 2015 Informa UK Ltd. DOI: 10.3109/09513590.2014.958992
AIR POLLUTION AND FERTILITY
Impact of air pollution on fertility: a systematic review Vı´ctor Frutos1,2, Mireia Gonza´lez-Comadra´n3,4, Ivan Sola`5,6, Benedicte Jacquemin4,7,8,9, Ramo´n Carreras2,3, and Miguel A. Checa Vizcaı´no2,3,4
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1
Facultat de Cie`ncies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain, 2Facultat de Medicina Universitat Auto`noma de Barcelona, Barcelona, Spain, 3Department of Obstetrics and Gynecology, Hospital del Mar, Barcelona, Spain, 4GRI-BCN (Barcelona Research Infertility Group), Barcelona, Spain, 5Iberoamerican Cochrane Centre, Institute of Biomedical Research, IIB Sant Pau, Barcelona, Spain, 6CIBER de Epidemiologı´a y Salud Pu´blica (CIBERESP), Barcelona, Spain, 7Respiratory and Environmental Epidemiology Team, INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France, 8UMRS 1018, Universite´ Paris Sud, Villejuif, France, and 9CREAL, Centre for Research in Environmental Epidemiology, Barcelona, Spain Abstract
Keywords
Air pollution has gained considerable interest because of the multiple adverse effects reported on human health, although its impact on fertility remains unclear. A systematic search was performed to evaluate the impact of air pollutants on fertility. Controlled trials and observational studies assessing animal model and epidemiological model were included. Occupational exposure and semen quality studies were not considered. Outcomes of interest included live birth, miscarriage, clinical pregnancy, implantation, and embryo quality. Ten studies were included and divided into two groups: animal studies and human epidemiological studies including the general population as well as women undergoing in vitro fertilization and embryo transfer (IVF/ET). Results from this systematic review suggest a significant impact of air pollution on miscarriage and clinical pregnancy rates in the general population, whereas among subfertile patients certain air pollutants seem to exert a greater impact on fertility outcomes, including miscarriage and live birth rates. Besides, studies in mammals observed a clear detrimental effect on fertility outcomes associated to air pollutants at high concentration. The lack of prospective studies evaluating the effect of air pollution exposure in terms of live birth constitutes an important limitation in this review. Thus, further studies are needed to confirm these findings.
Air pollution, diesel exhaust particles, fertility, live birth, miscarriage, nitrogen dioxide, particulate matter
Introduction Ambient air pollution is one of the most prevalent environmental hazards, affecting up to 100% of the population living in urban areas from womb to death. Several studies have described the negative impact of air pollutants on human health [1], serving as risk factors for cardiovascular [2–4] and respiratory disease [5–7], among others. The International Agency for Research on Cancer (IARC), the division of the World Health Organization (WHO) that coordinates cancer research, has recently classified outdoor air pollution as carcinogenic to humans [8], being transport, power generation, industrial and agricultural emissions, and domestic heating the main sources [9]. Furthermore, associations between outdoor air pollution and adverse reproductive outcomes have also been described by several authors, including a restricted fetal growth leading to low birth weight [10–12], small newborns for gestational age [13], and preterm birth [14]. In the reproductive sphere, the incidence of infertility has markedly increased over the past decade [15], and although advanced maternal age is known to be the most relevant,
History Received 7 May 2014 Revised 23 July 2014 Accepted 25 August 2014 Published online 12 September 2014
both male and female factors are involved and changes in environmental conditions over the last decades could also contribute. Therefore, a rise in the use of assisted reproduction techniques (ART) has ensued. According to the European voluntary ART registry, published recently by the European Society of Human Reproduction and Embryology (ESHRE), the number of in vitro fertilization and embryo transfer (IVF/ET) cycles performed in 2009 experienced an increase in 1% over the previous year [16]. Similarly, in the United States, according to the data collected by the compulsory registration of the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART), the number of ART cycles in 2010 increased 36% as compared with those performed in 2001, which implied an increase in 60.5% of live births ensued from these techniques [15]. Thereby, the assessment of environmental factors that could influence negatively the reproductive success has gained considerable interest. The aim of this review is to assess the impact of air pollution on fertility in humans and mammals.
Materials and methods Address for correspondence: Miguel A. Checa Vizcaı´no, Ph.D., Department of Obstetrics and Gynecology, Hospital del Mar, Passeig Marı´tim 25-29, Barcelona 08003, Spain. Tel: +34 93 2483129. Fax: +34 93 2483254. E-mail: [email protected]
The study was exempt from Institutional Review Board approval because this was a systematic review. We endorsed the preferred reporting items for systematic reviews (PRISMA statement) (Supplemental digital content (S1)) to report the results [17].
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We registered details of the protocol for this systematic review on PROSPERO and can be accessed at CRD42014007201.
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Search strategy We performed an exhaustive electronic search until February 2014 in MEDLINE and The Cochrane Central Register of Controlled Trials (CENTRAL). The search combined terms and descriptors related to air pollution and fertility, understanding air pollution as the presence of contaminants or pollutant substances (gases, particulate matter, or volatile organic chemicals) in the air that interfere with human health or welfare, or produce other harmful environmental effects [18]. We modified the search strategy to comply with the requirements of each database. We added validated filters to widen the search and retrieve cohort and case–control studies. We used the following keywords combining them with Boolean hints in the databases reported: air pollution AND (fertility OR miscarriage OR embryo quality OR embryo development OR pregnancy OR implantation OR live birth). No language limits were used. We screened the reference lists of all relevant articles and overviews. The complete search strategy is available upon request from the authors. Eligibility criteria The review included randomized controlled trials, cohort and case–control studies that analyzed the impact of air pollutants on fertility, including animal and human studies. In this regard, animal studies were included in order to assess the effect of air pollution in other species, particularly in cases of exposure to pollutant levels exceeding the reasonable environmental exposure. Studies analyzing the effect of air pollution on perinatal outcomes and semen quality as well as studies assessing the effect on fertility of occupational exposure, tobacco exposure or exposure to non-environmental toxics (alcohol, drugs of abuse, etc.) were excluded from the review. Outcome measures Our primary outcome was live birth, and secondary outcomes of interest included miscarriage, clinical pregnancy, implantation rate, and embryo quality. The outcomes were defined according to the terminology recommended in the International Committee Monitoring Assisted Reproductive Technologies (ICMART) glossary [19] and the updated and revised nomenclature for the description of early pregnancy events [20].
Data extraction The data were collected using standard forms in which the characteristics of the study design, participants, interventions, and/or comparisons and main results were recorded. Two independent authors (V. F. and M. A. C. V.) judged study eligibility, assessed the risk of bias and extracted data solving discrepancies by agreement, and if needed, reaching consensus with a third author (M. G. C.). Assessment of risk of bias We assessed the risk of bias in the included studies assessing the domains suggested in the Newcastle–Ottawa Scale (NOS) for assessing the quality of non-randomised studies [21]. The instrument assesses three specific domains for each study depending on its design: selection of participants, comparability, and outcome ascertainment.
Results A total of 250 studies were retrieved in the initial electronic search but 235 were excluded by title and/or abstract screening according to exclusion above-mentioned criteria. The remaining 15 studies were considered eligible by one or both reviewers. During the second phase of the inclusion process, out of the 15 studies, two were excluded because their study design did not comply with the eligibility criteria, and three because they did not evaluate the intervention or the outcomes of interest (Supplemental digital content (S2)). Finally, 10 studies met the inclusion criteria and were included (Supplemental digital content (S3)). The two reviewers achieved good agreement in the selection of trials for inclusion (weighted kappa 0.63, 95% CI: 0.35–0.86). After an exhaustive analysis, the included studies were grouped by the type of population under study. Thereby, we included three animal experimental studies [22–24] (Table 1), and seven epidemiological studies: four in the general population [25–28] (Table 2) and three in women undergoing IVF/ET [29–31] (Table 3). The results are presented according to the outcomes analyzed in the review. Outcomes Live birth Four studies reported a negative impact of high levels of air pollution on live birth rates [23,29–31]. In the study by Mohallem
Table 1. Characteristics and results of the animal studies included exposed to pollutants.
Reference
Study design
Subjects (N)
Janua´rio Experimental &1185 mice et al. [22] zygotes
Pollutants analyzed
Results DEP concentration (lg/cm2)
DEP (diesel exhaust particles) ICM cell count (mean ± SD) ICM/TE cell ratio (mean ± SD)
Mohallem Experimental et al. [23]
Hall Experimental et al. [24]
104 female mice
4260 mice embryos
NO2 and PM10 Live births per animal (median (range)) Implantation failure number (median (range)) Pregnancies (%) Acrolein (aldehyde)
0 29.9 ± 2.5
20 10.3 ± 4.1
p Value 50.05
0.31 ± 0.04
0.11 ± 0.05
50.05
Clean chamber 6.0 (6.0) 2.0 (8.0) 30
Polluted chamber p Value 4.0 (7.0) 0.037 3.5 (7.0) 24
0.048 NS
Treatment group (mM) No. of implants (%) No. of term fetuses (%)
Untreated (control) 108 (77.1) 80 (74.7)
0.01 87 (72.5) 47 (54.6)
p Value NS 50.05
Air pollution and fertility
DOI: 10.3109/09513590.2014.958992
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Table 2. Characteristics and results of the epidemiological studies in the general population exposed to pollutants.
Reference
Study design
Population (N)
Slama Retrospective 1916 et al. [25] cohort women
Pollutants analyzed PM2.5, NO2, SO2, O3, carcinogenic polycyclic aromatic hydrocarbons (c-PAH)
Faiz Retrospective 343,077 PM2.5; NO2; SO2; CO et al. [26] cohort total births
Results Pollutant
PM2,5 NO2 SO2 Pollutant (interquartile range) in first trimester
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PM2,5 (4 lg/m3) NO2 (10 ppb) SO2 (3 ppb) CO (0.4 ppm) Mohorovic Prospective et al. [27] cohort
Green Prospective et al. [28] cohort
260 women
4979 women
Products of coal combustion (SO2, NO2, CO2, CO, suspended particles, other products) Traffic pollutants: NO2, ozone, PM2,5, PM10, CO2, CH4, CO, H2S, NMHC (non-methane hydrocarbons), NMOC (non-methane organic compounds), SO2, sulfur, THC (total hydrocarbons)
FR* adjusted for potential cofounders (for each increase by 10 lg/m3 in the pollutant level) 0.78 0.72 0.94
95% CI
OR for miscarriage (adjusted for known risk factors and neighborhood socioeconomic status) 1.15 1.16 1.13 1.14
95% CI
0.96–1.37 1.03–1.31 1.01–1.28 0.98–1.32
Clean period
p Value
Exposure period 10
0.65–0.94 0.53–0.97 0.85–1.04
Miscarriages (number)
4
0.0369
Traffic metric: maximum daily traffic within 50 m [percentile (range)] 75–89th (1.090–15.199) 490th (415.200) 490th and African American 490th and non-smokers
OR for miscarriage (adjusted for known risk factors and socioeconomic status)
95% CI
0.91 1.18 3.11 1.47
0.68–1.21 0.87–1.60 1.26–7.66 1.07–2.04
*FR, fecundability ratio associated with exposure (average of the study period exposure). A value below 1 indicates a decreased probability of pregnancy.
et al. [23], a significant decrease in terms of live birth (p ¼ 0.037) were observed in mice when exposed at an early age to high concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameter between 2.5 and 10 lm (PM10) (Table 1). Similarly, Legro et al. [30] analyzed the impact of air pollution in women undergoing IVF/ET, and reported a consistent adverse effect of NO2 concentration on the odds of live birth during all phases of an IVF cycle, with the largest effect size from the embryo transfer onward (OR 0.76, 95% CI: 0.66–0.86). Interestingly, increased levels of ozone (O3) during ovulation induction were associated with an increase of live births, although they significantly decreased when increased levels occurred from the embryo transfer onward; however, after controlling for NO2 (Pearson’s correlation coefficient: 0.44), O3 was no longer significantly associated with IVF failure (Table 3). In addition, the group of Perin [31] also observed an adverse effect on live birth rate in preconceptional short-term exposure to high levels of PM10 (Q4 period) regardless of the method of conception (Table 3). However, in a retrospective study with a similar design [29] by the same group, this detrimental effect was not found (Table 3). Clinical pregnancy and implantation rates Four studies reported a significant detrimental effect of high concentrations of air pollutants on clinical pregnancy and implantation rates [23–25,30]. On one side, in the animal model, Mohallem et al. [23] observed an increase of implantation failure (p ¼ 0.048) in mice exposed to high levels of NO2 and PM10, but no significant differences were observed in clinical pregnancies when comparing mice exposed to high concentrations of air pollutants as compared with non-exposed mice (Table
1). On the other side, in the study by Hall et al. [24], a significant decrease of pregnancy rate in mice embryos was observed at a threshold of 0.01 mM of acrolein (an organic pollutant). However, no significant association was found in implantation rates at the same concentration of the compound (Table 1). In terms of exposure to diesel exhaust particles (DEP), Janua´rio et al. [22] showed no difference in implantation rates among the exposure groups of mice zygotes to increased levels of DEP (p ¼ 0.562) (data not shown in Table 1). In the general population, results from Slama et al. [25] showed a significant decrease of the likelihood of pregnancy, reflected as ‘‘fecundability ratio’’ (FR), with each increase by 10 lg/m3 in particulate matter with an aerodynamic diameter 2.5 lm (PM2.5) (FR 0.78, 95% CI: 0.65–0.94) and NO2 (FR 0.72, 95% CI: 0.53–0.97) during the study period. In addition, high levels of sulfur dioxide (SO2) seem to decrease pregnancy rates, although results were not statistically significant (Table 2). In the study by Legro et al. [30], increased concentrations of PM2.5 at the IVF clinic during embryo culture were associated with significant adverse effect on clinical pregnancy rate in women undergoing IVF/ET (OR 0.90, 95% CI: 0.82–0.99) (data not shown in Table 3). In contrast, exposure to high PM10 levels did not influence in clinical pregnancy or implantation rates in IVF/ET patients as it was observed in Perin et al. [29] (data not shown in Table 3). Miscarriage Faiz et al. [26] and Mohorovic et al. [27] showed a significant increased risk of miscarriage in general population with the exposure to high levels of NO2 and SO2, and products of coal combustion, respectively (Table 2). In Green et al. [28], although there was no statistically significant association between
Retrospective cohort
Retrospective cohort
Retrospective cohort
Legro et al. [30]
Perin et al. [31]
Study design
Perin et al. [29]
Reference
531 women
7403 women
348 women
Population (N)
Infertile women versus women who had conceived naturally for the first time
First IVF cycle from three centers
First IVF/ET cycle due to male factor infertility
Inclusion criteria to IVF study
PM10
PM2.5, PM10, SO2, NO2, O3
PM10
Pollutants analysed period period period period
(PM10 (PM10 (PM10 (PM10
levels 30.48 lg/m3) levels 30.49–42.00 lg/m3) levels 42.01–56.72 lg/m3) levels456.72 lg/m3)
Q1-3 period (PM10 levels556.72 lg/m3) Q4 period (PM10 levels456.72 lg/m3)
Q1–3 period (PM10 levels556.72 lg/m3) Q4 period (PM10 levels456.72 lg/m3)
Average daily concentration (ADC) from medication start to oocyte retrieval (patient home) ADC from oocyte retrieval to embryo transfer (patient home) ADC from embryo transfer to pregnancy test – 14 d – (patient home) ADC from embryo transfer to the date of live birth (patient home)
Q1 Q2 Q3 Q4
Table 3. Characteristics and results of the epidemiological studies in women undergoing IVF/ET exposed to pollutants.
p Value 0.968 0.721 0.224
1.06 (0.96–1.18) 1.23 (1.07–1.41) 0.62 (0.48–0.81)
0.87 (0.79–0.96) 0.76 (0.66–0.86) 0.76 (0.56–1.02)
p Value 0.000
Per 0.02 ppm increase O3 1.26 (1.10–1.44) Per 0.01 ppm increase NO2 0.80 (0.71–0.91)
OR of live birth (95% CI)
Live birth (%) 41.5 41.5 46.2 33.8
Results
Miscarriage (%) [OR] Natural conception IVF conception 13.7 14.5 30.2 [2.72] 28.3 [2.32] Live birth (%) Natural conception IVF conception 86.3 85.5 69.8 71.7
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DOI: 10.3109/09513590.2014.958992
maximum annual average traffic within 50 m and an increased risk of miscarriage in general population, a significant negative impact was observed when performing a subgroup analyses among African Americans and non-smokers in the higher percentiles of traffic exposure (Table 2). With regard to studies conducted in women undergoing IVF/ET, a significant increase in miscarriage rate among women in the quartile with higher exposure to PM10 (OR 5.05, 95% CI: 1.04–24.51) was observed in Perin et al. [29] (not shown in Table 3) and in Perin et al. [30] (Table 3).
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Embryo quality Embryo quality, reflected by the ICM (Inner Cell Mass)/TE (Trophectoderm) ratio and the ICM cell number in Janua´rio et al. [22], was negatively affected among mice zygotes exposed to higher concentrations of DEP (Table 1). Perin et al. [29] also studied the effect of PM10 on embryo quality in women undergoing IVF/ET, although no significant differences were observed between subgroups of patients (not shown in Table 3). Assessment of the risk of bias The quality of the studies with a cohort design [25–31], comprehended in the epidemiological group, were analyzed according to the NOS [21]. All studies showed a low risk of bias in terms of selection of the participants and the outcomes ascertained. Only the study by Mohorovic et al. [27] did not include details to assess a possible selection bias. However, a moderate risk of bias was observed in terms of comparability between cohorts [26,27,29,31]. Publication bias could not be quantified because of the methodological variability between the included studies. The assessment of the quality of the studies with a cohort design according to the NOS is shown in Supplemental digital content (S4).
Discussion This systematic review seeks to evaluate the impact of air pollution on fertility, in terms of live birth, miscarriage, clinical pregnancy and implantation rates, and embryo quality. Our objective was to observe all these outcomes at every type of study, but the existing literature about general population was limited to miscarriages [26–28] and clinical pregnancies [25]. The most relevant pollutants that exert a detrimental effect on fertility in terms of live birth are NO2 and PM10 [23,30–31]. Regarding the other outcomes evaluated, a wider variety of air pollutants seem to negatively affect clinical pregnancy (NO2, PM2.5, and acrolein) [24–25,30] and implantation rates (NO2 and PM10) [23], miscarriage (NO2, SO2, PM10, other products of coal combustion, and other traffic pollutants) [26–29,31] as well as embryo quality (DEP) [22]. According to this, there is evidence to suggest that an increased risk of miscarriage rate is associated with exposure to high concentrations of NO2 and SO2 in epidemiological studies among general population, although none of these studies provided data regarding live birth rates [26–28]. These two pollutants in turn are part of products of coal combustion and are closely related to traffic emissions, which also show an adverse effect on miscarriage rates. In addition, there is also evidence of a decreased clinical pregnancy rate with exposure to high concentrations of NO2 and PM2.5 [25]. Besides, a significant reduction in live birth rates was observed among subfertile women undergoing IVF exposed to high concentrations of NO2 [30] and PM10 [31], as well as an increased rate of miscarriage when exposed to high concentrations of PM10, although results across different studies are not
Air pollution and fertility
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entirely consistent (Table 3). All these pollutants, NO2, SO2 and PM10, are known to be products of coal combustion and thus are closely related to traffic emissions. Although the biological mechanisms by which air pollutants may affect fertility remain unclear, several theories have been proposed. It is thought that the direct transfer of pollutants through the placenta could lead to an irreversible damage of cells in division, hypoxic damage, and even immune-mediated injury at a critical moment of the embryo, which could potentially result in a miscarriage [32–33]. In this regard, Ziaei et al. [34] described an increase in levels of carboxyhemoglobin and circulating nucleated red blood cells, both markers of fetal hypoxia, among women exposed to CO air pollution during pregnancy. Additionally, Janua´rio et al. [22] reported a disruption of the normal pattern of segregation in the first two cell lines, ICM and TE, when mouse embryos were exposed to high concentrations of DEP as compared with a control group, as well as a significant alteration of the key regulators in the formation process of these two cell lines, Oct-4 for ICM and Cdx-2 for TE. Hence, it might be reasonable to consider that an impairment in implantation and embryo development could partially be explained by an exposure to high levels or certain air pollutants during pregnancy. Conversely, Veras et al. [35] suggested that the increased risk of miscarriage in relation to air pollution could be explained by maternal changes in the vascular compartment or uterine environment before pregnancy. Although this review focused particularly on the direct exposure of air pollution in humans, it would also be interesting to analyze the impact on gametes and embryos that occur within IVF laboratories. Several studies [36–38] have described an improvement in embryo quality, implantation, and pregnancy rates after the implementation of filters in IVF laboratories to reduce levels of air pollution. However, no effect on live birth rate has been observed. In an attempt to identify the impact of certain pollutants on fertility, mammals serve as an optimal model to develop experimental studies that could not be performed in humans due to ethical reasons, particularly when exposure to pollutant levels exceed the reasonable environmental exposure. Mohallem et al. [23], for instance, carried an experimental study in mice, and observed a reduction in live birth and an increase in implantation failure associated to high concentration of NO2 and PM10. Unfortunately, this effect has not been observed yet in the human model epidemiologically because of the lack of studies that assess the impact on live birth rate. Albeit, when we assess the effects of air pollutants in the range of environmental exposure levels, the number of patients included necessary to detect these differences could be excessive. The current systematic review has several limitations that need to be considered. First, there is a marked heterogeneity across the studies analyzed, thereby they have grouped according to the type of population evaluated. Besides, outcomes reported, pollutants analyzed, and reference levels for each pollutant vary across studies making cleaning difficult to draw firm and categorical conclusions. Moreover, a possible publication bias should not be disregarded. Additionally, protocols for ovarian stimulation in studies following an IVF human model are not standardized, which could potentially lead to bias. Another relevant limitation is the insufficiency of prospective cohort studies that exist in this field. Most studies published in human model use historical cohorts [25–26,29–31], hence the validity of the studies included relies largely on the quality of the records available. Yet, it is difficult to draw conclusions regarding the effect of air pollution exposure in terms of live birth in the general population since such data have not been published.
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Nevertheless, the increased risk of miscarriage rate observed across the epidemiological studies with high levels of air pollutants could be indirectly translated into a possible effect in live birth rates. Interestingly, when analyzing the impact of air pollutants among subfertile patients, a decrease in live birth rate has been described in a cohort of 7403 women exposed to higher levels of NO2 [30]. Besides, the group of Perin failed to find significant differences in live birth rates in a cohort of 348 women undergoing IVF exposed to levels of PM10 above 56.72 lg/m3 as compared with levels below 30.48 lg/m3 (33.8% live birth rate versus 41.5%, p ¼ 0.224, respectively) [29], meanwhile these differences became statistically significant with a larger cohort of 531 women (85.5% versus 71.7%, p50.000, respectively) [31]. When comparing these results with those observed in the general population, one could question whether the impact of air pollution is enhanced among subfertile patients, which should be assessed in studies properly designed to address this issue. Anyhow, it seems advisable for patients undergoing assisted reproduction techniques (ART) to beware of air pollution to a certain extend. In summary, a significant impact of air pollution has been observed on miscarriage and clinical pregnancy rates in the general population. Among subfertile patients undergoing IVF/ ET, exposure to air pollutants could have a greater impact on fertility outcomes, including miscarriage and live birth rates, but in both cases, information is limited. Thus, further prospective cohort studies are needed to confirm these findings.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Our research group is conducting a prospective cohort study, to analyze the impact of acute exposure to air pollution on success rated of IVF through a grant from the National Institute of Health Carlos III (Fund for Health Research FIS, Spain; PI13/00454).
References 1. Brunekreef B, Holgate ST. Air pollution and health. Lancet 2002; 360:1233–42. 2. Beelen R, Stafoggia M, Raaschou-Nielsen O, et al. Long-term exposure to air pollution and cardiovascular mortality: an analysis of 22 European cohorts. Epidemiology 2014;66:97–106. 3. Shah AS V, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet 2013;382:1039–48. 4. Uzoigwe JC, Prum T, Bresnahan E, Garelnabi M. The emerging role of outdoor and indoor air pollution in cardiovascular disease. N Am J Med Sci 2013;5:445–53. 5. Sava F, Carlsten C. Respiratory health effects of ambient air pollution: an update. Clin Chest Med 2012;33:759–69. 6. Laumbach RJ, Kipen HM. Respiratory health effects of air pollution: update on biomass smoke and traffic pollution. J Allergy Clin Immunol 2012;129:3–11; quiz 12–3. 7. Pope III CA, Dockery DW, Spengler JD, Raizenne ME. Respiratory health and PM10 pollution. A daily time series analysis. Am Rev Respir Dis 1991;144:668–74. 8. Loomis D, Grosse Y, Lauby-Secretan B, et al. The carcinogenicity of outdoor air pollution. Lancet Oncol 2013;14:1262–3. 9. Unger N, Bond TC, Wang JS, et al. Attribution of climate forcing to economic sectors. Proc Natl Acad Sci USA 2010;107:3382–7. 10. Dadvand P, Parker J, Bell ML, et al. Maternal exposure to particulate air pollution and term birth weight: a multi-country evaluation of effect and heterogeneity. Environ Health Perspect 2013;121:267–373. 11. Pedersen M, Giorgis-Allemand L, Bernard C, et al. Ambient air pollution and low birthweight: a European cohort study (ESCAPE). Lancet Respir Med 2013;1:695–704.
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12. Laurent O, Wu J, Li L, et al. Investigating the association between birth weight and complementary air pollution metrics: a cohort study. Environ Health 2013;12:18. 13. Estarlich M, Ballester F, Aguilera I, et al. Residential exposure to outdoor air pollution during pregnancy and anthropometric measures at birth in a multicenter cohort in Spain. Environ Health Perspect 2011;119:1333–8. 14. Candela S, Ranzi A, Bonvicini L, et al. Air pollution from incinerators and reproductive outcomes: a multisite study. Epidemiology 2013;24:863–70. 15. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2010 Assisted reproductive technology national summary report. Atlanta: U.S. Department of Health and Human Services; 2012. Available at: http://www.cdc.gov/art/ART2010/ PDFs/ART_2010_National_Summary_Report.pdf [last accessed March 2014]. 16. Ferraretti a P, Goossens V, Kupka M, et al. Assisted reproductive technology in Europe, 2009: results generated from European registers by ESHRE. Hum Reprod 2013;28:2318–31. 17. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. 18. MeSH ID: N06.850.460.100. Available at: http://www.ncbi.nlm. nih.gov/mesh/68000397 [last accessed 16 Jul 2014]. 19. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril 2009;92:1520–4. 20. Farquharson RG, Jauniaux E, Exalto N. ESHRE Special Interest Group for Early Pregnancy (SIGEP). Updated and revised nomenclature for description of early pregnancy events. Hum Reprod 2005; 20:3008–11. 21. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses [Internet]. [Ottawa]: Ottawa Hospital Research Institute; 2009. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [last accessed 31 Mar 2014]. 22. Janua´rio DANF, Perin PM, Maluf M, et al. Biological effects and dose-response assessment of diesel exhaust particles on in vitro early embryo development in mice. Toxicol Sci 2010;117: 200–8. 23. Mohallem SV, de Arau´jo Lobo DJ, Pesquero CR, et al. Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo. Environ Res 2005;98:196–202. 24. Hall J, Gilligan A, Schimmel T, et al. The origin, effects and control of air pollution in laboratories used for human embryo culture. Hum Reprod 1998;13:146–55. 25. Slama R, Bottagisi s, Solansky I, et al. Short-term impact of atmospheric pollution on fecundability. Epidemiology 2013;24: 871–9. 26. Faiz AS, Rhoads GG, Demissie K, et al. Ambient air pollution and the risk of stillbirth. Am J Epidemiol 2012;176:308–16. 27. Mohorovic L, Petrovic O, Haller H, Micovic V. Pregnancy loss and maternal methemoglobin levels: an indirect explanation of the association of environmental toxics and their adverse effects on the mother and the fetus. Int J Environ Res Public Health 2010;7: 4203–12. 28. Green RS, Malig B, Windham GC, et al. Residential exposure to traffic and spontaneous abortion. Environ Health Perspect 2009;117: 1939–44. 29. Perin PM, Maluf M, Czeresnia CE, et al. Impact of shortterm preconceptional exposure to particulate air pollution on treatment outcome in couples undergoing in vitro fertilization and embryo transfer (IVF/ET). J Assist Reprod Genet 2010;27: 371–82. 30. Legro RS, Sauer MV, Mottla GL, et al. Effect of air quality on assisted human reproduction. Hum Reprod 2010;25:1317–24. 31. Perin PM, Maluf M, Czeresnia CE, et al. Effects of exposure to high levels of particulate air pollution during the follicular phase of the conception cycle on pregnancy outcome in couples undergoing in vitro fertilization and embryo transfer. Fertil Steril 2010;93: 301–3.
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DOI: 10.3109/09513590.2014.958992
32. Sra´m R. Impact of air pollution on reproductive health. Environ Health Perspect 1999;107:A542–3. 33. Perera FP, Jedrychowski W, Rauh V, Whyatt RM. Molecular epidemiologic research on the effects of environmental pollutants on the fetus. Environ Health Perspect 1999;107:451–60. 34. Ziaei S, Nouri K, Kazemnejad A. Effects of carbon monoxide air pollution in pregnancy on neonatal nucleated red blood cells. Paediatr Perinat Epidemiol 2005;19:27–30. 35. Veras M, Damaceno-Rodrigues N, Caldini E, et al. Particulate urban air pollution affects the functional morphology of mouse placenta. Biol Reprod 2008;79:578–84. 36. Esteves SC, Bento FC. Implementation of air quality control in reproductive laboratories in full compliance with the Brazilian Cells
37. 38. 39. 40.
and Germinative Tissue Directive. Reprod Biomed Online 2013;26: 9–21. Khoudja RY, Xu Y, Li T, Zhou C. Better IVF outcomes following improvements in laboratory air quality. J Assist Reprod Genet 2013; 30:69–76. Boone WR, Johnson JE, Locke AJ, et al. Control of air quality in an assisted reproductive technology laboratory. Fertil Steril 1999;71: 150–4. Rieger D. Culture systems: physiological and environmental factors that can affect the outcome of human ART. Methods Mol Biol 2012; 912:333–54. Von Wyl S, Bersinger NA. Air quality in the IVF laboratory: results and survey. J Assist Reprod Genet 2004;21:283–4.
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13
AIR POLLUTION AND FERTILITY
Impact of air pollution on fertility: a systematic review Vı´ctor Frutos1,2, Mireia Gonza´lez-Comadra´n3,4, Ivan Sola`5,6, Benedicte Jacquemin4,7,8,9, Ramo´n Carreras2,3, and Miguel A. Checa Vizcaı´no2,3,4
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1
Facultat de Cie`ncies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain, 2Facultat de Medicina Universitat Auto`noma de Barcelona, Barcelona, Spain, 3Department of Obstetrics and Gynecology, Hospital del Mar, Barcelona, Spain, 4GRI-BCN (Barcelona Research Infertility Group), Barcelona, Spain, 5Iberoamerican Cochrane Centre, Institute of Biomedical Research, IIB Sant Pau, Barcelona, Spain, 6CIBER de Epidemiologı´a y Salud Pu´blica (CIBERESP), Barcelona, Spain, 7Respiratory and Environmental Epidemiology Team, INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France, 8UMRS 1018, Universite´ Paris Sud, Villejuif, France, and 9CREAL, Centre for Research in Environmental Epidemiology, Barcelona, Spain Abstract
Keywords
Air pollution has gained considerable interest because of the multiple adverse effects reported on human health, although its impact on fertility remains unclear. A systematic search was performed to evaluate the impact of air pollutants on fertility. Controlled trials and observational studies assessing animal model and epidemiological model were included. Occupational exposure and semen quality studies were not considered. Outcomes of interest included live birth, miscarriage, clinical pregnancy, implantation, and embryo quality. Ten studies were included and divided into two groups: animal studies and human epidemiological studies including the general population as well as women undergoing in vitro fertilization and embryo transfer (IVF/ET). Results from this systematic review suggest a significant impact of air pollution on miscarriage and clinical pregnancy rates in the general population, whereas among subfertile patients certain air pollutants seem to exert a greater impact on fertility outcomes, including miscarriage and live birth rates. Besides, studies in mammals observed a clear detrimental effect on fertility outcomes associated to air pollutants at high concentration. The lack of prospective studies evaluating the effect of air pollution exposure in terms of live birth constitutes an important limitation in this review. Thus, further studies are needed to confirm these findings.
Air pollution, diesel exhaust particles, fertility, live birth, miscarriage, nitrogen dioxide, particulate matter
Introduction Ambient air pollution is one of the most prevalent environmental hazards, affecting up to 100% of the population living in urban areas from womb to death. Several studies have described the negative impact of air pollutants on human health [1], serving as risk factors for cardiovascular [2–4] and respiratory disease [5–7], among others. The International Agency for Research on Cancer (IARC), the division of the World Health Organization (WHO) that coordinates cancer research, has recently classified outdoor air pollution as carcinogenic to humans [8], being transport, power generation, industrial and agricultural emissions, and domestic heating the main sources [9]. Furthermore, associations between outdoor air pollution and adverse reproductive outcomes have also been described by several authors, including a restricted fetal growth leading to low birth weight [10–12], small newborns for gestational age [13], and preterm birth [14]. In the reproductive sphere, the incidence of infertility has markedly increased over the past decade [15], and although advanced maternal age is known to be the most relevant,
History Received 7 May 2014 Revised 23 July 2014 Accepted 25 August 2014 Published online 12 September 2014
both male and female factors are involved and changes in environmental conditions over the last decades could also contribute. Therefore, a rise in the use of assisted reproduction techniques (ART) has ensued. According to the European voluntary ART registry, published recently by the European Society of Human Reproduction and Embryology (ESHRE), the number of in vitro fertilization and embryo transfer (IVF/ET) cycles performed in 2009 experienced an increase in 1% over the previous year [16]. Similarly, in the United States, according to the data collected by the compulsory registration of the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART), the number of ART cycles in 2010 increased 36% as compared with those performed in 2001, which implied an increase in 60.5% of live births ensued from these techniques [15]. Thereby, the assessment of environmental factors that could influence negatively the reproductive success has gained considerable interest. The aim of this review is to assess the impact of air pollution on fertility in humans and mammals.
Materials and methods Address for correspondence: Miguel A. Checa Vizcaı´no, Ph.D., Department of Obstetrics and Gynecology, Hospital del Mar, Passeig Marı´tim 25-29, Barcelona 08003, Spain. Tel: +34 93 2483129. Fax: +34 93 2483254. E-mail: [email protected]
The study was exempt from Institutional Review Board approval because this was a systematic review. We endorsed the preferred reporting items for systematic reviews (PRISMA statement) (Supplemental digital content (S1)) to report the results [17].
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V. Frutos et al.
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We registered details of the protocol for this systematic review on PROSPERO and can be accessed at CRD42014007201.
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Search strategy We performed an exhaustive electronic search until February 2014 in MEDLINE and The Cochrane Central Register of Controlled Trials (CENTRAL). The search combined terms and descriptors related to air pollution and fertility, understanding air pollution as the presence of contaminants or pollutant substances (gases, particulate matter, or volatile organic chemicals) in the air that interfere with human health or welfare, or produce other harmful environmental effects [18]. We modified the search strategy to comply with the requirements of each database. We added validated filters to widen the search and retrieve cohort and case–control studies. We used the following keywords combining them with Boolean hints in the databases reported: air pollution AND (fertility OR miscarriage OR embryo quality OR embryo development OR pregnancy OR implantation OR live birth). No language limits were used. We screened the reference lists of all relevant articles and overviews. The complete search strategy is available upon request from the authors. Eligibility criteria The review included randomized controlled trials, cohort and case–control studies that analyzed the impact of air pollutants on fertility, including animal and human studies. In this regard, animal studies were included in order to assess the effect of air pollution in other species, particularly in cases of exposure to pollutant levels exceeding the reasonable environmental exposure. Studies analyzing the effect of air pollution on perinatal outcomes and semen quality as well as studies assessing the effect on fertility of occupational exposure, tobacco exposure or exposure to non-environmental toxics (alcohol, drugs of abuse, etc.) were excluded from the review. Outcome measures Our primary outcome was live birth, and secondary outcomes of interest included miscarriage, clinical pregnancy, implantation rate, and embryo quality. The outcomes were defined according to the terminology recommended in the International Committee Monitoring Assisted Reproductive Technologies (ICMART) glossary [19] and the updated and revised nomenclature for the description of early pregnancy events [20].
Data extraction The data were collected using standard forms in which the characteristics of the study design, participants, interventions, and/or comparisons and main results were recorded. Two independent authors (V. F. and M. A. C. V.) judged study eligibility, assessed the risk of bias and extracted data solving discrepancies by agreement, and if needed, reaching consensus with a third author (M. G. C.). Assessment of risk of bias We assessed the risk of bias in the included studies assessing the domains suggested in the Newcastle–Ottawa Scale (NOS) for assessing the quality of non-randomised studies [21]. The instrument assesses three specific domains for each study depending on its design: selection of participants, comparability, and outcome ascertainment.
Results A total of 250 studies were retrieved in the initial electronic search but 235 were excluded by title and/or abstract screening according to exclusion above-mentioned criteria. The remaining 15 studies were considered eligible by one or both reviewers. During the second phase of the inclusion process, out of the 15 studies, two were excluded because their study design did not comply with the eligibility criteria, and three because they did not evaluate the intervention or the outcomes of interest (Supplemental digital content (S2)). Finally, 10 studies met the inclusion criteria and were included (Supplemental digital content (S3)). The two reviewers achieved good agreement in the selection of trials for inclusion (weighted kappa 0.63, 95% CI: 0.35–0.86). After an exhaustive analysis, the included studies were grouped by the type of population under study. Thereby, we included three animal experimental studies [22–24] (Table 1), and seven epidemiological studies: four in the general population [25–28] (Table 2) and three in women undergoing IVF/ET [29–31] (Table 3). The results are presented according to the outcomes analyzed in the review. Outcomes Live birth Four studies reported a negative impact of high levels of air pollution on live birth rates [23,29–31]. In the study by Mohallem
Table 1. Characteristics and results of the animal studies included exposed to pollutants.
Reference
Study design
Subjects (N)
Janua´rio Experimental &1185 mice et al. [22] zygotes
Pollutants analyzed
Results DEP concentration (lg/cm2)
DEP (diesel exhaust particles) ICM cell count (mean ± SD) ICM/TE cell ratio (mean ± SD)
Mohallem Experimental et al. [23]
Hall Experimental et al. [24]
104 female mice
4260 mice embryos
NO2 and PM10 Live births per animal (median (range)) Implantation failure number (median (range)) Pregnancies (%) Acrolein (aldehyde)
0 29.9 ± 2.5
20 10.3 ± 4.1
p Value 50.05
0.31 ± 0.04
0.11 ± 0.05
50.05
Clean chamber 6.0 (6.0) 2.0 (8.0) 30
Polluted chamber p Value 4.0 (7.0) 0.037 3.5 (7.0) 24
0.048 NS
Treatment group (mM) No. of implants (%) No. of term fetuses (%)
Untreated (control) 108 (77.1) 80 (74.7)
0.01 87 (72.5) 47 (54.6)
p Value NS 50.05
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Table 2. Characteristics and results of the epidemiological studies in the general population exposed to pollutants.
Reference
Study design
Population (N)
Slama Retrospective 1916 et al. [25] cohort women
Pollutants analyzed PM2.5, NO2, SO2, O3, carcinogenic polycyclic aromatic hydrocarbons (c-PAH)
Faiz Retrospective 343,077 PM2.5; NO2; SO2; CO et al. [26] cohort total births
Results Pollutant
PM2,5 NO2 SO2 Pollutant (interquartile range) in first trimester
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PM2,5 (4 lg/m3) NO2 (10 ppb) SO2 (3 ppb) CO (0.4 ppm) Mohorovic Prospective et al. [27] cohort
Green Prospective et al. [28] cohort
260 women
4979 women
Products of coal combustion (SO2, NO2, CO2, CO, suspended particles, other products) Traffic pollutants: NO2, ozone, PM2,5, PM10, CO2, CH4, CO, H2S, NMHC (non-methane hydrocarbons), NMOC (non-methane organic compounds), SO2, sulfur, THC (total hydrocarbons)
FR* adjusted for potential cofounders (for each increase by 10 lg/m3 in the pollutant level) 0.78 0.72 0.94
95% CI
OR for miscarriage (adjusted for known risk factors and neighborhood socioeconomic status) 1.15 1.16 1.13 1.14
95% CI
0.96–1.37 1.03–1.31 1.01–1.28 0.98–1.32
Clean period
p Value
Exposure period 10
0.65–0.94 0.53–0.97 0.85–1.04
Miscarriages (number)
4
0.0369
Traffic metric: maximum daily traffic within 50 m [percentile (range)] 75–89th (1.090–15.199) 490th (415.200) 490th and African American 490th and non-smokers
OR for miscarriage (adjusted for known risk factors and socioeconomic status)
95% CI
0.91 1.18 3.11 1.47
0.68–1.21 0.87–1.60 1.26–7.66 1.07–2.04
*FR, fecundability ratio associated with exposure (average of the study period exposure). A value below 1 indicates a decreased probability of pregnancy.
et al. [23], a significant decrease in terms of live birth (p ¼ 0.037) were observed in mice when exposed at an early age to high concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameter between 2.5 and 10 lm (PM10) (Table 1). Similarly, Legro et al. [30] analyzed the impact of air pollution in women undergoing IVF/ET, and reported a consistent adverse effect of NO2 concentration on the odds of live birth during all phases of an IVF cycle, with the largest effect size from the embryo transfer onward (OR 0.76, 95% CI: 0.66–0.86). Interestingly, increased levels of ozone (O3) during ovulation induction were associated with an increase of live births, although they significantly decreased when increased levels occurred from the embryo transfer onward; however, after controlling for NO2 (Pearson’s correlation coefficient: 0.44), O3 was no longer significantly associated with IVF failure (Table 3). In addition, the group of Perin [31] also observed an adverse effect on live birth rate in preconceptional short-term exposure to high levels of PM10 (Q4 period) regardless of the method of conception (Table 3). However, in a retrospective study with a similar design [29] by the same group, this detrimental effect was not found (Table 3). Clinical pregnancy and implantation rates Four studies reported a significant detrimental effect of high concentrations of air pollutants on clinical pregnancy and implantation rates [23–25,30]. On one side, in the animal model, Mohallem et al. [23] observed an increase of implantation failure (p ¼ 0.048) in mice exposed to high levels of NO2 and PM10, but no significant differences were observed in clinical pregnancies when comparing mice exposed to high concentrations of air pollutants as compared with non-exposed mice (Table
1). On the other side, in the study by Hall et al. [24], a significant decrease of pregnancy rate in mice embryos was observed at a threshold of 0.01 mM of acrolein (an organic pollutant). However, no significant association was found in implantation rates at the same concentration of the compound (Table 1). In terms of exposure to diesel exhaust particles (DEP), Janua´rio et al. [22] showed no difference in implantation rates among the exposure groups of mice zygotes to increased levels of DEP (p ¼ 0.562) (data not shown in Table 1). In the general population, results from Slama et al. [25] showed a significant decrease of the likelihood of pregnancy, reflected as ‘‘fecundability ratio’’ (FR), with each increase by 10 lg/m3 in particulate matter with an aerodynamic diameter 2.5 lm (PM2.5) (FR 0.78, 95% CI: 0.65–0.94) and NO2 (FR 0.72, 95% CI: 0.53–0.97) during the study period. In addition, high levels of sulfur dioxide (SO2) seem to decrease pregnancy rates, although results were not statistically significant (Table 2). In the study by Legro et al. [30], increased concentrations of PM2.5 at the IVF clinic during embryo culture were associated with significant adverse effect on clinical pregnancy rate in women undergoing IVF/ET (OR 0.90, 95% CI: 0.82–0.99) (data not shown in Table 3). In contrast, exposure to high PM10 levels did not influence in clinical pregnancy or implantation rates in IVF/ET patients as it was observed in Perin et al. [29] (data not shown in Table 3). Miscarriage Faiz et al. [26] and Mohorovic et al. [27] showed a significant increased risk of miscarriage in general population with the exposure to high levels of NO2 and SO2, and products of coal combustion, respectively (Table 2). In Green et al. [28], although there was no statistically significant association between
Retrospective cohort
Retrospective cohort
Retrospective cohort
Legro et al. [30]
Perin et al. [31]
Study design
Perin et al. [29]
Reference
531 women
7403 women
348 women
Population (N)
Infertile women versus women who had conceived naturally for the first time
First IVF cycle from three centers
First IVF/ET cycle due to male factor infertility
Inclusion criteria to IVF study
PM10
PM2.5, PM10, SO2, NO2, O3
PM10
Pollutants analysed period period period period
(PM10 (PM10 (PM10 (PM10
levels 30.48 lg/m3) levels 30.49–42.00 lg/m3) levels 42.01–56.72 lg/m3) levels456.72 lg/m3)
Q1-3 period (PM10 levels556.72 lg/m3) Q4 period (PM10 levels456.72 lg/m3)
Q1–3 period (PM10 levels556.72 lg/m3) Q4 period (PM10 levels456.72 lg/m3)
Average daily concentration (ADC) from medication start to oocyte retrieval (patient home) ADC from oocyte retrieval to embryo transfer (patient home) ADC from embryo transfer to pregnancy test – 14 d – (patient home) ADC from embryo transfer to the date of live birth (patient home)
Q1 Q2 Q3 Q4
Table 3. Characteristics and results of the epidemiological studies in women undergoing IVF/ET exposed to pollutants.
p Value 0.968 0.721 0.224
1.06 (0.96–1.18) 1.23 (1.07–1.41) 0.62 (0.48–0.81)
0.87 (0.79–0.96) 0.76 (0.66–0.86) 0.76 (0.56–1.02)
p Value 0.000
Per 0.02 ppm increase O3 1.26 (1.10–1.44) Per 0.01 ppm increase NO2 0.80 (0.71–0.91)
OR of live birth (95% CI)
Live birth (%) 41.5 41.5 46.2 33.8
Results
Miscarriage (%) [OR] Natural conception IVF conception 13.7 14.5 30.2 [2.72] 28.3 [2.32] Live birth (%) Natural conception IVF conception 86.3 85.5 69.8 71.7
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10 V. Frutos et al. Gynecol Endocrinol, 2015; 31(1): 7–13
DOI: 10.3109/09513590.2014.958992
maximum annual average traffic within 50 m and an increased risk of miscarriage in general population, a significant negative impact was observed when performing a subgroup analyses among African Americans and non-smokers in the higher percentiles of traffic exposure (Table 2). With regard to studies conducted in women undergoing IVF/ET, a significant increase in miscarriage rate among women in the quartile with higher exposure to PM10 (OR 5.05, 95% CI: 1.04–24.51) was observed in Perin et al. [29] (not shown in Table 3) and in Perin et al. [30] (Table 3).
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Embryo quality Embryo quality, reflected by the ICM (Inner Cell Mass)/TE (Trophectoderm) ratio and the ICM cell number in Janua´rio et al. [22], was negatively affected among mice zygotes exposed to higher concentrations of DEP (Table 1). Perin et al. [29] also studied the effect of PM10 on embryo quality in women undergoing IVF/ET, although no significant differences were observed between subgroups of patients (not shown in Table 3). Assessment of the risk of bias The quality of the studies with a cohort design [25–31], comprehended in the epidemiological group, were analyzed according to the NOS [21]. All studies showed a low risk of bias in terms of selection of the participants and the outcomes ascertained. Only the study by Mohorovic et al. [27] did not include details to assess a possible selection bias. However, a moderate risk of bias was observed in terms of comparability between cohorts [26,27,29,31]. Publication bias could not be quantified because of the methodological variability between the included studies. The assessment of the quality of the studies with a cohort design according to the NOS is shown in Supplemental digital content (S4).
Discussion This systematic review seeks to evaluate the impact of air pollution on fertility, in terms of live birth, miscarriage, clinical pregnancy and implantation rates, and embryo quality. Our objective was to observe all these outcomes at every type of study, but the existing literature about general population was limited to miscarriages [26–28] and clinical pregnancies [25]. The most relevant pollutants that exert a detrimental effect on fertility in terms of live birth are NO2 and PM10 [23,30–31]. Regarding the other outcomes evaluated, a wider variety of air pollutants seem to negatively affect clinical pregnancy (NO2, PM2.5, and acrolein) [24–25,30] and implantation rates (NO2 and PM10) [23], miscarriage (NO2, SO2, PM10, other products of coal combustion, and other traffic pollutants) [26–29,31] as well as embryo quality (DEP) [22]. According to this, there is evidence to suggest that an increased risk of miscarriage rate is associated with exposure to high concentrations of NO2 and SO2 in epidemiological studies among general population, although none of these studies provided data regarding live birth rates [26–28]. These two pollutants in turn are part of products of coal combustion and are closely related to traffic emissions, which also show an adverse effect on miscarriage rates. In addition, there is also evidence of a decreased clinical pregnancy rate with exposure to high concentrations of NO2 and PM2.5 [25]. Besides, a significant reduction in live birth rates was observed among subfertile women undergoing IVF exposed to high concentrations of NO2 [30] and PM10 [31], as well as an increased rate of miscarriage when exposed to high concentrations of PM10, although results across different studies are not
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entirely consistent (Table 3). All these pollutants, NO2, SO2 and PM10, are known to be products of coal combustion and thus are closely related to traffic emissions. Although the biological mechanisms by which air pollutants may affect fertility remain unclear, several theories have been proposed. It is thought that the direct transfer of pollutants through the placenta could lead to an irreversible damage of cells in division, hypoxic damage, and even immune-mediated injury at a critical moment of the embryo, which could potentially result in a miscarriage [32–33]. In this regard, Ziaei et al. [34] described an increase in levels of carboxyhemoglobin and circulating nucleated red blood cells, both markers of fetal hypoxia, among women exposed to CO air pollution during pregnancy. Additionally, Janua´rio et al. [22] reported a disruption of the normal pattern of segregation in the first two cell lines, ICM and TE, when mouse embryos were exposed to high concentrations of DEP as compared with a control group, as well as a significant alteration of the key regulators in the formation process of these two cell lines, Oct-4 for ICM and Cdx-2 for TE. Hence, it might be reasonable to consider that an impairment in implantation and embryo development could partially be explained by an exposure to high levels or certain air pollutants during pregnancy. Conversely, Veras et al. [35] suggested that the increased risk of miscarriage in relation to air pollution could be explained by maternal changes in the vascular compartment or uterine environment before pregnancy. Although this review focused particularly on the direct exposure of air pollution in humans, it would also be interesting to analyze the impact on gametes and embryos that occur within IVF laboratories. Several studies [36–38] have described an improvement in embryo quality, implantation, and pregnancy rates after the implementation of filters in IVF laboratories to reduce levels of air pollution. However, no effect on live birth rate has been observed. In an attempt to identify the impact of certain pollutants on fertility, mammals serve as an optimal model to develop experimental studies that could not be performed in humans due to ethical reasons, particularly when exposure to pollutant levels exceed the reasonable environmental exposure. Mohallem et al. [23], for instance, carried an experimental study in mice, and observed a reduction in live birth and an increase in implantation failure associated to high concentration of NO2 and PM10. Unfortunately, this effect has not been observed yet in the human model epidemiologically because of the lack of studies that assess the impact on live birth rate. Albeit, when we assess the effects of air pollutants in the range of environmental exposure levels, the number of patients included necessary to detect these differences could be excessive. The current systematic review has several limitations that need to be considered. First, there is a marked heterogeneity across the studies analyzed, thereby they have grouped according to the type of population evaluated. Besides, outcomes reported, pollutants analyzed, and reference levels for each pollutant vary across studies making cleaning difficult to draw firm and categorical conclusions. Moreover, a possible publication bias should not be disregarded. Additionally, protocols for ovarian stimulation in studies following an IVF human model are not standardized, which could potentially lead to bias. Another relevant limitation is the insufficiency of prospective cohort studies that exist in this field. Most studies published in human model use historical cohorts [25–26,29–31], hence the validity of the studies included relies largely on the quality of the records available. Yet, it is difficult to draw conclusions regarding the effect of air pollution exposure in terms of live birth in the general population since such data have not been published.
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Nevertheless, the increased risk of miscarriage rate observed across the epidemiological studies with high levels of air pollutants could be indirectly translated into a possible effect in live birth rates. Interestingly, when analyzing the impact of air pollutants among subfertile patients, a decrease in live birth rate has been described in a cohort of 7403 women exposed to higher levels of NO2 [30]. Besides, the group of Perin failed to find significant differences in live birth rates in a cohort of 348 women undergoing IVF exposed to levels of PM10 above 56.72 lg/m3 as compared with levels below 30.48 lg/m3 (33.8% live birth rate versus 41.5%, p ¼ 0.224, respectively) [29], meanwhile these differences became statistically significant with a larger cohort of 531 women (85.5% versus 71.7%, p50.000, respectively) [31]. When comparing these results with those observed in the general population, one could question whether the impact of air pollution is enhanced among subfertile patients, which should be assessed in studies properly designed to address this issue. Anyhow, it seems advisable for patients undergoing assisted reproduction techniques (ART) to beware of air pollution to a certain extend. In summary, a significant impact of air pollution has been observed on miscarriage and clinical pregnancy rates in the general population. Among subfertile patients undergoing IVF/ ET, exposure to air pollutants could have a greater impact on fertility outcomes, including miscarriage and live birth rates, but in both cases, information is limited. Thus, further prospective cohort studies are needed to confirm these findings.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Our research group is conducting a prospective cohort study, to analyze the impact of acute exposure to air pollution on success rated of IVF through a grant from the National Institute of Health Carlos III (Fund for Health Research FIS, Spain; PI13/00454).
References 1. Brunekreef B, Holgate ST. Air pollution and health. Lancet 2002; 360:1233–42. 2. Beelen R, Stafoggia M, Raaschou-Nielsen O, et al. Long-term exposure to air pollution and cardiovascular mortality: an analysis of 22 European cohorts. Epidemiology 2014;66:97–106. 3. Shah AS V, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet 2013;382:1039–48. 4. Uzoigwe JC, Prum T, Bresnahan E, Garelnabi M. The emerging role of outdoor and indoor air pollution in cardiovascular disease. N Am J Med Sci 2013;5:445–53. 5. Sava F, Carlsten C. Respiratory health effects of ambient air pollution: an update. Clin Chest Med 2012;33:759–69. 6. Laumbach RJ, Kipen HM. Respiratory health effects of air pollution: update on biomass smoke and traffic pollution. J Allergy Clin Immunol 2012;129:3–11; quiz 12–3. 7. Pope III CA, Dockery DW, Spengler JD, Raizenne ME. Respiratory health and PM10 pollution. A daily time series analysis. Am Rev Respir Dis 1991;144:668–74. 8. Loomis D, Grosse Y, Lauby-Secretan B, et al. The carcinogenicity of outdoor air pollution. Lancet Oncol 2013;14:1262–3. 9. Unger N, Bond TC, Wang JS, et al. Attribution of climate forcing to economic sectors. Proc Natl Acad Sci USA 2010;107:3382–7. 10. Dadvand P, Parker J, Bell ML, et al. Maternal exposure to particulate air pollution and term birth weight: a multi-country evaluation of effect and heterogeneity. Environ Health Perspect 2013;121:267–373. 11. Pedersen M, Giorgis-Allemand L, Bernard C, et al. Ambient air pollution and low birthweight: a European cohort study (ESCAPE). Lancet Respir Med 2013;1:695–704.
Gynecol Endocrinol, 2015; 31(1): 7–13
12. Laurent O, Wu J, Li L, et al. Investigating the association between birth weight and complementary air pollution metrics: a cohort study. Environ Health 2013;12:18. 13. Estarlich M, Ballester F, Aguilera I, et al. Residential exposure to outdoor air pollution during pregnancy and anthropometric measures at birth in a multicenter cohort in Spain. Environ Health Perspect 2011;119:1333–8. 14. Candela S, Ranzi A, Bonvicini L, et al. Air pollution from incinerators and reproductive outcomes: a multisite study. Epidemiology 2013;24:863–70. 15. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2010 Assisted reproductive technology national summary report. Atlanta: U.S. Department of Health and Human Services; 2012. Available at: http://www.cdc.gov/art/ART2010/ PDFs/ART_2010_National_Summary_Report.pdf [last accessed March 2014]. 16. Ferraretti a P, Goossens V, Kupka M, et al. Assisted reproductive technology in Europe, 2009: results generated from European registers by ESHRE. Hum Reprod 2013;28:2318–31. 17. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. 18. MeSH ID: N06.850.460.100. Available at: http://www.ncbi.nlm. nih.gov/mesh/68000397 [last accessed 16 Jul 2014]. 19. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril 2009;92:1520–4. 20. Farquharson RG, Jauniaux E, Exalto N. ESHRE Special Interest Group for Early Pregnancy (SIGEP). Updated and revised nomenclature for description of early pregnancy events. Hum Reprod 2005; 20:3008–11. 21. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses [Internet]. [Ottawa]: Ottawa Hospital Research Institute; 2009. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [last accessed 31 Mar 2014]. 22. Janua´rio DANF, Perin PM, Maluf M, et al. Biological effects and dose-response assessment of diesel exhaust particles on in vitro early embryo development in mice. Toxicol Sci 2010;117: 200–8. 23. Mohallem SV, de Arau´jo Lobo DJ, Pesquero CR, et al. Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo. Environ Res 2005;98:196–202. 24. Hall J, Gilligan A, Schimmel T, et al. The origin, effects and control of air pollution in laboratories used for human embryo culture. Hum Reprod 1998;13:146–55. 25. Slama R, Bottagisi s, Solansky I, et al. Short-term impact of atmospheric pollution on fecundability. Epidemiology 2013;24: 871–9. 26. Faiz AS, Rhoads GG, Demissie K, et al. Ambient air pollution and the risk of stillbirth. Am J Epidemiol 2012;176:308–16. 27. Mohorovic L, Petrovic O, Haller H, Micovic V. Pregnancy loss and maternal methemoglobin levels: an indirect explanation of the association of environmental toxics and their adverse effects on the mother and the fetus. Int J Environ Res Public Health 2010;7: 4203–12. 28. Green RS, Malig B, Windham GC, et al. Residential exposure to traffic and spontaneous abortion. Environ Health Perspect 2009;117: 1939–44. 29. Perin PM, Maluf M, Czeresnia CE, et al. Impact of shortterm preconceptional exposure to particulate air pollution on treatment outcome in couples undergoing in vitro fertilization and embryo transfer (IVF/ET). J Assist Reprod Genet 2010;27: 371–82. 30. Legro RS, Sauer MV, Mottla GL, et al. Effect of air quality on assisted human reproduction. Hum Reprod 2010;25:1317–24. 31. Perin PM, Maluf M, Czeresnia CE, et al. Effects of exposure to high levels of particulate air pollution during the follicular phase of the conception cycle on pregnancy outcome in couples undergoing in vitro fertilization and embryo transfer. Fertil Steril 2010;93: 301–3.
Air pollution and fertility
DOI: 10.3109/09513590.2014.958992
32. Sra´m R. Impact of air pollution on reproductive health. Environ Health Perspect 1999;107:A542–3. 33. Perera FP, Jedrychowski W, Rauh V, Whyatt RM. Molecular epidemiologic research on the effects of environmental pollutants on the fetus. Environ Health Perspect 1999;107:451–60. 34. Ziaei S, Nouri K, Kazemnejad A. Effects of carbon monoxide air pollution in pregnancy on neonatal nucleated red blood cells. Paediatr Perinat Epidemiol 2005;19:27–30. 35. Veras M, Damaceno-Rodrigues N, Caldini E, et al. Particulate urban air pollution affects the functional morphology of mouse placenta. Biol Reprod 2008;79:578–84. 36. Esteves SC, Bento FC. Implementation of air quality control in reproductive laboratories in full compliance with the Brazilian Cells
37. 38. 39. 40.
and Germinative Tissue Directive. Reprod Biomed Online 2013;26: 9–21. Khoudja RY, Xu Y, Li T, Zhou C. Better IVF outcomes following improvements in laboratory air quality. J Assist Reprod Genet 2013; 30:69–76. Boone WR, Johnson JE, Locke AJ, et al. Control of air quality in an assisted reproductive technology laboratory. Fertil Steril 1999;71: 150–4. Rieger D. Culture systems: physiological and environmental factors that can affect the outcome of human ART. Methods Mol Biol 2012; 912:333–54. Von Wyl S, Bersinger NA. Air quality in the IVF laboratory: results and survey. J Assist Reprod Genet 2004;21:283–4.
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