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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

2009; Elsevier BV; Volume: 93; Issue: 1 Linguagem: Inglês

10.1016/j.fertnstert.2009.06.031

1556-5653

P.M. Perin, Mariângela Maluf, Carlos Eduardo Czeresnia, Daniela Aparecida Nicolosi Foltran Januário, Paulo Hilário Nascimento Saldiva,

Pregnancy and preeclampsia studies

The objective of this retrospective cohort study was to assess the potential effects of preconceptional short-term exposure to particulate air pollution in a real-world situation on pregnancy outcome in infertile women evaluating the possible role of IVF/embryo transfer treatment on this outcome using women who had conceived naturally for the first time during the same time frame as a matched control group. The study provides evidence for an association between brief exposure to high levels of ambient particulate matter (aerodynamic diameter ≤10 μm) during the preconceptional period and early pregnancy loss, regardless of the method of conception, and showed a 2.6-fold increase in risk of miscarriage, suggesting a threshold instead of a monotonic effect of this exposure on reproductive outcome. The objective of this retrospective cohort study was to assess the potential effects of preconceptional short-term exposure to particulate air pollution in a real-world situation on pregnancy outcome in infertile women evaluating the possible role of IVF/embryo transfer treatment on this outcome using women who had conceived naturally for the first time during the same time frame as a matched control group. The study provides evidence for an association between brief exposure to high levels of ambient particulate matter (aerodynamic diameter ≤10 μm) during the preconceptional period and early pregnancy loss, regardless of the method of conception, and showed a 2.6-fold increase in risk of miscarriage, suggesting a threshold instead of a monotonic effect of this exposure on reproductive outcome. The preimplantation period of development represents a critical time during which the embryo is highly susceptible to exogenous insults that can affect future growth and developmental potential, either prenatally or postnatally (1Fleming T. Kwong W. Porter R. Ursell E. Fesenko I. Wilkins A. et al.The embryo and its future.Biol Reprod. 2004; 71: 1046-1054Crossref PubMed Scopus (240) Google Scholar, 2Xu G. Umezawa M. Takeda K. Early development origins of adult disease caused by malnutrition and environmental chemical substances.J Health Sci. 2009; 55: 11-19Crossref Scopus (22) Google Scholar). Previous experimental studies conducted in our laboratory have provided evidence that both short-term and long-term exposure to particulate air pollution has a significant impact on female reproductive function, affecting embryonic development before and after implantation. Preconception acute exposure to diesel exhaust particles (DEP) and chronic exposure to fine particulate matter (PM; diameter ≤2.5 μm, PM2.5) present in ambient air were implicated in the disruption of the segregation pattern of the inner cell mass (ICM) and trophectoderm cell lineages at the blastocyst stage, an important marker of embryo viability and developmental potential (3Maluf M, Perin P, Januário D, Saldiva P. In vitro fertilization, embryo development, and cell lineage segregation after pre- and/or postnatal exposure of female mice to ambient fine particulate matter. Fertil Steril. Published online October 23, 2008 [Epub ahead of print].Google Scholar, 4Perin P. Maluf M. Januário D. Saldiva P. Effects of short-term exposure of female mice to diesel exhaust particles on in vitro fertilization and embryo development.Fertil Steril. 2008; 90 (S206)Google Scholar). Defective embryonic development after implantation resulted in an increased number of implantation failures, decreased number of viable fetuses, and higher rates of miscarriage (5Mohallem S. Lobo D. Pesquero C. Assunção J. Andre P. Saldiva P. et al.Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo.Environ Res. 2005; 98: 196-202Crossref PubMed Scopus (76) Google Scholar, 6Silva I. Lichtenfels A. Pereira L. Saldiva P. Effects of ambient levels of air pollution generated by traffic on birth and placental weights in mice.Fertil Steril. 2008; 90: 1921-1924Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Despite the ubiquitous and unavoidable nature of traffic-related particulate air pollution exposure in metropolitan areas and the possibility of women trying to conceive, naturally or otherwise, being exposed to high concentrations of environmental toxins during this period, at present no studies focused on the effects of this exposure on early embryo development. Therefore, the current study was designed to assess the potential effects of short-term exposure to particulate air pollution during the follicular phase of the conception cycle on pregnancy outcome in infertile women evaluating the possible role of IVF/embryo transfer treatment on this outcome using women who had conceived naturally for the first time during the same time frame as a matched control group. The outcome of clinical pregnancies achieved after IVF treatment of infertile patients (study group; n = 177) or spontaneous conception (control group; n = 354) between January 1, 1997 and December 31, 2006 was compared. The retrospective matched (1:2) study was approved by our institutional review board (IRB) and written informed consent was provided by all participants. The median age of the women showed no difference between groups. Pregnancies in the control group were selected from our obstetric database if they met the following criteria: [1] first pregnancy; [2] similar last menstrual period (LMP; LMP ± 2 days) for every patient in the control group with regard to the study group; [3] regular menstrual cycle (28 ± 2 days) before pregnancy; and [4] same ethnic origin (white) and socioeconomic stratum as the study group. All patients lived in the São Paulo metropolitan area and had no previous history of smoking, chronic diseases, medications, and abuse of alcohol or drugs. Pregnancy outcome measurements were the first trimester loss (fetal loss before 12 weeks) or term pregnancy (delivery ≥37 weeks of gestation). No second trimester pregnancy losses were observed in this study. Daily records of PM10 concentrations during the study period were taken from 14 monitoring stations covering nearly all areas of the city and the arithmetic average of PM10 across all monitoring stations was considered representative of the citywide exposure status. The short-term PM10 average concentration for the 14 days postdating each patient's LMP was determined as the average follicular phase exposure for both the study and control groups to represent the exposure of interest. The PM10 was categorized into quartiles (Q1: ≤30.48 μg/m3, Q2: 30.49–42.00 μg/m3, Q3: 42.01–56.72 μg/m3, and Q4: >56.72 μg/m3) and exposure risk was divided into two periods according to the months of the year in which average concentrations and confidence intervals (CI) for PM10 were in the upper quartile (Q4 period) or not (Q1– Q3 period) and exceeded health-based national air quality standard of 50 μg/m3 annual mean (7CETESB. Companhia de Tecnologia de Saneamento Ambiental (São Paulo State Environmental Protection Agency). Poluentes do ar. São Paulo: Secretaria de Estado do Meio Ambiente do Governo do Estado de São Paulo, 2006. Available at: http://wwwcetesbspgovbr/Ar/ar_saudeasp.Google Scholar). The Q4 period coincided with the winter months (June through August) in Brazil. Multivariate logistic regression was used to evaluate the effect of follicular phase PM10 exposure period and age on pregnancy outcome. The risk of early pregnancy loss in the study and control populations was compared using the Mantel-Haenszel method. The effect of follicular phase PM10 exposure either as a continuous or a categorical variable was expressed as an odds ratio (OR) with 95% CI and associated P values. The data were analyzed using the Statistics Package for Social Sciences version 13.0 (SPSS Inc., Chicago, IL). No significant modification in the risk of early pregnancy loss according to baseline exposure (first PM10 quartile) was seen for each interquartile range increase up to the third quartile. However, follicular phase exposure to PM10 average level observed in the last quartile significantly increased the OR (Wald Z-value = 5.53; P=.019; OR: 2.90) for early pregnancy loss in the expectant population. For the logistic regression model, the risk of early pregnancy loss increased 3% per unit increase in follicular phase PM10 (Wald Z-value = 17.97; P=.000; OR: 1.03). Based on this observation and the a priori assumption that early pregnancy loss risk could be increased during the winter months, the Q1–Q3 periods were collapsed into a single group (Q1–Q3 period). The early pregnancy loss and live birth rates for both study and control patients are shown in Table 1. The OR obtained was 2.58 (95% CI: 1.63–4.07; χ2 = 16.75; P=.000), showing that for women exposed to the Q4 period during the follicular phase of their conception cycle, the risk of early pregnancy loss was increased 2.6-fold, regardless of the method of conception. Odds ratios were 2.72 (95% CI: 1.51–4.89) and 2.32 (95% CI: 1.00–5.43) for control and study patients, respectively, and no heterogeneity was observed across groups.Table 1Pregnancy outcome by particulate matter (PM10) exposure during the follicular phase after natural or IVF conception.ConceptionPregnancy outcomeExposureQ1–3 periodQ4 periodNo.%No.%NaturalFirst trimester loss3413.73230.2Term pregnancy21486.37469.8IVFFirst trimester loss1814.51528.3Term pregnancy10685.53871.7χ2 = 16.75; P = .000; odds ratio = 2.582. Open table in a new tab χ2 = 16.75; P = .000; odds ratio = 2.582. In the current study we found that early pregnancy loss rates among patients that conceived either spontaneously or after IVF/embryo transfer treatment and were exposed to Q1–Q3 periods during the follicular phase of their conception cycle were similar (13.7% and 14.5%, respectively) and in accordance with the rates of reported miscarriage (12%–15%) that occur in the general population (8Zinaman M. Clegg E. Brown C. O'Connor J. Selevan S. Estimates of human fertility and pregnancy loss.Fertil Steril. 1996; 65: 503-509Abstract Full Text PDF PubMed Google Scholar). Conversely, the risk of early pregnancy loss in women exposed to high levels of ambient PM10 (Q4 period) during the preconceptional period was 2.6-fold higher than expected in the group of women exposed to lower levels of ambient PM10 (Q1–Q3 periods) independently of the mode of conception (by IVF/embryo transfer, 2.32; by spontaneous conception, 2.72). In the group of patients exposed to high levels of ambient PM10 (Q4 period) during the preconceptional period, similar rates of spontaneous miscarriage observed in patients who achieved pregnancy spontaneously or through IVF/embryo transfer (30.2% and 28.3%, respectively) led us to conclude that infertile women were not more susceptible than fertile women to the effects of the exposure on pregnancy outcome. The results of this study bring into the clinical arena what previous experimental observations involving mice showed—a significant decrease in the number of viable mouse fetuses and an increase in the number of implantation failures in animals chronically exposed to air pollution (5Mohallem S. Lobo D. Pesquero C. Assunção J. Andre P. Saldiva P. et al.Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo.Environ Res. 2005; 98: 196-202Crossref PubMed Scopus (76) Google Scholar). The observation of a threshold instead of a monotonic effect of ambient PM10 exposure on reproductive outcome may suggest that female gametes, due to a functional compartmentalization, are more protected and less susceptible to direct effects of PM10 than the cardiorespiratory system. The disruption of the normal segregation pattern of the first two-cell lineages at the blastocyst stage, as well as the loss of ICM morphological integrity, have been documented in an experimental model used by our group for the evaluation of the effects of short-term exposure to DEP on fertilization and embryo development in vitro (4Perin P. Maluf M. Januário D. Saldiva P. Effects of short-term exposure of female mice to diesel exhaust particles on in vitro fertilization and embryo development.Fertil Steril. 2008; 90 (S206)Google Scholar). The size of first two-cell lineages, as well as their ratio, influence future growth, viability, and implantation potential of the blastocyst (1Fleming T. Kwong W. Porter R. Ursell E. Fesenko I. Wilkins A. et al.The embryo and its future.Biol Reprod. 2004; 71: 1046-1054Crossref PubMed Scopus (240) Google Scholar, 9Kovacic B. Vlaisavljevic V. Reljic M. Sajko M. Developmental capacity of different morphological types of day 5 human morulae and blastocysts.Reprod Biomed Online. 2004; 8: 687-694Abstract Full Text PDF PubMed Scopus (92) Google Scholar, 10Richter K. Harris D. Daneshmand S. Shapiro B. Quantitative grading of a human blastocyst: optimal inner cell mass size and shape.Fertil Steril. 2001; 76: 1157-1167Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Based on our experimental data and on these findings we hypothesize that the lineage specification defect and the loss of ICM integrity may suggest one of the possible pathways through which increased risk of early pregnancy loss is triggered in women exposed to high levels of ambient PM10. The current study benefited from the methodological and statistical approaches through which we controlled specific characteristics of study and control populations that could bias the observed effects by associations of exposure and outcome to confounding variables. The selection of pregnant patients in the control group with a regular menstrual cycle interval (∼ 28-day cycle) and known LMP (confirmed by ultrasound), who were exposed to ambient PM10 during the same time-frame as case patients (with follicular phase duration precisely known), significantly reduced the exposure to misclassification despite the retrospective nature of the analysis. To properly analyze the complex and interrelated nature of the IVF/embryo transfer treatment dependent variables, multiple logistic regression was selected as the statistical method to assess the effects of different ovarian response patterns to gonadotrophins, exposure, patient's age, and the year of IVF treatment, as well as their interactions in this case-control study, eliminating the possibility of an observed effect being caused by chance (type I error). However, we do recognize some limitations to our study. Exposure assessment was limited because we used the ambient PM10 levels derived from a network average across a number of sites in the city, an approach that could introduce some bias by not considering geographic microclimate differences in exposure (11Ritz B. Wilhelm M. Ambient air pollution and adverse birth outcomes: methodologic issues in an emerging field.Basic Clin Pharmacol Toxicol. 2008; 102: 182-190Crossref PubMed Scopus (188) Google Scholar). The selection of a single pollutant from a complex mixture of compounds present in air pollution to evaluate its effects on IVF/embryo transfer pregnancy outcome may represent another important source of bias, as the reported effect may be attributed to other pollutants. Finally, extrapolation of the results to the general population may be limited because our population lived in areas of higher socioeconomic status and had the same ethnic origin—two important covariates that may influence and interact with environmental conditions (12Briggs D. Environmental pollution and the global burden of disease.Br Med Bull. 2003; 68: 1-24Crossref PubMed Scopus (264) Google Scholar). To our knowledge, this is the first study of its kind conducted to evaluate the possible effects of preconceptional short-term exposure to ambient PM10 on pregnancy outcome of infertile women undergoing IVF/embryo transfer who live in a large metropolitan area. The results presented here provide evidence for an association between brief exposure to high levels of ambient PM10 during the preconceptional period and early pregnancy loss, regardless of the method of conception and show for the first time a threshold instead of a monotonic effect of ambient PM10 exposure on reproductive outcome. The 2.6-fold increase in the risk of early pregnancy loss during the winter time has potential public health implications and warrants stronger environmental policies aimed at reducing urban air pollution during this period. To avoid conceiving during high pollution alerts issued by environmental agencies would be a wise approach.